Population Pharmacokinetic Analysis of Compound A and Its Metabolite in Healthy Subjects and Patients with Diabetic Nephropathy
Tadakatsu Nakamura (1), Tomoko Kubota (1), David Jaworowicz (2), Kuan-Ju Lin (2), Atsuhiro Kawaguchi (1)
(1) Mitsubishi Tanabe Pharma Corporation, (2) Cognigen Corporation, a Simulations Plus Company
Objective: Compound A is a potent and highly selective non-steroidal mineralocorticoid receptor (MR) antagonist being developed for the treatment of diabetic nephropathy and other potential indications. Richly sampled PK data collected in phase 1 studies exhibited complex PK profiles for Compound A (secondary and tertiary peaks as well as prolonged absorption profiles following initial peak concentrations in conjunction with dose-dependent reductions in exposure with increasing doses) and its major metabolite (Metabolite B; slow formation and elimination). The objectives of the analyses were to develop population pharmacokinetic models that describe these characteristics of Compound A and Metabolite B.
Methods: PK data were pooled from 6 Phase 1 studies conducted in healthy subjects and 3 Phase 2a studies in patients with type 2 diabetic nephropathy. Plasma concentrations of Compound A and Metabolite B were sequentially fit by population pharmacokinetic models using nonlinear mixed effects modeling implemented in NONMEM 7.1.2.
Results: Exploratory models incorporating enterohepatic recirculation were tested to describe the multiple peak phenomenon, but were not adopted because they conferred limited improvement in the characterization of overall Compound A PK disposition. Compound A concentration-time profiles were best described by a 2-compartment model with 2 parallel absorption inputs (a first-order process to describe initial peaks and a zero-order process to describe prolonged absorption), dose-dependent relative bioavailability (described by a sigmoid Hill function), and first-order elimination. Metabolite B concentration-time profiles were best described by a 1-compartment model with linear elimination. The formation of metabolite was characterized by 2 input processes, with 1 formation pathway described as a fraction of the systemic elimination of Compound A and the second formation pathway described as a proportion of Compound A lost to apparent first-pass effect.
Conclusions: The atypical PK profiles observed in these data were adequately described by modeling the absorption of Compound A via parallel input processes as well as modeling the formation of Metabolite B as a function of both first-pass and systemic parent drug elimination.