Pharmacokinetics and Bioavailability of Oral 9-Aminocamptothecin Capsules in Adult Patients with Solid Tumors

Vol. 4, 1915-19/9, August /998 Clinical Cancer Research 1915

Alex Sparreboom,’ Maja J. A. de Jonge, synthesis, this will lead to irreversible DNA damage with dou- Cornelis J. A. Punt, Kees Nooter, Walter J. Loos, ble-strand DNA breaks, S-phase cell cycle arrest and, ulti- mately, cell death. Studies on structure-activity relationships Maria Grazia Porro, and Jaap Verweij have revealed that the terminal lactone ring of the campto- Department of Medical Oncology. Rotterdam Cancer Institute (Daniel thecins, which is in equilibrium with an open-ring carboxylate den Hoed Kliniek) and University Hospital Rotterdam. 3008 AE Rotterdam, the Netherlands [A. S., M. J. A. d. J., K. N., W. J. L., form at constant pH, is essential for this topoisomerase I inhi- J. V.]: University Hospital Nijmegen, 6500 HB Nijmegen, the bition (3). Netherlands [C. J. A. P.]: and Pharmacia & Upjohn. 20152 Milan. The high specificity in the mechanism of action of camp- Italy fM G. P.]. tothecins for the S-phase in the cell cycle has led to the recog- nition that the compounds may require prolonged exposure to ABSTRACT maximize the fractional cell kill. This finding has been con- Preclinical studies indicate enhanced antitumor activity firmed experimentally in nude mice bearing human tumor xe- of 9-amino-20(S)-camptothecin (9-AC) when it is adminis- nografts given 9-AC, demonstrating the importance of main- tered in a manner that provides prolonged systemic expo- taming a minimal threshold drug level in plasma for at least 48 h sure. In view of this observation, the pharmacokinetics and (4). On the basis of these preclinical data. several Phase I oral bioavailability of 9-AC polyethylene glycol 1000 cap- clinical trials have been initiated with the drug administered sules were evaluated in 12 patients with solid tumors. Pa- according to continuous iv. infusion schedules (5-8). tients were randomized to receive either 1.5 mg/rn2 9-AC The availability of a clinically useful oral formulation of p.o. on day 1 and 1.0 mg/m2 9-AC i.v. on day 8 or vice versa. 9-AC would provide increased convenience for the administra- Serial plasma samples were collected up to 55 h after dosing tion of chronic dosing regimens and the opportunity for cost- and analyzed for 9-AC by liquid chromatography. Plasma effective outpatient therapy (9). Furthermore, preclinical evi- concentrations of the lactone and carboxylate forms of 9-AC dence of efficacy and toxicity of 9-AC given p.o. to rodents and rapidly reached an equilibrium, with the active lactone ac- dogs is suggestive of significant gastrointestinal absorption of the drug (10, 11). Here, we explored the bioavailability of 9-AC counting for < 10% of total drug at the terminal disposition phase. The drug demonstrated peak levels at 1.2 h and an after oral administration in patients to provide a basis for further overall bioavailability of48.6 ± 17.6% (range, 24.5- 80.4%), clinical development of the drug using chronic oral dosing. indicating significant systemic exposure to the drug, which may enable chronic oral treatment. PATIENTS, MATERIALS, AND METHODS Chemicals. Analytical reference material used for quan- INTRODUCTION titation of 9-AC (lot 93L07A) and camptothecin (lot 93K05A; 9-AC2 (NSC 60307 1) is a semisynthetic analogue of camp- internal standard) were supplied by Pharmacia Inc. (Albuquer- tothecin, a cytotoxic plant alkaloid derived from the bark and que, NM). With reversed-phase HPLC (see below), the purity of Camptotheca accuminata, wood of the oriental tree Decaisne 9-AC and camptothecin was judged to be >99.0%. Perchloric ( 1 ). The mechanism of action of 9-AC and structurally related acid was purchased from Baker (Deventer, the Netherlands) as derivatives is believed to stem from the unique propensity to a ready-to-use solution [70% (v/v)]. All other chemicals were of inhibit mammalian DNA topoisomerase I activity, causing sta- analytical or HPLC grade and originated from Rathburn (Walk- bilization of cleavable complexes during DNA replication, tran- erburn, United Kingdom). Drug-free human plasma was ob- scription, and repair (2). In the presence of ongoing DNA tamed from the Central Laboratory of the Blood Transfusion Service (Amsterdam, the Netherlands). Purified deionized water was prepared by the Milli-Q UF system (Millipore, Milford. MA) and was used throughout. Received 10/8/97: revised 4/30/98: accepted 5/5/98. Patients. All patients included in this study had a histo- The costs of publication of this article were defrayed in part by the logically or cytologically proven malignant solid tumor, for payment of page charges. This article must therefore be hereby marked which no standard therapy was available. Eligibility criteria advertisement in accordance with 18 U.S.C. Section 1734 solely to included the following: (a) age between 18 and 75 years; (b) an indicate this fact. Eastern Cooperative Oncology Group performance status of I To whom requests for reprints should be addressed, at Department of Medical Oncology, Rotterdam Cancer Institute (Daniel den Hoed <2; (c) life expectancy of at least 12 weeks; (d) adequate Kliniek) and University Hospital Rotterdam, P.O. Box 5201, 3008 AE hematopoietic (absolute peripheral granulocyte count of >2000 Roflerdam, the Netherlands. Phone: 3 1 10 4391 132; Fax: 3 1 104851618: il ‘ and platelet counts of > 100,000 jil ‘ ), hepatic (total E-mail: [email protected]. bilirubin levels within normal limits and aspartate aminotrans- 2 The abbreviations used are: 9-AC. 9-amino-20(S)-camptothecin: HPLC, high-performance liquid chromatography: PEG. polyethylene ferase, alanine aminotransferase, and alkaline phosphatase 1ev- glycol: AUC, area under the plasma concentration versus time curve. els of <2 times the upper normal limits), and renal (creatinine

