Abstracts Accepted for American Conference on Pharmacometrics 2016 (Acop7)

J Pharmacokinet Pharmacodyn (2016) 43:S11–S122 DOI 10.1007/s10928-016-9485-x ABSTRACTS Abstracts accepted for American Conference on Pharmacometrics 2016 (ACoP7) Ó Springer Science+Business Media New York 2016 M-01 Population Pharmacokinetics of AZD-5847 in Adults with Tuberculosis Abdullah Alsultan1,2, Jennifer J. Furin3, Jeannine Du Bois4, Elana van Brakel4, Phalkun Chheng3, Amour Venter5, Bonnie Thiel3, Sara A. Debanne6, W. Henry Boom3, Andreas H. Diacon4,5, and John L. Johnson3, Charles A. Peloquin2 1King Saud University College of Pharmacy, 2University of Florida College of Pharmacy, 3Tuberculosis Research Unit, Case Western Reserve University, 4TASK Applied Science, 5 MRC Centre for Tuberculosis Research, 6Department of Epidemiology and Biostatistics, Case Western Reserve University Objective: AZD-5847 is an oxazolidinone derivative being developed for the treatment of tuberculosis (TB). A phase II trial to M-02 evaluate its pharmacokinetics and early bactericidal activity in adults with pulmonary TB was recently completed. We developed a population pharmacokinetic (PK) model for AZD-5847 using data from Population Pharmacokinetic Analysis of ABT-493 Exposures patients in this phase 2 study. in HCV-Infected Subjects Methods: The study included 60 adults with newly-diagnosed, drug- Aksana K. Jones1,*, Chih-Wei Lin1, Wei Liu1, Sandeep Dutta1 susceptible TB. Patients were randomized to four treatment arms - 1 500 mg once daily, 500 mg twice daily, 800 mg twice daily or 1200 Clinical Pharmacology and Pharmacometrics, AbbVie mg once daily. PK sampling occurred on day 1 and 14. Blood samples Objectives: To characterize population pharmacokinetics of ABT- were collected at 0, 1, 2, 3, 4, 5, 6, 8, 12, 13, 15, 16, 17, 18, 20 and 24 493, a nonstructural protein 3/4 A protease inhibitor discovered by hours. AbbVie and Enanta, in HCV genotypes 1 to 6 subjects when co- Results: A total of 1723 samples were used for the analysis. A two administered with ABT-530, a nonstructural protein 5A inhibitor. compartment model with linear elimination and Tlag for absorption Identify demographics, pathophysologic, and treatment factors that adequately described the data. AZD-5847 showed non-linear impact the exposure. absorption likely due to saturable absorption. Bioavailability started Methods: Plasma concentration samples from 641 subjects enrolled to decrease at the 800 mg daily dose and was 67% at the 1200 mg in 4 Phase 2 studies were analyzed using non-linear mixed-effects dose. Typical values (relative standard error %) for Tlag, Ka, Cl, V1, modeling using NONMEM 7.3. One, two and three compartment Q and V2 were 0.27 hours (18%), 0.38 hour-1 (9%), 7.96 L/hour models were explored for structural model development. To charac- (3%), 43.3 L (7%), 8.9 L/hour (13%) and 31.9 L (9%). The coefficient terize the greater than dose-proportional increase in ABT-493 of variation (relative standard error %) for Tlag, Ka, Cl, V1, Q and V2 exposure, a dose-dependent relative bioavailability was incorporated were 68.6% (22%), 21.6% (19%), 22% (10%), 14.9% (36%), 47.1% into the structural model. Both, categorical and continous measures (28%), 55.6% (13%). The figure below shows the typical PK profile for demographics, pathophysiologic and treatment factors were tested for AZD-5847 at steady state. for their effects on ABT-493 pharmacokinetics. Model evaluation and Conclusion: AZD-5847 shows biphasic elimination. Absorption of validation techniques were used to assess adequacy and robustness of AZD-5847 is nonlinear and administering doses above 800 mg might the pharmacokinetic models. not be beneficial. Results: A two-compartment PK model with first-order absorption and elimination optimally described the ABT-493 concentration-time 123 S12 J Pharmacokinet Pharmacodyn (2016) 43:S11–S122 profile. The ABT-493 model-predicted concentration-time profile was pathophysiologic and treatment factors were tested for their effect on comparable to the median (IPRED) profile of the observed data ABT-530 exposure. Model evaluation and validation techniques were (Figure, left). A polynomial function fitted to the log-transformed used to assess adequacy and robustness of the pharmacokinetic AUC values was used to describe the non-linear dose-dependent models. increase in ABT-493 exposures (Figure, right). The identified sources Results: Observed ABT-530 pharmacokinetic profile was well char- of variability in the population pharmacokinetics were: body weight acterized by a two-compartment PK model with first-order on volume of distribution (10% increase per 10 kg increase), and absorption. An Emax function for relative bioavailability was used to cirrhotic status on bioavailability (increased to 2.2 fold in cirrhotics). characterize the dose-dependent non-linear increase in ABT-530 Genotype and ABT-530 dose were not significant factors. The pop- exposure (Figure, left) and the effect of ABT-493 on ABT-530 ulation mean estimates (at the model’s reference covariate value) of bioavailability. The identified