Supplemental material to this article can be found at: http://dmd.aspetjournals.org/content/suppl/2016/07/26/dmd.116.069906.DC1
1521-009X/44/9/1450–1458$25.00 http://dx.doi.org/10.1124/dmd.116.069906 DRUG METABOLISM AND DISPOSITION Drug Metab Dispos 44:1450–1458, September 2016 Copyright ª 2016 by The American Society for Pharmacology and Experimental Therapeutics The Absolute Bioavailability and Effect of Food on the Pharmacokinetics of Odanacatib: A Stable-Label i.v./Oral Study in Healthy Postmenopausal Women s
Stefan Zajic, Stefaan Rossenu, David Hreniuk, Filippos Kesisoglou, Jacqueline McCrea, Fang Liu, Li Sun, Rose Witter, Don Gauthier, Roy Helmy, Darrick Joss, Tong Ni, Randall Stoltz, Julie Stone, and S. Aubrey Stoch Merck & Co., Inc., Kenilworth, New Jersey (S.Z., S.R., D.H., F.K., J.M., F.L., L.S., R.W., D.G., R.H., D.J., T.N., J.S., S.A.S.); and Covance Clinical Research Unit, Evansville, Indiana (R.S.)
Received February 22, 2016; accepted July 8, 2016 Downloaded from ABSTRACT A stable-label i.v./oral study design was conducted to investigate meals, respectively. This magnitude of the food effect is unlikely to the pharmacokinetics (PK) of odanacatib. Healthy, postmeno- be clinically important. The volume of distribution was ∼100 liters. pausal women received oral doses of unlabeled odanacatib The clearance was ∼0.8 l/h (13 ml/min), supporting that odanaca- administered simultaneously with a reference of 1 mg i.v. stable tib is a low–extraction ratio drug. Population PK modeling in- 13C-labeled odanacatib. The absolute bioavailability of odanacatib dicated that 88% of individuals had completed absorption of >80% dmd.aspetjournals.org was 30% at 50 mg (the phase 3 dose) and 70% at 10 mg, which is bioavailable drug within 24 hours, with modest additional absorp- consistent with solubility-limited absorption. Odanacatib expo- tion after 24 hours and periodic fluctuations in plasma concen- sure (area under the curve from zero to infinity) increased by 15% trations contributing to late values for time to Cmax in some and 63% when 50 mg was administered with low-fat and high-fat subjects. at ASPET Journals on September 27, 2021 Introduction permeability (consistent with absorption via passive diffusion) and very , Odanacatib is an oral, selective cathepsin K inhibitor that is in low solubility across the gastrointestinal tract ( 0.001 mg/ml in water). development as a treatment for osteoporosis (Langdahl et al., 2012). The primary objectives of this study were to determine the absolute The pharmacokinetics (PK) of odanacatib have been investigated in phase bioavailability (and other fundamental PK parameters, such as volume 1 single-dose (Stoch et al., 2013) and multiple-dose (Stoch et al., 2009; of distribution and clearance) of odanacatib in fasted and fed conditions Anderson et al., 2014) studies. In addition, an absorption, distribution, to assess the effect of food (low-fat and high-fat meals) on PK, to characterize the absorption profile, and to assess the safety and metabolism, and excretion study was conducted in humans (Kassahun 13 et al., 2014), after detailed characterization of metabolism in rats, dogs, tolerability of odanacatib and C-odanacatib. The secondary objectives and monkeys (Kassahun et al., 2011). PK in humans are characterized by a were to evaluate whether the systemic disposition is linear, and to determine the influence of 13C isotopic labeling on odanacatib i.v. PK relatively long apparent terminal half-life (t1/2) of approximately 80 hours, which is consistent with low metabolic intrinsic clearance, and less than (as a control). As part of characterizing absorption and disposition, this dose-proportional increases in concentration and exposure [area under the study also aimed to evaluate secondary peaks and late time to Cmax – curve (AUC)] with increasing dose. Metabolism (principally mediated by (Tmax) values occasionally observed in the concentration time profile. CYP3A) and biliary and/or intestinal excretion of intact parent compound The anticipated clinical dose of odanacatib is 50 mg, and this dose was account for approximately 70% and 30%, respectively, of the clearance studied in fasted and fed meal conditions. A 10-mg dose was also studied of odanacatib in humans (Kassahun et al., 2014). Odanacatib is a in one period to characterize the dependence of bioavailability on dose. biopharmaceutics classification system class II compound with high To accomplish these objectives, a relatively unusual study design was used: in each period of the study, stable-labeled (13C) odanacatib was administered i.v., whereas unlabeled odanacatib was administered either This study, including editorial assistance, was funded by Merck & Co., Inc., orally or i.v. (in one period, as a control to test the effect of labeling). In Kenilworth, NJ. S.Z., S.R., D.H., F.K., J.M., F.L., L.S., R.W., D.G., R.H., D.J., T.N., contrast, traditional assessment of bioavailability typically involves J.S., S.A.S. are employees or former employees of Merck Sharp & Dohme Corp. crossover study designs in which the oral and i.v. PK of a drug are and may own stock and/or hold stock options in the company. R.S. has no assessed in separate periods in the same group of individuals, and then competing interests, as defined by the American Society for Clinical Pharmacol- ogy and Therapeutics, or other interests that might be perceived to influence the compared (Musib et al., 2013). The i.v. labeled/oral unlabeled approach results and/or discussion reported in this article. has been available for some time (Strong et al., 1975), although its use dx.doi.org/10.1124/dmd.116.069906. has been relatively limited (Dobson et al., 1994; Bianchetti et al., 1995; s This article has supplemental material available at dmd.aspetjournals.org. Bode et al., 1996; Yeh et al., 1999; Schwab et al., 2013).
ABBREVIATIONS: AUC, area under the curve; AUC0-‘, area under the curve from zero to infinity; Ceoi,Cend-of-infusion; CI, confidence interval; F, bioavailability; GCP, Good Clinical Practices; GMR, geometric mean ratio; PK, pharmacokinetics; t1/2, half-life; Tmax, time to Cmax; Vss, volume of distribution at steady state.
1450 Pharmacokinetics of Odanacatib: Effect of Food 1451
Materials and Methods TABLE 1 Study Design Allocation of subjects to treatment
This was an open-label, randomized, four-period, partial crossover study Allocation number Period 1 Period 2 Period 3 Period 4 (protocol number 045). Postmenopausal women (N =24,46–65 years of age) 007, 023 A B C D received single doses of 1 mg i.v. 13C-odanacatib in each of four treatment 001, 016 B C A D periods, plus unlabeled odanacatib 1 mg i.v. (as a control to test the effect of the 010, 024 C A B D label on PK), 50 mg oral fasted, or 10 mg oral fasted in the first three periods. In 009, 022 A C B D the fourth period, 12 subjects also each received 50 mg of oral odanacatib with 003, 019 B A C D either a low- or high-fat meal. There was at least a 28-day washout between doses. 002, 013 C B A D For PK assessment, blood samples were collected over 336 hours after odanacatib 006, 015 A B C E 012, 014 B C A E administration. The allocation schedule for this study is shown in Table 1. 008, 017 C A B E The protocol and other applicable study documentation was reviewed and 004, 018 A C B E approved by Independent Investigational Review Board, Inc. In addition, this trial 011, 020 B A C E had an investigator meeting at the outset to review all protocol procedures and 005, 021 C B A E investigator responsibilities under Good Clinical Practices (GCP). The investi- A, 13C-odanacatib 1-mg i.v. solution coadministered with unlabeled odanacatib 1-mg i.v. gator understood that by signing the Protocol Investigator Signature Page he/she solution in a fasted state; B, 13C-odanacatib 1-mg i.v. solution after a 50-mg oral dose of provided commitment to comply with applicable GCP regulations and guidance, odanacatib in a fasted state; C, 13C-odanacatib 1 mg i.v. solution after a 10-mg oral dose 13 and to conduct the study in accordance with the protocol. This study was of odanacatib in a fasted state; D, C-odanacatib 1 mg i.v. solution after a 50-mg oral dose of odanacatib after a low-fat meal; E, 13C-odanacatib 1 mg i.v. solution after a 50-mg oral dose of Downloaded from conducted in conformance with GCP standards, the Declaration of Helsinki, and odanacatib after a high-fat meal. applicable country and/or local statutes and regulations regarding ethics committee review, informed consent, and the protection of human subjects participating in 13 biomedical research. For odanacatib and C6-odanacatib, intrarun mean accuracy (N = 5) was between 98.7% and 105% of the nominal concentrations, with precision between 1.12% Synthesis of Stable-Labeled Odanacatib and 3.38%, and inter-run mean accuracy (N = 100) was between 94.7% and 99.6% of the nominal with precision between 2.80% and 6.34%. The synthesis of [phenyl-U-13C]-odanacatib follows a similar route (Fig. 1) to dmd.aspetjournals.org a previously reported nonlabeled version of odanacatib (Hughes et al., 2007). 13 PK Analysis Commercially available [ C6]-4-bromobenzenemethylsulfone 1 (Sigma- ‘ Aldrich) was converted to boronic acid 2. Suzuki coupling of 2 with arylbromide For i.v. treatments, plasma AUC from 0 to (AUC0-‘), Cend-of-infusion (Ceoi), 3 produced hydrated ketone 4. Reductive amination of 4 with fluoroleucine terminal t1/2, clearance, and steady-state volume of distribution were derived from – 13 bisulfate 5 was mediated by ZnCl2 and NaBH4 to give the desired diastereomer 6 the concentration time profiles of C-odanacatib and unlabeled odanacatib for each with high selectivity. The final coupling with amino 7 was promoted with 1-ethyl- individual. For oral treatments, plasma AUC0-‘, Cmax, Tmax, and apparent terminal – 3-(3-dimethylaminopropyl)carbodiimide and hydroxybenzotriazole to produce t1/2 were determined from the concentration time profiles of unlabeled odanacatib
13 at ASPET Journals on September 27, 2021 [phenyl-U- C]-odanacatib with greater than 99% purity. for each individual. Certain PK parameters, including AUC0-‘ and t1/2, could not be determined for all subjects due to insufficient data in the terminal phase. Formulation of Stable-Labeled Odanacatib Absolute bioavailability (F) was calculated as the dose-adjusted ratio of AUC ‘ values for the oral and i.v. treatments, as shown below in eq. 1. The i.v. formulation was provided as a 0.1 mg/ml solution of 13C-odanacatib 0- (as a neutral form) in 35% w/v sulfobutylether beta-cyclodextrin sodium salt ð%Þ¼ DoseIV AUCoral: ð Þ (Captisol solubilizer/stabilizer; CyDex Inc., Lenexa, KS) and 0.01% w/v Poly- F 100 1 Doseoral AUCIV sorbate 80 (surfactant) in water for injection with a final pH ranging from 3 to 7. The final density of the resulting formulation was 1.14 mg/ml. The unlabeled i.v. Plasma concentrations for odanacatib, converted into molar units using the formulation was prepared in an identical solution. molecular weight of 525.57 g/mol for unlabeled odanacatib or 531.50 g/mol for 13C-odanacatib, and actual sampling times were used to estimate PK parameters for Drug Concentration Assays each treatment in each subject. Apparent terminal t1/2 values and AUC0-‘ values (the calculation of which requires terminal elimination rate constant) were determined Plasma odanacatib and 13C-odanacatib concentrations were determined simul- only for those subjects in which at least three odanacatib plasma concentrations were taneously using an analytical method that involved supported-liquid extraction collected at 96 hours postdose or greater, with at least one time point collected at followed by liquid chromatography–tandem mass spectrometry (Sun et al., 2012). 240 hours (approximately three times the estimated t of odanacatib) or greater. For The lower limit of quantitation for this method was 0.500 ng/ml with a linear 1/2 i.v. treatments, clearance was calculated as the ratio of dose to AUC, and steady-state calibration range from 0.500 to 500 ng/ml for both analytes. volume was calculated as the product of clearance and mean residence time. Plasma samples basified with ammonium hydroxide were extracted with In some subjects, nonzero predose concentrations of odanacatib were observed methyl tert-butyl ether on a 96-well supported-liquid extraction plate. The eluent as a result of treatment in a prior period. In all cases, these values were less than was evaporated to dryness, and the residue was reconstituted in a 50%:50% v/v 5% of C and were not used to adjust the PK analysis. The PK analysis was acetonitrile/water solution. A portion of the resulting solution was then injected max conducted using the Phoenix software package (Certara, Princeton, NJ). into the liquid chromatography–tandem mass spectrometry system interfaced with a turbo ion spray source operated in positive ionization mode. For LC separation, Statistical Analysis the mobile phases consisted of 65/35 acetonitrile/0.1% formic acid in water 13 (solvent A) and acetonitrile (solvent B). The analytes (odanacatib and C6- Primary Estimation of Absolute Bioavailability. Individual ratios (F)of 13 odanacatib) and internal standard ( C12-odanacatib) were eluted under an [dose-normalized (to 1 mg) 10-mg oral fasted AUC0-‘ over 1-mg labeled i.v. isocratic mobile phase composition of 100% solvent A at a flow rate of AUC0-‘], and [dose-normalized (to 1 mg) 50-mg oral fasted AUC0-‘ over 1-mg 0.2 ml/min. A step gradient was then applied to wash the column with 100% labeled i.v. AUC0-‘] were calculated within each treatment period and for each solvent B at a flow rate of 0.4 ml/min, then the column was re-equilibrated at individual in the first three periods. Actual doses administered rather than planned 13 100% solvent A. The retention time for both odanacatib and C6-odanacatib was doses were used in the analysis. A log transformation was applied to the individual 13 approximately 1.5 minutes. MS ion transitions used for odanacatib, C6- ratio data and analyzed using a mixed-effects model appropriate for a three-period 13 odanacatib, and C12-odanacatib detection were m/z 526 → 313, 532 → 319, and crossover design. The model contained treatment and period as fixed effects, and 538 → 325, respectively. subject as a random effect with a compound symmetry–heterogeneous variance Assay intrarun and inter-run variability was assessed by the analysis of plasma structure (i.e., the CSH covariance structure in SAS, in which variances can differ quality control samples prepared at concentrations of 1.5, 37.5, and 375 ng/ml. across different repeated measures, but covariances, across subjects, are identical) 1452 Zajic et al.
Fig. 1. Synthesis of 13C-odanacatib.