levels of < 133 fLM) functions; and (e) all patients’ informed Sample Collection. Serial blood samples (--4.5 ml) were written consents according to institutional guidelines before collected in heparinized tubes by iv. sampling from the arm treatment. opposite to the one in which the drug was infused. This was Dosage Forms. 9-AC is a drug with a very unfavorable performed after oral administration at 0 (predose), 20, and 40 solubility profile in aqueous fluids. At acidic pH, its solubility is minandl,l.5,2,3,5,7.5,ll,24,28,31,48,52,and55h.With very low (-0. 125 and 0.02 mg/mi at pH 1 and pH 3, respec- the 5-mn i.v. infusion, the sampling was performed at 0, 5, 15, tively), whereas at pH values above 4, the opening of the lactone 25, and40min and 1, 2, 3, 5, 7.5, 11, 24, 28, 31,48, 52, and55 h ring occurs, resulting in a degradation product with low activity after the start of infusion. Immediately after sampling, tubes (3). Because poor solubility characteristics may cause absorp- were briefly immersed into an ice bath kept at the bedside, and tion and bioavailability problems, a semisolid matrix formula- plasma was separated within 10 mm by centrifugation at 3000 X tion in hard gelatin capsules has been viewed as the first-choice g for 5 mm (4#{176}C)to prevent significant degradation of the dosage form. The semisolid matrices evaluated for development lactone form. The supernatant was transferred to a clean tube of the oral dosage form were prepared by mixing 9-AC with the and stored at -80#{176}C,until the time of analysis (within 2 weeks), which is a period short enough to prevent potential stability carrier at a temperature higher than the melting point of the problems (12). matrix. The molten dispersion was then filled into gelatin cap- Drug Analysis. 9-AC lactone and total drug (lactone sules under continuous stirring to enable the dosage form to be plus carboxylate) concentrations in plasma were determined processed from the liquid phase. After filling, the melt was according to a validated reversed-phase HPLC method reported cooled at room temperature to obtain a drug dispersion at solid in detail previously by Loos et a!. (12). In summary, sample state. pretreatment for the lactone involved a solvent extraction of the The solubility of 9-AC in several carriers suitable for such analyte from l-ml samples with 7.5 ml of acetonitrile-n-butyl- technology was evaluated, and PEGs gave the most interesting chloride (1:4, v/v) in glass screw-cap tubes containing 0.8 g of results, with solubility ranging from 1 .2 to 1.5 mg/mI (i.e., >50 sodium chloride and 100 p.1 of 2.5 ng/ml camptothecin (used as times higher than an aqueous solution at pH 3). In subsequent internal standard) in methanol, water, and perchloric acid (500: experiments, the in vitro drug release performance was thor- 500: 1, vlvlv). After centrifugation for 5 mm at 4000 X g, the oughly investigated using PEGs of different molecular weights organic layer was collected in a tube containing 50 al of DMSO as vehicles (e.g., PEG400, PEG600, and PEG1000). Dissolution and evaporated at 50#{176}Cunder nitrogen. To the residue, 50 p.1 of rate was determined with the basket apparatus, rotating at 100 methanol and 150 xl of perchloric acid-water (1:500, v/v) were rpm, in 0.001 N aqueous hydrochloric acid solution at 37#{176}C.All added. Subsequently, the sample was transferred to a low- experiments were performed under sink conditions. The results volume insert, and 150 xl were