F. Hourcade-Potelleret, C. Weber, B. Fotteler and N. Frey
Clinical Pharmacology, F. Hoffmann-La Roche, Basel
Objective: Characterize the pharmacokinetics including effects of covariates of a tested drug, based on a phase II dose-ranging study (5, 10 and 20 mg) in patients during daily repeated administration.
Material and Methods: Trough PK samples were taken at steady-state during three occasions. Two additional samples were taken between 1 and 8 hours postdose based on the investigator’s choice after 6 and 12 weeks of treatment. These data were pooled with full PK profiles from a phase I study (3 to 40 mg) performed in patients in order to facilitate the structural pharmacokinetic model definition. The potential influence of the following baseline covariates on drug clearance was explored: gender, age, BMI, albumin, AST, ALT, bilirubin, creatinine clearance and dose, time, disease duration, drug naïve or pre-treated patients, comedication with ACE-inhibitors, CYP2C19 genotype (homozygous extensive metabolizers versus heterozygous extensive and 3 homozygous poor metabolizers). A non-linear mixed effect model approach using NONMEM software version V level 1.1 was used to analyze the 1829 exploitable concentrations from 209 patients.
Results: A two-compartment model with first order absorption and lag-time was used to fit the data. IOV was coded on clearance and central volume. Pharmacokinetics was linear with time. A non linearity with dose occurred at the highest doses and was coded on F. The degree of accumulation was close to 1. AST and genotype for CYP2C19 exhibited a statistically significant influence on CL/F. CL/F was 233 mL/min for a homozygous extensive metabolizer and was 13 % lower for the combined subgroup of heterozygous extensive and poor metabolizers. CL/F decreased as AST increased and reached a plateau at the upper values of AST normal range. The residual error expressed as a coefficient of variation was 37 %.
Discussion and Conclusion: The PK seems easy to handle in clinical routine: linearity with time, no drug accumulation for the dose regimen selected. Although the interaction between CL/F and CYP2C19 genotype is very small and not clinically relevant, this covariate merits further investigation. Regarding AST, patients with higher values are likely to have lower drug clearance. This relationship is rational as the drug is mainly metabolized but needs to be confirmed in phase III. The residual variability is high as expected with a fragmentary PK sampling design.
Reference: PAGE 13 () Abstr 507 [www.page-meeting.org/?abstract=507]
Poster: poster