Profile of once-daily darunavir/cobicistat fixed-dose combination for the treatment of HIV/AIDS

Abstract

Efficacy is the main objective of antiretroviral treatment and adherence is one of the cornerstones to achieve it. For this reason, treatment simplification is of key importance with regard to antiretroviral regimens. Rezolsta® (darunavir/cobicistat) is the first fixed-dose combination containing a protease inhibitor approved for HIV treatment. This coformulation includes darunavir, a protease inhibitor that has shown its efficacy and safety in naïve and treatment-experienced patients, and cobicistat, the new pharmacokinetic enhancer that is expected to replace ritonavir. Bioequivalence between ritonavir and cobicistat as darunavir boosters has been shown in studies involving healthy volunteers. Furthermore, efficacy and safety of darunavir/cobicistat observed in phase III studies, including naïve and pretreated patients without darunavir-associated resistance mutations, are comparable to historical data of darunavir/ritonavir 800/100 mg once-daily formulation. Adverse events with darunavir/cobicistat are scarce and mild, and basically include skin reactions and gastrointestinal disturbances. Although small increases in plasma creatinine are expected in patients receiving cobicistat due to the inhibition of creatinine transporters in kidney tubules, actual glomerular filtrate rate remains unaltered. Cobicistat does not have an inducer effect on metabolic pathways and shows much more selective inhibition than ritonavir. Therefore, isoenzyms different from CYP3A4 are supposed to be less affected by cobicistat, and thus fewer drug–drug interactions are expected.

Comparative Population Pharmacokinetics of Darunavir in SARS-CoV-2 Patients vs. HIV Patients: The Role of Interleukin-6

“…The rationale for considering this study design as being reliable for population pharmacokinetic modeling is based on the findings of comparative pharmacokinetic studies between DRV/COBI (800/150 mg/day), either as single agents or in a fixed-drug combination, and DRV/RTV (800/100 mg/day). The full bioequivalence of darunavir was shown, in terms of area under the concentration-time curve (AUC) and peak concentration (C max ), between the two formulations (AUC geometric mean ratio range 0.96-1.02; C max geometric mean ratio range 0.97-1.03) [8,9], even if the trough concentrations (C min ) were approximately 30% lower for DRV/COBI.…”

Lack of Antiviral Activity of Darunavir against SARS-CoV-2

“…The copyright holder for this preprint (which this version posted April 8, 2020. . https://doi.org/10.1101/2020.04.03.20052548 doi: medRxiv preprint profile of boosted-DRV combination therapy is well-established in the HIV setting, based on phase III clinical studies as well as real-world evidence (8)(9)(10)(11).…”

Darunavir–cobicistat–emtricitabine–tenofovir alafenamide: safety and efficacy of a protease inhibitor in the modern era

“…Importantly, while Rtv has activity against HIV, possibly leading to the development of drug-resistance mutations to PIs in cases of suboptimal regimens, Cobi is devoid of intrinsic activity against HIV replication. 19 , 20 Recently, Drv 800 mg and Cobi 150 mg have become available in an FDC (Rezolsta; Johnson and Johnson, New Brunswick, NJ, USA).…”

“… 26 Mean Drv AUC, C max , and Ctrough values ± SD were 81,646±26,322 ng⋅h/mL, 7,663±1,920 ng/mL, and 1,311±969 ng/mL, respectively, comparable to results observed in healthy volunteers. 20 , 25 , 27 , 28 Geometric mean values 24 hours after the observed dose for Cobi-boosted Drv were reported to be 43 ng/mL in saliva and 11,878 ng/mL in urine. Concentration decay in saliva/urine was found to mirror plasma concentrations.…”

“…However, other enzymes and transporters are weakly inhibited by Cobi (see Figure 1 ). 20 , 21 , 27 In comparison to Rtv, Cobi is a more selective CYP3A4 inhibitor, as it is devoid of effects on other isoenzymes. It also lacks the induction activity of Rtv on several enzymes and transporters, including CYP isoenzymes, Pgp, and glucuronyltransferases.…”