injected into the HPLC system. of these tests demonstrated that the fastest in vitro release could Sample preparation for 9-AC total involved vigorous mixing of be attained with the semisolid matrix formulation in PEG 1000, 250 p.1 of plasma with an equal volume of 5% (v/v) perchloric with 100% of the drug dissolved within 30 mm. The dissolution acid-methanol (1: 1, v/v), followed by centrifugation for 5 mm at performance of this formulation was also superior to physical 24,000 x g. The clear supernatant was transferred to a low- mixtures of the drug and either PEG400 or PEG2O,000 (<80% volume insert, and an aliquot of 200 pA was subjected to of the drug dissolved after 90 mm) or conventional capsule chromatography. The reversed-phase chromatographic system formulations, i.e. , a powder formulation containing microcrys- consisted of a constaMetric 3200 pump (LDC Analytical, Rivera talline cellulose as filter/disintegrant and glyceryl palmitostear- Beach, CA), a Waters 7l7Plus auto-sampler (Milford, MA), and ate as lubricant (<50% of the drug dissolved after 30 mm). a fluoriMonitor 4100 detector (LDC Analytical). Compounds of Drug Administration. Eventually, for oral drug admin- interest were separated on an Inertsil ODS-80A stationary phase istration, 9-AC was supplied as hard gelatin capsules containing (150 X 4.6 mm inner diameter; 5-j.m particle size) from GL a yellow waxy mass with 0.25 mg (size N.4) or 1 mg (size N.2) Science Inc. (Tokyo, Japan). The mobile phases were comprised of the active drug substance, with PEG1000 as excipient (Phar- of methanol-water [40:60 (v/v) for 9-AC lactone and 32.5:67.5 macia & Upjohn, Pharmaceutical Development Department, (v/v) for 9-AC total] with the pH adjusted to 2. 1, and they were Nerviano, Italy). Each patient received 1.5 mg/m2 9-AC with delivered at 1.0 ml/min. Detection was performed at excitation 150-200 ml of water. For i.v. administration, 9-AC was pro- and emission wavelengths of 370 and 450 nm, respectively. vided as 1- or 2-ml vials containing 1 or 2 mg of lyophilized Peak detection was done with the Fisons ChromCard data anal- drug and a mathx of soybean phospholipids and mannitol as ysis system (Milan, Italy). cryoprotectant (Pharmacia & Upjohn, Milan, Italy). The vials Drug concentrations were determined from linear calibra- were reconstituted in a mixture of 20% dextrose, 0.9% sodium tion curves, constructed in blank human plasma, by linear re- chloride, and sterile water for injection (pH 3.5) and diluted gression analysis of peak heights versus l/x. The mean percent- further in the same diluent to obtain a concentration of -20 age deviation (accuracy) and precision (within-run and between- J.g/ml of 9-AC. Each patient received a single i.v. dose of 1.0 run) were always < 10%. The lower limits of quantification mg/m2 through a peripheral venous-access device in 5 mm. All were 50 and 100 pg/ml for the lactone and total forms, respec- patients were randomized to receive 9-AC either p.o. on day 1 tively. The 9-AC carboxylate at each time point was quantitated and i.v. on day 8 or vice versa. On both days of drug adminis- indirectly from the difference in concentration of total and tration, patients had fasted for at least 8 h before and 0.5 h after lactone forms. dosing. Patients were subsequently offered participation in a Pharmacokinetic Analysis. Individual 9-AC plasma- Phase I study with chronic oral dosing of 9-AC. concentration data were analyzed by both noncompartmental

