In silico modeling of non-linear drug absorption for the P-gp substrate talinolol and of consequences for the resulting pharmacodynamic effect.

PURPOSE: The aim of the present work was to demonstrate P-glycoprotein's involvement in the non-linear talinolol pharmacokinetics using an advanced compartment and transit model (ACAT) and to compare the results predicted from the model to the finding of a phase I dose escalation study with oral talinolol doses increasing from 25 to 400 mg. MATERIALS AND METHODS: Besides minimum input parameters for the compound (pKa(s), solubility at one or more pH's, Peff, doses, formulation, diffusivity), physiological and pharmacokinetic properties, transporter data are included in these predictions. The simulations assumed higher expression levels in lower gastrointestinal regions, in particular in the colon, which is in accordance with the results of intestinal rat perfusion studies and intestinal distribution data from rats, catfishes, micropigs and humans reported in the literature. Optimized values for P-glycoprotein (P-gp) Km and Vmax were used for the final simulation results and for a stochastic virtual trial with 12 patients. RESULTS: Talinolol, a P-gp substrate, exhibits non-linear dose AUC relationship after administration of 25, 50, 100 and 400 mg immediate-release tablets. This dose dependency is due to a decrease of efflux transport caused by saturation of P-gp by talinolol. It was found that oral bioavailability increases after administration of higher doses of talinolol. The predicted bioavailability of the p.o. 25, 50, 100 and 400 mg doses of talinolol was 64, 76, 85, 94%, respectively. Pharmacokinetic parameters (AUC, Cmax) from in silico simulations are within acceptable range comparing with data, observed in vivo. However, the in vitro value of Km for talinolol's interactions with P-gp could not be used in the simulation and still reproduce the observed non-linear dose dependence. For each of the four doses, GastroPlus was used to model pharmacodynamic (PD) response and to optimize the values of CLe, Emax, and EC5o with the effect compartment linked indirectly to the central compartment. For all simulations, EC50 was 114 nM and E0 was 83 bpm. CONCLUSION: Comparison between the results of the in vivo study and the in silico simulations determined the quality and reliability of the in silico predictions and demonstrate the simulation of dose dependent absorption. In contrast to previous simulation work for the non-linear dose dependence of interaction with intestinal transporters or enterocyte metabolism, optimized Km and Vmax values were required to reproduce the clinically observed non-linear dose dependence. The model developed may be useful in the prediction of absorption of other P-gp substrates including pharmacodynamic consequences.

Effects of controlled-release on the pharmacokinetics and absorption characteristics of a compound undergoing intestinal efflux in humans.

OBJECTIVE: The number of active pharmaceutical ingredients (API) undergoing inhibitable and saturable intestinal efflux is considerable. As a consequence, absorption and bioavailability may depend on the intestinal concentration profile of the drug and may vary as a function of dose and release rate of the drug from the dosage form. The impact of controlled versus immediate-release on the absorption of P-glycoprotein substrates is currently unknown. Thus, the main focus of the present study was a comparison of the pharmacokinetics of the P-gp model substrate talinolol following administration of immediate-release (IR) and controlled-release (CR) tablets to healthy human volunteers with a particular focus on the absorption characteristics of the active pharmaceutical ingredients. METHODS: Talinolol immediate-release (Cordanum), 100mg), one controlled-release (100mg) and two controlled-release tablets (200mg) were administered as single doses to fasting healthy volunteers in a crossover design with a 1 week washout period between treatments. Sufficient blood and urine samples were drawn and analysed using a specific HPLC method with UV detection to describe the resulting plasma and urinary excretion versus time profiles. RESULTS: The bioavailability of talinolol in term of AUC(0-->infinity) for IR talinolol was approximately twice as high as compared to the administration of the same dose in a controlled-release dosage form. After administration of talinolol IR tablets, the drug was rapidly absorbed and reached maximum concentrations C(max) of 204.5 ng/ml+/-121.8 (means+/-S.D.) 2h after dosing. The terminal half-life of the drug averaged 19.8h following IR administration in comparison to 32 h under CR dosing conditions. Following administration of the IR dosage form, significant secondary peaks were observed in one healthy subject. Secondary peaks were not clearly apparent in the CR plasma profiles. CONCLUSION: The present study demonstrates a considerable loss of bioavailability of drugs that are substrates of intestinal secretory transporters upon their administration in controlled-release dosage forms.