Population pharmacokinetic modelling of darifenacin and its hydroxylated metabolite using pooled data, incorporating saturable first-pass metabolism, CYP2D6 genotype and formulation-dependent bioavailability

Abstract

Aims: A model describing the population pharmacokinetics of darifenacin and its hydroxylated metabolite was developed from a combined analysis of 18 studies. The relationships between explanatory covariates and pharmacokinetic parameters were explored.

Methods: Plasma concentration data from 337 individuals were pooled from 17 Phase 1 studies (median 28/33 darifenacin/metabolite observations per healthy subject), and one Phase 2 study (median 7/7 darifenacin/metabolite observations per subject) encompassing one intravenous and five different oral formulations (1-45 mg).

Results: Non-linear Mixed Effects Models (NONMEM Version VI) described both the population pharmacokinetics of darifenacin and its hydroxylated metabolite with a two-compartment disposition model with first order absorption. The values (mean +/- standard error of the mean) for clearance (CL) and volume of distribution of the central compartment were 40.2 +/- 2.0 l h-1 and 34.7 +/- 4.6 l h-1, respectively, in a typical male CYP2D6 homozygote-extensive metabolizer (Hom-EM). The absolute bioavailability (F) of darifenacin in a Hom-EM after doses of 7.5, 15 or 30 mg extended release formulation (CR) was 15, 19 and 25%, respectively. Factors influencing F were formulation (70-110% higher for CR compared with immediate release following equivalent daily doses), CYP2D6 genotype [heterozygote-extensive metabolizers (Het-EM) and poor metabolizers (PM) experienced 40 and 90%, respectively, higher exposure than Hom-EM irrespective of dose administered] and saturable first-pass metabolism (dose nonlinearity 1.05-1.43-fold). Race affected F, which was 56% lower in Japanese males. The CYP3A4 inhibitors ketoconazole and erythromycin increased F to approximately 100% and ketoconazole decreased CL by 67.5%. CL was 31% lower in females and 10% lower at night. Formulation affected the metabolite absorption/formation rate. Ketoconazole and erythromycin administration resulted in a decrease of 61.2 and 28.8% in exposure to the metabolite, respectively. The covariates race, gender and circadian rhythm accounted for only approximately half of the variability in the estimated exposures to darifenacin.

Conclusions: The pooled analysis provided a descriptive integration of all characteristics and covariates of the pharmacokinetics of darifenacin and its metabolite, enabling interpolation and extrapolation of these key factors.

Figures

Figure 1

The ‘final’ structural pharmacokinetic model for darifenacin (two compartments with first-order absorption) and its hydroxylated metabolite (two compartments with first-order absorption). Presystemic metabolite formation was described by simultaneous oral darifenacin and metabolite dosing of equal magnitude.

Figure 2

The observed darifenacin concentrations (DV) vs. the population predictions (PRED) and individual predictions (IPRED) on normal and log-log scale (grey line: spline).

Figure 3

The individual weighted residuals (IWRES) vs. the individual predictions (IPRED) of darifenacin and its metabolite concentrations on normal and log-log scale.

Figure 4

Model predictions of the bioavailability (F) and area under the concentration-time curve (AUC) of darifenacin administered as immediate release (IR, SOL) or extended release formulation (CR, CRM, CRF) in typical CYP2D6 poor (PM) and homozygote (Hom-EM) and heterozygote extensive metabolizers (Het-EM) vs. the dose. CR, CRM, CRF (CYP2D6 PM) (▪); IR, SOL (CYP2D6 PM) (□); CR, CRM, CRF (CYP2D6 Het-EM) (•); IR, SOL (CYP2D6 Het-EM) (○); CR, CRM, CRF (CYP2D6 Hom-EM) (▴); and IR, SOL (CYP2D6 Hom-EM) (▵).

Figure 5

The observed metabolite concentrations (DV) vs. the population predictions (PRED) and individual predictions (IPRED) on normal and log-log scale (grey line: spline).

Figure 6

Deterministically simulated concentration-time profiles of darifenacin at steady state (day 10) after receiving 7.5, 15 or 30-mg CR doses for 10 days every day. Simulations were performed using all 337 individuals with model estimates of the typical parameters and their associated interindividual variabilities. The thick line represents median concentration-time profile and grey surface the boundaries of the 1st and 3rd quartile of the population.