Purpose: Intestinal permeability is one of the primary determinants affecting the Cmax, AUC and bioavailability of orally administered drugs. However, the ability to predict these pharmacokinetic parameters, based on animal permeability data, is very difficult. Thus, the aim of this study was to evaluate the absorption profiles of cefadroxil in humans based on a segmental permeability approach using data from humanized PepT1 mice.
Methods: Using GastroPlus 9.0 software, predicted plasma concentration-time profiles of cefadroxil were compared to that observed in humans when simulations were based on intestinal permeability data scaled from in silico estimates, and from rat, wildtype and humanized PepT1 mice. Drug-drug interactions and multiple dose regimens of cefadroxil absorption were also assessed using Peff values scaled from humanized PepT1 mice.
Results: Parameter sensitivity analyses showed that the Cmax, AUC and % absorbed of cefadroxil were most sensitive to changes in intestinal permeability, along with clearance and volume of distribution. Significant differences were observed in the predicted plasma concentration-time profiles of cefadroxil at low doses (5 mg/kg in humans) when based on intestinal permeability data from in silico and rodent sources. For example, the predicted absorption was 52.6% for in silico, 53.1% for rats, 97.7% for wildtype and 92.6% for humanized mice, as compared to 92.0% observed in humans. The Cmax, AUC0-t, and compartmental absorption fraction were also influenced by species-dependent permeability. Moreover, the population simulation of cefadroxil absorption profiles at higher doses (15 and 30 mg/kg in humans) demonstrated an advantage when the intestinal permeability was scaled from humanized mice, as opposed to other models. Finally, drug-drug interaction and multiple dose regimen performance showed a good correlation between the predicted absorption profiles and clinical observations.
Conclusion: Combining segmental intestinal permeability data from humanized PepT1 mice and their disposition parameters using GastroPlus 9.0 resulted in excellent predictions of the Cmax, AUC and % absorbed of cefadroxil in human clinical studies. This approach may prove useful for predicting the pharmacokinetics, systemic exposure and potential toxicity of other hPepT1 substrates in humans.