Pharmacokinetic interactions between cobicistat-boosted elvitegravir and darunavir in HIV-infected patients

Gutiérrez‐Valencia, Alicia; BenMarzouk-Hidalgo, Omar J.; Llaves, Silvia; Fernandez-Magdaleno, Tamara; Espinosa, Núria; Viciana, Pompeyo; López‐Cortés, Luis F.

doi:10.1093/jac/dkw487

Cited by 4 publications

(15 citation statements)

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“…Mean and median elvitegravir C trough,ss are shown in Table 3 for the purpose of comparison with data from the literature. Our observed elvitegravir C trough,ss were somewhat lower than the manufacturer’s population pharmacokinetic estimates for E/C/F/TDF without darunavir [ 26 ], but generally similar to 24-h C trough,ss measured by Gutierrez-Valencia et al among patients taking E/C/F/TDF either with or without darunavir [ 24 ].…”

Section: Resultssupporting

confidence: 80%

“…The darunavir C trough,ss we observed with ritonavir prior to the switch to E/C/F/TDF tended to be lower than C trough,ss published in the literature for darunavir/ritonavir 800 mg/100 mg once daily [ 22 , 23 ]. After the switch to E/C/F/TDF, the darunavir C trough,ss we observed were higher than the extrapolated C trough,ss reported in the presence of E/C/F/TDF by Ricard et al [ 12 ], but lower than the measured 24-h darunavir C trough,ss with the same regimen reported by Gutierrez-Valencia et al [ 24 ].…”

Section: Resultscontrasting

confidence: 60%

“…Among the 5 patients receiving once-daily darunavir/ritonavir at baseline, darunavir C trough,ss levels were significantly lower after the switch to E/C/F/TDF plus darunavir (the median decreased from 981 to 431 ng/mL), and darunavir C trough,ss levels were low for all 9 subjects with drug levels available on E/C/F/TDF plus darunavir (median 482 ng/mL). Previous studies have shown darunavir C trough,ss to be lower when boosted with cobicistat than with ritonavir, both in healthy volunteers (21–24% lower with cobicistat) [ 27 ] and HIV-infected patients (30% lower with cobicistat) [ 24 ]. However, the magnitude of the effect we observed (> 50% reduction in darunavir C trough,ss ) was greater than that observed in the previous studies.…”

Section: Discussionmentioning

confidence: 99%

“…The reason for this is unclear, as drug–drug interactions are not expected between darunavir and either raltegravir or dolutegravir (taken concomitantly by 4 subjects and 1 subject, respectively) [ 28 – 30 ]. Possibly as a result of these low baseline levels, our patients’ darunavir C trough,ss levels on E/C/F/TDF plus darunavir were less than 40% of those expected with darunavir /cobicistat without elvitegravir (darunavir C trough,ss approximately 1300 ng/mL) [ 24 , 25 ]. The low darunavir C trough,ss seen in our patients on E/C/F/TDF plus darunavir support an earlier retrospective study that used extrapolated levels and suggested a significant drug–drug interaction between darunavir and E/C/F/TDF [ 12 ]; however, a subsequent larger study showed darunavir C trough,ss were similar in 24 patients receiving E/C/F/TDF plus darunavir as in 32 patients receiving darunavir /cobicistat without elvitegravir [ 24 ].…”

Section: Discussionmentioning

confidence: 99%

“…Possibly as a result of these low baseline levels, our patients’ darunavir C trough,ss levels on E/C/F/TDF plus darunavir were less than 40% of those expected with darunavir /cobicistat without elvitegravir (darunavir C trough,ss approximately 1300 ng/mL) [ 24 , 25 ]. The low darunavir C trough,ss seen in our patients on E/C/F/TDF plus darunavir support an earlier retrospective study that used extrapolated levels and suggested a significant drug–drug interaction between darunavir and E/C/F/TDF [ 12 ]; however, a subsequent larger study showed darunavir C trough,ss were similar in 24 patients receiving E/C/F/TDF plus darunavir as in 32 patients receiving darunavir /cobicistat without elvitegravir [ 24 ]. Although our study is small, we were able to prospectively measure darunavir C trough,ss in the same patients before and after the switch from darunavir/ritonavir to E/C/F/TDF plus darunavir, and to demonstrate a statistically significant decrease in darunavir C trough,ss after the switch.…”

Section: Discussionmentioning

confidence: 99%

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HIV treatment simplification to elvitegravir/cobicistat/emtricitabine/tenofovir disproxil fumarate (E/C/F/TDF) plus darunavir: a pharmacokinetic study

