Bioequivalence of a Darunavir/Cobicistat Fixed-Dose Combination Tablet versus Single Agents and Food Effect in Healthy Volunteers

Kakuda, Thomas N.; Casteele, Tom Van de; Petrovic, Romana; Neujens, Mark; Salih, Hiba; Opsomer, Magda; Hoetelmans, Richard M. W.

doi:10.3851/imp2814

Cited by 39 publications

(43 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…14 Steady-state DRV pharmacokinetic parameters were consistent with those observed in previous Phase I studies in healthy volunteers; 15,16 a summary of the impact of Cobi on DRV bioavailability in patients with HIV-1 infection is given in Table 3. 17 Cobi is not extensively metabolized, with unchanged drug accounting for 99% of the radioactivity circulating in plasma following oral administration of radiolabelled Cobi.…”

Section: Overview Of Pharmacologysupporting

confidence: 66%

“…Following the administration of a single dose of Cobi 150 mg plus DRV 800 mg to healthy volunteers under fed (n=38) and fasted (n=72) conditions, Cobi had a mean C max of 823 and 664 ng/mL, a mean AUC from the time of administration to the last measurable concentration (AUC last ) of 6,401 and 4,962 ng ⋅ h/mL, and a median time to C max of 4.0 and 2.5 hours. 16 These data suggest that Cobi should be taken with food.…”

Section: Overview Of Pharmacologymentioning

confidence: 99%

See 1 more Smart Citation

Impact and differential clinical utility of cobicistat-boosted darunavir in HIV/AIDS

Cossu¹,

Astuti²,

Capetti³

et al. 2015

VAAT

View full text Add to dashboard Cite

Cobicistat (Cobi) is a pharmacoenhancer, without anti-HIV activity, that optimizes systemic exposures of protease inhibitors (PIs) such as atazanavir (ATV) and darunavir (DRV). In particular, Cobi is a potent inhibitor of cytochrome P450 (CYP) 3A enzymes, the main metabolizing pathway of this class of antiretrovirals. Due to its more selective inhibition of CYP3A, Cobi has a lower potential for off-target drug interactions than the standard boosting agent ritonavir (RTV), and lower likelihood for enzymatic induction. In pharmacokinetic studies of healthy volunteers, DRV boosted with Cobi attains plasma concentrations that are comparable to those achieved with 100 mg RTV as booster. In Phase III clinical trials, conducted in naïve subjects, the coformulation yielded high rates of suppression of viral replication, on average 82%-83% of treated patients reaching undetectable viremia after 48 weeks of therapy. The selection of resistance associated with mutations was a rare event and no phenotypic resistance to DRV emerged in viral failures. Generally, Cobi was well tolerated; however, it has been shown to decrease estimated creatinine clearance (ClCr) due to inhibition of tubular secretion of creatinine. Cobi, therefore, should not be initiated in patients with ClCr less than 70 mL/min, if any coadministered agent (eg, emtricitabine, lamivudine, tenofovir disoproxil fumarate, or adefovir) requires dose adjustment based on ClCr.DRV/Cobi fixed-dose combination is part of an important evolution of antiretroviral therapy toward simpler yet potent formulations. In this setting, it is important to combine potency, simplicity, safety, and high genetic barrier, as in this case.

show abstract

Section: Overview Of Pharmacologysupporting

confidence: 66%

Section: Overview Of Pharmacologymentioning

confidence: 99%

Impact and differential clinical utility of cobicistat-boosted darunavir in HIV/AIDS

Cossu¹,

Astuti²,

Capetti³

et al. 2015

VAAT

View full text Add to dashboard Cite

show abstract

“…The approval of once-daily darunavir/cobicistat 800 mg/ 150 mg for the treatment of HIV-infection in adults in combination with other antiretroviral medicinal products is supported by the results of bioequivalence studies of cobicistat [18,20,21] and phase 3 trials of darunavir in patients with HIV-1 infection [2,22,23].…”

Section: How Do the Individual Drugs Work?mentioning

confidence: 99%

“…Table 1 presents a summary of the prescribing information of darunavir/cobicistat in the EU [2]. Of note, darunavir/cobicistat fixed-dose single tablets should be taken with food [2,3], as this increases exposure to darunavir [20].…”

Section: How Do the Individual Drugs Work?mentioning

confidence: 99%

Darunavir/cobicistat fixed-dose single tablet (Rezolsta™): a guide to its use in HIV-1 infection in adults in the EU

Lyseng‐Williamson

2015

Drugs Ther Perspect

View full text Add to dashboard Cite

Oral darunavir/cobicistat 800 mg/150 mg fixed-dose single tablets [Rezolsta TM (EU); Prezcobix TM (USA, Canada)] are indicated as a component of antiretroviral treatment of HIV-1 infection in treatment-naïve and treatment-experienced adults without known darunavir resistance-associated mutations. Treatment with cobicistator ritonavir-boosted regimens of the protease inhibitor darunavir have been shown to reduce viral load in these patient populations. Relative to the use of low-dose ritonavir to boost darunavir, the use of cobicistat reduces the potential for drug interactions involving enzymatic induction, provides bioequivalent exposure to darunavir, and has similar virological efficacy and tolerability profiles, and allows co-formulation of the agents in a single tablet.Adis evaluation of darunavir/cobicistat fixed-dose single tablet as a antiretroviral therapy in adults with HIV-1 infection What are its key clinical benefits?Convenient oral once-daily, single-tablet regimen that combines a protease inhibitor (darunavir) with a pharmacokinetic enhancer that selectively inhibits cytochrome P450 3A (cobicistat)Boosted darunavir provides marked and durable suppression of plasma HIV-1 RNA to \50 copies/mL in treatment-naïve and treatment-experienced patients without known darunavir resistance-associated mutationsRelative to boosting darunavir with low-dose ritonavir, boosting darunavir with cobicistat has a lower potential for drug interactions involving enzymatic induction, provides bioequivalent exposure to darunavir, and achieves similar virological efficacy Generally well tolerated; \4 % of patients discontinued treatment because of adverse eventsWhat are its key clinical limitations? Regular monitoring of hepatic function is requiredAlthough the potential for drug interactions is lower with cobicistat than with low-dose ritonavir, the concomitant use of darunavir/cobicistat and many other drugs is contraindicated, not recommended or requires caution

