BACKGROUND: Islatravir (ISL) is a deoxyadenosine analog reverse transcriptase inhibitor being studied for HIV-1 treatment. Because people living with HIV often have comorbidities such as dyslipidemia and/or type 2 diabetes mellitus, we investigated the effects of ISL coadministration on atorvastatin (ATV) and metformin (MET) pharmacokinetics (PK). Based on preclinical drug interaction data, no interaction was expected.
METHODS: MK-8591-040 was a 2-period fixed-sequence, open-label, drug-drug interaction study of ISL on ATV and MET PK in healthy adult participants. In Period 1, participants were coadministered a single dose of ATV (20 mg) + MET (1000 mg). Following a 5-day minimum washout period, participants received ATV (20 mg) + MET (1000 mg) coadministered with a single oral dose of ISL (60 mg) in Period 2. Blood samples were collected up to 72 hours postdose in each period to characterize the plasma PK of ATV and MET. PK parameters assessed included area under the concentration-time curve from 0 hours to infinite time (AUC_0-8), maximal concentration (C_max), and trough concentration at 24 hours (C₂₄). Safety and tolerability were monitored throughout the study.
RESULTS: Fourteen participants (n = 10 male, n = 4 female) aged 22-55 years were enrolled and completed the study. Atorvastatin and MET plasma PK profiles were generally similar after administration of ATV + MET with or without ISL. The geometric least-squares mean ratios (GMRs; 90% confidence interval [CI]; ATV + MET + ISL / ATV + MET) for ATV and MET PK parameters are summarized in the Table. Coadministration of a single oral dose of ISL with ATV + MET was generally well tolerated.

Table. Summary Statistics of ATV and MET Plasma PK Parameters (n = 14)
PK Parameter	ATV	MET
	ATV + MET + ISL / ATV + MET	ATV + MET + ISL / ATV + MET
	GMR (90% CI)	GMR (90% CI)
AUC0-8	1.04 (1.00, 1.10)	0.87 (0.79, 0.96)
Cmax	0.86 (0.72, 1.04)	0.80 (0.70, 0.91)
C24	1.01 (0.93, 1.10)	1.13 (1.00, 1.26)

CONCLUSIONS: Coadministration of ATV + MET with a single oral dose of ISL did not have a clinically meaningful effect on the PK profiles of either ATV or MET.

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