(Kincaid, 2005) to model the errors. The assumption of compound symmetry time profiles, using the corresponding i.v. profiles as reference, was also used to covariance structure was examined by Levene’s test, and the P value was 0.0295 determine absorption profiles in a model-independent manner. (less than a = 0.05), which indicates that the null hypothesis of equality of
variances was rejected. As there was evidence of unequal variances, a Safety Downloaded from heterogeneous compound symmetry covariance structure was used. The geo- Subjects were queried daily regarding the occurrence of adverse experiences; metric mean and 90% confidence interval (CI) for true ratio F after 10- and 50-mg none were suggested, and all reported adverse experiences were documented. doses was generated from the above mixed-effects model to estimate the absolute Subjects were monitored throughout for adverse experiences. All adverse bioavailability of 10- and 50-mg oral doses of odanacatib administered in the experiences reported by the subject or observed by the investigator were graded fasted state. Additional individual absolute bioavailability ratios of (dose-adjusted with respect to maximum intensity, seriousness, action taken, and relationship to 50-mg oral with low-fat meal AUC ‘ over 1-mg labeled i.v. AUC ‘) and (dose- 0- 0- the drug. Adverse experiences rated as possibly, probably, or definitely were adjusted 50-mg oral with high-fat meal AUC ‘ over 1-mg labeled i.v. AUC ‘) dmd.aspetjournals.org 0- 0- considered to be drug related. Safety was also assessed by physical examination, were also estimated. A log transformation was applied to the individual ratio data collection of vital signs, electrocardiogram, hematology, serum chemistry, and and analyzed using a t test to generate the geometric mean and 90% CI. urinalysis. Primary Estimation of Food Effect. A linear mixed-effects model with treatment (fasted, low-fat and high-fat) as a fixed effect and subject as a random Linear Systemic Disposition of Odanacatib effect was used to analyze log-transformed AUC0-‘ using data from a 50-mg oral dose of odanacatib in the fasted and fed states. Compound symmetry was used as To assess the linearity of the systemic disposition of odanacatib, the labeled i.v. the covariance structure. Two-sided 90% CIs were constructed for the geometric PK parameter data from all five treatments were used in a mixed-effects model, mean ratios (GMRs) (low-fat/fasted and high-fat/fasted) of AUC0-‘. In addition, with treatment as a fixed effect and subject as a random effect (and a compound at ASPET Journals on September 27, 2021 90% CIs were obtained for GMRs of Cmax. symmetric covariance structure). An overall F test was used to test whether the labeled i.v. AUC0-‘ differed among the five treatments. Note that the study was Absorption Modeling not sufficiently powered for this test. If the test was not statistically significant at the significance level of 0.05, then there was not enough evidence from the study A population PK model was developed to characterize the rate and duration to claim that the i.v. PK was different among the five treatments; that is, the of absorption, and to explore the mechanism of the secondary peaks in the systemic disposition of odanacatib was linear, otherwise, it would be concluded odanacatib concentration–time profile. The population PK dataset contained that the systemic disposition of odanacatib is not linear. C was analyzed in a 2562 PK samples from 24 postmenopausal women (age range 45 to 65 years). eoi similar manner. Measurements below the limit of quantification and missing values were excluded from the dataset. Nonlinear mixed-effects modeling was performed using The Effect of 13C Isotopic Labeling NONMEM, version 7.2 (ICON Development Solutions, Ellicott City, MD) in a UNIX environment with Intel FORTRAN Complier, version 11.1 (Intel The effect of the 13C isotopic labeling of odanacatib was assessed by estimating Corporation, Santa Clara, CA) using the Navigator interface (Mango Solutions, the true ratio F after the unlabeled i.v. dose along with a 90% CI. If the 90% CI Chippenham, UK). Xpose (xpose.sourceforge.net), PsN (psn.sourceforge.net), was contained within the interval (0.80–1.25), then it was concluded that and R (R-project, www.r-product.org, version 2.14.1 or higher) were used for odanacatib was not affected by 13C isotopic labeling. Additional individual ratios 13 exploratory analyses and postprocessing of NONMEM output. testing the effect of the C isotopic labeling, including 1-mg unlabeled i.v. Ceoi Population PK model development was staged, with separate structural models over 1-mg labeled i.v. Ceoi and 1-mg unlabeled i.v. terminal t1/2 over 1-mg labeled for i.v. and oral data used as a starting point to characterize the distribution and i.v. terminal t1/2 were also estimated. A log transformation was applied to the absorption profiles, respectively, which were then combined into a base reference individual ratio data and analyzed using a t test to generate the geometric mean model. Because dose and food (light and heavy meal) effects on bioavailability and 90% CI. were known (Stoch et al., 2009), these covariates were included a priori in the model. The influence of food on absorption was tested as a covariate in the model, the residual error model structure was evaluated, and outlier evaluation was Results conducted to arrive at a final model. Model selection was based on the log- Absolute Bioavailability at 10 and 50 mg likelihood criterion, goodness-of-fit plots, and scientific plausibility. Reliability of the final model was checked with diagnostic plots and visual predictive check. The absolute bioavailability of 10- and 50-mg oral doses of The final model included a Hill function to describe input from absorption to odanacatib was 70% and 30%, respectively, as presented in Table 2. provide sufficient flexibility to capture a range of absorption behaviors: The absolute bioavailability of 50-mg oral doses of odanacatib administered with low-fat and high-fat meals was 36% and 49%, D :Tn Hill function ¼ À max Á; ð2Þ respectively. n þ n T50 T Determination of Volume of Distribution and Clearance where Dmax is the maximum bioavailable dose, T is time, T50 is the time at which 50% of the drug is bioavailable, and n is the Hill factor. This was used to simulate The volume of distribution at steady state (Vss) of odanacatib was the input profile after oral administration. Deconvolution of individual concentration– estimated to be approximately 100 liters. Because this exceeds the Pharmacokinetics of Odanacatib: Effect of Food 1453
TABLE 2 consistent with observed values, and, as shown in Fig. 3, periodic The absolute bioavailability of 10- and 50-mg oral doses of odanacatib fluctuations in concentration after the first absorption peak (clearly visible in the mean profiles presented in Fig. 2; individual profiles a Dose and food status N Geometric mean (90% CI) for two individuals after oral doses are also included in Fig. 6; 10 mg fasted 17 0.70 (0.64–0.77) and i.v./oral profiles of 12 individuals are shown in Supplemental – 50 mg fasted 18 0.30 (0.27 0.34) Fig. 1) were adequately described by a circadian rhythm function 50 mg with low-fat meal 9 0.36 (0.31–0.42) 50 mg with high-fat meal 9 0.49 (0.43–0.57) on the volume of the central compartment with the following equation: All doses listed above reflect oral administration, and were administered with a reference i.v. dose of 1 mg 13C-labeled odanacatib to determine absolute bioavailability. ¼ ðð 2 Þ:p= Þ: ð Þ aN is less than 24 for fasted treatments and less than 12 for fed treatments because, for some circ cos clock acro 12 amp 3 subjects, AUC0-‘ could not be determined due to insufficient data in the terminal phase. where clock is the actual clock time of PK sampling, acro is the acrophase, and amp is the amplitude. This approach is compared volumes of extracellular fluid (approximately 10 liters) and total body graphically with model-independent deconvolution in Supplemental water (approximately 60 liters), this supports the idea that odanacatib Fig. 2. Although the two approaches were qualitatively similar, a distributes into tissues. Total clearance from plasma was estimated to be circadian rhythm–based model was better able to capture the periodic 0.8 l/h (approximately 13 ml/min or approximately 9 ml/min after taking fluctuations in the profiles, which deconvolution treated as additional into account an in vitro blood/plasma ratio of approximately 0.7), which drug input. The population PK parameter estimates for the final i.v. and Downloaded from is small relative to hepatic blood flow (approximately 1 to 1.5 l/min), oral combined model of data from this study are included in Supplemental supporting that odanacatib is a low extraction ratio drug. Detailed Table 1, and visual predictive check plots for this model are presented in summary statistics for Vss and total clearance can be found in Supplemental Fig. 3. Tables 3 and 4. This model of odanacatib absorption allowed for simulation of the cumulative absorption profile. On average, the majority of the
Effect of Low- and High-Fat Meals on Exposure/Bioavailability compound is absorbed between 6 and 10 hours postdose (i.e., in dmd.aspetjournals.org In this study, administration with food moderately increased 97% of individuals, .50% of the amount of drug that will be odanacatib concentrations and exposures, with higher fat content absorbed has been absorbed by 10 hours postdose) with .80% associated with greater increases, as shown in Fig. 2. Specifically, the absorbed within 24 hours (i.e., in 88% of individuals, .80% of the administration with a low-fat meal resulted in increases of 15% for amount of drug that will be absorbed has been absorbed by 24 hours AUC0-‘ and 16% for Cmax relative to fasted, whereas administration postdose), as illustrated in Fig. 4. In addition, Fig. 4 also illustrates with a high-fat meal resulted in increases of 63% for AUC0-‘ and 91% that a high-fat meal increases the extent and slows the rate of C absorption (i.e., the absorption rate constant) of odanacatib, whereas for max relative to fasted (Table 5). Observed PK values for all at ASPET Journals on September 27, 2021 treatment groups for both labeled and unlabeled odanacatib can be a low-fat meal more modestly increases the extent of absorption found in Tables 3 and 4. with no impact on rate.
Absorption Modeling Periodic Fluctuations, Evidence for Systemic Effect The PK of oral and i.v. administered unlabeled odanacatib were Both oral and i.v. administration of odanacatib resulted in periodic best described by a three-compartment model with first-order fluctuations in the postdose concentration–time profiles, as illus- absorption and first-order elimination. The initial combined model trated in Fig. 5, which compares profiles after administration of used a first-order absorption rate, but the final model replaced this 50 mg orally after fasting and 1 mg i.v., suggesting that these with a Hill function to describe absorption input as this allowed for fluctuations are the result of systemic effects, rather than due to greater flexibility in describing the range of absorption profile continued absorption in the second and third days postdose, after oral shapes. Model-based estimates of bioavailability were closely doses. In addition, the examination of individual concentration–time
TABLE 3 Summary statistics for PK parameters of unlabeled odanacatib after single doses of 13C-odanacatib 1 mg i.v. with oral or i.v. doses of unlabeled odanacatib
Dose of unlabeled odanacatib PK parameter 1 mg i.v. 10 mg fasted 50 mg fasted 50 mg with low-fat meal 50 mg with high-fat meal (N =21–24) (N =23–24) (N = 24) (N = 12) (N =12)
Geometric mean (%CV) a AUC0-‘ (mM-h) 2.7 (41.0) 15.8 (40.3) 33.6 (44.3) 40.5 (55.9) 52.5 (40.2) a AUC0-last (mM-h) 2.1 (44.2) 14.9 (37.1) 33.1 (40.2) 37.0 (50.8) 49.7 (36.9) a Cmax (nM) 56.2 (43.9) 120.8 (19.9) 240.3 (20.6) 283.3 (20.4) 450.4 (19.7) b Tmax (h) 7.5 (1.7, 48.0) 6.0 (1.7, 96.0) 5.0 (2.8, 84.0) 10.5 (2.8, 24.1) a Vss (liters) 103.1 (20.4) Cla (l/h) 0.7 (52.9) c Terminal t1/2 (h) 104.4 (32.7) 85.8 (21.7) 84.5 (19.7) 87.9 (20.9) 78.7 (13.2) a AUC%extrap 11.0 (38.6) 6.6 (103.8) 6.0 (76.7) 6.4 (102.7) 4.5 (67.7)
N is less than 24 for certain PK parameters because for some subjects AUC0-‘ and t1/2 values could not be determined due to insufficient data in the terminal phase. AUC0-last, AUC from 0 to last time point; AUC%extrap, percentage of AUC extrapolated beyond last time point; Cl, clearance. aGeometric means for indicated parameters are directly calculated, not model based. bValues are reported as the median (minimum, maximum). c Harmonic mean (pseudo-S.D.). Values are observed for terminal t1/2 for i.v. treatments and apparent terminal t1/2 for oral treatments. 1454 Zajic et al.
TABLE 4 Summary statistics for PK parameters of 13C-odanacatib after single doses of 13C-odanacatib 1 mg i.v. with oral or i.v. doses of unlabeled odanacatib
Dose of unlabeled odanacatib PK parameter 1 mg i.v. 10 mg fasted 50 mg fasted 50 mg low-fat meal 50 mg high-fat meal (N =20–24) (N =18–24) (N =18–24) (N =9–12) (N =9–12)
Geometric mean (%CV) a AUC0-‘ (mM-h) 2.3 (30.7) 2.4 (32.4) 2.3 (23.1) 2.7 (15.8) 2.2 (26.7) a AUC0-last (mM-h) 1.8 (34.3) 1.8 (33.7) 1.8 (32.8) 2.0 (39.5) 1.8 (36.0) a Ceoi (nM) 52.6 (43.2) 52.5 (34.1) 55.9 (39.5) 58.2 (27.5) 54.9 (29.2) a Vss (liters) 114.8 (17.4) 103.4 (19.7) 93.8 (14.8) 96.8 (17.3) 88.6 (16.8) Cla (l/h) 0.8 (37.8) 0.8 (40.5) 0.8 (35.0) 0.8 (41.6) 0.9 (35.2) b Terminal t1/2 (h) 108 (27.3) 95.6 (29.9) 81.7 (21.0) 100.3 (19.9) 73.9 (21.0) a AUC%extrap 10.7 (38.7) 8.9 (57.8) 7.6 (35.8) 8.0 (46.3) 6.5 (39.9)
N is less than 24 for certain PK parameters because for some subjects, AUC0-‘ and t1/2 could not be determined due to insufficient data in the terminal phase. AUC0-last, AUC from 0 to last time point; AUC%extrap, percentage of AUC extrapolated beyond last time point; Cl, clearance. aGeometric means for indicated parameters are directly calculated, not model-based. bHarmonic mean (pseudo-S.D.). Downloaded from profiles (a representative set is shown in Supplemental Fig. 1) profiles, typically an initial peak at around 4–10 hours and a peak at indicates that secondary fluctuations generally occur at the same time 24 hours or later, which was occasionally higher than the first peak. in oral and i.v. profiles. Thus, Tmax values of 24 hours or as late as 72 hours have been As the nature of these fluctuations is not fully understood, two different observed. Results from the population PK modeling indicate that, dmd.aspetjournals.org possible mechanisms that could explain the secondary peaks were although absorption is largely finished within 24 hours, in some explored as part of the population PK modeling. First, the increase of individuals late Tmax values can arise from a combination of a odanacatib plasma concentrations every 24 hours was modeled as an extra sustained minor absorption component combined with the input from a peripheral compartment into the central compartment; this periodic fluctuations in concentration (described in the model as a structure was intended to mimic an enterohepatic recycling mechanism. circadian function on the volume of the central compartment), as Alternatively, a circadian rhythm function on the volume of the central illustrated in Fig. 6, which shows observed concentration–time compartment was introduced to mimic a mechanism of diurnal variation profiles for two individuals. Note that even when late Tmax values in plasma protein concentrations, and thus the distribution of odanacatib occur, a majority of the bioavailable drug is still absorbed at ASPET Journals on September 27, 2021 (which is highly protein bound) between plasma and tissue. Both model during the first day (i.e., delayed absorption is not the cause of structures could describe the fluctuations satisfactorily, and thus the the late Tmax values). results support that either mechanism is feasible. The second, circadian rhythm, model was selected as it was more parsimonious and resulted in Safety shorter runtimes. Odanacatib was generally well tolerated in postmenopausal women In several phase 1 studies (Stoch et al., 2013), including this one, in this study. No serious clinical adverse experiences were reported, multiple peaks were observed in individual concentration–time and no subject discontinued participation in the study because of an
Fig. 2. Odanacatib exposures were increased when administered with food (N = 24 for fasted, N = 12 for high-fat and low-fat meals). ODN, odanacatib. Pharmacokinetics of Odanacatib: Effect of Food 1455
TABLE 5 with less-than-dose-proportional PK being due to dose-dependent Administration with food moderately increases odanacatib plasma concentrations bioavailability, rather than to nonlinear disposition. These two comple- and exposures mentary assessments together support that the systemic disposition of odanacatib appears to be linear. PK parameter Low-fat meal/fasted High-fat meal/fasted – – AUC0-‘ 1.15 (1.04 1.28) 1.63 (1.47 1.81) Effect of Isotopic Labeling Cmax 1.16 (1.07–1.25) 1.91 (1.77–2.07) a 13 Tmax 5.0 (2.8, 84.0) 10.5 (2.8, 24.1) The geometric mean AUC ‘ ratio for unlabeled/ C-labeled was 1.18 b 0- t1/2 87.9 (20.9) 78.7 (13.2) (90% CI 1.12–1.24), falling within the prespecified bounds of 0.8–1.25 Data are reported as the GMR (90% CI), unless otherwise indicated. (Supplemental Table 3). In addition, Ceoi and terminal t1/2 values were a 13 Median values (minimum, maximum), not ratio, are reported for Tmax. similar. Taken together, these data confirm that C-isotopic labeling of bHarmonic mean values (jack-knife S.D.), not ratio, are reported for t . 1/2 odanacatib does not substantially alter the PK of i.v.-administered odanacatib. adverse experience. All adverse experiences were rated mild in intensity, with the exception of one instance of headache that was Discussion rated moderate. The most common adverse experience was headache, This study used concurrent administrations of 13C-labeled and which was reported by eight subjects. No laboratory adverse unlabeled odanacatib to allow for simultaneous assessments of i.v. experiences were reported. There were no consistent treatment-related and oral PK. In the past, this approach has been used to study the PK Downloaded from changes in laboratory values, vital signs, or electrocardiogram safety of drugs with known or suspected clearance nonlinearities (Yeh et al., parameters. 1999), but in this case, the aim was primarily to use the reference stable-labeled i.v. treatment to gain a clearer understanding of the Systemic Linearity absorption profile for a low–intrinsic clearance drug, including to 13 The PK of 1 mg i.v. C-labeled odanacatib, as assessed by the AUC0-‘ better understand which aspects of the oral concentration–time and Ceoi, were statistically similar (P values of 0.515 and 0.823, profile derived from absorption versus systemic phenomena (i.e., dmd.aspetjournals.org respectively; see Supplemental Table 2). distribution, metabolism, or elimination). In addition, population PK modeling also supported the linearity Compared with a traditional (i.e., crossover) bioavailability study disposition for all treatments over the dose range studied of 1–50 mg, design, the use of a stable-label approach was particularly useful in at ASPET Journals on September 27, 2021
Fig. 3. Population PK model predictions are consistent with observed data (only the first 96 hours postdose are shown for clarity). Dotted line, mean individual i.v. PK profile (including covariate effects); solid line, mean population i.v. PK profile; symbol: mean (S.D.) observed data. ODN, odanacatib. 1456 Zajic et al.