sources of variability were sex on ABT-493 CL/F was 1090 L/day and V2/F was 134 L. apparent clearance (21% higher in male) and body weight on apparent Conclusions: The population pharmacokinetic model described the volume of distribution (9% increase per 10 kg increase). These effects concentration-time profiles, as well as the non-linearity and variability on ABT-530 exposures were minimal and not clinically meaningful. of ABT-493 across ABT-493 doses, in HCV infected subjects with or Prediction corrected visual predictive checks indicated that the final without cirrhosis well. Genotype and ABT-530 dose have no impact model incorporating these covariates described the central tendency on ABT-493 exposures. of the data well and the variability of the data adequately (Figure, right). The non-parametric bootstrap evaluation demonstrated good agreement with the estimated parameter values. The population mean Observed 11 Observed Median (5th and 95th Percentile) 10 Population Predicted (PRED) estimates (at the model’s reference covariate values) of ABT-530 CL/ Individual Predicted (IPRED) Median 9 ) F was 6520 L/day and V2/F was 1270 L. 8 1 /mg) 7 Conclusions: The ABT-530 population pharmacokinetic model pro- mg/L) mL ( / . vided robust characterization of the observed ABT-530 exposures in r c 6 0.1 on C HCV infected patients. None of the tested covariates have clinically 5 (ng*h 93 4 meaningful impacts on ABT-530 exposure and do not require dose 0.01 BT- 4 A adjustment. log(AUC 0.001 3 Non-Cirrhotic Cirrhotic 8 1 0 6 12 18 24 0 100 200 300 400 500 600 700 ABT-493 Dose (mg) Time Since Last Dose (hours) ) ) (µg/mL) on mg 6 i 0.1 / Figure 1 Observed and Model-Predicted ABT-493 Concentration mL / hr Versus Time (Time After Last Dose) Profile for 300/120 mg ABT * 4 0.01 (ng 493/ABT 530 (Left) and Log-Transformed AUC Versus ABT-493 Dose C U A (Right). Left Panel: Gray circles: individual subject concentration; Black ( 2 g o 0.001 Circles and Error Bars: median of the observed binned concentrations l ABT-530 Monotherapy ABT-530 + 200 mg ABT-493 and 5th and 95th percentile; Black Line (solid): model-predicted ABT-530 + 300 mg ABT-493 0 Pred.-corrected ABT-530 Concentrat individual (IPRED) median concentration-time profile; Black Line 0.0001 0 100 200 300 400 500 (dotted): model-predicted population (PRED) median concentration- 06121824 ABT-530 Dose (mg) TALD (time after last dose, hrs) time profile. Right Panel: Open blue circles and yellow triangles represent individual observed AUC values for non-cirrhotic and cirrhotic Figure 1 Log-transformed AUC Versus ABT-530 Dose (Left) and Filled blue circles yellow triangles subjects, respectively. and with error Prediction Corrected Visual Predictive Check (Right). Left Panel: bars respresent the median and 5th and 95th percentile of observed data Open symbols represent individual observed AUC values, filled Solid blue and for non-cirrhotic and cirrhotic subjects, respectively. symbols with error bars respresenting the median and 5th and 95th yellow line represent the model fit for non-linearity for non-cirrhotic and percentile. Solid lines represent the model fit for non-linearity. Right cirrhotic subjects, respectively (Color figure online) Panel: Open circles represent prediction corrected observed ABT-530 concentrations. The shaded gray area represents the 90% prediction M-03 interval of the prediction corrected simulated ABT-530 concentrations. The solid red line represents median, the dashed red lines Population Pharmacokinetics of a Pangenotypic NS5A inhibitor, represent the 5th and 95th percentile of the prediction corrected ABT-530, in HCV infected Patients with and without Cirrhosis : observed ABT-530 concentrations (Color figure online) A Pooled Analysis from Phase 2 Studies Aksana K. Jones1,*, Chih-Wei Lin1, Wei Liu1, Sandeep Dutta1 M-04 1 Clinical Pharmacology and Pharmacometrics, AbbVie Understanding and Characterizing the Bystander Effect Objectives: ABT-530 in combination with ABT-493 is a novel 2 for Antibody Drug Conjugates direct-acting antiviral agents (DAA) combination being developed for Aman P. Singh1, Sharad Sharma1, Dhaval K. Shah1 the treatment of HCV genotypes 1 to 6. The purpose of this analysis was to characterize the population pharmacokinetics of ABT-530 and Kapoor Hall, Department of Pharmaceutical Sciences, School of explore demographics, pathophysologic, and treatment factors that Pharmacy and Pharmaceutical Sciences, University at Buffalo may impact ABT-530 exposure. Background: Once processed by the Antigen-positive (Ag+) cells, Methods : Population pharmacokinetic models were built using non- Antibody-drug conjugates (ADCs) can release cytotoxic drug mole- linear mixed-effects modeling approach in NONMEM 7.3. ABT-530 cules that can diffuse into the neighboring antigen-negative (Ag-) concentration data from 634 subjects from 4 Phase 2 studies were cells to induce their cytotoxicity. This additional efficacy of ADCs is analyzed. Categorical and continous measures for demographics, known as the ‘bystander effect’.

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