Feasibility of radiolabeled small molecule permeability as a quantitative measure of microbicide candidate toxicity

• Published in: Contraception (Stoneham) 2016-04, Vol.93 (4), p.331-336
• Main Authors: Coleman, Jenell S, Fuchs, Edward, Aung, Wutyi S, Marzinke, Mark A, Bakshi, Rahul P, Spiegel, Hans M.L, Robinson, Jennifer, Hendrix, Craig W
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Anti-Infective Agents; Cell Membrane Permeability; Cellulose - administration & dosage; Cellulose - analogs & derivatives; Cellulose - pharmacokinetics; Female; Gels; Glycerol - administration & dosage; Glycerol - pharmacokinetics; HIV; HIV Infections - prevention & control; Humans; Microbicide; Middle Aged; N-9; Nonoxynol - administration & dosage; Nonoxynol - pharmacokinetics; Obstetrics and Gynecology; Permeability; Phosphates - administration & dosage; Phosphates - pharmacokinetics; Propylene Glycols - administration & dosage; Propylene Glycols - pharmacokinetics; Prospective Studies; Spermicide; Technetium Tc 99m Pentetate - pharmacokinetics; Vagina - metabolism; Vaginal Creams, Foams, and Jellies - chemistry; Vaginal Creams, Foams, and Jellies - pharmacokinetics
• ISSN: 0010-7824; 1879-0518
• DOI: 10.1016/j.contraception.2016.01.002

Abstract Objective To determine the feasibility of using quantitative changes in vaginal permeability to small molecules as a measure of candidate microbicide toxicity. Study design Controlled, open-labeled, prospective study. Seven healthy women received a single vaginal dose of hydroxyethylcellulose gel (HEC), nonoxynol-9 (N-9) or K-Y Jelly. Each gel was radiolabeled with a small molecule (99m Tc-DTPA) followed by 12-h blood and urine collection. Pharmacokinetic (PK) parameters of99m Tc-DTPA were calculated to compare the impact of each gel on vaginal permeability. Each woman served as her own control. The Friedman test with post hoc Wilcoxon test was used to detect differences among the gels. Results Vaginal permeability of99m Tc-DTPA was highest for the N-9 radiolabel. N-9 plasma area under the concentration curve was 2.7-fold higher (p = .04), and peak concentration was threefold higher (p = .04) compared to HEC. There were no significant PK parameter differences between HEC and K-Y Jelly or between N-9 and K-Y Jelly. Cumulative dose-adjusted median (interquartile range) 12-h timed urine gamma activity was 66.70 × 10 − 4 μCi (27.90–152.00) following HEC dosing, 103.00 × 10 − 4 μCi (98.20–684.00) following N-9 gel dosing and 20.30 × 10 − 4 μCi (11.10–55.90) following K-Y gel dosing. The differences between urine HEC and K-Y Jelly (p = .047) and between N-9 and K-Y Jelly (p = .016) were statistically significant. Conclusions It is feasible to measure differences in vaginal permeability among vaginal gels using a radiolabeled small molecule, though there are permeability differences that require a nuanced understanding of gel composition to interpret the results. Implications Establishing the safety of both vehicle and active pharmaceutical ingredient is an essential task in microbicide development, to be determined as soon as possible. This study suggests that a combination of microbicide toxicity assessments, that is, cervicovaginal permeability, inspection and histopathology, may need to be studied simultaneously.