and compartmental analysis using the Siphar version 4.0 soft- ware package (SIMED, Creteil, France). The AUC for 9-AC A total was calculated by the linear-trapezoidal rule up to the last sampling point with detectable levels (C), with extrapolation to E ‘5. k1 infinity (AUCt)_J by the equation AUC + C/ku,, where C represents the terminal disposition rate constant. The latter term C was calculated from the slope of data points in the final log- 0 S linear part of the drug concentration-time curve by weighted C

(l/v) least-squares linear regression analysis. Maximum plasma U C concentration (C,,iax) and the time to maximum concentration 0 U (tmax) following oral administration were estimated by visual inspection of the semilogarithmic plot of the concentration-time curve. The absolute oral bioavailability (F) expressed as a 0 10 20 30 40 percentage was calculated by dividing the AUCt,rI by the

AUCIV normalized to dose [F = (AUCrai/AUCiv)(doseiv/ doseoraj)lOO%], assuming a linear pharmacokinetic behavior during both study periods. B The apparent absorption rate constant (ku) was estimated by the numerical point-area deconvolution technique ( I 3). Other E pharmacokinetic parameters, including the terminal disposition 55. Q half-life [t,,,(y)], the total body clearance (CL), and the volume C of distribution (Vd) were calculated applying standard equations C 0 (14). S

U C RESULTS 0 U Twelve patients were enrolled onto this study (seven fe- males and five males), with a median age of 60 years (range, 49-70 years) and a median Eastern Cooperative Oncology 0 10 20 30 40

