Simultaneous pharmacokinetic model for rolofylline and both M1-trans and M1-cis metabolites

Abstract

Rolofylline is a potent, selective adenosine A1 receptor antagonist that was under development for the treatment of patients with acute congestive heart failure and renal impairment. Rolofylline is metabolized primarily to the pharmacologically active M1-trans and M1-cis metabolites (metabolites) by cytochrome P450 (CYP) 3A4. The aim of this investigation was to provide a pharmacokinetic (PK) model for rolofylline and metabolites following intravenous administration to healthy volunteers. Data included for this investigation came from a randomized, double-blind, dose-escalation trial in four groups of healthy volunteers (N=36) where single doses of rolofylline, spanning 1 to 60 mg ,were infused over 1-2 h. The rolofylline and metabolite data were analyzed simultaneously using NONMEM. The simultaneous PK model comprised, in part, a two-compartment linear PK model for rolofylline, with estimates of clearance and volume of distribution at steady-state of 24.4 L/h and 239 L, respectively. In addition, the final PK model contained provisions for both conversion of rolofylline to metabolites and stereochemical conversion of M1-trans to M1-cis. Accordingly, the final model captured known aspects of rolofylline metabolism and was capable of simultaneously describing the PK of rolofylline and metabolites in healthy volunteers.

Fig. 1

Structure of rolofylline and both M1-trans and M1-cis metabolites

Fig. 2

The pharmacokinetic models considered during three rounds of exploratory pharmacokinetic modeling of rolofylline and metabolite data. Compartments 1, 3, and 5 represent the first compartments for rolofylline, M1-trans, and M1-cis, respectively. a In round 1, only rolofylline data were considered. b The model from round 1 was brought forward to round 2; the pharmacokinetic parameters which influenced the concentration–time profile of rolofylline were held fixed to those from round 1, and parameters which influenced the pharmacokinetics of M1-trans were optimized. c and d For round 3, the model selected from round 2 was brought forward. The model parameters which influenced the pharmacokinetics of both rolofylline and M1-trans were held fixed to the optimal parameterization of round 2, and parameters which influenced the pharmacokinetics of M1-cis were optimized. Two structural models were considered for M1-cis; d the second of the two models had a provision for conversion of rolofylline to M1-cis, while c the first did not. The depiction of panel d is the final model brought forward; a definition of the model terms in panel d (i.e., V, CL, and FM) is provided in Table I

Fig. 3

Diagnostic plots following fit of the simultaneous PK model to observed rolofylline (circles), M1-trans (squares), and M1-cis (dots) plasma concentrations. Progressing clockwise from the top-left corner, the model diagnostic plots are comprised of a observed versus population predicted concentrations, b observed versus individual predicted concentrations, c residual and d weighted residual plots

Fig. 4

Visual predictive check for rolofylline (left-most panels), M1-trans (center panels) and M1-cis (right-most panels). Concentration profiles corresponding to 1 and 2 h infusion times were dose-normalized to the 10- and 50-mg dose levels, respectively, and depicted on the top and bottom panels, respectively. Observed data are indicated as points; the solid and dashed lines represent median and both 10% and 90% intervals of the model-predicted concentrations. For clarity, only data up to 25 h post-start of infusion are depicted in this representation