Brendel K.(1), Tessier A(2), Chenel M(1).
(1)Department of Clinical Pharmacokinetics and Pharmacometrics, SERVIER, France. (2)INSERM, IAME, UMR 1137 France
Introduction: Human microdosing (MD) studies are used in the context of drug development in order to have a better knowledge of pharmacokinetics (PK) of a drug (i.e. absolute bioavailability determination)(1). MD studies are usully performed in a limited number of volunteers. However the integration of MD data in PK models can significantly improved modelling by decreasing the number of assumptions made.
Objectives: To develop a population PK model of a BCS class 2 compound (drug S) taking into account MD data to better understand absorption process (non-linearity due to the dissolution process) and the presence of a second peak in the concentration-time profile.
Methodology: Data came from 10 phase I studies, including 257 healthy volunteers, who received a single or repeated oral administration (tablet) and 10 who received single MD iv perfusion also or single MD oral solution.
First a population PK model was built using MD data from iv and oral solution administration, especially to estimate the absolute bioavailabity and to fit the absorption process independently of tablet dissolution.
Secondly a model with all data was developed by fixing parameters obtained previously with MD data. The adequacy of the model to describe the data was assessed based on uncertainty on parameter estimates (RSE), and on advanced evaluation methods such as VPC and NPDE.
Estimation of the population parameters was performed using NONMEM 7.3 and FOCE algorithm.
Results: Informations from the MD data were used to identify the dissolution process from the absorption, bioavailability and to explain the presence of a second peak due to the EHC (after iv and oral solution administrations).
All data were described by a 2-compartments model with first-order absorption and linear elimination; the second peak in concentrations was described using EHC. A fraction of drug S was excreted from the central into a gall bladder compartment with a first-order constant, while a periodic drug release from the gall bladder to depot compartment was used through MTIME. Some parameters of EHC and dissolution were fixed due to model identifiability.
A non-linear dose relationship was also added in the absorption process. The RSE, VPC and NPDE were satisfactory for both MD and therapeutic doses models.
Conclusion: Informations from the MD data were used to explain non-liearity to the dose due to the dissolution process, and to confirm the presence of a second peak due to the EHC.
References:
[1] Rowland M. Microdosing: a critical assessment of human data. J Pharm Sci 2012, 101(11): 4067-74.
Reference: PAGE 24 (2015) Abstr 3423 [www.page-meeting.org/?abstract=3423]
Poster: Drug/Disease modeling - Other topics