Fig. 4. Simulated mean cumulative absorption profiles (using model with Hill function) illustrate that odanacatib absorption is well behaved in both the fed and fasted states. ODN, odanacatib. Downloaded from dmd.aspetjournals.org this study because it allowed the evaluation of oral and i.v. profiles solubility, and thus bioavailability, of a lipophilic biopharmaceutics simultaneously in the same individuals to provide information classification system class II molecule such as odanacatib (log P = about whether certain features of the profiles (e.g., secondary 3.11). This magnitude of food effect is unlikely to be clinically concentration peaks) were due to absorption behavior or factors meaningful, which is consistent with the decision to conduct the related to systemic disposition. This approach also corrects for any phase 3 trial for odanacatib with dosing without regard to food (Bone potential systemic nonlinearities, should they exist, and still et al., 2015).
provides accurate estimates of bioavailability, unlike crossover The rate and duration of odanacatib absorption is fairly consistent, at ASPET Journals on September 27, 2021 designs. Further, this design also produced a dataset that was well despite widely varying Tmax values. Most absorption occurs within suited for model-based assessment of the absorption rate and 24 hours of dosing, with consistent absorption in the first 10 hours profile. postdose in all subjects with a median of 70% of the bioavailable The mean oral bioavailability of odanacatib at 50 mg in fasted drug absorbed. Continued absorption results in .80% of the conditions was moderate at 30%, with reasonable precision (90% CI bioavailable drug being absorbed within 24 hours for the majority of 27–34%). Odanacatib AUC0-‘ increased by 15% and 63% when subjects (88%). 50 mg was administered with low-fat and high-fat meals, corre- Both oral and i.v. administration of odanacatib resulted in sponding to bioavailabilities of 36% and 49%, respectively. This is periodic fluctuations in postdose concentration–time profiles (both consistent with the expectation that dietary lipids may improve the mean and individual), suggesting that these fluctuations are due to
Fig. 5. Periodic fluctuations occur in concentration– time profiles after both oral and i.v. administration (note: left y-axis is abbreviated for clarity). ODN, odanacatib. Pharmacokinetics of Odanacatib: Effect of Food 1457
Fig. 6. Late Tmax values are likely due to a combination of moderate sustained absorption and periodic fluctuation in plasma concentra- tions: representative examples of model predic-
tions. Dashed black line, individual fit Downloaded from (including covariate effects); gray symbols, observed data; solid black line, population fit (typical profile). ODN, odanacatib. dmd.aspetjournals.org at ASPET Journals on September 27, 2021
systemic effects, rather than delayed absorption. Although they (calculations supporting this estimate are described in detail by have been observed in most phase 1 studies of odanacatib after Kassahun et al., 2014; absorbed drug in feces accounts for approxi- either single or multiple doses, the cause of these fluctuations is mately 20% of the dose). unknown. Potential mechanisms for this behavior include enter- In summary, the stable-label i.v./oral design used for this study was ohepatic recirculation of intact drug eliminated by hepatic efflux or valuable in providing insights beyond its previous use to characterize circadian variation in endogenous levels of plasma proteins or bioavailability in settings of saturable or nonlinear clearance. In addition, lipoproteins to which odanacatib binds. Lipoprotein binding can results from this study provide a clear understanding of the absorption alter the PK of lipophilic drugs (Wasan et al., 2008), and the properties of odanacatib in the intended patient population of post- magnitude of the variation observed in this study with odanacatib menopausal women, further supporting its use for the treatment of (approximately 10% of total distribution volume) is consistent with osteoporosis. the diurnal variation observed in lipoprotein levels (Bremner et al., 2000). Overall, these fluctuations are relatively small and unlikely Acknowledgments to be clinically relevant for a drug that will be administered The authors thank Lihong Du and Eric Mangin for contributing to the chronically. noncompartmental pharmacokinetics analysis for this study. The authors also The linearity of disposition was confirmed across a dose range of thank Denise Graham of Complete Medical Communications, Macclesfield, UK, 1–50 mg by both statistical comparison and model-based assessment. for providing editorial assistance. Thus, it is reasonable to continue to attribute the less than dose- proportional oral PK to dose-dependent bioavailability associated with Authorship Contributions low solubility and saturable absorption. Participated in research design: Zajic, Hreniuk, Witter, Helmy, Joss, Stone, The estimates of volume (;100 liters) and clearance (;0.8 l/h) and Stoch observed in this study support the idea that odanacatib distributes into Conducted experiments: Zajic, Hreniuk, Sun, Witter, Gauthier, Helmy, Ni, Stoltz, and Stoch tissues and is a low–extraction ratio drug, respectively. Based on the Contributed new reagents or analytic tools: Sun, Gauthier, Joss, and Stoch amounts of odanacatib recovered in feces and urine in the human Performed data analysis: Zajic, Rossenu, Kesisoglou, McCrea, Liu, Sun, absorption, distribution, metabolism, and excretion study, it can be Helmy, and Stoch estimated that metabolism (principally mediated by CYP3A) and Wrote or contributed to the writing of the manuscript: Zajic, Rossenu, excretion of intact parent compound account for approximately 70% Kesisoglou, McCrea, Liu, Sun, Witter, Gauthier, Helmy, Stone, and and 30%, respectively, of the clearance of odanacatib in humans Stoch 1458 Zajic et al.
References Langdahl B, Binkley N, Bone H, Gilchrist N, Resch H, Rodriguez Portales J, Denker A, Lombardi A, Le Bailly De Tilleghem C, and Dasilva C, et al. (2012) Odanacatib in the treatment of post- Anderson MS, Gendrano IN, Liu C, Jeffers S, Mahon C, Mehta A, Mostoller K, Zajic S, Morris D, menopausal women with low bone mineral density: five years of continued therapy in a phase and Lee J, et al. (2014) Odanacatib, a selective cathepsin K inhibitor, demonstrates comparable 2study.J Bone Miner Res 27:2251–2258. pharmacodynamics and pharmacokinetics in older men and postmenopausal women. JClin Musib L, Choo E, Deng Y, Eppler S, Rooney I, Chan IT, and Dresser MJ (2013) Absolute Endocrinol Metab 99:552–560. bioavailability and effect of formulation change, food, or elevated pH with rabeprazole on Bianchetti G, Dubruc C, Sultana V, Houin G, and Rosenzweig P (1995) Pharmacokinetics and cobimetinib absorption in healthy subjects. Mol Pharm 10:4046–4054. bioavailability of a sustained-release diltiazem formulation (Mono-Tildiem LP 300 MG) after Schwab D, Portron A, Backholer Z, Lausecker B, and Kawashima K (2013) A novel double-tracer repeated administration in healthy volunteers. Eur J Clin Pharmacol 48:259–264. technique to characterize absorption, distribution, metabolism and excretion (ADME) of Bode H, Brendel E, Ahr G, Fuhr U, Harder S, and Staib AH (1996) Investigation of nifedipine [14C]tofogliflozin after oral administration and concomitant intravenous microdose adminis- absorption in different regions of the human gastrointestinal (GI) tract after simultaneous ad- tration of [13C]tofogliflozin in humans. Clin Pharmacokinet 52:463–473. ministration of 13C- and 12C-nifedipine. Eur J Clin Pharmacol 50:195–201. Stoch SA, Zajic S, Stone JA, Miller DL, van Bortel L, Lasseter KC, Pramanik B, Cilissen C, Liu Q, Bone HG, Dempster DW, Eisman JA, Greenspan SL, McClung MR, Nakamura T, Papapoulos S, and Liu L, et al. (2013) Odanacatib, a selective cathepsin K inhibitor to treat osteoporosis: safety, Shih WJ, Rybak-Feiglin A, and Santora AC, et al. (2015) Odanacatib for the treatment of tolerability, pharmacokinetics and pharmacodynamics—results from single oral dose studies in postmenopausal osteoporosis: development history and design and participant characteristics of healthy volunteers. Br J Clin Pharmacol 75:1240–1254. LOFT, the Long-Term Odanacatib Fracture Trial. Osteoporos Int 26:699–712. Stoch SA, Zajic S, Stone J, Miller DL, Van Dyck K, Gutierrez MJ, De Decker M, Liu L, Liu Q, Bremner WF, Sothern RB, Kanabrocki EL, Ryan M, McCormick JB, Dawson S, Connors ES, and Scott BB, et al. (2009) Effect of the cathepsin K inhibitor odanacatib on bone resorption Rothschild R, Third JL, and Vahed S, et al. (2000) Relation between circadian patterns in levels biomarkers in healthy postmenopausal women: two double-blind, randomized, placebo- of circulating lipoprotein(a), fibrinogen, platelets, and related lipid variables in men. Am Heart J controlled phase I studies. Clin Pharmacol Ther 86:175–182. 139:164–173. Strong JM, Dutcher JS, Lee WK, and Atkinson AJ, Jr (1975) Absolute bioavailability in man of Dobson RL, Kelm GR, and Neal DM (1994) Automated gas chromatography/tandem mass N-acetylprocainamide determined by a novel stable isotope method. Clin Pharmacol Ther 18: spectrometry assay for tebufelone and a 13C,(18)O-labeled analog in plasma: applicability to 613–622. absolute bioavailability determination. Biol Mass Spectrom 23:75–81. Sun L, Forni S, Schwartz MS, Breidinger S, and Woolf EJ (2012) Quantitative determination of Hughes G, Devine PN, Naber JR, O’shea PD, Foster BS, McKay DJ, and Volante RP (2007) odanacatib in human plasma using liquid-liquid extraction followed by liquid chromatography- Diastereoselective reductive amination of aryl trifluoromethyl ketones and alpha-amino esters. tandem mass spectrometry analysis. J Chromatogr B Analyt Technol Biomed Life Sci 885-886:15–23. Downloaded from Angew Chem Int Ed Engl 46:1839–1842. Wasan KM, Brocks DR, Lee SD, Sachs-Barrable K, and Thornton SJ (2008) Impact of lipoproteins Kassahun K, Black WC, Nicoll-Griffith D, McIntosh I, Chauret N, Day S, Rosenberg E, on the biological activity and disposition of hydrophobic drugs: implications for drug discovery. and Koeplinger K (2011) Pharmacokinetics and metabolism in rats, dogs, and monkeys of the Nat Rev Drug Discov 7:84–99. cathepsin k inhibitor odanacatib: demethylation of a methylsulfonyl moiety as a major metabolic Yeh KC, Stone JA, Carides AD, Rolan P, Woolf E, and Ju WD (1999) Simultaneous investigation of pathway. Drug Metab Dispos 39:1079–1087. indinavir nonlinear pharmacokinetics and bioavailability in healthy volunteers using stable isotope Kassahun K, McIntosh I, Koeplinger K, Sun L, Talaty JE, Miller DL, Dixon R, Zajic S, labeling technique: study design and model-independent data analysis. J Pharm Sci 88:568–573. and Stoch SA (2014) Disposition and metabolism of the cathepsin K inhibitor odanacatib in humans. Drug Metab Dispos 42:818–827. Kincaid C (2005) Guidelines for selecting the covariance structure in mixed model analysis, in Address correspondence to: dmd.aspetjournals.org Proceedings of the SAS Users Group International (SUGI) 30; 2005 April 10–13; Philadelphia, Stefan Zajic, Merck & Co., Inc., 2000 Galloping Hill PA. Paper 198-30, SAS Institute, Cary, NC. Available at: http://www2.sas.com/proceedings/ Road, Kenilworth, NJ 07033. E-mail: [email protected]. sugi30/198-30.pdf. at ASPET Journals on September 27, 2021 Merck’s policy on posting of redacted study protocols on journal websites is described in Merck Guidelines for Publication of Clinical Trials in the Scientific Literature on the www.merck.com website.
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Copyright © 2015 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. All Rights Reserved. Not for regulatory or commercial use. 045-00
A Single Dose Study to Assess the Bioavailability of Odanacatib in Subjects 0822, Protocol 045-00 Issue Date: 27-Jan-2011 2 Product: MK-0822 Protocol/Amendment No.: 045-00
THIS PROTOCOL AND ALL OF THE INFORMATION RELATING TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY MERCK SHARP & DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., WHITEHOUSE STATION, NJ, U.S.A.
SPONSOR: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. (hereafter referred to as the SPONSOR or Merck) One Merck Drive P.O. Box 100 Whitehouse Station, NJ, 08889-0100, U.S.A.
Protocol-specific Sponsor Contact information can be found in the Administrative Binder.
TITLE: A Single Dose Study to Assess the Bioavailability of Odanacatib in Subjects
INVESTIGATOR: PRIMARY:
CLINICAL PHASE:
US IND NUMBER:
SITE:
INSTITUTIONAL REVIEW BOARD/ETHICS REVIEW COMMITTEE:
0822_045-00_ProtTitle APPROVED 27-Jan-2011 U.S. IND, U.S. Study Restricted Confidential – Limited Access 0822, Protocol 045-00 Issue Date: 27-Jan-2011 3
PROTOCOL A Single Dose Study to Assess the Bioavailability of Odanacatib in Subjects
TABLE OF CONTENTS
Application Starting Contents Page
1. SUMMARY 7 1.1 Title 7 1.2 Indication 7 1.3 Summary of Rationale 7 1.4 Summary of Study Design 7 1.5 Sample 7 1.6 Dosage/Dosage Form, Route, and Dose Regimen 7 1.7 Study Flow Chart 9 2. CORE PROTOCOL 11 2.1 Objectives and Hypotheses 11 2.1.1 Primary 11 2.1.2 Secondary 11 2.2 Subject/Patient Inclusion Criteria 11 2.3 Subject/Patient Exclusion Criteria 12 2.4 Study Design and Duration 14 2.4.1 Summary of Study Design 14 2.4.2 Treatment Plan 14 2.5 List of Efficacy/Pharmacokinetic/Immunogenicity, etc., 15 Measurements 2.6 List of Safety Measurements 15 2.7 statistical Analysis Plan Summary 15 3. PROTOCOL DETAILS 18 3.1 Rationale 18 3.1.1 Rationale for This Study 18 0822, Protocol 045-00 Issue Date: 27-Jan-2011 4
TABLE OF CONTENTS (CONT.)
