Predicting intestinal absorption of raltegravir using a population-based ADME simulation.

OBJECTIVES: Raltegravir pharmacokinetics (PK) show high intra- and inter-patient variability and are also influenced by co-administered substances that alter the gastrointestinal tract environment, such as pH-altering or metal-containing agents. The aim of this investigation was to develop a population-based absorption, distribution, metabolism and excretion (ADME) model to investigate the effects of gastrointestinal pH and ingested magnesium on raltegravir PK. METHODS: In vitro data describing the disposition of raltegravir were obtained from literature sources or generated by standard methods. Raltegravir (400 mg single dose) PK were simulated in healthy volunteers (50 subjects per group, 20-50 years old, 0.5 proportion female subjects) over a 12 h period. RESULTS: Simulated raltegravir PK correlated well with data from clinical trials, with a mean deviation in C(max), AUC(0-12) and C(trough) of <20%. Solubility of raltegravir in the gastrointestinal tract was increased at higher luminal pH. Increased intestinal pH and transit time both correlated with higher raltegravir absorption (P<0.001). Magnesium ingestion reduced raltegravir exposure in simulated subjects, with mean C(trough) reduced by 32% (P<0.001). CONCLUSIONS: The in vitro-in vivo extrapolation model developed in this study predicted raltegravir PK in virtual individuals with different gastrointestinal pH profiles. The main PK variables were predicted with good accuracy compared with reference data, and both luminal pH and magnesium were able to influence drug absorption. This modelling system provides a tool for investigating the absorption of other drugs, including HIV integrase inhibitors currently in development, which have also shown interactions with food and metal-containing products.