Group performance score of 1 . All patients completed the pharmacokinetic and oral bioavailability studies during both periods of drug administration and subsequently participated in an on- time (h) going Phase I and pharmacokinetic study of oral 9-AC in a daily Fig. I Representative plasma concentration-time profiles of the lac- times fourteen schedule. Except for one patient who experienced tone (A) and carboxylate (#{149})forms of 9-AC after iv. (A) and oral (B) mild nausea, neither iv. nor oral administration of 9-AC was drug administration of 1.0 and I .5 mg/m2, respectively. All curves were associated with any adverse effect, including myelosuppression fitted to a three-compartment model. and diarrhea. The plasma concentration-time profiles of the lactone and carboxylate forms of 9-AC after iv. or oral administration were -50% of the total plasma concentration already present at 10 similar for the twelve patients studied, with typical examples mm after cessation of the 5-mm infusion. The maximum con- shown in Fig. 1 . Concentrations of 9-AC lactone and carboxy- centration of 9-AC carboxylate occurred at I .6 h, and the late (calculated as the difference between the total drug and relative amount of this form increased until an apparent equi- intact lactone) in plasma were always below the lower limit of librium was established at -3 h, with the lactone accounting for quantitation of our HPLC assay (50 pg/ml) before administra- 2.92 ± 0.50% (mean ± SD: ii = 12) of 9-AC total concentration of the second course (data not shown). Applying compart- tions. The AUC of the lactone was found to represent 9. 1 ± mental analysis for 9-AC lactone and carboxylate data, model 3.4% of the total AUCIV. The relatively low values of the discrimination was assessed by minimization of the sum of volume of distribution at steady state for 9-AC lactone and squares, dispersion of the residuals, visual inspection of fitted 9-AC carboxylate (92.9 ± 25.5 and 15.9 ± 8.8 liters, respec- curves, and Akaike’s information criterion. Eventually, all con- tively) suggest that overall clearance is mainly dictated by actual centration-time profiles were best fitted to a three-compartment elimination from the body, rather than extensive accumulation model after zero-order input (lactone iv. data only) or after in peripheral tissues. extravascular bolus with lag time (tiag) using the Powell mini- The absorption of 9-AC lactone after oral administration mization algorithm and weighted least-squares analysis with a was associated with a tbag of 0.24 ± 0. 13 h, peak drug levels at weighting factor of 1/v. 1.2 ± 0.3 h, and a mean ka of 3.0 ± 0.9 h ‘ (Table 1). Plasma The two initial disposition phases of the intact lactone after levels of the carboxylate form already exceeded the lactone the iv. bolus were characterized by half-lives of 6.6 and 38 mm, component at the first sampling time point (20 mm: Fig. I). whereas the terminal biological half-life was -8 h (Table 1). Approximately 7.5 h after treatment, an apparent distribution The conversion of 9-AC into the E ring-opened carboxylate equilibrium was achieved between the components, character- species in plasma appeared from the first sample acquired, with ized by similar terminal rates of elimination at a ratio of lactone

Table 1 Pharmacokinetic parameters of 9-AC lactone, 9-AC carboxylate, and 9-AC total in I 2 patients after iv. ( 1.0 mg/m2) and oral ( 1.5 mg/m2) administration”

iv. Oral

Parameter 9-AC lactone 9-AC carboxylate 9-AC total 9-AC lactone 9-AC carboxylate 9-AC total

tlag (h) 0.01 ± 0.01 0.24 ± 0.13 0.31 ± 0.11 Cn,ax 83.1 ± 48.6 57.6 ± 18.6 140 ± 33.6 6.82 ± 2.98 35.4 ± 19.2 42.2 ± 1 1.1 tmax 1.59 ± 0.45 1.17 ± 0.33 2.39 ± 1.05

AUC (ng . h/ml) 45.5 ± 13.5 548 ± 339 580 ± 333 31.9 ± 14.3 510 ± 354 535 ± 377 CL (ml/min) 732 ± 210 87.4 ± 59.0 52.9 ± 29.1 ka (h’) 3.03 ± 0.90 t112(a) (h) 0.1 1 ± 0.19 0.63 ± 0.30 0.38 ± 0.21 1.04 ± 0.78 t,,,(3) (h) 0.64 ± 0.1 1 1.79 ± 0.91 1.13 ± 0.59 2.83 ± 1.96 t112(’y) (h) 7.91 ± 2.14 11.7 ± 3.39 12.6 ± 4.20 12.4 ± 6.48 Vd (liters) 92.9 ± 25.5 15.9 ± 8.8 F (%) 48.6 ± 17.6 62.5 ± 24.9

(1 Data represent mean values ± SD.