Application Starting Contents Page
3.1.2 Rationale for Dose Regimen and Assay Method 19 3.1.3 Formulation Details Chemistry and Formulation of 21 Odanacatib 3.1.4 Safety/Toxicology of Intravenous Formulation 22 3.2 Study Procedures 23 3.2.1 Concomitant Medication(s)/Treatment(s) 23 3.2.2 Diet/Activity/Other 24 3.2.3 Procedures 25 3.2.3.1 Prestudy 26 3.2.3.2 Pretreatment: All Treatment Periods 27 3.2.3.3 Treatment (All Periods) 28 3.2.3.4 Poststudy 30 3.2.3.5 Study Design/Procedures Modifications Permitted Within 30 Protocol 3.2.3.6 Informed Consent 31 3.2.3.6.1 General Informed Consent 31 3.2.3.7 Assignment of Baseline Number/Screening/Washout 31 (optional) 3.2.3.8 Randomization/Allocation 31 3.2.3.9 Blinding/Unblinding 31 3.2.3.10 Discontinuation/Withdrawal from Study 31 3.3 Efficacy/Pharmacokinetic/Immunogenicity, etc. Measurements 32 3.3.1 Clinical and Laboratory Measurements for 32 Efficacy/Pharmacokinetic/Immunogenicity, etc. 3.4 Safety Measurements 33 3.4.1 Clinical and Laboratory Measurements for Safety 33 3.4.2 Recording Adverse Experiences 33 3.4.3 Definition of an Overdose for This Protocol 33 0822, Protocol 045-00 Issue Date: 27-Jan-2011 5
TABLE OF CONTENTS (CONT.)
Application Starting Contents Page
3.4.3.1 Reporting of Overdose to SPONSOR 33 3.4.4 Reporting of Pregnancy to SPONSOR 34 3.4.5 Immediate Reporting of Adverse Experiences to the 34 SPONSOR 3.4.5.1 Serious Adverse Experiences 34 3.4.5.2 Selected Nonserious Adverse Experiences (if applicable) 34 3.4.6 Evaluating Adverse Experiences 34 3.4.7 SPONSOR Responsibility for Reporting Adverse Experiences 37 3.5 Statistical Analysis Plan 37 3.5.1 Hypotheses 37 3.5.2 Analyses Endpoints 37 3.5.3 Approaches to Analyses 38 3.5.4 Statistical Methods 38 3.5.5 Multiplicity 39 3.5.6 Sample Size and Power Calculations 40 3.6 Packaging, Labeling, Storage, Dispensing, and Return of 41 Clinical Supplies 3.6.1 Patient and Replacements Information 41 3.6.2 Product Descriptions 41 3.6.3 Primary Packaging and Labeling Information 41 3.6.4 Secondary Packaging and Labeling Information (kit) 42 3.6.5 Clinical Supplies Disclosure 43 3.6.6 Storage and Handling Requirements 43 3.6.7 Standard Policies / Return of Clinical Supplies 43 3.6.8 Site Retention Samples 44 3.7 Data Management 44 3.8 Biological Specimens 44 0822, Protocol 045-00 Issue Date: 27-Jan-2011 6
TABLE OF CONTENTS (CONT.)
Application Starting Contents Page
4. DMINISTRATIVE AND REGULATORY DETAILS 45 4.1 Confidentiality 45 4.1.1 Confidentiality of Data 45 4.1.2 Confidentiality of Subject/Patient Records 45 4.1.3 Confidentiality of Investigator Information 45 4.2 Compliance with Law, Audit, and Debarment 46 4.3 Compliance with Financial Disclosure Requirements 47 4.4 Quality Control and Quality Assurance 48 4.5 Compliance with Information Program on Clinical Trials for 48 Serious or Life Threatening Conditions 4.6 Publications 48 5. LIST OF REFERENCES 49 6. APPENDICES 50 6.1 Laboratory Analyses for Safety and Screening 50 6.2 Algorithm for Assessing Out-of-Range Laboratory Values 51 6.3 Blood Volume Requirements 52 6.4 Odanacatib Plasma Assay – Sample Collection, Handling, 53 Labeling, Storage and Shipment 6.5 Procedure for Storage and Administration of the Intravenous 54 Doses of Odanacatib 7. ATTACHMENTS 56 8. SIGNATURES 58 8.1 SPONSOR’S REPRESENTATIVE 58 8.2 INVESTIGATOR 58 0822, Protocol 045-00 Issue Date: 27-Jan-2011 7 Product: MK-0822 1 Protocol/Amendment No.: 045-00
1. SUMMARY
1.1 TITLE A Single Dose Study to Assess the Bioavailability of Odanacatib in Subjects
1.2 INDICATION Postmenopausal osteoporosis
1.3 SUMMARY OF RATIONALE Redacted
1.4 SUMMARY OF STUDY DESIGN This is an open-label, randomized, 4-period, partial crossover study. Treatment A will consist of an intravenous (I.V.) 1-mg dose of [13C]-odanacatib that will be co- administered with unlabeled odanacatib 1-mg IV solution in a fasted state. Plasma samples will be obtained at specified intervals during the subsequent 336 hours after initiation of the infusion. In Treatment B, subjects will be administered a single dose of [13C]-odanacatib 1 mg I.V. following a 50-mg oral dose of odanacatib in a fasted state. In Treatment C, subjects will be administered a single dose of [13C]-odanacatib 1-mg I.V. following a 10-mg oral dose of odanacatib in a fasted state. Treatment A, B and C will be administered to 24 postmenopausal females in cross-over fashion in Periods 1-3. The fourth period will be a fixed period with 12 subjects being administered a single dose of [13C]-odanacatib 1 mg I.V. following a 50-mg oral dose of odanacatib following a low-fat meal (Treatment D) and 12 subjects being administered a single dose of [13C]-odanacatib 1 mg I.V. following a 50-mg oral dose of odanacatib following a high-fat meal (Treatment E). Plasma samples will be obtained at specified intervals during the subsequent 336 hours after administration of the tablet during each period. There will be at least a 28-day washout between doses.
1.5 SAMPLE Twenty-four (24) postmenopausal females between 45 and 65 years of age will be enrolled in this study.
1.6 DOSAGE/DOSAGE FORM, ROUTE, AND DOSE REGIMEN Subjects will be administered a single dose of [13C]-odanacatib 1 mg I.V. with odanacatib 1 mg I.V. in Treatment A of this study. In Treatment B, subjects will be administered a single dose of [13C]-odanacatib 1 mg I.V. following a 50-mg oral dose of odanacatib in a fasted state. In Treatment C, subjects will be administered a single dose of
0822_045-00_ProtCore APPROVED 27-Jan-2011 U.S. IND, U.S. Study Restricted Confidential – Limited Access 0822, Protocol 045-00 Issue Date: 27-Jan-2011 8 Product: MK-0822 2 Protocol/Amendment No.: 045-00
[13C]-odanacatib 1 mg I.V. following a 10-mg oral dose of odanacatib in a fasted state. The fourth period will be a fixed period with 12 subjects being administered a single dose of [13C]-odanacatib 1 mg I.V. following a 50-mg oral dose of odanacatib following a low- fat meal (Treatment D) and 12 subjects being administered a single dose of [13C]- odanacatib 1 mg I.V. following a 50-mg oral dose of odanacatib following a high-fat meal (Treatment E) The I.V. odanacatib infusion will begin 1 hour and 45 minutes following the oral dose and will be infused over 15 minutes.
0822_045-00_ProtCore APPROVED 27-Jan-2011 U.S. IND, U.S. Study Restricted Confidential – Limited Access
Product: MK-0822 3 Protocol/Amendment No.: 045-00 1.7 STUDY FLOW CHART
All Periods; Study Day (Hours Postdose) Day Day Day Day Day Day Day Day Day Day Post Pre- Pre- Day 1 2 3 4 5 6 8 10 11 12 15 Study Procedure study dose t=0 0.5 1 1.75 2 4 6 9 12 16 24 36 48 60 72 84 96 120 168 216 240 264 336 0822, Informed consent X Medical history X Evaluation of Inclusion/Exclusion X Protocol Safety Evaluation Physical examination X† X‡ X Heart rate and blood pressure§ X X X X X X § Respiratory rate and temperature X X¶ X § 12-lead ECG X X¶ X 045 Laboratory safety tests# X X X X X
HIV/Hepatitis screen/drug screen (per site X - 00 SOPs)
Pharmacokinetics Evaluations Issue Blood for odanacatib plasma assay †† X X------X Other Procedures
Odanacatib IV administration only X
Date: (Treatment A)‡‡ Odanacatib IV administration (Treatments X B, C, D and E)‡‡
Odanacatib oral dose (Treatments B, C, D, X 27 and E)‡‡
- Standard meal§§ X Jan High-fat or low fat breakfast X
- 2011
0822_045-00_ProtCore APPROVED 27-Jan-2011 U.S. IND, U.S. Study Restricted Confidential – Limited Access
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Product: MK-0822 4 Protocol/Amendment No.: 045-00 All Periods; Study Day (Hours Postdose) Day Day Day Day Day Day Day Day Day Day Post Pre- Pre- Day 1 2 3 4 5 6 8 10 11 12 15 Study Procedure study dose t=0 0.5 1 1.75 2 4 6 9 12 16 24 36 48 60 72 84 96 120 168 216 240 264 336 † Including height and weight. ‡
Perform within 72 hours prior to drug administration. 0822, § Subjects should be resting semi-recumbent for 10 minutes prior obtaining HR, BP, RR, temperature and 12-lead ECG. Heart rate (HR) and blood pressure (BP) to be obtained twice within 60 minutes of dosing. Subjects should be resting semi-recumbent for 10 minutes prior to the initial HR and BP measurement. ¶ Obtain within 3 hours prior to drug administration. # Subjects to fast for at least 8 hours prior to obtaining laboratory safety tests. Protocol †† Blood samples for determination of odanacatib plasma concentration will be collected as follows: Treatment A: predose and 5, 10, 15 (to be collected 30 seconds BEFORE the end of infusion), 20, 30 and 45 minutes and 1, 2, 4, 6, 9, 12, 16, 24, 36, 48, 60, 72, 84, 96, 120, 168, 216, 240, 264, and 336 hours post dose. Treatments B, C, D and E: predose and 1 hr, 1 hr 40 min, 1 hr 45 min, 1 hr 50 min, 1 hr 55 min, 2 hr (to be collected 30 seconds BEFORE the end of infusion), 2 hr 5 min, 2 hr 30 min, 2 hr 45 min, 4, 6, 9, 12, 16, 24, 36, 48, 60, 72, 84, 96, 120, 168, 216, 240, 264, and 336 hours post oral dose. ‡‡ In Treatment A, the labeled and unlabeled IV odanacatib solution will be given at t=0. The IV solutions will be infused over 15 minutes after at least an 8-hour fast. In Treatments B and C, the oral dose of odanacatib (t=0) will be 045 given with 240 mL of water after at least an 8-hour fast with water restricted one hour prior to and 2 hours after oral study drug administrations. The infusion of the IV odanacatib solution will start 1 hour and 45 minutes after dosing 13
of the oral odanacatib. The IV solution will be infused over 15 minutes and completion will be at approximately 2 hours post the oral dose of odanacatib. In Treatment D, subjects will be administered a single dose of [ C]- - odanacatib 1 mg I.V. following a 50-mg oral dose of odanacatib following a low-fat meal. In Treatment E, subjects will be administered a single dose of [13C]-odanacatib 1 mg I.V. following a 50-mg oral dose of odanacatib 00
following a high-fat meal.
Issue §§ Subjects to fast for 4 hours postdose on Day 1. A standard lunch will be served at approximately 4 hours postdose. Timing and contents of subsequent meals will be at the discretion of the investigator and should be uniform for all subjects in all periods. In Treatments D and E will receive a low-fat meal and high-fat meal 30 minutes prior to the oral dose and must consume the entire contents within 20 minutes
Date:
27
- Jan
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2011
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2. CORE PROTOCOL
2.1 OBJECTIVES AND HYPOTHESES 2.1.1 rimary Objectives
(1) To determine the bioavailability and pharmacokinetics of 10- and 50-mg oral doses of odanacatib. (2) To characterize the odanacatib absorption profile. (3) To assess the safety and tolerability of odanacatib and [13C]-odanacatib. (4) To assess the definitive food effect of a single 50-mg oral dose of odanacatib following either a high-fat or low- fat meal.
Hypotheses
(Estimation) To estimate the absolute bioavailability of 10- and 50-mg oral doses of odanacatib administered in the fasted state.
(Estimation) The effect of a standard low-fat and high-fat meal on the plasma pharmacokinetics (AUC0- and Cmax) following a 50-mg oral dose of odanacatib will be estimated.
2.1.2 Secondary Objectives
(1) To determine the influence of [13C] isotopic labeling on odanacatib I.V. pharmacokinetics.
(2) To characterize systemic disposition of odanacatib, including linearity
Hypotheses
[13C] isotopic labeling of odanacatib does not substantially alter the pharmacokinetics of intravenously administered odanacatib (geometric mean ratio of [13C]-odanacatib to odanacatib AUC0- , is contained within the interval [0.80, 1.25).
2.2 SUBJECT/PATIENT INCLUSION CRITERIA Demographics a. Subject is a postmenopausal female between 45 to 65 years of age at prestudy (screening) visit. A female who is postmenopausal has been without menses for at least 1 year and an FSH value in the postmenopausal range upon prestudy (screening) evaluation
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0822, Protocol 045-00 Issue Date: 27-Jan-2011 12 Product: MK-0822 6 Protocol/Amendment No.: 045-00 b. The subject has a Body Mass Index (BMI) 32 kg/m2 at the prestudy (screening) visit. BMI is calculated by taking the subject’s weight in kg and dividing by the subject’s height in meters, squared.
Note: BMI will be rounded to the nearest whole number according to the standard convention of 0.1-0.4 round down and 0.5-0.9 round up.
Medical history, physical examinations, laboratory safety tests and ECG measurements c. Subject is judged to be in good health based on medical history, physical examination, vital sign measurements, and laboratory safety tests (see Appendices 6.1 and 6.2) performed at the prestudy (screening) visit and/or prior to administration of the initial dose of study drug d. Subject has no clinically significant abnormality on electrocardiogram (ECG) performed at the prestudy (screening) visit and/or prior to administration of the initial dose of study drug.
Diet/Activity/Other f. Subject has been a nonsmoker and/or has not used nicotine or nicotine-containing products for at least approximately 6 months; subjects who have discontinued smoking or the use of nicotine/nicotine containing products for at least approximately 3 months may be enrolled in the study at the discretion of the investigator. g. Subject understands the study procedures and agrees to participate in the study by giving written informed consent. h. Subject is willing to comply with the study restrictions (see Sections 3.2.1 and 3.2.2. for a complete summary of study restrictions).
2.3 SUBJECT/PATIENT EXCLUSION CRITERIA Medical history, physical examinations, laboratory safety tests and ECG measurements. a. Subject is under the age of legal consent. b. Subject is mentally or legally incapacitated, has significant emotional problems at the time of prestudy (screening) visit or expected during the conduct of the study or has a history of a clinically significant psychiatric disorder over the last 5 years. Subjects who have had situational depression may be enrolled in the study at the discretion of the investigator. c. Subject has a history of any illness that, in the opinion of the study investigator, might confound the results of the study or poses an additional risk to the subject by their participation in the study.
