The induction of metabolizing enzymes and efflux transporters mediated by rifampicin (Rif) affected ritonavir-boosted darunavir (DRV/r) and dolutegravir (DTG). It affected the treatment of tuberculosis in persons living with HIV (PLWH). According to research, doubling the DRV/r dose did not compensate for this effect, and liver safety was poor. In peripheral blood mononuclear cells (PBMCs), researchers sought to determine how DRV, ritonavir (RTV), and DTG pharmacokinetics changed in the presence and absence of RIF. A dose-escalation crossover trial with 7-day 6 treatment periods was conducted on PLWH. Participants received DRV/r 800/100 mg QD, RIF, and DTG before the RTV dose was increased, and then DRV/r 800/100 twice daily (BD) and subsequently 1,600/200 QD or vice versa. RIF was eventually phased out. Validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods were used to assess medication concentrations in plasma and intra-PBMCs. Only 4 of the 17 subjects completed all research stages due to a significant prevalence of liver damage. The median (interquartile range [IQR]) beginning value of 261 ng/mL (158 to 577) for intra-PBMC DRV trough serum concentration (Ctrough) following the addition of RIF was reduced to 112 ng/mL (18 to 820) and 31 ng/mL (12 to 331) for 800/100 BD and 1,600/200 QD DRV/r dosages, respectively. The DRV intra-PBMC/plasma ratio considerably increased (P=0.003). In the absence of RIF or DRV/r, DTG and RIF intra-PBMC concentrations were consistent with prior results. The impact of enzyme and transporter induction on DRV/r concentrations in plasma and PBMCs was distinct in this investigation, underscoring the importance of examining intra-PBMC pharmacokinetics with drug-drug interactions.
Source:journals.asm.org/doi/10.1128/aac.00136-22
