Analysis of Complex Absorption After Multiple Dosing: Application to the Interaction Between the P-glycoprotein Substrate Talinolol and Rifampicin

Abstract

Purpose: In order to clarify the effect of rifampicin on the bioavailability of the P-glycoprotein substrate talinolol, its absorption kinetics was modeled after multiple-dose oral administration of talinolol in healthy subjects.

Methods: A sum of two inverse Gaussian functions was used to calculate the time course of the input rate into the systemic circulation.

Results: The estimated rate of drug entry into the systemic circulation revealed two distinct peaks at 1 and 3.5 h after administration. Rifampicin did not affect bioavailability of talinolol, but did shift the second peak of the input function by 1.3 h to later times. Elimination clearance and one of the intercompartmental distribution clearances increased significantly under rifampicin treatment.

Conclusions: Rifampicin changes the time course of absorption rate but not the fraction absorbed of talinolol. The model suggests the existence of two intestinal absorption windows for talinolol.

Keywords: absorption kinetics; interaction; multiple dosing; rifampicin; talinolol.

Fig. 1

Fits of talinolol data after 100 mg/24 h talinolol in 3 subjects before (left) and after coadministration of rifampicin (middle). The resulting time courses of input rate are shown on the right hand side. The first dose was given at Time 0.

Fig. 2

Goodness-of-fit plots showing the observed concentration data of talinolol after multiple oral dosing versus the individual model-predicted values for all 7 subjects without (left) and with rifampicin (right). The regression lines are nearly coincident with the lines of identity.

Fig. 3

Visual predictive checks showing the 90% prediction interval (5th to 95th percentiles, dashed lines) and the median on the simulated data (solid line) together with the observed data (open dots).

Fig. 4

Mean cumulative amount of talinolol absorbed as fraction of dose. The curves were simulated using the mean parameter estimates of the input function.

Fig. 5

The first peak of the input rate decrease linearly (p < 0.05) with the time at which peak concentrations are reached (left) and the time point of the second peak increases with that of the first peak (p < 0.05) (right).