A flexible approach to modeling variable absorption in the context of repeated dosing: illustrated with rifampicin
Justin J Wilkins (1,2), Radojka M Savic (2), Mats O Karlsson (2), Grant Langdon (1), Helen McIlleron (1), Goonaseelan (Colin) Pillai (3), Peter J Smith (1), Ulrika SH Simonsson (2,4)
(1) Division of Clinical Pharmacology, Department of Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa; (2) Division of Pharmacokinetics and Drug Therapy, Department of Biopharmaceutical Sciences, Uppsala University, Uppsala, Sweden; (3) Modeling & Simulation, Clinical Development & Medical Affairs, Novartis Pharmaceuticals AG, Basel, Switzerland; (4) Clinical Pharmacology, AstraZeneca R&D, Mölndal, Sweden
Introduction and Objectives: A flexible transit compartment absorption model (TCAM), in which a delay in the onset of absorption and a gradually changing absorption rate were modeled as drug passage through a chain of hypothetical compartments before reaching the absorption compartment, has been demonstrated previously [1]. The original approach, which allowed for numerical estimation of the number of transit compartments in the chain, was extended to support its application to data arising from a multiple-dosing schedule. We present this approach, demonstrating its superiority over a range of other techniques, using the complex and variable absorption of rifampicin in pulmonary tuberculosis patients as an example.
Methods: Three datasets containing 2 913 rifampin plasma concentration-time data points, collected from 261 South African pulmonary tuberculosis patients receiving regular daily treatment for at least 10 days, were pooled. The pharmacokinetics were analyzed using nonlinear mixed-effect modeling. Various approaches to characterizing the absorption of rifampicin were tested, including nonlinear absorption, dual absorption compartments, lag time parameters, and the extended TCAM.
Results: The best fit was provided by the adaptation of the TCAM for multiple dosing, which proved superior to the other methods tested for describing the absorption phase. The adjusted TCAM successfully described atypical profiles in the data, produced a substantial improvement in overall goodness-of-fit, and was able to reproduce the central tendency and variability of the data in simulations.
Discussion: The model assumes a gradual increase in the absorption rate, which results in a smoother initial rise in the plasma concentration towards the maximum than that offered by the other approaches tested. The extended TCAM provides the same benefits as the previously-described method – despite its fundamentally empirical nature, it offers a better approximation of underlying physiological processes, as well as desirable computational properties – and adds support for multiple dose regimens, which are much more common in practice than single-dose scenarios. The extension of the TCAM to multiple dose data relies on the assumption that the complete dose has reached the absorption compartment before the next dose is given. Further, the pharmacokinetics of rifampicin were successfully described in a patient population.
Conclusions: The multiple-dose adaptation of the TCAM is shown to be a robust and flexible method for dealing with highly variable absorption.
References:
[1] Radojka M. Savić, Daniël M. Jonker, Thomas Kerbusch, Mats O. Karlsson. Evaluation of a transit compartment model versus a lag time model for describing drug absorption delay. PAGE 13 (2004) Abstr 513 [www.page-meeting.org/?abstract=513].
