Background: The optimization of antiretroviral regimens in HIV-infected patients co-administered with anti-TB drugs is challenging since rifampicin (RIF), a principal element of the anti-TB therapy, is a strong inducer of key metabolic enzymes. Physiologically-based pharmacokinetic (PBPK) modelling represents an innovative approach to simulate clinical scenarios in the absence of clinical data, by integrating in vitro data in mathematical models. The aim of this research was to develop a PBPK model for the co-administration of ritonavir-boosted darunavir (DRV/r) and RIF and predict optimal dosing strategies to overcome the drug-drug interaction (DDI).
Methods: In vitro data describing physicochemical properties, absorption, distribution, metabolism and elimination (ADME) of DRV, ritonavir (RTV) and RIF, as well as the inhibition and induction potential of RTV and RIF were determined experimentally or obtained from the literature. A PBPK model was developed integrating experimental in vitro data in algorithms representing molecular, physiological and anatomical processes defining ADME. The PK of DRV/r and RIF was simulated in 100 virtual individuals. The impact of RIF (600mg qd) on DRV/r was determined and DRV and RTV qd and bid dose adjustments were simulated.
Results: Simulated DRV/r pharmacokinetic parameters were (mean ± SD) Ctrough (2.02 ± 1.17 μg/ml), Cmax (8.23 ± 1.73 μg/ml) and AUC (115.6 ± 32.9 μg/mL.h), which is in agreement with observed PK data for DRV/r 800/100 mg qd in HIV-infected patients: Ctrough (2.11 ± 1.22 µg/ml), Cmax (6.75 ± 1.68 μg/ml) and AUC (75.62 ± 26.44 μg/mL.h). The simulated effect of RIF on DRV exposure resulted in a decrement of 57.7% for AUC, 79.5% for Ctrough and 34.6% for Cmax. The effect of RIF was overcome by increasing the DRV/ r dose to 1600/200 mg qd or 800/100 mg bid (Table 1).
Conclusions: The developed PBPK model predicted the in vivo pharmacokinetics of DRV/r and the interaction with RIF. Based on these findings, a DRV/r regimen of 1600/200 mg qd or 800/100 mg bid could mitigate the effect of RIF on DRV/r PK. Mechanistic evaluation of ADME can inform PBPK models and prediction of interaction between drugs. PBPK may be particularly helpful for the rational design of clinical trials evaluating dose adjustment strategies to overcome DDIs in patients concomitantly receiving antiretrovirals and anti-TB drugs.