Enterohepatic circulation model for population pharmacokinetic analysis

T. Funaki

Nippon Roche, Japan

Entero-hepatic circulation may affect the terminal half-life, the area under the plasma concentration-time course and bioavailability. Although several pharmacokinetic models have been reported for entrohepatic circulated drugs, no enterohepatic circulation model for population pharmacokinetics based on the physiological aspect of biliary excretion has yet been reported. Therefore, an entero-hepatic circulation model which based on the physiological aspect of biliary excretion was developed for population pharmacokinetic analysis. Mycophenolate mofetil, an immunosuppressant, was selected as a model drug to validate the model.

The plasma concentration can be described by Eq. 1 at the time window of lag time (t_lag) to t < time of expulsion from the gallbladder (t_gap)

C=k_a·D/((k_a-k) ·V) ·(e^-k(t-tlag)–e^-ka(t-tlag))

At t > t_gap, the plasma concentration can be described by Eq. 2

C=k_a·D/((k_a-k) ·V) ·(e^-k(t-tlag)–e^-ka(t-tlag))
+ (k_d·D/k)·{1+(1/(k_a-k))(k·e^-ka·tgap – k_a·e^-k·tgap)} ·
(k_a/((k_a-k)·V))·{e^-k·(t-tgap) – e^-ka·(t-tgap}

As shown below, the newly developed entero-hepatic model was well described posthoc plasma concentration-time course and a secondary peak arising from entero-hepatic circulation was also well defined. The covariates founded by the model well agreed with the literature results.

Reference: PAGE 8 (1999) Abstr 150 [www.page-meeting.org/?abstract=150]

Poster: poster