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0822, Protocol 045-00 Issue Date: 27-Jan-2011 13 Product: MK-0822 7 Protocol/Amendment No.: 045-00 d. Subject has an estimated creatinine clearance of 80 mL/min based on the Cockcroft- Gault equation; the Cockcroft-Gault equation is :
ClCr = (140-age[yr])(body wt [kg]) (72)(serum creat [mg/dL])
An actual creatinine clearance, as determined by a 24-hour urine collection, may be used in place of, or in conjunction with, the Cockcroft-Gault equation; subjects who have an actual or estimated creatinine clearance within 10% lower than 80 mL/min may be enrolled at the discretion of the investigator. e. Subject has a history of stroke, chronic seizures, or major neurological disorder. f. Subject has a history of clinically significant endocrine, gastrointestinal, cardiovascular, hematological, hepatic, immunological, renal, respiratory, or genitourinary abnormalities or diseases. Subjects with a history of uncomplicated kidney stones or childhood asthma may be enrolled in the study at the discretion of the investigator. g. Subject has a history of clinically significant neoplastic disease.
Diet/Activity/Other h. Subject is unable to refrain from or anticipates the use of any medication, including prescription and non-prescription drugs or herbal remedies (such as St. John’s Wort [hypericum perforatum]) and any kind of multivitamin supplements beginning 2 weeks (or 5 half-lives) prior to administration of the initial dose of study drug, throughout the study (including washout intervals between treatment periods), until the poststudy visit. Exceptions can be made at the discretion of the investigator with consultation of the Merck monitor (see Section 3.2.1). i. Subject consumes excessive amounts of alcohol, defined as greater than 3 glasses of alcoholic beverages (1 glass is approximately equivalent to: beer [284 mL/10 ounces], wine [125 mL/4 ounces], or distilled spirits [25 mL/1 ounce]) per day on average. Subjects who consume 4 glasses of alcoholic beverages per day on average may be enrolled at the discretion of the investigator. j. Subject consumes excessive amounts on average, defined as greater than 6 servings (1 serving is approximately equivalent to 120 mg of caffeine) of coffee, tea, cola, or other caffeinated beverages per day. k. Subject has had major surgery (as deemed by investigator and Merck monitor), donated blood or lost 1 unit of blood (approximately 500 mL) or participated in another investigational study within 4 weeks prior to the prestudy (screening). Exceptions can be made at the discretion of the investigator with consultation of the Merck monitor.
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0822, Protocol 045-00 Issue Date: 27-Jan-2011 14 Product: MK-0822 8 Protocol/Amendment No.: 045-00 l. Subject has a history of significant multiple and/or severe allergies (including latex allergy), or has had an anaphylactic reaction or significant intolerability to prescription or non-prescription drugs or food as assessed by the investigator and Merck monitor. m. Subject is currently a regular user (including illicit drugs or has a history of drug (including alcohol) abuse within approximately 1 year. n. There is any concern by the investigator regarding the safe participation of the subject in the study or for any other reason, the investigator considers the subject inappropriate for participation in the study. o. Subject does not have adequate venous access. p. Subject has an allergy or sensitivity to Captisol®.
2.4 STUDY DESIGN AND DURATION 2.4.1 Summary of Study Design This is an open-label, randomized, 4-period, partial crossover study. Treatment A will consist of an intravenous (I.V.) 1-mg dose of [13C]-odanacatib that will be co- administered with unlabeled odanacatib 1-mg IV solution in a fasted state. Plasma samples will be obtained at specified intervals during the subsequent 336 hours after initiation of the infusion. For Treatment B, subjects will be administered a single dose of [13C]-odanacatib 1 mg I.V. following a 50-mg oral dose of odanacatib in a fasted state. For Treatment C, subjects will be administered a single dose of [13C]-odanacatib 1-mg I.V. following a 10-mg oral dose of odanacatib in a fasted state. Treatment A, B and C will be administered to 24 postmenopausal females in cross-over fashion in Periods 1-3. The fourth period will be a fixed period with 12 subjects being administered a single dose of [13C]-odanacatib 1 mg I.V. following a 50-mg oral dose of odanacatib following a low- fat meal (Treatment D) and 12 subjects being administered a single dose of [13C]- odanacatib 1 mg I.V. following a 50-mg oral dose of odanacatib following a high-fat meal (Treatment E). Plasma samples will be obtained at specified intervals during the subsequent 336 hours after administration of the tablet during each period. There will be at least a 28-day washout between doses.
2.4.2 Treatment Plan A sample allocation schedule for the treatment plan is in Table 2-1.
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Table 2-1
Sample Allocation Schedule
N Period 1 Period 2 Period 3 Period 4 2 A B C D 2 B C A D 2 C A B D 2 A C B D 2 B A C D 2 C B A D 2 A B C E 2 B C A E 2 C A B E 2 A C B E 2 B A C E 2 C B A E A = [13C]-odanacatib 1 mg IV solution coadministered with unlabeled odanacatib 1 mg IV solution in a fasted state. B = [13C]-odanacatib 1 mg IV solution following a 50-mg oral dose of odanacatib in a fasted state. C = [13C]-odanacatib 1 mg IV solution following a 10-mg oral dose of odanacatib in a fasted state. D= [13C]-odanacatib 1 mg IV solution following a 50-mg oral dose of odanacatib following a low-fat meal. E= [13C]-odanacatib 1 mg IV solution following a 50-mg oral dose of odanacatib following a high-fat meal
2.5 LIST OF EFFICACY/PHARMACOKINETIC/IMMUNOGENICITY, ETC., MEASUREMENTS
For IV treatments, plasma AUC0- , Cend-of-infusion, C168hr, t1/2, clearance, steady-state volume of distribution, and for oral treatments plasma AUC0- , Cmax, Tmax, C168hr, elimination t½ and absolute bioavailability will be derived from time-concentration profiles of [13C]-odanacatib and odanacatib as appropriate.
2.6 LIST OF SAFETY MEASUREMENTS Vital signs, weight, physical examination, 12-lead ECG and routine hematology and chemistry laboratories will be obtained for each subject at screening and at poststudy.
2.7 STATISTICAL ANALYSIS PLAN SUMMARY
Method: Individual ratio (F) of 1-mg unlabeled IV AUC0- over 1-mg labeled IV AUC0- , dose-adjusted (to 1 mg) 10-mg AUC0- over 1-mg labeled IV AUC0- , and dose- adjusted 50-mg AUC0- over labeled IV AUC0- will be calculated within each treatment period and for each individual in the first three periods. The ratio data will be log- transformed and analyzed using a mixed effect model appropriate for a 3-period crossover design. The model will contain fixed effects for treatment and period and a random effect for subject. The assumption of compound symmetry covariance structure
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0822, Protocol 045-00 Issue Date: 27-Jan-2011 16 Product: MK-0822 10 Protocol/Amendment No.: 045-00 will be examined; other covariance structures will be explored if the assumption does not seem to be satisfied.
Primary Estimation of Absolute Bioavailability: To estimate the absolute bioavailability of 10- and 50-mg oral doses of odanacatib administered in the fasted state, the geometric mean and 90% confidence interval (CI) for true ratio F following 10- and 50-mg doses will be provided.
Secondary Hypothesis on Effect of [13C] Isotopic Labeling: The effect of the [13C] isotopic labeling of odanacatib will be assessed by estimating the true ratio F following the unlabeled IV dose along with a 90% CI. If the 90% CI is contained within the interval (0.80, 1.25), then it will be concluded that odanacatib is not affected by [13C] isotopic labeling.
Primary Estimation of Food effect: A linear mixed effect model with treatment (fasted, low-fat and high-fat) as a fixed effect and subject as a random effect will be used to analyze log-transformed AUC0- using data from 50-mg oral dose of odanacatib in the fasted and fed states. The assumption of compound symmetry covariance structure will be examined; other covariance structures will be explored if the assumption does not seem to be satisfied. Two-sided 90% CIs will be constructed for the geometric mean ratios (GMRs) (low-fat / fasted and high-fat / fasted) of AUC0- . 90% CI will be obtained for Cmax GMR as well.
Linear systemic disposition of odanacatib: To assess linearity of systemic disposition of odanacatib, only the labeled IV PK data from the first three treatment periods will be used. An overall F test will be used to test if the labeled IV AUC0- in three treatments are different using the same mixed effect model as above but with labeled IV AUC0- as an endpoint. If the test is not statistically significant at the significance level of 0.05, then it will be claimed that there is no evidence from the study to suggest the IV PK is different among the three treatments or the systemic disposition of odanacatib is not linear; otherwise, it will be concluded that the systemic disposition of odanacatib is not linear. For estimation purposes, 95% CIs will also be constructed for the GMRs on labeled IV AUC0- co-administered with both the 10- or 50-mg oral doses vs. the unlabeled IV treatment.
Power: Since there is no human IV data available for odanacatib, the AUC0-and Cmax variability estimates based on oral formulation is used. Note that the oral variability will be likely to overestimate the IV variability, as variability in absorption, which is believed to be significant for odanacatib, will not contribute to the IV variability. In the following power calculations, the within subject standard deviation for ln-AUC0-and ln-Cmax of odanacatib are assumed to be 0.21 ln(µM*hr) and 0.18 ln(µM). The variability estimate was obtained from the pooled data in MK-0822 Protocols 055 and 056.
Primary Estimation of Absolute Bioavailability: With 24 subjects, the half width of the 90% confidence interval for the least square mean difference (oral - IV) of the AUC0-of odanacatib on the log scale will be 0.104. Assuming that the observed
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0822, Protocol 045-00 Issue Date: 27-Jan-2011 17 Product: MK-0822 11 Protocol/Amendment No.: 045-00 absolute bioavailability for either oral dose is 1.00, the 90% confidence interval for the true value will be 0.90 to 1.11.
Primary Estimation of Food effect: The following statement assume that there will be 24 available subjects with a 50-mg oral dose of odanacatib in the fasted state and half of them will receive a 50-mg oral dose of odanacatib either with a low-fat meal or with a high-fat meal in the last period. AUC0-: The half width of the 90% confidence interval for the least square mean difference (high-fat – fasted or low-fat – fasted) of the AUC0- of odanacatib on the log scale will be 0.154. Assuming that the observed GMR for either fat state is 2.00, the 90% confidence interval for the true value will be 1.71 to 2.33. Cmax: The half width of the 90% confidence interval for the least square mean difference (high- fat – fasted or low-fat – fasted) of the Cmax of odanacatib on the log scale will be 0.132. Assuming that the observed GMR for either fat state is 2.00, the 90% confidence interval for the true value will be 1.75 to 2.28.
Secondary Hypothesis on Effect of [13C] Isotopic Labeling: With 24 subjects, there is at least 94% probability that the two-sided 90% CI for F following the unlabeled IV dose falls within the pre-specified bound of (0.80, 1.25), assuming the true geometric mean is 1.0. If the true geometric mean of F lies within the interval (0.94, 1.06), then there is at least 80% probability that the 90% CI will fall within the interval (0.80, 1.25).
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3. PROTOCOL DETAILS Redacted
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3.2 STUDY PROCEDURES 3.2.1 Concomitant Medication(s)/Treatment(s) If a subject does not discontinue all prior medications within 14 days or 5 half-lives of study start, he/she may be included in the study if the investigator can rationalize that the specific use of a prior medication is not clinically relevant within the context of this study.
Concurrent therapy (including vaccines) with any medication during the course of the protocol (after randomization) including both prescription and nonprescription drugs must first be discussed with the investigator and Sponsor Medical Monitor prior to administration, unless appropriate medical care necessitates that therapy should begin before the investigator and Sponsor Medical Monitor can be consulted.
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Use of concurrent therapy (including vaccines) after randomization will be discussed with the Sponsor Medical Monitor. The subject will be allowed to continue in the study if both the Sponsor Medical Monitor and the investigator agree.
Paracetamol/acetaminophen may be used for minor ailments without prior consultation with the Merck clinical monitor.
3.2.2 Diet/Activity/Other Dietary Restrictions
In each treatment period, subjects will fast from all food and drink except water for at least 8 hours prior to the oral dose (t=0) in Treatments B and C and at least 8 hours prior to the IV dose (t=0) in Treatment A. In Treatments D and E, subjects will be administered a low-fat or high-fat meal, respectively, 30 minutes prior to dosing. All oral doses will be administered with 240 mL of water, with water restricted 1 hour prior to and 2 hours after study drug administration. A standard lunch at 4 hours postdose, respectively; subjects will fast from all food and drink except water between meals and snacks. The caloric content and composition of meals will be the same in each treatment period. After the 24-hour postdose procedures have been completed, subsequent meals and snacks will be unrestricted in caloric content and composition and timing.
Activity Restrictions
Subjects will avoid strenuous physical activity (i.e., strenuous or unaccustomed weight lifting, running, bicycling, etc.) from the prestudy (screening) visit until administration of the initial dose of study drug, throughout the study (including washout intervals between treatment periods) and until the poststudy visit.
Alcohol Restrictions
Subjects will refrain from consumption of alcohol from 24 hours prior to and after study drug administration in each treatment period and for 24 hours prior to the pre- and poststudy visits. At all other times, alcohol consumption is limited to no more than approximately 3 alcoholic beverages or equivalent (beer [284 mL], wine [125 mL] or distilled spirits [25 mL]) per day.
Caffeine Restrictions
Subjects will refrain from consumption of caffeinated beverages from 12 hours prior to and after study drug administration in each treatment period and for 12 hours prior to the pre- and poststudy visits. At all other times, caffeinated beverages will be limited to no more than 6 units per day amounts (>6 units: 1 unit=120 mg of caffeine).
Fruit Juice Restrictions
Subjects will refrain from consumption grapefruit juice, grapefruits and grapefruit products beginning approximately 2 weeks prior to administration of the initial dose of
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Subject also will refrain from consumption of all juices 24 hours prior to and after administration of each dose of study drug on pharmacokinetic days. All fruits except for grapefruits are allowed on all days of the study.
Smoking Restrictions
Smoking is not permitted during the study.
3.2.3 rocedures Study procedures should be completed as close to the prescribed/scheduled time as possible. Procedures will be performed in the following order of proximity (below) with regard to the prescribed time. These procedures can be done prior or after the timepoint. For this study the blood sample for odanacatib is the critical parameter and needs to be collected as close to the exact time point as possible.
1. Blood sample collection for odanacatib 2. Laboratory safety tests 3. 12-lead ECG 4. Vital signs 5. Physical examinations 6. Weight
The order of priority can be changed during the study with joint agreement of the investigator and the Sponsor Clinical Monitor.
Any nonscheduled procedures required for urgent evaluation of safety concerns take precedence over all routine scheduled procedures.
Weight
Body weight will be obtained with the subjects shoes off, jacket or coat removed.
Laboratory Safety Tests
Laboratory safety tests will be performed after an 8-hour fast.
Vital Sign Measurements
Subjects should be resting in a semi-recumbent position for at least 10 minutes prior to having vital sign measurements obtained. All vital signs will include heart rate and blood pressure. All blood pressure measurements are to be determined with an automated blood pressure machine.
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12-Lead ECGs
Special care must be taken for proper lead placement. All females must remove their bras prior to lead placement
Subjects should be resting in a semi-recumbent position for at least 10 minutes prior to having ECG readings obtained. ECGs will be performed within 2 hours prior to study drug administration (after the subject has remained in a semi-recumbent position for 10 minutes).
See the Study Flow Chart in Section 1.7 for a complete outline of all study procedures.
3.2.3.1 Prestudy Within approximately 2 to 3 weeks prior to administration of the initial dose of study drug in each part, potential subjects will be evaluated to determine that they fulfill the entry requirements as set forth in Sections 2.2 and 2.3. The investigator will discuss with each subject the nature of the study, its requirements, and its restrictions. Written informed consent will be obtained.
