Elien De Thaye (1), Pieter Colin (1), Anouk Vervaeck (2), Jean Paul Remon (2), An Vermeulen (1), Jan Van Bocxlaer (1)
(1) Laboratory of Medical Biochemistry and Clinical Analysis, Faculty of Pharmaceutical Sciences, Ghent University, Belgium, (2) Laboratory of Pharmaceutical Technology, Faculty of Pharmaceutical Sciences, Ghent University, Belgium
Objectives: Metoprolol, a selective adrenergic β1-receptor antagonist, is commonly prescribed for a variety of cardiovascular conditions. This drug is available in different salt forms and as different modified-release formulations. In our institution, dogs and rabbits are used interchangeably to study preclinical pharmacokinetics of in-house developed pharmaceutical dosage forms. Purpose of the current study was to investigate absorption kinetics of different metoprolol (model BCS class I compound) modified-release formulations in beagle dogs and rabbits, using compartmental modeling methods.
Methods: Metoprolol tartrate (50 to 200 mg) was administered to 6-8 beagle dogs and rabbits as a single intravenous bolus or oral dose (p.o.). Three modified-release formulations were administered p.o.: an in-house produced prill formulation and two commercially available formulations, ZOK-ZID® and Slow-lopresor®. A non-linear mixed-effect model was developed using NONMEM®. Different published absorption model approaches were fitted to the data. Furthermore, the M3 method [1] was used to study the impact of observations below the limit of detection (BLoD) on parameter estimates. Consistency in parameter estimates across both species was investigated.
Results: Following intravenous bolus dosing, plasma concentration-time profiles in both species were best described by a two-compartment model with first-order elimination. Plasma concentration-time curves in beagle dogs following p.o. dosing were best described using a sequential zero- and first-order absorption model. The absorption phase in rabbits was best described using a first order absorption process. Compared to rabbits, the fraction of BLoD data in dogs was similar. Pharmacokinetic variability in bioavailability and absorption rate constant was observed between oral formulations and across preclinical species.
Conclusions: Our current approach led to different selected absorption models for both preclinical species, thereby hampering a consistent comparison between the different drug products in both species. Research is ongoing to compare our findings in these animals with the pharmacokinetic profile of metoprolol in humans and use of an IVIVC approach will be explored. We expect that these approaches will provide the necessary guidance to establish an experimental design for future studies and motivate our choice of which preclinical species should be included in our routine preclinical testing.
References:
[1] Ahn JE, Karlsson MO, Dunne A, Ludden TM. Likelihood based approaches to handling data below the quantification limit using NONMEM VI. J Pharmacokinet Pharmacodyn. 2008;35(4):401–421.
Reference: PAGE 24 () Abstr 3534 [www.page-meeting.org/?abstract=3534]
Poster: Drug/Disease modeling - Absorption & PBPK