Fluoride Pharmacokinetics in Urine and Plasma Following Multiple Doses of MK-8507, an Investigational, Oral, Once-Weekly Non-Nucleoside Reverse Transcriptase Inhibitor.

MK-8507 is an investigational human immunodeficiency virus-1 (HIV-1) non-nucleoside reverse transcriptase inhibitor being developed for the treatment of HIV-1 infection. MK-8507 contains two trifluoromethyl groups that may result in fluoride release through metabolism, but the extent of MK-8507-related fluoride release in humans has yet to be determined. This double-blind, placebo-controlled, 2-period, parallel-group, multiple-dose trial in healthy participants without HIV-1 administered a fluoride-restricted diet and once-weekly doses of MK-8507 aimed to estimate the relationship between MK-8507 dose and fluoride exposure. Fifteen adult male and 3 adult female (of non-childbearing potential) participants were randomized to receive MK-8507 200 mg (n = 6), MK-8507 800 mg (n = 6), or placebo (n = 6). Change from baseline in mean daily fluoride excretion averaged over 7 days following the administration of MK-8507 200 mg resulted in a net mean increase of 19.8 μmol (90% confidence interval [CI]: 12.2, 27.4) relative to placebo and did not exceed 57 μmol, a threshold related to the mean difference between the daily reference dose set by the US Environmental Protection Agency (EPA) and the average dietary fluoride intake in the United States. However, daily urinary fluoride excretion exceeded the threshold following administration of 800 mg MK-8507 (75.1 μmol [90% CI: 67.5, 82.7]). Assuming a linear relationship between MK-8507 dose and estimated mean daily fluoride released at steady-state, data interpolation suggests that the US EPA reference dose for fluoride would not be exceeded in most patients when administering MK-8507 at doses currently under clinical investigation (≤400 mg once-weekly). This article is protected by copyright. All rights reserved.