Subjects will be instructed about the restrictions for diet, activity, concomitant medications, alcohol, caffeine, grapefruit/fruit juice and smoking as noted in the Study Restrictions (Section 3.2.2).
All subjects will be given a card identifying them as a participant in a research protocol. The card will contain information detailing an appropriate contact and corresponding telephone number to be utilized in the event of an emergency.
Prestudy procedures are listed in Table 3-1.
Table 3-1
Prestudy Procedures Procedure Study Informed Consent Evaluation of inclusion/exclusion criteria Medical history Physical examination Weight Height 12-Lead electrocardiogram Vital signs (heart rate, blood pressure, respiratory rate, temperature) with automated blood pressure machine Laboratory safety tests (hematology, chemistry, urinalysis) Hepatitis screen Urine drug screen/HIV screen (per site’s SOPs)
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3.2.3.2 Pretreatment: All Treatment Periods Subjects will report to the CRU the day prior to the scheduled day of administration of each dose of study drug (Day 1). After the predose procedures have been completed, prior to study drug administration, subjects will be assigned to treatment according to a randomized allocation schedule (Section 2.4.2, Table 2-1).
In the morning of Day 1 at the discretion of the investigator/study coordinator, an indwelling venous catheter may be inserted into a forearm vein for sampling of blood (or blood sampling) at least 1 hour prior to dosing. The indwelling venous catheter may be flushed with saline to maintain patency. Special care must be taken to ensure proper sampling from the catheter. The volume of discard for each blood sample taken for pharmacokinetic or pharmacodynamic measurements must be twice the dead space volume of the catheter. Alternatively, blood samples may be obtained by direct venipuncture for each scheduled time point.
In Treatments D and E, subjects will be randomized to receive a low-fat and high-fat meal approximately 30 minutes prior to dosing, respectively.
The standard high-fat breakfast (see Table 3-2) and the standard low-fat breakfast (see Table 3-3) will be administered 30 minutes prior to dosing and must be consumed within 20 minutes.
Table 3-2
Content of a Standard High-Fat Breakfast (827 kcal, 57% fat content)
2 fried or scrambled eggs 2 strips bacon 2 slices toast with 2 pats of butter 4-oz (113 g) hash browns (fried potato) 240-mL whole milk The nutritional content of the high-fat breakfast is as follows: total fat = 55.6 g total carbohydrates = 55 g total protein = 31.1 g
Subjects will consume a low-fat breakfast as listed in Table 3-3.
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Table 3-3
Standard Low-Fat Breakfast
Fat Calorie Contents Protein (g) Carbohydrate (g) (g) (Kcal)
2 oz plain small bagel 6 30.9 1.4 163 1 oz Philadelphia 2.9 1.8 4.7 62 light cream cheese 6 oz 2% milk 6.1 8.8 3.5 91 Total 15 41.5 9.6 316
Predose procedures are listed in Table 3-4.
Table 3-4
Predose Procedures
Procedures 12 lead electrocardiogram (within 2 hours of oral dosing) Vital signs (heart rate, blood pressure, respiratory rate, oral temperature) (within 2 hours of oral dosing)
Laboratory safety tests (serum chemistry, hematology, urinalysis) (within 24 hours of oral dosing) High-fat or low-fat breakfast Plasma for odanacatib assay Local IV site tolerability assessment
3.2.3.3 Treatment (All Periods) Procedures for study drug administration and postdose procedures are listed in Table 3-5.
See Appendix 6.5 for procedures for administration of intravenous doses of odanacatib.
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Table 3-5
Postdose Procedures (All Treatment Periods)
Time Relative to Odanacatib Drug Procedures Administration (t=0)
Odanacatib oral administration† Treatments B, C, D, and E (t=0)
[13C]-odanacatib + unlabeled odanacatib intravenous Treatment A (IV) administration‡ t=0
[13C]-odanacatib intravenous (IV) administration§ Treatments B, C, D, and E 1 hour and 45 minutes postdose (oral dose)
Vital signs (heart rate and blood pressure) 2, 4, and 24 hours postdose
Laboratory safety tests (serum chemistry, 24 and 72 hours postdose hematology, urinalysis) Plasma for odanacatib assay Treatment A: 5, 10, 15 (to be collected 30 seconds BEFORE the end of infusion), 20, 30, 45 minutes and 1, 2, 4, 6, 9, 12, 16, 24, 36, 48, 60, 72, 84, 96, 120, 168, 216, 240, 264, and 336 hours post dose
Treatments B, C, D, and E: 1 hr, 1 hr 40 min, 1 hr 45 min, 1 hr 50 min, 1 hr 55 min, 2 hr (to be collected 30 seconds BEFORE the end of infusion), 2 hr 5 min, 2 hr 30 min, 2 hr 45 min, 4, 6, 9, 12, 16, 24, 36, 48, 60, 72, 84, 96, 120, 168, 216, 240, 264, and 336 hours post oral dose † In Treatments D and E, subjects will be administered the 13C-labeled IV odanacatib solution following a 50-mg oral dose (t=0) of odanacatib following a low-fat and high-fat meal, respectively. ‡ In Treatment A, the 13C-labeled and unlabeled IV odanacatib solutions will be given at t=0. The IV solution will be infused over 15 minutes after at least an 8-hour fast. § In Treatments B, C, D and E the oral dose of odanacatib (t=0) will be given with 240 mL of water after at least an 8-hour fast with water restricted one hour prior to and 2 hours after study drug administrations. The infusion of the IV odanacatib solution will start 1 hour and 45 minutes after dosing of the oral odanacatib. The IV solution will be infused over 15 minutes and completion will be at approximately 2 hours post the oral dose of odanacatib.
Subjects will remain in the CRU for 24 hours after oral study drug administration. A subject may be required to remain at the CRU for more than 24 hours after study drug administration for any safety concerns at the discretion of the investigator or at the request of the Merck clinical monitor.
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3.2.3.4 Poststudy Approximately 10 to 14 days after administration of the last dose of study drug, subjects will return for a poststudy visit. Following this, participation in this study will be complete.
Poststudy procedures (all panels) are listed in Table 3-6.
Table 3-6
Poststudy Procedures
Procedure
Physical examination Weight 12-Lead Electrocardiogram Vital signs (heart rate, blood pressure) with automated blood pressure machine Oral temperature and respiratory rate
Laboratory safety tests (hematology, chemistry, urinalysis)
3.2.3.5 Study Design/Procedures Modifications Permitted Within Protocol The total blood volume withdrawn from any single subject will not exceed the maximum allowable volume during his/her participation in the entire study (Appendix 6.4).
The timing of procedures for assessment of safety parameters (e.g., vital signs, ECG, safety laboratory tests, etc.) currently outlined in the protocol may be modified during the study based on newly available safety, tolerability, pharmacokinetic or pharmacodynamic data (e.g., to obtain data closer to the time of peak plasma concentrations). These changes will not increase the number of study procedures for a given subject during his/her participation in the entire study.
If a subject discontinues from the study due to a non-adverse experience, a replacement subject may be enrolled and begin dosing at the subsequent dose level for that panel, as long as the lower doses were concluded to be well tolerated based on investigator and sponsor review.
It is understood that the current study may employ some or none of the alterations described above. Any alteration made to this protocol to meet the study objectives must be detailed by the Sponsor in a memo to the Study File and forwarded to the Investigator for retention. The memo may be forwarded to the IRB/ERC at the discretion of the Investigator.
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3.2.3.6 Informed Consent 3.2.3.6.1 General Informed Consent The investigator must obtain documented consent from each potential subject in biomedical research or when an investigational drug is administered to the subject in a clinical study, prior to any study related procedures being performed.
Consent must be documented by the subject’s dated signature on a Consent Form along with the dated signature of the person conducting the consent discussion. A copy of the signed and dated consent form should be given to the subject before participating in the trials.
3.2.3.7 Assignment of Baseline Number/Screening/Washout (optional) A baseline or screening number is assigned to the subject upon signing the consent form to identify the subject for all procedures that occur prior to randomization. Each baseline or screening number will be assigned to only one subject.
3.2.3.8 Randomization/Allocation A single patient/subject cannot be assigned more than 1 allocation number.
In a situation where rerandomization of the subjects/patients is planned (e.g., study extension periods), the rerandomization is done based on a new allocation schedule, however each subject/patient retains his/her original allocation number. Only the treatment regimen associated with the rerandomization period or phase may change.
3.2.3.9 Blinding/Unblinding This is an open-label study.
3.2.3.10 Discontinuation/Withdrawal from Study Subjects/patients may withdraw at any time or be dropped from the study at the discretion of the investigator should any untoward effects occur. In addition, a subject/patient may be withdrawn by the investigator or the SPONSOR if he/she violates the study plan or for administrative and/or other safety reasons. The investigator or study coordinator must notify the SPONSOR immediately when a subject/patient has been discontinued/withdrawn due to an adverse experience (telephone or FAX). When a subject/patient discontinues/withdraws prior to study completion, all applicable activities scheduled for the final study visit should be performed at the time of discontinuation. Any adverse experiences which are present at the time of discontinuation/withdrawal should be followed in accordance with the safety requirements outlined in section 3.4 SAFETY MEASUREMENTS - DETAILS.
Subjects/patients who discontinue from the study for reasons unrelated to the study (e.g., personal reasons) will be replaced as required for the study to meet its objectives. The decision to remove a subject/patient and to replace dropouts will be made jointly by the
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Biological specimens obtained prior to subject/patient discontinuation can be analyzed unless consent is withdrawn.
Study Completion and Termination
Definition of Study Completion
Study completion is defined as the date the last subject completes the final visit in the study.
Given the unpredictable nature of early phase I studies, it may exceptionally be necessary to keep the study open for gathering/reviewing additional supportive data (preclinical and/or clinical) to optimally complete the objective(s) of the study. In this case the competent authority(ies) and the ethics committee(s) will be appraised of the maximum extension of the duration of the study beyond the last subject out and the justification for keeping the study open. If necessary, the appropriate amendments to the protocol will be generated.
Definition of Study Termination
Study termination is defined as a permanent discontinuation of the study due to unanticipated concerns of safety to the study subjects or availability of other new data (pharmacokinetic, pharmacodynamic, efficacy, biologic etc.) arising from clinical or preclinical studies with this study drug. A study may be paused during review of newly available preclinical/clinical safety, pharmacokinetic, pharmacodynamic, efficacy, or biologic data, or other issues of interest or potential concern prior to a final decision for continuation or termination of the study.
3.3 EFFICACY/PHARMACOKINETIC/IMMUNOGENICITY, ETC. MEASUREMENTS 3.3.1 Clinical and Laboratory Measurements for Efficacy/Pharmacokinetic/Immunogenicity, etc. The decision as to which plasma samples collected will be assayed for evaluation of pharmacokinetics/pharmacodynamics will be collaboratively determined by the Departments of Drug Metabolism and Clinical Pharmacology, (e.g., samples at lower doses may not be assayed if samples at higher doses reveal undetectable drug concentrations). If indicated, these samples may also be assayed and/or pooled for assay in an exploratory manner for metabolites and/or additional pharmacodynamic markers.
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3.4 SAFETY MEASUREMENTS 3.4.1 Clinical and Laboratory Measurements for Safety The safety and tolerability of odanacatib and [13C]-odanacatib will be monitored by clinical assessment of adverse experiences and by repeated measurements of vital signs, physical examinations, 12-lead electrocardiograms (ECGs) and standard safety tests.
3.4.2 Recording Adverse Experiences An adverse experience is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the SPONSOR’s product, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with the use of the SPONSOR’s product, is also an adverse experience.
Changes resulting from normal growth and development which do not vary significantly in frequency or severity from expected levels are not to be considered adverse experiences. Examples of this may include, but are not limited to, teething, typical crying in infants and children, and onset of menses or menopause occurring at a physiologically appropriate time.
Adverse experiences may occur in the course of the use of a Merck product in clinical studies or within the follow-up period specified by the protocol, or prescribed in clinical practice, from overdose (whether accidental or intentional), from abuse, and from withdrawal.
Adverse experiences may also occur in screened subjects/patients during any preallocation baseline period as a result of a protocol-specified intervention including washout or discontinuation of usual therapy, diet, placebo treatment, or a procedure.
Such events will be recorded at each examination on the Adverse Experience Case Report Forms/Worksheets.
3.4.3 Definition of an Overdose for This Protocol 3.4.3.1 Reporting of Overdose to SPONSOR If an adverse experience(s) is associated with ( vaccine, the adverse experience(s) is reported as a serious adverse experience, even if no other criteria for serious are met.
If a dose of test drug or vaccine meeting the protocol definition of overdose is taken without any associated clinical symptoms or abnormal laboratory results, the overdose is reported as a non-serious Event of Clinical Interest (ECI), using the terminology l overdose without adverse effect.
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All reports of overdose with and without an adverse experience must be reported within 24 hours to one of the individuals listed on the sponsor contact information page found in the Administrative Binder.
3.4.4 Reporting of Pregnancy to SPONSOR Although not considered an adverse experience, it is the responsibility of investigators or their designees to report any pregnancy in a subject/patient (spontaneously reported to them) which occurs during the study or within 14 days of completing the study. All subjects/patients who become pregnant must be followed to the completion/termination of the pregnancy. If the pregnancy continues to term, the outcome (health of infant) must also be reported to one of the individuals listed on the SPONSOR Contact Information page found in the Administrative Binder.
3.4.5 mmediate Reporting of Adverse Experiences to the SPONSOR 3.4.5.1 Serious Adverse Experiences Any serious adverse experience, including death due to any cause, which occurs to any subject/patient entered into this study or within 14 days following cessation of treatment or within the established off therapy follow-up period for safety described in the protocol, whether or not related to the investigational product, must be reported within 24 hours to one of the individual(s) listed on the contact information page.
Additionally, any serious adverse experience considered by an investigator who is a qualified physician to be possibly, probably, or definitely related to the investigational product that is brought to the attention of the investigator at any time outside of the time period specified in the previous paragraph also must be reported immediately to one of the individuals listed on the sponsor contact information page found in the administrative binder.
All subjects/patients with serious adverse experiences must be followed up for outcome.
3.4.5.2 Selected Nonserious Adverse Experiences (if applicable) These selected non-serious adverse experiences are also known as Events of Clinical Interest (ECI) and must be recorded as such on the Adverse Experience Case Report Forms/Worksheets.
3.4.6 Evaluating Adverse Experiences Refer to Table 3-7 for instructions in evaluating adverse experiences.
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Product: MK-0822 18 Protocol/Amendment No.: 045-00 Table 3-7 An investigator who is a qualified physician, will evaluate all adverse experiences as to: Maximum Mild awareness of sign or symptom, but easily tolerated (for pediatric studies, awareness of symptom, but easily tolerated)
Intensity Moderate discomfort enough to cause interference with usual activity (for pediatric studies, definitely acting like something is wrong) 0822, Severe incapacitating with inability to work or do usual activity (for pediatric studies, extremely distressed or unable to do usual activities) Seriousness A serious adverse experience is any adverse experience occurring at any dose that:
†Results in death; or Protocol †Is life threatening; or places the subject/patient, in the view of the investigator, at immediate risk of death from the experience as it occurred [Note: This does not include an adverse experience that, had it occurred in a more severe form, might have caused death.]; or †Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the hospitalization is a precautionary measure for continued observation. (Note: Hospitalization [including hospitalization for an elective procedure] for a preexisting condition which has not worsened 045 does not constitute a serious adverse experience.); or
- †Is a congenital anomaly/birth defect (in offspring of subject/patient taking the product regardless of time to diagnosis); or 00
Is a cancer; or
Issue Is an overdose (Whether accidental or intentional.) Any overdose whether or not associated with an adverse experience must be reported within 24 hours to one of the individuals on the Contact Information Page found in the Administrative Binder.
