Brendel K., Campagne O., Chenel M.
SERVIER
Introduction: Enterohepatic recycling (EHC) occurs when there is biliary excretion followed by intestinal reapsorption of a compound, sometimes with hepatic conjugation. Multiple peaks in a plasma concentration profile may be a consequence of this recycling. A change-point model, which is a model in which a parameter’s value discontinuously changes at a given time is often used to mimic EHC (1).
Objectives: To develop a population PK model for both the parent and its main active metabolite including a EHC for the metabolite.
Methods: Data after single administration, coming from 3 Phase I study, including a total of 61 healthy volunteers, were used to build a population PK model for both the parent (S1) and its main active glucuronide metabolite (S2).
The high molecular weight of both compounds, the glucuronidation of the metabolite and the time of second peak around meal-time, suggest the hypothesis of EHC to describe the second peak in the plasma concentration-time profile. EHC was implemented with a change-point model using model event time parameter (MTIME) directly implemented in NONMEM. Several model structures and assumptions (e.g. first pass effect) were tested during model building. The adequacy of the model to describe the data was assessed based on asessement of uncertainty on parameter estimates (RSE), and on advanced evaluation methods such as VPC and NPDE. Estimation of the population parameters was performed using NONMEM 7.2.
Results:S1 concentration-time data were described by a 2-compartment model with first-order absorption with no renal elimination. S2 data were also described by a 2-compartment model linked to the central compartment of S1. EHC was modelled with a semi-mechanistic model where a fraction of S2 from the central compartment was excreted into a gall bladder compartment with a first-order rate constant and a periodic drug release from the gall bladder using MTIME. Some parameters like the fraction going to gall bladder were fixed due to the lack of information and therefore model identifiability. Expected first-pass effect was not identified. The RSE, VPC and NPDE were satisfactory for both S1 and S2.
Conclusions:In order to implement a EHC, a change-point model was used to describe the concentration-time data of a parent and its glucuronide metabolite. Further studies (e.g. IV microdose study) will be performed to better characterize PK parameters (e.g. first pass effect, intrinsic clearance of S2).
References:
[1] Brendel K. PAGE 22 (2013) Abstr 2912 [www.page-meeting.org/?abstract=2912].
Reference: PAGE 23 () Abstr 3066 [www.page-meeting.org/?abstract=3066]
Poster: Drug/Disease modeling - Other topics