No Meaningful Drug Interactions with Doravirine, Lamivudine and Tenofovir Disoproxil Fumarate Coadministration

Anderson, Matt S.; Gilmartin, Jocelyn; Li, Fan; Yee, Ka Lai; Kraft, Walter K.; Triantafyllou, Ilias; Reitmann, Christina; Guo, Ying; Liu, Rachael; Iwamoto, Marian

doi:10.3851/imp3324

Cited by 8 publications

(13 citation statements)

References 19 publications

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“…To support the development of a single-tablet regimen with doravirine, two DDI trials were conducted with doravirine and two commonly used NRTIs, 3TC and TDF [31]. 3TC and tenofovir are primarily eliminated via organic cationic secretion, glomerular filtration, and active tubular secretion, pathways that are not affected by doravirine [48,49].…”

Section: Doravirine and Nucleoside Reverse Transcriptase Inhibitors (mentioning

confidence: 99%

“…Doravirine was shown to have limited potential for clinically meaningful DDIs based on data obtained from in vitro studies of drug-metabolizing enzymes and drug transporters [10,45] and clinical studies [15,20,21,[26][27][28][29][30][31]. Since doravirine is a substrate of CYP3A4 [10], the most likely route of its involvement in DDIs is via inhibition and induction of CYP3A activity by strong and moderate CYP3A inhibitors/inducers.…”

Section: Clinical Perspectivementioning

confidence: 99%

“…As doravirine will be co-administered with other antiretroviral agents, the favorable drug-interaction profile supports the combination of doravirine with the most commonly used drugs, including 3TC and TDF [31]. These results contrast with the alterations in pharmacokinetics seen with other agents.…”

Section: Clinical Perspectivementioning

confidence: 99%

“…Steady-state AUC was selected as the exposure measure from which to judge clinical relevance from a safety perspective, as this parameter is an integration of concentrations over the 24-h dosing interval in which individuals are exposed to doravirine at steady state. In phase I trials, there was no evidence that the incidence of overall AEs or specific AEs was temporally associated with doravirine T max [ 11 , 15 , 20 – 31 ], therefore suggesting that C max does not play a major role in safety or tolerability. In the phase IIb trial, there was no evidence of exposure- or dose-related toxicities across the range of 25–200 mg doses evaluated, and no meaningful association between doravirine steady-state exposure and the incidence of neuropsychiatric AEs or fasting lipid levels that would further limit the exposure of doravirine from a safety perspective [ 17 ].…”

Section: Definition Of the Bounds Of Clinical Relevancementioning

confidence: 99%

“…Consistent with the disposition of all three agents, the DDI trials demonstrated no clinically meaningful effect on doravirine, tenofovir, or 3TC pharmacokinetics (Tables 2 and 3 , Figs. 3 and 4 ), supporting co-administration without the need for dose adjustment [ 31 ] and the co-formulation of these agents into a single-tablet regimen.…”

Section: In Vivo Ddi Assessmentmentioning

confidence: 99%

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Clinical Pharmacokinetics of the Novel HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitor Doravirine: An Assessment of the Effect of Patient Characteristics and Drug–Drug Interactions

et al. 2020

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Doravirine (MK-1439) is a novel non-nucleoside reverse transcriptase inhibitor indicated for the combination treatment of human immunodeficiency virus type-1 (HIV-1) infection. The recommended dose is 100 mg once daily. This review summarizes the pharmacokinetics of doravirine, the influence of intrinsic factors, and its drug-drug interaction (DDI) profile. Following oral administration, doravirine is rapidly absorbed (median time to maximum plasma concentration, 1-4 h) and undergoes cytochrome P450 (CYP)3A-mediated oxidative metabolism. Steady-state geometric means for AUC 0-24 , C 24 , and C max in individuals with HIV-1 following administration of doravirine 100 mg once daily are 37.8 μM•h, 930 nM, and 2260 nM, respectively. Age, gender, severe renal impairment, and moderate hepatic impairment have no clinically meaningful effect on doravirine pharmacokinetics, and there is limited potential for DDIs. No dose adjustment is necessary when doravirine is co-administered with strong CYP3A inhibitors. However, doravirine is contraindicated with strong CYP3A inducers (e.g., rifampin), and dose adjustment of doravirine is recommended for co-administration with the moderate CYP3A inducer, rifabutin. Included in this review are clinical trial data from phase I pharmacokinetic trials, including DDI trials and trials in participants with renal and hepatic disease but without HIV-1 infection (N = 326), as well as phase I, II, and III safety and efficacy trials in participants living with HIV-1 (N = 991). Based on these data, the pharmacokinetic profile of doravirine supports its use in diverse populations living with HIV-1 and allows co-administration with various antiretroviral agents and treatments for commonly occurring co-morbidities.

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Section: Doravirine and Nucleoside Reverse Transcriptase Inhibitors (mentioning

confidence: 99%

Section: Clinical Perspectivementioning

confidence: 99%

Section: Clinical Perspectivementioning

confidence: 99%

Section: Definition Of the Bounds Of Clinical Relevancementioning

confidence: 99%

Section: In Vivo Ddi Assessmentmentioning

confidence: 99%

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Clinical Pharmacokinetics of the Novel HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitor Doravirine: An Assessment of the Effect of Patient Characteristics and Drug–Drug Interactions

et al. 2020

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Lack of a Clinically Meaningful Drug Interaction Between the HIV‐1 Antiretroviral Agents Islatravir, Dolutegravir, and Tenofovir Disoproxil Fumarate

Rudd

Zhang

Fillgrove

et al. 2021

Clinical Pharm in Drug Dev

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Islatravir, an investigational nucleoside reverse transcriptase translocation inhibitor, is in clinical development for the treatment and prevention of HIV-1 infection. Because islatravir may be coadministered with other antiretroviral agents, assessment of potential drug-drug interactions are warranted. This phase 1, open-label, fixed-sequence, 2-period trial in adults without HIV (N = 12) assessed the safety and pharmacokinetic interactions of islatravir administered with dolutegravir and tenofovir disoproxil fumarate (TDF). In period 1, participants received a single oral dose of islatravir (20 mg). In period 2, participants received oral doses of dolutegravir (50 mg) and TDF (300 mg) once daily on days 1 through 11, with a single oral dose of islatravir (20 mg) coadministered on day 8. There were no clinically significant changes in islatravir, dolutegravir, or TDF pharmacokinetics following coadministration. Islatravir was generally well tolerated when administered alone or in combination with dolutegravir and TDF. Coadministration of islatravir, dolutegravir, and TDF is supported, with no clinically meaningful effect on pharmacokinetics, safety, or tolerability in participants without HIV.

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Approved HIV reverse transcriptase inhibitors in the past decade

Wang

Clercq

2022

Acta Pharmaceutica Sinica B

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No Meaningful Drug Interactions with Doravirine, Lamivudine and Tenofovir Disoproxil Fumarate Coadministration

Abstract: No meaningful drug interactions with doravirine, lamivudine and tenofovir disoproxil fumarate co-administration

Cited by 8 publications

References 19 publications

Clinical Pharmacokinetics of the Novel HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitor Doravirine: An Assessment of the Effect of Patient Characteristics and Drug–Drug Interactions

Clinical Pharmacokinetics of the Novel HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitor Doravirine: An Assessment of the Effect of Patient Characteristics and Drug–Drug Interactions

Lack of a Clinically Meaningful Drug Interaction Between the HIV‐1 Antiretroviral Agents Islatravir, Dolutegravir, and Tenofovir Disoproxil Fumarate

Approved HIV reverse transcriptase inhibitors in the past decade

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