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse experience when, based
Date: upon appropriate medical judgment, the event may jeopardize the subject/patient and may require medical or surgical intervention to prevent one of the outcomes listed previously (designated above by a †).
Duration Record the start and stop dates of the adverse experience. If less than 1 day, indicate the appropriate length of time and units
27 Action taken Did the adverse experience cause the test drug to be discontinued?
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Relationship Did the test drug cause the adverse experience? The determination of the likelihood that the test drug caused the adverse experience will be provided by an investigator who is a Jan to test drug qualified physician. The investigator’s signed/dated initials on the source document or worksheet, that supports the causality noted on the AE form, ensures that a medically
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qualified assessment of causality was done. This initialed document must be retained for the required regulatory time frame. The criteria below are intended as reference 2011 guidelines to assist the investigator in assessing the likelihood of a relationship between the test drug and the adverse experience based upon the available information. The following components are to be used to assess the relationship between the test drug and the AE; the greater the correlation with the components and their respective elements (in number and/or intensity), the more likely the test drug caused the adverse experience (AE): Exposure Is there evidence that the subject/patient was actually exposed to the test drug such as: reliable history, acceptable compliance assessment (pill count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen? Time Course Did the AE follow in a reasonable temporal sequence from administration of the test drug? Is the time of onset of the AE compatible with a drug-induced effect? Likely Cause Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental factors
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Product: MK-0822 19 Protocol/Amendment No.: 045-00 Relationship The following components are to be used to assess the relationship between the test drug and the AE: (continued) to test drug Dechallenge Was the dose of test drug discontinued or reduced? (continued) If yes, did the AE resolve or improve? If yes, this is a positive dechallenge. If no, this is a negative dechallenge. (Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved despite continuation of the test drug; or (3) the study is a single-dose drug study.) 0822, Rechallenge Was the subject/patient reexposed to the test drug in this study? If yes, did the AE recur or worsen?
If yes, this is a positive rechallenge. If no, this is a negative rechallenge. Protocol (Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or (2) the study is a single-dose drug study.) NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN CAUSED BY THE TEST DRUG, OR IF REEXPOSURE TO THE TEST DRUG POSES ADDITIONAL POTENTIAL SIGNIFICANT RISK TO THE
SUBJECT/PATIENT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE U.S. CLINICAL MONITOR AND THE INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE. 045 Consistency Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the test drug or drug class pharmacology or toxicology?
- with Study 00
Drug Profile
Issue The assessment of relationship will be reported on the case report forms/worksheets by an investigator who is a qualified physician according to his/her best clinical judgment, including consideration of the above elements.
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of a drug relationship). Definitely There is evidence of exposure to the test drug. The temporal sequence of the AE onset relative to administration of the test drug is reasonable. The AE is more Date: related likely explained by the test drug than by another cause. Dechallenge is positive. Rechallenge (if feasible) is positive. The AE shows a pattern consistent with
previous knowledge of the test drug or test drug class. Probably There is evidence of exposure to the test drug. The temporal sequence of the AE onset relative to administration of the test drug is reasonable. The AE is more 27
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related likely explained by the test drug than by another cause. Dechallenge (if performed) is positive. Jan Possibly related There is evidence of exposure to the test drug. The temporal sequence of the AE onset relative to administration of the test drug is reasonable. The AE could
have been due to another equally likely cause. Dechallenge (if performed) is positive. -
2011 Probably not There is evidence of exposure to the test drug. There is another more likely cause of the AE. Dechallenge (if performed) is negative or ambiguous. related Rechallenge (if performed) is negative or ambiguous. Definitely not The subject/patient did not receive the test drug. OR Temporal sequence of the AE onset relative to administration of the test drug is not reasonable. OR There related is another obvious cause of the AE.
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3.4.7 SPONSOR Responsibility for Reporting Adverse Experiences All adverse experiences will be reported to regulatory agencies, IRB/IECs, and investigators in accordance with all applicable global laws and regulations.
3.5 STATISTICAL ANALYSIS PLAN The statistical analysis of the data obtained from this study will be conducted by, or under the direct auspices of, the Clinical Pharmacology Statistics Department in collaboration with the Clinical PK/PD and Clinical Pharmacology Departments of the Sponsor.
If, after the study has begun, changes are made to the statistical analysis plan stated below, then these deviations to the plan will be listed, along with an explanation as to why they occurred, in the Clinical Study Report.
3.5.1 Hypotheses Primary
(Estimation) To estimate the absolute bioavailability of 10- and 50-mg oral doses of odanacatib administered in the fasted state.
(Estimation) The effect of a standard low-fat and high-fat meal on the plasma pharmacokinetics (AUC0- and Cmax) following a 50-mg oral dose of odanacatib will be estimated.
Secondary
[13C] isotopic labeling of odanacatib does not substantially alter the pharmacokinetics of intravenously administered odanacatib (geometric mean ratio of [13C]-odanacatib to odanacatib AUC0- , is contained within the interval [0.80, 1.25]).
3.5.2 Analyses Endpoints Primary
The primary endpoints will include individual ratio of dose-adjusted 10-mg AUC0- over labeled IV AUC0- , and dose-adjusted 50-mg AUC0- over labeled IV AUC0- within each treatment period in the first three periods, and AUC0- and Cmax following a 50-mg oral dose of odanacatib in the fasted, low-fat and high-fat states.
Secondary
Secondary endpoint will be individual ratio of unlabeled IV AUC0- over labeled IV AUC0- . All other pharmacokinetic parameters after oral (e.g., AUC0- , Cmax, Tmax, C168hr, and elimination t½) and IV (AUC0- , Cend-of-infusion, C168hr, t1/2, clearance, and steady-state volume of distribution) administration are also of secondary interest.
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3.5.3 Approaches to Analyses The following populations are defined for the analysis and reporting of data. All subjects will be reported, and their data analyzed, according to the treatment(s) they actually received.
All Subjects as Treated (AST) – All subjects who will receive at least one dose of the investigational drug. This population will be used for assessments of safety and tolerability.
Per-Protocol (PP) – The set of data generated by the subset of subjects who comply with the protocol sufficiently to ensure that these data will be likely to exhibit the effects of treatment, according to the underlying scientific model. Compliance covers such considerations as exposure to treatment, availability of measurements and absence of major protocol violations. Major protocol violators will be identified to the extent possible prior to unblinding by individuals responsible for data collection/compliance, and its analysis and interpretation. Any subjects or data values excluded from analysis will be identified, along with their reason for exclusion, in the CSR. At the end of the study, all subjects who are compliant with the study procedure as aforementioned and have available data from at least one treatment will be included in the primary analysis dataset. This population will be used for the PK analyses.
3.5.4 Statistical Methods
Individual ratio (F) of 1-mg unlabeled IV AUC0- over 1-mg labeled IV AUC0- , dose- adjusted (to 1 mg) 10-mg AUC0- over 1-mg labeled IV AUC0- , and dose-adjusted 50- mg AUC0- over labeled IV AUC0- will be calculated within each treatment period and for each individual in the first three periods. The ratio data will be log-transformed and analyzed using a mixed effect model appropriate for a 3-period crossover design. The model will contain fixed effects for treatment and period and a random effect for subject. The assumption of compound symmetry covariance structure will be examined; other covariance structures will be explored if the assumption does not seem to be satisfied.
Primary Estimation of Absolute Bioavailability
To estimate the absolute bioavailability of 10- and 50-mg oral doses of odanacatib administered in the fasted state, the geometric mean and 90% confidence interval (CI) for true ratio F following 10- and 50-mg doses will be provided.
Secondary Hypothesis on Effect of [13C] Isotopic Labeling
The effect of the [13C] isotopic labeling of odanacatib will be assessed by estimating the true ratio F following the unlabeled IV dose along with a 90% CI. If the 90% CI is contained within the interval (0.80, 1.25), then it will be concluded that odanacatib is not affected by [13C] isotopic labeling.
Basic summary statistics (arithmetic mean, standard deviation) will be provided for F by treatment.
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Primary Estimation of Food effect
A linear mixed effect model with treatment (fasted, low-fat and high-fat) as a fixed effect and subject as a random effect will be used to analyze log-transformed AUC0- using data from 50-mg oral dose of odanacatib in the fasted and fed states. The assumption of compound symmetry covariance structure will be examined; other covariance structures will be explored if the assumption does not seem to be satisfied. Two-sided 90% CIs will be constructed for the geometric mean ratios (GMRs) (low-fat / fasted and high-fat / fasted) of AUC0- . 90% CI will be obtained for Cmax GMRs as well. Geometric means and 95% confidence intervals will be calculated for AUC0- and Cmax by treatment. Summary statistics for Tmax and apparent t1/2 will be provided. Basic summary statistics (arithmetic mean, standard deviation) will be reported AUC0-, Cmax, Tmax, C168hr, and elimination t½.
Linear systemic disposition of odanacatib
To assess linearity of systemic disposition of odanacatib, only the labeled IV PK data from the first three treatment periods will be used. An overall F test will be used to test if the labeled IV AUC0- in three treatments are different using the same mixed effect model as above but with labeled IV AUC0- as an endpoint. If the test is not statistically significant at the significance level of 0.05, then it will be claimed that there is no evidence from the study to suggest the IV PK is different among the three treatments or the systemic disposition of odanacatib is not linear; otherwise, it will be concluded that the systemic disposition of odanacatib is not linear.
Other Pharmacokinetic Parameters
For estimation purposes, 95% CIs will also be constructed for the on labeled IV AUC0- co-administered with both the 10- or 50-mg oral doses vs. the unlabeled IV treatment.
13 AUC0- , Cend-of-infusion, C168hr, t1/2, clearance, steady-state volume of distribution for [ C]- odanacatib 1 mg I.V. from the first three periods will be log transformed and analyzed using a linear mixed effect model with fixed effect for period and subject as a random effect. The geometric mean AUC0- , Cend-of-infusion, C168hr, t1/2, clearance, steady-state volume of distribution and the corresponding 95% confidence interval will be calculated for each period.
Data will be examined for departures from the assumptions of the statistical model(s) as appropriate; e.g., heteroscedasticity, nonnormality of the error terms. Distribution-free methods may be used if a serious departure from the assumptions of the models(s) is observed, or suitable data transformations may be applied.
3.5.5 ultiplicity No multiplicity adjustment procedure will be applied because there is no testing hypothesis in the primary hypotheses.
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3.5.6 Sample Size and Power Calculations
Since there is no human IV data available for odanacatib, the AUC0- and Cmax variability estimates based on oral formulation is used. Note that the oral variability will be likely to overestimate the IV variability, as variability in absorption, which is believed to be significant for odanacatib, will not contribute to the IV variability. In the following power calculations, the within subject standard deviation for ln-AUC0- and ln-Cmax of odanacatib are assumed to be 0.21 ln(µM*hr) and 0.18 ln(µM). The variability estimate was obtained from the pooled data in MK-0822 Protocols 055 and 056.
Primary Estimation of Absolute Bioavailability
With 24 subjects, the half width of the 90% confidence interval for the least square mean difference (oral - IV) of the AUC0-of odanacatib on the log scale will be 0.104. Assuming that the observed absolute bioavailability for either oral dose is 1.00, the 90% confidence interval for the true value will be 0.90 to 1.11.
Primary Estimation of Food effect
The following statement assume that there will be 24 available subjects with a 50-mg oral dose of odanacatib in the fasted state and half of them will receive a 50-mg oral dose of odanacatib either with a low-fat meal or with a high-fat meal in the last period.
AUC0-: The half width of the 90% confidence interval for the least square mean difference (high-fat – fasted or low-fat – fasted) of the AUC0-of odanacatib on the log scale will be 0.154. Assuming that the observed GMR for either fat state is 2.00, the 90% confidence interval for the true value will be 1.71 to 2.33.
Cmax: The half width of the 90% confidence interval for the least square mean difference (high-fat – fasted or low-fat – fasted) of the Cmax of odanacatib on the log scale will be 0.132. Assuming that the observed GMR for either fat state is 2.00, the 90% confidence interval for the true value will be 1.75 to 2.28.
Secondary Hypothesis on Effect of [13C] Isotopic Labeling
With 24 subjects, there is at least 94% probability that the two-sided 90% CI for F following the unlabeled IV dose falls within the pre-specified bound of (0.80, 1.25), assuming the true geometric mean is 1.0. If the true geometric mean of F lies within the interval (0.94, 1.06), then there is at least 80% probability that the 90% CI will fall within the interval (0.80, 1.25).
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3.6 PACKAGING, LABELING, STORAGE, DISPENSING, AND RETURN OF CLINICAL SUPPLIES 3.6.1 atient and Replacements Information Clinical supplies will be packaged to support enrollment of approximately 24 subjects and approximately 12 replacement subjects. When a replacement subject is required the SPONSOR needs to be contacted prior to dosing the replacement supplies.
Clinical supplies will be packaged according to an allocation schedule generated by the SPONSOR.
3.6.2 Product Descriptions Investigational materials will be provided by the SPONSOR as summarized in the Table 3-8.
Table 3-8
Product Descriptions
Product Name & Potency Dosage form Comments odanacatib 50 mg Oral compressed tablet Phase III clinical image (OCT) odanacatib 5 mg OCT Clinical image odanacatib 0.1 mg/mL Sterile solution for injection 11 mL fill per 20 mL vial. To deliver 10 mL. [13C]-odanacatib 0.1 mg/mL Sterile solution for injection 11 mL fill per 20 mL vial. To deliver 10 mL.
Other clinical supplies will be supplied by the investigator or by the site as needed. Every attempt will be made to source these supplies from a single lot/batch number. The investigator or designee will record the lot number, expiration date, and drug dispensed.
3.6.3 rimary Packaging and Labeling Information Supplies will be packaged in HDPE bottles (tablets) and glass vials (IV) as described in Table 3-9 below.
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Table 3-9
Packaging of Clinical Supplies
Interval ID/ Product name & Container ID potency Fill count Dosing Instructions Period X / Vial A [13C]-odanacatib 0.1 11 mL to deliver 10 Administer per mg/mL mL protocol (X = 1, 2, 3 or 4) Period X / Vial B odanacatib 0.1 11 mL to deliver 10 Administer per mg/mL mL protocol (X = 1, 2, 3 or 4) Period X / Bottle A odanacatib 50 mg 1 tablet Administer per OCT protocol (X = 1, 2, 3 or 4) Period X / Bottle B odanacatib 5 mg OCT 2 tablets Administer per protocol (X = 1, 2, 3 or 4)
Container label text may include the following:
Lot Trace ID # Dosing Instructions Allocation # Storage Conditions Fill Count & Dosage Form Compound ID - Protocol # Container ID Country regulatory requirements Interval ID SPONSOR address (If applicable) Product Name & Potency Re-evaluation date
3.6.4 Secondary Packaging and Labeling Information (kit) Supplies will be packaged in patient specific kit boxes. Each patient will receive a kit with 5 vials and a separate kit with 3 bottles. Kit configuration is subject to change as a result of packaging constraints.
Label text may include the following:
Lot Trace ID # Dosing Instructions Allocation # Storage Conditions Kit Contents Compound ID - Protocol # Container ID Country regulatory requirements Interval ID SPONSOR address (If applicable) Product Name & Potency Re-evaluation date
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3.6.5 Clinical Supplies Disclosure This study is open-label; therefore, the patient, the investigator’s site personnel and the SPONSOR are not blinded to treatment. Drug identity (name, strength) is included in the label text; disclosure envelopes are not provided.
