Bart A.W. Jacobs (1), Jelte Meulenaar (2), Bastiaan Nuijen (2), Serena Marchetti (1), Jos H. Beijnen (2,3), Jan H.M. Schellens (1,3), Alwin D.R. Huitema (2)
(1) Department of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands, (2) Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands, (3) Department of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands
Introduction: Capecitabine (CAP) is an oral prodrug of 5-fluorouracil (5-FU) and is commonly used for the treatment of solid tumours. After intake, CAP is rapidly absorbed, followed by fast metabolism and clearance from the body [1]. As a consequence, there is no relevant exposure to CAP and 5-FU during approximately 6 hours of each 12-hour dosing interval. A controlled release formulation might improve CAP exposure by reducing peak levels and avoiding exposure gaps in between doses. The objective of the current study was to optimize a novel controlled release formulation of CAP with regard to tablet coating thickness using a population PK model.
Methods: Controlled release CAP tablets (500 mg) were developed by using the controlled release excipient Kollidon® SR. These tablets were coated with variable thicknesses varying from 3 – 12 mg/cm2. Pharmacokinetics of the controlled release formulations were compared with the approved CAP formulation (Xeloda®) in a phase 0 clinical cross-over study. Patients underwent intensive pharmacokinetic (PK) sampling after administrations of Xeloda® (1000 mg) on day 1 and controlled release CAP (1000 mg) on day 2. PK data were incorporated in an earlier developed PK model for CAP, in which CAP PK from Xeloda® was described by 2-transit absorption and 2-compartmental disposition. Data analysis was performed using NONMEM, Piraña, R, Xpose and PsN.
Results: PK data from 8 patients receiving a formulation coated with 3, 6 or 9 mg/cm2 showed controlled release and were included for analysis. A 1-transit absorption model described CAP absorption for controlled release CAP best. Increasing tablet coating thickness reduced CAP absorption rate and relative bioavailability. The effects of coating thickness on absorption rate and relative bioavailability were successfully described relatively to Xeloda® by using sigmoidal models including Hill coefficients. The effects of other coating thicknesses on CAP pharmacokinetics were simulated. Based on simulations, a coating thickness of 4 mg/cm2 would result in CAP exposure for up to 24 h with reduced CAP plasma peak levels.
Conclusions: The absorption rate and relative bioavailability of CAP are modulated by tablet coating thickness. This study enables quick identification of formulation characteristics for in vivo controlled release of CAP. A tablet formulation with a coating of 4 mg/cm2 should be considered for further clinical testing with controlled release CAP.
References:
[1] Mackean M et al. J Clin Oncol. 1998; 16:2977–85.
Reference: PAGE 23 (2014) Abstr 3203 [www.page-meeting.org/?abstract=3203]
Poster: Drug/Disease modeling - Oncology