Transit Compartment Model Useful for Describing Absorption of Quetiapine XR and IR
Jacob Brogren(1) Svante Nyberg(2)
(1) Clinical Pharmacology & DMPK, AstraZeneca R&D, Södertälje, Sweden; (2) Global Clinical Development, AstraZeneca R&D, Södertälje, Sweden
Objectives: Quetiapine fumarate is an atypical antipsychotic that has demonstrated efficacy in patients with schizophrenia, bipolar mania, bipolar depression, major depressive disorder, and generalized anxiety disorder. Quetiapine is available in two different formulations: XR (extended release) and IR (immediate release). Quetiapine XR exhibits a slower absorption compared with quetiapine IR, with generally lower Cmax and longer tmax. The objective of this work was to develop a population PK model for both these quetiapine formulations in order to facilitate simulations of quetiapine PK across formulations, regimens, and the clinical dose range.
Methods: The population PK model was developed based on data from a randomized, double-blind, crossover study in healthy volunteers (n=58, ClinicalTrials.gov Identifier NCT00702676) with the aim to study the sedation profile following administration of quetiapine XR and IR. The details of the study have been reported elsewhere [1]. In order to simultaneously describe the quetiapine PK profiles obtained with both formulations, a population PK model utilizing transit compartments [2] was applied to data using NONMEM VI.
Results: A two-compartment model with transit compartment absorption feeding directly into the central compartment was successfully fitted to data. Separate estimates of mean transit time (MTT) and number of transit compartments (NB) were obtained for the different formulations. MTT for XR and IR was estimated to be 4.65 h and 1.14 h, respectively. Other structural model population parameters were the same regardless of formulation. CL/F for quetiapine was estimated to be 96.8 L/h and Vss to be 515 L/h. Interindividual variability (IIV) in bioavailability was similar (40%-45%) for both formulations. The IIV in MTT was 45% for the IR formulation and 23% for the XR formulation. As opposed to the original noncompartmental analysis, it could be shown in this study that quetiapine XR gave similar exposure in terms of AUC as quetiapine IR. This was because a single value of CL/F was valid for both of the formulations.
Conclusions: The transit compartment model was able to describe absorption characteristics of both quetiapine XR and IR. The exposure in terms of AUC as well as the variability in bioavailability was similar following administration of either quetiapine XR or IR, thus providing further support for the bioequivalence of the two formulations.
References:
[1] Datto C., et al. Self-reported sedation profile of immediate-release quetiapine fumarate compared with extended-release quetiapine fumarate during dose initiation: a randomized, double-blind, crossover study in healthy adult subjects. Clin Ther. 2009;31:492-502.
[2] Savic R., et al. Evaluation of a transit compartment model versus a lag time model for describing drug absorption delay. PAGE 13 (2004) Abstract 513 [www.page-meeting.org/?abstract=513].