3.6.6 Storage and Handling Requirements The storage conditions will be as indicated on the label.
IV supplies will be shipped to the sites on dry ice to be stored at -20˚C. Upon receipt at the investigational site, the vials should be removed from the outer secondary shipping box and placed immediately into the freezer. The temperature monitoring device must be deactivated upon receipt of the shipment. Directions for inactivation are specified in the Instructions to Site, which are enclosed with each shipment. The temperature monitoring device will indicate whether the shipment has remained within the specified temperatures. Return the temperature monitoring device according to instructions accompanying the shipment. Notify the SPONSOR immediately if the temperature monitoring device is in alarm. Store and hold product until instructed otherwise.
The clinical supplies storage area at the site must be monitored by the site staff for temperature consistency with the acceptable storage temperature range specified in this protocol or in the product label attached to the protocol. Documentation of temperature monitoring should be maintained.
3.6.7 Standard Policies / Return of Clinical Supplies Investigational clinical supplies must be received by a designated person at the study site, handled and stored safely and properly, and kept in a secured location to which only the investigator and designated assistants have access. Clinical supplies are to be dispensed only in accordance with the protocol. The investigator is responsible for keeping accurate records of the clinical supplies received from the SPONSOR, the amount dispensed to and returned by the subjects/patients, and the amount remaining at the conclusion of the study. In accordance with Good Pharmacy Practices, gloves should always be worn by study personnel if directly handling tablets or capsules that are returned (i.e., when counting returns). The Clinical Monitor should be contacted with any questions concerning investigational products where special or protective handling is indicated.
NOTE: Clinical supplies from this study are not to be returned to the SPONSOR at the end of the study. All clinical supplies including full, partial, and empty containers for all subjects (primary supplies, replacement supplies, and bulk supplies) must be retained and properly stored at the investigator’s study site in order to comply with the FDA regulations of Bioavailability and Bioequivalence Testing Samples. This FDA regulation appeared in the Federal Register, Volume 5P, No. 80 on 28-Apr-1993 and is specifically stated within 21 CFR 320.38.
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3.6.8 Site Retention Samples Definitive Bioequivalence/Bioavailability Studies with solid oral dosage forms will require packaging according to the following: all subjects and replacement subjects are assigned 2 complete subject packages. At the site, the investigator will randomly select one of the 2 packages per primary subject to be used for dosing and 1 of 2 packages to be used if a replacement subject is required. The remaining bottles will be retained at the site as retention samples and stored in a secure area/controlled environment.
3.7 DATA MANAGEMENT Information regarding Data Management procedures for this protocol will be provided by the SPONSOR.
3.8 BIOLOGICAL SPECIMENS Information regarding biological specimens for this protocol will be provided by the SPONSOR.
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4. DMINISTRATIVE AND REGULATORY DETAILS
4.1 CONFIDENTIALITY 4.1.1 Confidentiality of Data For Studies Conducted Under the U.S. IND Particular attention is drawn to the regulations promulgated by the Food and Drug Administration under the Freedom of Information Act providing, in part, that information furnished to clinical investigators and Institutional Review Boards will be kept confidential by the Food and Drug Administration only if maintained in confidence by the clinical investigator and Institutional Review Board.
For All Studies By signing this protocol, the investigator affirms to the SPONSOR that information furnished to the investigator by the SPONSOR will be maintained in confidence and such information will be divulged to the Institutional Review Board, Ethics Review Committee, or similar or expert committee; affiliated institution; and employees only under an appropriate understanding of confidentiality with such board or committee, affiliated institution and employees. Data generated by this study will be considered confidential by the investigator, except to the extent that it is included in a publication as provided in the Publications section of this protocol.
4.1.2 Confidentiality of Subject/Patient Records For All Studies By signing this protocol, the investigator agrees that the SPONSOR (or SPONSOR representative), Institutional Review Board/Independent Ethics Committee (IRB/IEC), or Regulatory Agency representatives may consult and/or copy study documents in order to verify worksheet/case report form data. By signing the consent form, the subject/patient agrees to this process. If study documents will be photocopied during the process of verifying worksheet/case report form information, the subject/patient will be identified by unique code only; full names/initials will be masked prior to transmission to the SPONSOR.
For Studies Conducted Under the U.S. IND By signing this protocol, the investigator agrees to treat all patient data used and disclosed in connection with this study in accordance with all applicable privacy laws, rules and regulations, including all applicable provisions of the Health Insurance Portability and Accountability Act and its implementing regulations, as amended from time to time. ( PAA
4.1.3 Confidentiality of Investigator Information For All Studies By signing this protocol, the investigator recognizes that certain personal identifying information with respect to the investigator, and all subinvestigators and study site
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0822, Protocol 045-00 Issue Date: 27-Jan-2011 46 Product: MK-0822 2 Protocol/Amendment No.: 045-00 personnel, may be used and disclosed for study management purposes, as part of a regulatory submissions, and as required by law. This information may include:
name, address, telephone number, and email address;
hospital or clinic address and telephone number;
curriculum vitae or other summary of qualifications and credentials; and
other professional documentation.
Consistent with the purposes described above, this information may be transmitted to the SPONSOR, and subsidiaries, affiliates and agents of the SPONSOR, in your country and other countries, including countries that do not have laws protecting such information. Additionally, the investigator’s name and business contact information may be included when reporting certain serious adverse events to regulatory agencies or to other investigators. By signing this protocol, the investigator expressly consents to these uses and disclosures.
For Multicenter Studies In order to facilitate contact between investigators, the SPONSOR may share an investigator’s name and contact information with other participating investigators upon request.
4.2 COMPLIANCE WITH LAW, AUDIT, AND DEBARMENT By signing this protocol, the investigator agrees to conduct the study in an efficient and diligent manner and in conformance with this protocol; generally accepted standards of Good Clinical Practice; and all applicable federal, state, and local laws, rules and regulations relating to the conduct of the clinical study.
The Code of Conduct, a collection of goals and considerations that govern the ethical and scientific conduct of clinical investigations sponsored by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., is attached.
The investigator also agrees to allow monitoring, audits, Institutional Review Board/Independent Ethics Committee review, and regulatory agency inspection of trial- related documents and procedures and provide for direct access to all study-related source data and documents.
The investigator agrees not to seek reimbursement from subjects/patients, their insurance providers, or from government programs for procedures included as part of the study reimbursed to the investigator by the SPONSOR.
The Investigator shall prepare and maintain complete and accurate study documentation in compliance with Good Clinical Practice standards and applicable federal, state, and local laws, rules and regulations; and, for each subject/patient participating in the study,
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0822, Protocol 045-00 Issue Date: 27-Jan-2011 47 Product: MK-0822 3 Protocol/Amendment No.: 045-00 provide all data, and upon completion or termination of the clinical study submit any other reports to the SPONSOR as required by this protocol or as otherwise required pursuant to any agreement with the SPONSOR.
Study documentation will be promptly and fully disclosed to the SPONSOR by the investigator upon request and also shall be made available at the investigator’s site upon request for inspection, copying, review, and audit at reasonable times by representatives of the SPONSOR or any regulatory agencies. The investigator agrees to promptly take any reasonable steps that are requested by the SPONSOR as a result of an audit to cure deficiencies in the study documentation and worksheets/case report forms.
International Conference of Harmonization Good Clinical Practice guidelines (Section 4.3.3) recommend that the investigator inform the subject’s primary physician about the subject’s participation in the trial if the subject has a primary physician and if the subject agrees to the primary physician being informed.
According to European legislation, a SPONSOR must designate a principal or coordinating investigator (CI) to review the report (summarizing the study results) and confirm that to the best of his/her knowledge the report accurately describes conduct and results of the study. The SPONSOR may consider one or more factors in the selection of the individual to serve as the CI (e.g., thorough understanding of clinical trial methods, appropriate enrollment of subject/patient cohort, timely achievement of study milestones, availability of the CI during the anticipated review process).
The investigator will promptly inform the SPONSOR of any regulatory agency inspection conducted for this study.
Persons debarred from conducting or working on clinical studies by any court or regulatory agency will not be allowed to conduct or work on this SPONSOR’s studies. The investigator will immediately disclose in writing to the SPONSOR if any person who is involved in conducting the study is debarred, or if any proceeding for debarment is pending or, to the best of the investigator’s knowledge, threatened.
In the event the SPONSOR prematurely terminates a particular trial site, the SPONSOR will promptly notify that site’s IRB/IEC.
4.3 COMPLIANCE WITH FINANCIAL DISCLOSURE REQUIREMENTS By signing this protocol, the investigator agrees to provide to the SPONSOR accurate financial information to allow the SPONSOR to submit complete and accurate certification and disclosure statements as required by U.S. Food and Drug Administration regulations (21 CFR Part 54). The investigator further agrees to provide this information on a Financial Disclosure/Certification Form that is provided by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.. This requirement also extends to subinvestigators. The investigator also consents to the transmission of this information to Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc, in the United States for
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0822, Protocol 045-00 Issue Date: 27-Jan-2011 48 Product: MK-0822 4 Protocol/Amendment No.: 045-00 these purposes. This may involve the transmission of information to countries that do not have laws protecting personal data.
4.4 QUALITY CONTROL AND QUALITY ASSURANCE By signing this protocol, the SPONSOR agrees to be responsible for implementing and maintaining quality control and quality assurance systems with written SOPs to ensure that trials are conducted and data are generated, documented, and reported in compliance with the protocol, accepted standards of Good Clinical Practice, and all applicable federal, state, and local laws, rules and regulations relating to the conduct of the clinical study.
4.5 COMPLIANCE WITH INFORMATION PROGRAM ON CLINICAL TRIALS FOR SERIOUS OR LIFE THREATENING CONDITIONS Under the terms of The Food and Drug Administration Modernization Act (FDAMA), the SPONSOR of the study is solely responsible for determining whether the study is subject to the requirements for submission to the Clinical Trials Data Bank, http://clinicaltrials.gov/. Merck, as SPONSOR of this study, will review this protocol and submit the information necessary to fulfill this requirement. Merck entries are not limited to FDAMA mandated trials. Merck’s voluntary listings, beyond those mandated by FDAMA, will be in the same format as for treatments for serious or life-threatening illnesses. Information posted will allow patients to identify potentially appropriate trials for their disease conditions and pursue participation by calling a central contact number for further information on appropriate study locations and site contact information.
By signing this protocol, the investigator acknowledges that the statutory obligation under FDAMA is that of the SPONSOR and agrees not to submit any information about this study to the Clinical Trials Data Bank.
4.6 PUBLICATIONS Publications derived from this study should include input from the investigator(s), and SPONSOR personnel. Such input should be reflected in publication authorship, and whenever possible, preliminary agreement regarding the strategy for order of authors’ names should be established before conducting the study.
The SPONSOR must have the opportunity to review all proposed abstracts, manuscripts, or presentations regarding this study 60 days prior to submission for publication/presentation. Any information identified by the SPONSOR as confidential must be deleted prior to submission. SPONSOR review can be expedited to meet publication guidelines.
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Supplemental data
The absolute bioavailability and effect of food on the pharmacokinetics of odanacatib: a stable-label IV/oral study in healthy post-menopausal women
Stefan Zajic, Stefaan Rossenu, David Hreniuk, Filippos Kesisoglou, Jacqueline McCrea, Fang Liu, Li
Sun, Rose Witter, Don Gauthier, Roy Helmy, Darrick Joss, Tong Ni, Randall Stoltz, Julie Stone, S.
Aubrey Stoch
Drug Metabolism and Disposition
1
Supplemental Table 1. Population PK parameter estimates for the final IV and oral combined model of the P045 data
Parameter Estimate RSE(%) Parameter Estimate RSE(%)
Cl (L/h) 0.849 8.22 IIV (CL) (%) 41.0 22.1
Vc (L) 28.3 14.3 IIV (Vc) (%) 60.3 23.3
Vp,1 (L) 13.0 FIX IIV (Vp,1) (%) 86.6 FIX
Q1 (L/h) 98.8 FIX IIV (Vp,2) (%) 24.6 FIX
Vp,2 (L) 52.8 FIX IIV (Ka) (%) 22.5 38.7
Q2 (L/h) 13.5 FIX IIV (F1) (%) 16.7 29.1
-1 Ka (h ) 13.0 FIX IOV (Ka) (%) 28.9 19.3
F1 50 mg fasted 0.297 4.81
F1 10 mg fasted 0.717 5.05
F1 50 mg low fat 0.336 4.97
F1 50 mg high fat 0.502 6.33 Covariance
Acrophase (h) 13.0 4.68 Ka – F1 (%) 90.2 24.3
Amplitude 0.290 14.9
Residual error
Covariate Proportional (%) 20.1 12.3
a Food on Ka 0.601 16.8 Additive (ng/mL) 0.451 44.0
aShift in the first order absorption constant when drug was taken after high-fat breakfast CL, clearance; F1, absolute bioavailability; IIV, inter-individual variability; IOV, inter-occasion
variability; IV, intravenous; Ka, absorption rate constant; PK, pharmacokinetics; Q1 and Q2,
inter-compartmental flows; RSE, relative standard error; Vc, central volume of distribution; Vp,1 and Vp,2, volume of peripheral compartments
2
Supplemental Table 2. The systemic disposition of odanacatib appears to be linear, as assessed by
comparison of 13C -labeled odanacatib PK resulting from 1 mg IV administration when co-administered with varying doses of unlabeled odanacatib
Co- Na Geometric mean P-value for N Geometric mean P-value for
administered AUC0-∞ (µM-hr) treatment Ceoi (nM) (95% treatment
unlabeled oral (95% CI) effect, AUC0-∞ CI) effect, Ceoi
dose
1 mg IV 20 2.3 (2.1, 2.6) 24 52.6 (46.5, 59.5)
10 mg oral fasted 18 2.3 (2.0, 2.6) 24 52.5 (46.4, 59.4)
50 mg oral fasted 18 2.2 (1.9, 2.5) 24 55.9 (49.4, 63.2)
0.515 0.823 50 mg oral with 9 2.3 (2.1, 2.7) 12 56.5 (47.5, 67.1)
low-fat meal
50 mg oral with 9 2.3 (2.0, 2.6) 12 56.5 (47.6, 67.2)
high-fat meal
P-values are from overall F-test for treatment effect a N is less than 24 (for first three treatments) or 12 (for latter two) because for some subjects, AUC0-∞ and t1/2 could not be determined due to insufficient data in the terminal phase
AUC0-∞, area under the curve from zero to infinity; Ceoi, Cend-of-infusion; CI, confidence interval; IV, intravenous; PK, pharmacokinetics
3
Supplemental Table 3. 13C -isotopic labeling does not alter the pharmacokinetics of IV-administered odanacatib, as assessed following 1 mg IV unlabeled and 13C -labeled doses
Unlabeled/labeled comparison parameter Na Geometric mean (90% CI)
AUC0-∞ 19 1.18 (1.12, 1.24)
Ceoi 24 1.08 (1.04, 1.11)
Terminal t1/2 19 1.04 (0.98, 1.09)
a N is less than 24 for some comparisons because for some subjects, AUC0-∞ and t1/2 could not be determined due to insufficient data in the terminal phase
AUC0-∞, area under the curve from zero to infinity; Ceoi, Cend-of-infusion; CI, confidence interval;IV,
intravenous; t1/2, half-life
4
Supplemental Figure 1. Individual concentration-time plots for subjects who received 1 mg IV
13C-odanacatib and 50 mg oral unlabeled odanacatib with a high-fat meal: examples of concordance between fluctuations in IV and oral profiles (panel titles indicate AN)
IV, intravenous
5
Supplemental Figure 2. Comparison of the absorption profile for different doses and fed states after either model-independent deconvolution (solid) or using a Hill function (dashed)
6
Supplemental Figure 3. Visual predictive check for the final IV/oral combined model
Solid black line: median prediction
Grey area: 90% prediction interval
Black symbol: observed data
Dashed black line: BQL (0.5 ng/mL)
BQL, below quantifiable limit; IV, intravenous; ODN, odanacatib
7