Lack of pharmacokinetic interaction between the HIV‐1 maturation inhibitor GSK3640254 and combination oral contraceptives in healthy women

Dumitrescu, Teodora Pene; Greene, Thomas; Joshi, Samit R; Xu, Jiaming; Johnson, Mark; Halliday, Fiona; Butcher, Laurie; Zimmerman, Eric I.; Webster, Lindsey O.; Pham, Theresa T.; Lataillade, Max; Min, Sherene

doi:10.1111/bcp.15051

Cited by 6 publications

(18 citation statements)

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“…As a large proportion of PLWH are becoming older and have increased use of concomitant medications, 14–16 it is important to assess potential DDIs between GSK'254 and commonly administered non‐antiretroviral drugs. A lack of clinically significant interaction between GSK'254 and various drugs (DTG, FTC/TAF and combination oral contraceptives) has already been demonstrated in phase I studies 9,11,12 . In this phase I study, we evaluated the PK, safety and tolerability of GSK'254 administered with a cocktail containing multiple CYP enzyme and drug transporter probe substrates.…”

Section: Discussionmentioning

confidence: 99%

Open‐label, drug–drug interaction study between the HIV‐1 maturation inhibitor GSK3640254 and a metabolic probe cocktail in healthy participants

Zhang

Johnson²,

Joshi³

et al. 2023

Brit J Clinical Pharma

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Aims GSK3640254 (GSK'254) is an HIV‐1 maturation inhibitor with pharmacokinetics (PK) supporting once‐daily dosing. GSK'254 will be co‐administered with cytochrome P450 enzyme substrates and drug transporters, including other antiretrovirals, in people living with HIV‐1 (PLWH). Methods In this open‐label study, healthy participants received a single dose of a cocktail of eight cytochrome P450 and transporter probe substrates on Day 1, followed by a 10‐day washout before receiving GSK'254 200 mg once daily from Days 11 to 20 and a single dose of cocktail + GSK'254 200 mg on Day 21. Geometric least‐squares mean ratios and 90% confidence intervals were obtained using linear mixed‐effects models. Adverse events (AEs) were monitored. Results Of 20 participants enrolled, 19 completed the study. Plasma concentrations of all cocktail substrates were generally similar with or without GSK'254 co‐administration. All 90% confidence intervals around geometric least‐squares mean ratios for cocktail substrate PK parameters indicated no to weak interactions. Steady‐state plasma GSK'254 concentrations were achieved by Day 17 and maintained through Day 21. Nine participants (45%) reported 17 AEs; most (88%) were grade 1. Two grade 2 treatment‐related AEs (maculopapular rash [leading to withdrawal] and papular rash) were reported during GSK'254 administration alone. Conclusions Co‐administration of GSK'254 with a metabolic probe cocktail in healthy participants indicated very low risk of clinically relevant effect on PK of any substrates or associated metabolites. No new safety/tolerability concerns were identified. These results support ongoing phase IIb and planned phase III studies of GSK'254 in people living with HIV‐1.

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Section: Discussionmentioning

confidence: 99%

Open‐label, drug–drug interaction study between the HIV‐1 maturation inhibitor GSK3640254 and a metabolic probe cocktail in healthy participants

Zhang

Johnson²,

Joshi³

et al. 2023

Brit J Clinical Pharma

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“…GSK3640254 is an inhibitor of uridine diphosphate glucuronosyltransferase 1A1 and organic anion‐transporting polypeptide 1B3 in vitro 7,8 . Drug interaction studies have demonstrated no meaningful effect of GSK3640254 on the pharmacokinetics of dolutegravir, tenofovir alafenamide, or combined oral contraceptives 7–9 …”

Section: Figurementioning

confidence: 99%

“…7,8 Drug interaction studies have demonstrated no meaningful effect of GSK3640254 on the pharmacokinetics of dolutegravir, tenofovir alafenamide, or combined oral contraceptives. [7][8][9] In both phase I and phase IIa proof-of-concept studies, GSK3640254 was formulated as a mesylate salt in a capsule. 5,6 In planned phase IIb studies, the proposed formulation for GSK3640254 is a mesylate salt in a tablet.…”

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Relative Bioavailability and Food Effect of GSK3640254 Tablet and Capsule Formulations in Healthy Participants

