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No Interactions Between HIV-1 Maturation Inhibitor and TAF/FTC
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International Workshop on Clinical Pharmacology of HIV, Hepatitis, and Other Antiviral Drugs Virtual Meeting, September 28-30, 2020
By Mark Mascolini for NATAP and Virology Education
An open-label study in healthy volunteers detected no clinically relevant drug-drug interactions between the HIV-1 maturation inhibitor GSK3640254 (GSK'254) and tenofovir alafenamide (TAF)/emtricitabine (FTC) [1]. The 16-person trial suggested that GSK'254 taken with food may be combined with TAF/FTC in people with HIV infection. (Two other studies presented at the Virology Education workshop detected no significant interactions between GSK'254 and the integrase inhibitor dolutegravir [2] or the oral contraceptive ethinyl estradiol/levonorgestrel [3].)
By disrupting the last step of HIV-1 protease cleavage, GSK'254 therapy yields immature, noninfectious virus and thus inhibits HIV replication. Two phase 1 trials of GSK'254 found the maturation inhibitor generally safe in healthy volunteers [4]. A phase 2 trial of GSK'254 in previously untreated adults with HIV is underway [5].
The fixed-sequence multiple-dose TAF/FTC study involved healthy volunteers 18 to 55 years old with a body mass index from 18.5 to 31 kg/m2, putting them in the normal weight to slightly obese range. On days 1 through 14 participants took TAF/FTC at a dose of 25/200 mg once daily. On days 15 through 21 they continued TAF/FTC and added GSK'254 at a dose of 200 mg once daily. Participants took all doses with a moderate-fat meal, and researchers collected serial blood samples up to 24 hours after the final dose in each treatment period. The investigators used linear mixed effects models to determine geometric mean ratios (GMR) and 90% confidence intervals (CI) for the three antiretrovirals.
Sixteen healthy volunteers, all men, received study drugs and 15 finished both treatment periods. One person withdrew because of treatment-related grade 1 urticaria during dosing on the day GSK'254 was added to TAF/FTC. Nine people (56%) had 22 adverse events. Only 1 adverse event was worse than grade 1: grade 2 nausea and vomiting judged unrelated to study drugs. Two people had 3 adverse events considered related to study drugs: nausea, somnolence, and the just-mentioned case of urticaria. The researchers saw no clinically meaningful trends in adverse events, lab values, or electrocardiograms.
When combined with TAF/FTC, pharmacokinetics of GSK'254 were similar to those seen in prior studies of the maturation inhibitor.
When participants added GSK'254 to TAF/FTC, TAF area under the concentration-time curve (AUC) fell 11% and maximum concentration (Cmax) dropped 13%: GMR (90% CI) 0.886 (0.753 to 1.043) for AUC and 0.874 (0.680 to 1.125) for Cmax. These modestly lower TAF levels were similar to those seen when TAF is given with standard-dose efavirenz and are not judged clinically meaningful.
Levels of tenofovir (TFV, the active form of TAF) and FTC were similar when these antiretrovirals were given alone and when given with GSK'254. For TFV with GSK'254, GMR (and 90% CI) were 1.036 (1.008 to 1.066) for AUC and 1.018 (0.972 to 1.066) for Cmax. For FTC with GSK'254, GMR (and 90% CI) were 0.963 (0.930 to 0.997) for AUC and 0.941 (0.844 to 1.049) for Cmax.
References
1. Pene Dumitrescu T, Joshi S, Xu J, et al. Open-label, drug-drug interaction study between HIV-1 maturation inhibitor (MI) GSK3640254 and tenofovir alafenamide (TAF)/emtricitabine (FTC) in healthy participants. International Workshop on Clinical Pharmacology of HIV, Hepatitis, and Other Antiviral Drugs Virtual Meeting, September 28-30, 2020. Abstract 13C.
2. Pene Dumitrescu T, Joshi S, Xu J, et al. Lack of a pharmacokinetic (PK) interaction between HIV-1 maturation inhibitor (MI) GSK3640254 and dolutegravir. International Workshop on Clinical Pharmacology of HIV, Hepatitis, and Other Antiviral Drugs Virtual Meeting, September 28-30, 2020. Abstract 13B.
3. Pene Dumitrescu T, Joshi S, Xu J, et al. Lack of a pharmacokinetic (PK) interaction between HIV-1 maturation inhibitor (MI) GSK3640254 (GSK'254) and oral contraceptive (OC) ethinyl estradiol (EE)/levonorgestrel PBPK models. international Workshop on Clinical Pharmacology of HIV, Hepatitis, and Other Antiviral Drugs Virtual Meeting, September 28-30, 2020. Abstract 13A.
4. Mascolini M. Phase 1 results show safety and once-daily potential of new HIV maturation inhibitor. 20th International Workshop on Clinical Pharmacology of HIV, Hepatitis & Other Antiviral Drugs. May 14-16, 2019. Noordwijk, the Netherlands. Abstract 4. https://www.natap.org/2019/Pharm/Pharm_01.htm
5. ClinicalTrials.gov. A proof of concept study of GSK3640254 in human immunodeficiency virus-1 (HIV-1) infected treatment-naive adults. ClinicalTrials.gov identifier NCT03784079. https://clinicaltrials.gov/ct2/show/NCT03784079
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