Thierry Wendling (1, 2), Kayode Ogungbenro (1), Etienne Pigeolet (3), Ralph Woessner (2) and Leon Aarons (1)
(1) Manchester School of Pharmacy, The University of Manchester, Manchester, United-Kingdom, (2) Drug Metabolism and Pharmacokinetics, Novartis Institutes for Biomedical Research, Basel, Switzerland, (3) Advanced Quantitative Sciences, Novartis Pharma AG, Basel, Switzerland
Objectives: To develop a nonlinear mixed-effects model to characterise the absorption rate of mavoglurant following a single oral administration of an immediate-release (IR) and a modified-release (MR) formulation in healthy subjects under fasted and fed conditions, and to predict concentration-time profiles after twice-daily multiple doses..
Methods: Data were available from a clinical study designed to compare the pharmacokinetics of the MR and the IR forms. 43 healthy Caucasian male subjects received three doses of mavoglurant as a crossover: 50 mg in IR capsules under fasted conditions (IR-fasted), and 100 mg in a MR tablet under fasted (MR-fasted) and fed conditions (MR-fed). PK data from a study conducted to assess the effect of single intravenous (IV) doses of mavoglurant on QTc intervals in 120 healthy subjects were pooled to the oral data and analysed using NONMEM 7.2.0 [1]. Drug absorption was modelled sequentially for each oral treatment using a weighted sum of n inverse Gaussian (IG) density functions as an input function [2]. The input model was used to predict the typical time course of the absorption rate and of the fraction absorbed after a single administration of each treatment. NONMEM was used to simulate 1000 individual PK profiles after repeated administration of each treatment. Dose superposition was performed using n user-supplied functions defined in a FORTRAN subroutine [3].
Results: Mavoglurant pharmacokinetics was best described by a two-compartment model with linear elimination. While an input function equal to a sum of two IG functions was sufficiently flexible to provide a reasonable fitting to IR-fasted and MR-fed data, a sum of three IG functions best captured the multiple-peak phenomenon observed in MR-fasted data. Simulations suggest that at equal doses, a twice-daily repeated administration of the IR capsule and of the MR tablet provides a similar concentration range with lower peaks for the MR formulation, whereas concomitant administration of the MR tablet with a high fat meal leads to a higher and wider concentration range in comparison with the fasted state.
Conclusions: Modelling and simulation of mavoglurant pharmacokinetics indicate that a prolonged release of the drug in the gastrointestinal tract allows a reduction of peak plasma concentrations without substantial change in the systemic exposure provided by a prompt release. However, fatty food is likely to alter drug absorption and thus its pharmacokinetics.
References:
[1] Beal SL, Sheiner LB, Boeckmann AJ and Bauer RJ. NONMEM 7.2.0 Users’ Guides. 2011. ICON Development Solutions, Ellicott City, Maryland, USA.
[2] Csajka C, Drover D and Verotta D. The use of a sum of inverse Gaussian functions to describe the absorption profile of drugs exhibiting complex absorption. Pharmaceutical research. (2005) 22:1227-1235.
[3] Shen J, Boeckmann A and Vick A. Implementation of dose superimposition to introduce multiple doses for a mathematical absorption model (transit compartment model). Journal of pharmacokinetics and pharmacodynamics. (2012) 39:251-262.
Reference: PAGE 23 () Abstr 3067 [www.page-meeting.org/?abstract=3067]
Poster: Drug/Disease modeling - Absorption & PBPK