et al. 2017

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BackgroundAs a simplification strategy for treatment-experienced HIV-infected patients who have achieved virologic suppression on a multi-drug, multi-class antiretroviral regimen, the aim of this study was to evaluate the safety, efficacy, and pharmacokinetics of once-daily elvitegravir/cobicistat/emtricitabine/tenofovir disproxil fumarate (E/C/F/TDF) with darunavir.MethodsA single arm, open-label 48-week study was conducted of regimen simplification to E/C/F/TDF plus darunavir 800 mg daily from stable therapy including two nucleoside/nucleotide reverse transcriptase inhibitors, a ritonavir-boosted protease inhibitor, and an integrase inhibitor. Participants had plasma HIV viral load consistently < 200 copies/mL for ≥ 6 months, estimated glomerular filtration rate (eGFR) ≥ 60 mL/min, and no genotypic resistance to major components of the study regimen. Plasma viral load was measured at weeks 2 and 4, then every 4 weeks throughout the study. Safety laboratory assessments were conducted at baseline and at weeks 12, 24, 36, and 48. Antiretroviral drug concentrations were measured at baseline and once ≥ 2 weeks after the regimen change.ResultsTen HIV-infected adults (8 male and 2 female; median age 50.5 years) were enrolled. All maintained virologic suppression on the new regimen for 48 weeks. One subject experienced a decrease in eGFR from 62 mL/min at baseline to 52 mL/min at week 12; study medications were continued and his eGFR remained stable (50–59 mL/min) thereafter. No subjects discontinued study medications for renal function changes or other adverse events. Darunavir trough concentration were lower on the new regimen than on darunavir/ritonavir 800/100 mg (n = 5; p < 0.05).ConclusionsDespite low darunavir trough concentrations, treatment simplification to a two-pill, once-daily regimen of E/C/F/TDF plus darunavir was safe and effective for 48 weeks among 10 selected treatment-experienced HIV-infected patients. Trial registration The study protocol was registered with ClinicalTrials.gov (NCT02199613) on July 22, 2014

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Section: Resultssupporting

confidence: 80%

Section: Resultscontrasting

confidence: 60%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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HIV treatment simplification to elvitegravir/cobicistat/emtricitabine/tenofovir disproxil fumarate (E/C/F/TDF) plus darunavir: a pharmacokinetic study

et al. 2017

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Pharmacokinetic drug interactions of integrase strand transfer inhibitors

Bednarczyk

Catanzaro

et al. 2021

Current Research in Pharmacology and Drug Discovery

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The integrase strand transfer inhibitor (INSTI)-containing regimens are currently considered as the first-line treatment of human immunodeficiency virus (HIV) infection. Although possessing a common mechanism of action to inhibit HIV integrase irreversibly to stop HIV replication cycle, the INSTIs, including raltegravir, elvitegravir, dolutegravir, and bictegravir, differ in pharmacokinetic characteristics. While raltegravir undergoes biotransformation by the UDP-glucuronosyltransferases (UGTs), elvitegravir is primarily metabolized by cytochrome P450 (CYP) 3A4 and co-formulated with cobicistat to increase its plasma exposure. The metabolism pathways of dolutegravir and bictegravir are similar, both including CYP3A and UGT1A1, and both agents are substrates to different drug transporters. Because of their differences in metabolism, INSTIs interact with other medications differently through CYP enzymes and transporters as inducers or inhibitors. These drug interactions may become an important consideration in the long-term clinical use because the life expectancy of people with HIV (PWH) approaches to that of the general population. Also, common geriatric challenges such as multimorbidity and polypharmacy have been increasingly recognized in PWH. This review provides a summary of pharmacokinetic interactions with INSTIs and future perspectives in implications of INSTI drug interactions.

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Combination Therapy with Tenofovir Disoproxil Fumarate/Emtricitabine/Elvitegravir/Cobicistat Plus Darunavir Once Daily in Antiretroviral-Naive and Treatment-Experienced Patients: A Retrospective Review

Naccarato

Yoong

Fong

et al. 2018

J Int Assoc Provid AIDS Care

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Background: : Patients with drug-resistant HIV often require complex antiretroviral regimens. However, combining fixed-dose combination tablets such as tenofovir-disoproxil-fumarate, emtricitabine, and cobicistat-boosted elvitegravir (TDF/FTC/EVG/ cobi) with darunavir (DRV) can provide a simple, once-daily (QD), 2-tablet regimen for patients with drug-resistant HIV. Primary objective was to determine the percentage of patients with HIV-1 RNA <40 copies/mL at 48 weeks. Methods: We performed a retrospective chart review of patients initiated on TDF/FTC/EVG/cobi plus DRV. Results: Among the 21 included patients, prior resistance showed a median of 2 nucleoside reverse transcriptase inhibitor mutations, 1 nonnucleoside reverse transcriptase mutation, and 1 protease inhibitor mutation. At week 48, 14 (67%) patients achieved HIV-1 RNA <40 copies/mL, 1 patient experienced viral rebound, and 6 (29%) had missing data or discontinued therapy. No patient discontinued for adverse events. Conclusion: According to this observational study, QD TDF/FTC/EVG/cobi plus DRV is considered safe, well tolerated, and generally effective in suppressing HIV drug-resistant virus.

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Pharmacokinetic interactions between cobicistat-boosted elvitegravir and darunavir in HIV-infected patients

Abstract: The results provide evidence of similar elvitegravir and darunavir C 24 concentrations when these drugs are co-administered as co-formulated elvitegravir, cobicistat, emtricitabine and tenofovir disoproxil fumarate plus 800 mg darunavir or dosed separately.

Cited by 4 publications

References 7 publications

HIV treatment simplification to elvitegravir/cobicistat/emtricitabine/tenofovir disproxil fumarate (E/C/F/TDF) plus darunavir: a pharmacokinetic study

HIV treatment simplification to elvitegravir/cobicistat/emtricitabine/tenofovir disproxil fumarate (E/C/F/TDF) plus darunavir: a pharmacokinetic study

Pharmacokinetic drug interactions of integrase strand transfer inhibitors

Combination Therapy with Tenofovir Disoproxil Fumarate/Emtricitabine/Elvitegravir/Cobicistat Plus Darunavir Once Daily in Antiretroviral-Naive and Treatment-Experienced Patients: A Retrospective Review

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