A Phase 1 Trial to Evaluate the Relationship Between Fluoride Intake and Urinary Fluoride Excretion in Healthy Participants

Abstract

Chronic overexposure to fluoride can have deleterious effects in the musculoskeletal system. Some fluorine‐containing therapeutics, such as voriconazole, release fluoride through metabolism. Therefore, drug‐related fluoride exposure should be assessed for novel therapeutics suspected of releasing fluoride through metabolism. Two trials were conducted to identify the optimal method of assessing drug‐related fluoride exposure. In trial 1, designed to assess reproducibility of fluoride pharmacokinetics in urine and plasma, 14 participants were administered a fluoride‐restricted diet and once‐daily doses of sodium fluoride (2.2 mg [1 mg of fluoride] on days 1 and 2; and 13.2 mg of sodium fluoride [6 mg of fluoride] on days 3 and 4). In trial 2, designed to confirm the selected method for fluoride detection, 12 participants were administered a fluoride‐restricted diet and randomized to receive voriconazole (400 mg twice, 12 hours apart, on day 1 [131 mg/d of fluoride maximum], then 3 doses of 200 mg every 12 hours [65.3 mg/d of fluoride maximum]) or placebo. Plasma fluoride concentrations and urinary fluoride excretion were assessed in each trial. Assessment of plasma fluoride concentrations in trial 1 was limited by 301 of 854 samples (35.2%) below the lower limit of quantitation. Urine fluoride excretion was readily measured and demonstrated a decrease from baseline during the fluoride‐restricted diet phase, as well as dose‐proportional increases with fluoride administration. In trial 2, increases in urine fluoride were successfully observed in participants administered voriconazole. In conclusion, fluoride exposure was optimally assessed by urinary fluoride excretion in conjunction with strict dietary fluoride restrictions, as measurements were consistent and reproducible.

Fluoride Pharmacokinetics in Urine and Plasma Following Multiple Doses of MK‐8507, an Investigational, Oral, Once‐Weekly Nonnucleoside Reverse Transcriptase Inhibitor

“…These findings are consistent with a corresponding trial that indicated that urine sampling offers a more consistent and accurate method of assessing fluoride exposure in participants administered a fluoride‐restricted diet relative to plasma measurement. 9 Data from the current trial demonstrated readily detectable fluoride levels in urine samples, which increased in a dose‐dependent manner.…”

“…To decrease variability due to dietary fluoride intake, the trial incorporated a fluoride restricted diet run‐in phase of 5 days, which was determined to be sufficient based on previously collected data. 9 However, urine fluoride excretion continued to decline slightly in some participants receiving placebo in period 2 (Table S1 ), indicating the value of comparing outcomes with a within‐group baseline and a parallel group receiving placebo in this trial. Fluorosis is not known to be an adverse event that is commonly observed in PLWH, but the risk of bone‐related adverse events needs to be considered when investigating new antiretroviral therapies.…”

“…Using data from an earlier pilot trial of urinary fluoride excretion PK, 9 an increase in fluoride intake of 1.89 mg/d (the difference between the maximum recommended intake of 4.8 mg and the mean US population intake of 2.91 mg) is expected to result in a mean increase of 57 μmol in urinary fluoride Ae 0‐24 (averaged over a 7‐day dosing interval). Therefore, an increase from baseline of 57 μmol in urinary fluoride Ae 0‐24 (averaged over 7 days and corrected for placebo) was defined as the upper limit for acceptable change in fluoride excretion at steady state for participants administered MK‐8507.…”

“…To assess steady‐state urine fluoride, individual urine fluoride Ae 0‐24 changes from baseline were evaluated in a linear mixed‐effects model. 9 The 95% confidence intervals (CIs) for the least‐squares means (LSM) by treatment were constructed. Similarly, the LSM differences (each of the 2 MK‐8507 dose levels vs placebo) and 90%CIs from this model were constructed.…”

“…At the design stage, a between‐subject standard deviation (SD) estimate of 7 (at low dose, or 27 at high dose) for Ae 0‐24 change from baseline was obtained using data from an earlier pilot trial of urinary fluoride excretion PK. 9 Assuming that the true between‐subject SD for change from baseline following multiple dosing was similar to this value, then with 6 subjects receiving MK‐8507 per panel and 6 subjects receiving placebo (pooled across 2 MK panels), a type I error rate of 0.05, and a 1‐sided test, there was 80% probability that the upper limit of the 2‐sided 90%CI for the true mean difference (MK‐8507–placebo) in change from baseline at period 2, week 3 would be ≤57 μmol, if the true mean difference was ≤49 (or ≤25 if SD = 27) μmol.…”