to carboxylate of 3.52 ± 0.36%. On average, the active lactone open carboxylate form and vice versa (3). Here, we observed accounted for 7.1 ± 3.2% of the total AUCOraI. Terminal dis- that, after both iv. and oral drug administration, interconversion position half-lives for the lactone and carboxylate forms of the of the lactone and carboxylate rapidly reached an in vivo equi- drug were estimated to be 12.6 ± 4.20 h and 12.4 ± 6.48 h, librium with the pharmacologically active lactone accounting respectively, which is not significantly different from data ob- for < 10% of total drug at steady state. Combined with a tamed after i.v. administration. The mean percentage of the significantly reduced volume of distribution for the carboxylate AUC extrapolated was <7%, justifying the use of compartmen- form, this suggests that there is preferential uptake of 9-AC tal methods for calculation of the bioavailability. The absolute lactone in peripheral tissues at early times, thereby accelerating oral bioavailability of 9-AC lactone averaged 48.6 ± 17.6% predominance of the carboxylate in blood. This hypothesis is in (range, 24.5-80.4%), with an interindividual coefficient of var- line with available data indicating that a closed lactone form is iability of 36.2%. Calculations based on noncompartmental also an important structural requisite for (passive) diffusion modeling of 9-AC total data resulted in slight overestimation of across cell membranes in addition to successful interactions the oral bioavailability as a result of the disparity in the extent with topoisomerase I (3). of lactone-carboxylate interconversion between iv. and oral The finding that the carboxylate form is the predominant dosing (Table 1). species in plasma is also consistent with previous reports dem- Significant linear correlations were observed between the onstrating preferential affinity of 9-AC carboxylate for human AUCs of 9-AC total and that of the pharmacologically active serum albumin as compared to the corresponding lactone, shift- 9-AC lactone after both iv. (r = 0.77) and oral (r = 0.87) drug ing the equilibrium hydrolysis toward the former species (18). administration. The significant degree of interpatient variability with regard to the oral bioavailability of 9-AC in this study might thus be DISCUSSION related in part to differences in albumin levels in individual In view of preclinical data indicating enhanced antineo- patients. More importantly, the coefficients of variation of the plastic activity of 9-AC when it is administered in a manner that AUC after i.v. and oral administration were not significantly provides prolonged systemic exposure (reviewed in Ref. 1), the different, suggesting that oral delivery is not associated with pharmacokinetics and oral bioavailability of the drug (formulat- increased interpatient differences in systemic exposure. ed in PEG1000) were evaluated in 12 patients with various types The steady-state lactone to total-AUC ratio in plasma was of solid tumors. The iv. and oral dosages were selected on the of the same order after iv. and oral drug administration. Al- basis of toxicological data in dogs (10), which is the most though this ratio for 9-AC is the lowest relative to all other sensitive species to 9-AC, to be safe yet allow pharmacokinetic camptothecin analogues (4), recent findings indicated that 9-AC analysis after both routes of administration. The overall bio- lactone is the predominant species within tumors and that the availability of this formulation of 9-AC averaged 48.6 ± 17.6% carboxylate may itself have a role in inhibiting cell growth by a (range, 24.5-80.4%). Compared to other camptothecin ana- mechanism other than the ability to bind topoisomerase I (1 1).

logues, including topotecan [bioavailability (F) = 30.0%; Ref. The clinical implication of differences in the lactone:total AUC 15], 7-(4-methylpiperazinomethylene)-lO,l 1-ethyl-enedioxy- ratio for camptothecin analogues with respect to antitumor ef-

20-(S)-camptothecin (GI14721 1; F = 1 1.3%; Ref. 16), and ficacy remains, therefore, unclear at present. Although, in our

irinotecan (F = 12-21%; Ref. 17), 9-AC has a higher oral study, the AUC0ra1 Of 9-AC total was significantly correlated bioavailability, which may be an advantage with potential phar- with that of 9-AC lactone, measurement of systemic exposure to macodynamic importance. both the lactone and carboxylate forms separately is still pivotal Similar to all other camptothecin analogues in clinical to our understanding of the pharmacology of 9-AC, until a development, 9-AC can undergo a reversible, pH-dependent well-designed study shows 9-AC total to be predictive of out- hydrolysis in which the closed lactone form is converted to the come (e.g. , toxicity or efficacy).

Disappearance of 9-AC from the central plasma compart- of camptothecin: inhibition of mammalian topoisomerase I and biolog- ment was characterized by terminal disposition half-lives of ical activity. J. Med. Chem., 32: 715-721. 1989.

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A Sparreboom, M J de Jonge, C J Punt, et al.

Clin Cancer Res 1998;4:1915-1919.

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