Johnson¹,

Dumitrescu

Joshi³

et al. 2022

Clinical Pharm in Drug Dev

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GSK3640254 is a next-generation maturation inhibitor with demonstrated potency across HIV-1 subtypes and a high barrier to emergent resistance. This phase I, 2-part, randomized, open-label study (ClinicalTrials.gov identifier, NCT04263142) in healthy participants assessed the relative bioavailability of a single dose of GSK3640254 200 mg in tablet and capsule formulations (part 1) and the effect of food on the pharmacokinetic profile of the tablet formulation (part 2). Overall, 39 participants were randomized to treatment (part 1, n = 18; part 2, n = 21). All participants in part 1 completed the study; 2 participants in part 2 withdrew before study completion (adverse event, n = 1; physician decision, n = 1). In part 1, plasma exposures of the GSK3640254 tablet formulation were not meaningfully different from those of the capsule formulation when administered in the presence of a moderate-fat meal. In part 2, GSK3640254 plasma exposures increased by ≈3to 4-fold under high-and moderate-fat conditions, respectively, compared with fasted conditions. No major safety or tolerability findings were observed. The highest incidence of adverse events (24%) was reported under high-fat conditions. Taken together, these data support the use of the tablet formulation coadministered with food in the clinical development of GSK3640254 for treatment of HIV-1.

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“…Previous phase I clinical studies of GSK'254 have demonstrated pharmacokinetics (PK) supportive of once‐daily (QD) therapy and a desirable drug–drug interaction profile, with no relevant interactions with common antiretroviral agents, including dolutegravir and tenofovir alafenamide/emtricitabine, or common drug‐metabolizing enzymes (such as cytochrome P450 enzymes and organic anion transporting polypeptide transporters) 3,5–7 . Under short‐term administration, GSK'254 was generally well tolerated in healthy participants and people living with HIV‐1 1–3,5,6,8 . Moreover, QD administration of GSK'254 200 mg in treatment‐naive people living with HIV‐1 demonstrated a mean reduction from baseline in HIV‐1 RNA of 2 log 10 copies/mL in a phase IIa, proof‐of‐concept study 8 …”

Section: Introductionmentioning

confidence: 99%

Effects of the HIV‐1 maturation inhibitor GSK3640254 on QT interval in healthy participants

Zhang,

Bush,

Yazdani

et al. 2023

Pharmacology Res & Perspec

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GSK3640254 (GSK'254) is a novel HIV‐1 maturation inhibitor with pharmacokinetics supporting once‐daily (QD) therapy for HIV‐1 treatment. This thorough QT/corrected QT (QTc) study evaluated the effect of GSK'254 on cardiac repolarization. In this two‐part, randomized study, healthy participants received GSK'254 or placebo QD for 7 days (part 1) to determine safety and pharmacokinetics of a 500‐mg supratherapeutic dose. Four sequential treatment periods composed the main QTc study (part 2): GSK'254 100 mg, GSK'254 500 mg, placebo QD for 7 days, or placebo QD for 6 days with a 400‐mg moxifloxacin dose on Day 7 (all with a moderate‐fat meal). Concentration‐QTc analyses modeled the relationship between GSK'254 plasma concentrations and placebo‐adjusted change from baseline in QT interval corrected with Fridericia's formula (ΔΔQTcF). Of 50 participants enrolled, 48 completed the study (part 1, 8/8; part 2, 40/42). Least‐squares (LS) mean change from baseline in QTcF for GSK'254 100 mg followed the placebo pattern across time points (maximum LS mean ΔΔQTcF, 1.7 ms); the upper bound of the 90% CI remained <10 ms. Maximum LS mean ΔΔQTcF for GSK'254 500 mg exceeded the 10‐ms threshold: 10.6 ms (90% CI 7.75–13.38). Neither GSK'254 dose had clinically relevant effects on heart rate or cardiac conduction. By concentration‐QTc analysis, no effect on ΔΔQTcF >10 ms is expected up to GSK'254 concentrations of ~3070 ng mL−1. No clinically relevant effects on cardiac parameters were seen in healthy participants with GSK'254 at the 100‐mg dose.

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Lack of pharmacokinetic interaction between the HIV‐1 maturation inhibitor GSK3640254 and combination oral contraceptives in healthy women

Cited by 6 publications

References 20 publications

Open‐label, drug–drug interaction study between the HIV‐1 maturation inhibitor GSK3640254 and a metabolic probe cocktail in healthy participants

Open‐label, drug–drug interaction study between the HIV‐1 maturation inhibitor GSK3640254 and a metabolic probe cocktail in healthy participants

Relative Bioavailability and Food Effect of GSK3640254 Tablet and Capsule Formulations in Healthy Participants

Effects of the HIV‐1 maturation inhibitor GSK3640254 on QT interval in healthy participants

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