2003
   Verona, Italy

Assessment of the in vivo relative potency of the hydroxylated metabolite of darifenacin for the reduction of salivary flow using a population pharmacokinetic-pharmacodynamic meta-analysis

T. Kerbusch (1,2), U. Wählby (2), A. Skerjanec (3), P.A. Milligan (1), M.O. Karlsson(2)

(1)Pfizer Global Research & Development, Clinical Sciences, Department of Clinical Pharmacokinetics and Pharmacodynamics, Sandwich, Kent, UK, (2)Division of Pharmacokinetics & Drug Therapy, Department of Pharmaceutical Biosciences, Faculty of Pharmacy, Uppsala University, Uppsala, Sweden, (3)Novartis, Department of Clinical Pharmacology, Basel, Switzerland

Objectives: To estimate the in vivo potency of the hydroxylated metabolite (UK-148,993) to reduce salivary flow (SF) relative to that of the parent drug darifenacin (UK-88,525) in a wide range of studies using a population PK-PD approach (meta-analysis).

Methods: PK and SF data from 337 and 262 individuals, respectively, were pooled from 17 Phase 1 studies and 1 Phase 2 study (median 28/33/30 and 7/7/8 darifenacin/metabolite/SF observations per healthy volunteer and patient, respectively). Data encompassed 1 i.v., 5 different p.o. formulations (1-45 mg total daily dose) and CYP3A4 inhibitors resulting in a wide range of parent-metabolite concentration ratios.

Results: NONMEM (V & VI) was used to describe the population PK of darifenacin and its hydroxylated metabolite with a two-compartment disposition models with first order absorption. The PK model for darifenacin included covariates characterising the influence of formulation (70–110% higher bioavailability (F) for extended release compared with immediate release), dose (dose-nonlinearity 1.1 to 1.35-fold over the dose range studied) and CYP2D6 genotype (heterozygote-EM and PM 40 and 90% higher exposure than a homozygote-EM, respectively). The presence of ketoconazole or erythromycin increased darifenacin F to approximately 100% and ketoconazole additionally decreased clearance (CL) by 68%. CL was 31% lower in females and 10% lower at night. F was 56% lower in Japanese males. Ketoconazole and erythromycin also decreased metabolite exposure by 61.2 and 28.8%, respectively. Interindividual variability in the residual error model of darifenacin was described using a generalized least squares approach.

A binding-model yielded a better description of the decrease in SF compared to a direct-effect, indirect-effect or link model, by fully accounting for the time-course of the PD effect. Internal validation demonstrated robustness. Covariate analysis identified a circadian rhythm in SF. The model, with confidence intervals (CI) determined by likelihood profiling, indicated the relative potency of the metabolite to darifenacin to reduce SF at 11.1% (95% CI: 3.8%, 19.6%). This implied that the metabolite was 9-fold less potent than darifenacin in vivo. The in vivo protein binding-corrected relative potency was estimated at 2.1% (metabolite 50-fold less potent). The model indicated that no other metabolites contributing to the SF were likely to be formed during first-pass and that no sensitisation or tolerance development was evident over time. The subjective measurement of dry mouth (DM) is not directly linked with the objective measurement of drug-induced SF.

Conclusions: The meta-analysis provided a descriptive integration of main characteristics and covariates of the PK of darifenacin and its metabolite, enabling interpolation and extrapolation of these key-factors. Population PK-PD modelling was used to assess the in vivo potency of the metabolite for the decrease in SF relative to that of the parent drug. Metabolite contribution to this effect was negligible.

References:
[1] Thomas Kerbusch, Ulrika Wählby, Peter A. Milligan, Mats O. Karlsson. Population pharmacokinetic modelling of saturable first pass metabolism, CYP2D6-genotype and formulation-dependent bioavailability of darifenacin and its hydroxylated metabolite in a meta-analysis (submitted).
[2] Thomas Kerbusch, Peter A. Milligan, Mats O. Karlsson. Assessment of the in vivo relative potency of the hydroxylated metabolite of darifenacin for the reduction of salivary flow using a population pharmacokinetic-pharmacodynamic meta-analysis (submitted).