show abstract

“…Darunavir (DRV) is chiefly metabolized by CYP3A4 (17), and coadministration of a low dose of either RTV or COBI together with DRV increases the systemic bioavailability of DRV (18,19). In addition, the high barrier to genetic resistance, as well as the tolerability, safety profile, and potency of DRV when it is administered in combination with a low dose of either RTV (DRV/r) or COBI (DRV/c), has made these fixed-dose combinations important options for the treatment of HIV-infected patients (20)(21)(22).…”

mentioning

confidence: 99%

Interaction of Rifampin and Darunavir-Ritonavir or Darunavir-Cobicistat In Vitro

Roberts

Khoo

Owen

et al. 2017

Antimicrob Agents Chemother

View full text Add to dashboard Cite

Treatment of HIV-infected patients coinfected with Mycobacterium tuberculosis is challenging due to drug-drug interactions (DDIs) between antiretrovirals (ARVs) and antituberculosis (anti-TB) drugs. The aim of this study was to quantify the effect of cobicistat (COBI) or ritonavir (RTV) in modulating DDIs between darunavir (DRV) and rifampin (RIF) in a human hepatocyte-based in vitro model. Human primary hepatocyte cultures were incubated with RIF alone or in combination with either COBI or RTV for 3 days, followed by coincubation with DRV for 1 h. The resultant DRV concentrations were quantified by high-performance liquid chromatography with UV detection, and the apparent intrinsic clearance (CL int.app. ) of DRV was calculated. Both RTV and COBI lowered the RIF-induced increases in CL int.app. in a concentrationdependent manner. Linear regression analysis showed that log 10 RTV and log 10 COBI concentrations were associated with the percent inhibition of RIF-induced elevations in DRV CL int.app. , where ␤ was equal to Ϫ234 (95% confidence interval [CI] ϭ Ϫ275 to Ϫ193; P Ͻ 0.0001) and Ϫ73 (95% CI ϭ Ϫ89 to Ϫ57; P Ͻ 0.0001), respectively. RTV was more effective in lowering 10 M RIF-induced elevations in DRV CL int.app. (half-maximal [50%] inhibitory concentration [IC 50 ] ϭ 0.025 M) than COBI (IC 50 ϭ 0.223 M). Incubation of either RTV or COBI in combination with RIF was sufficient to overcome RIF-induced elevations in DRV CL int.app. , with RTV being more potent than COBI. These data provide the first in vitro experimental insight into DDIs between RIF and COBI-boosted or RTV-boosted DRV and will be useful to inform physiologically based pharmacokinetic (PBPK) models to aid in optimizing dosing regimens for the treatment of patients coinfected with HIV and M. tuberculosis. KEYWORDS antiretroviral agents, cobicistat, darunavir, drug-drug interaction, human immunodeficiency virus, in vitro, rifampin, ritonavirA pproximately 25% of human immunodeficiency virus (HIV) type 1 (HIV-1)-infected patients worldwide are coinfected with Mycobacterium tuberculosis (1, 2) (referred to here as HIV-tuberculosis [TB] patients), with such coinfections accounting for 390,000 deaths in 2014 (3). The clinical management of HIV-TB patients presents significant challenges, especially in resource-limited settings (2, 4), where virological failure or intolerance to first-line antiretroviral therapy requires the use of HIV protease inhibitors (PIs) (5). PIs largely undergo phase I metabolism by cytochrome P450 3A4 (CYP3A4) and are also substrates of P-glycoprotein (P-GP; ABCB1) (6). Consequently, PIs are commonly administered in combination with pharmacokinetic (PK) boosters, such as ritonavir (RTV) or cobicistat (COBI), which act by inhibiting CYP3A4-mediated PI metabolism and P-GP-mediated PI efflux, thereby improving the PK profile of PIs by prolonging PI half-life and increasing PI bioavailability (7-9).Rifampin (RIF) is an essential component of short-course anti-TB treatment regimens (2, 10); however, RIF is also a potent...

show abstract

Bioequivalence of a Darunavir/Cobicistat Fixed-Dose Combination Tablet versus Single Agents and Food Effect in Healthy Volunteers

Abstract: Bioequivalence of the darunavir/cobicistat 800/150-mg FDC was demonstrated versus darunavir and cobicistat co-administered as single agents under fasted or fed conditions. Food increased darunavir exposure, therefore, darunavir/cobicistat should be administered with food.

Cited by 39 publications

References 27 publications

Impact and differential clinical utility of cobicistat-boosted darunavir in HIV/AIDS

Impact and differential clinical utility of cobicistat-boosted darunavir in HIV/AIDS

Darunavir/cobicistat fixed-dose single tablet (Rezolsta™): a guide to its use in HIV-1 infection in adults in the EU

Interaction of Rifampin and Darunavir-Ritonavir or Darunavir-Cobicistat In Vitro

Contact Info

Product

Resources

About