Population pharmacokinetics of PF-04447943 in healthy volunteers (HV), adult patients with Alzheimer's disease (AD) and patients with Sickle Cell Disease (SCD)
Rujia Xie (1), Beesan Tan (2) and Lutz O. Harnisch (3)
Pfizer (1) Clinical Pharmacology/Pharmacometrics, Shanghai, China, (2) Clinical Pharmacology, Cambridge, MA, USA, (3) Clinical Pharmacology/Pharmacometrics, Sandwich, UK
Objectives: PF-04447943 is a selective inhibitor of the cyclic guanosine monophosphate (cGMP)-specific PDE9A enzyme, being developed for the prophylactic treatment of SCD. The purposes of our analyses were to characterize PF-04447943 pharmacokinetics (PK) in HV and adult patients with AD or SCD and to identify factors that may differentiate the populations treated and impact the PK relationship of PF-04447943.
Methods: A total of 10 studies (7 in HV, 2 in AD and 1 in SCD patients) were included in the analyses. Subjects received single or multiple doses (BID) of PF-04447943 ranging from 1 mg to 150 mg. Plasma concentrations over time were analyzed using a nonlinear mixed effects modeling approach (NONMEM). The first order conditional estimation with interaction method was used throughout. Potential covariates (body weight (BWT), age, gender, disease state, race, food, formulation and creatinine clearance) were evaluated using stepwise inclusion/deletion as implemented in the Stepwise Covariate Model (SCM)1 building procedure. Prediction-corrected visual predictive checks were used to assess model performance.
Results: A total of 261 subjects (163 male and 98 female); including 142 White, 64 Black, 31 Asian and 24 other race, with 3467 concentration records were analyzed. The PK of PF-04447943 was best characterized by a two-compartment model with 1st order absorption (Ka) with lag time (tlag) and 1st order elimination. BWT was incorporated as a structural covariate on clearance (CL/F), central (V1/F) and peripheral (V2/F) volume and distributional clearance (Q/F). The other covariates identified were age on CL/F; race on V2/F; race, sex and population on Q/F and age and food on Ka. The parameter estimates for a typical healthy white male (70kg and 40years) under fasted conditions were 13.9 L/h, 87.3 L, 7.61 L, 0.546 L/h, 4.7 h-1 and 0.196 h for CL/F, V1/F, V2/F, Q/F, Ka and tlag, respectively. Feeding reduced Ka by 89.9%. Black subjects showed a 11-fold higher V2/F and a 3.5 fold higher Q/F than White subjects. However, predicted Cmax and AUC0-¥ values at clinically relevant doses were similar across races.
Conclusions: The proposed population PK model adequately describes the available data on PF-04447943. Although a few statistically significant covariates were identified they are not expected to result in clinically relevant differences in exposure. Understanding of the PK of PF-04447943 across a range of populations will assist future drug development.
References:
[1] Jonsson EN, Karlsson MO. Automated covariate model building within NONMEM. Pharm Res (1988) 15: 1463–1468.
