Examining the Safety, Pharmacokinetics, and Pharmacodynamics of a Rectally Administered IQP-0528 Gel for HIV Pre-Exposure Prophylaxis: A First-In-Human Study

Abstract

A lubricating microbicide gel designed for rectal and vaginal use would provide a behaviorally congruent strategy to enhance pre-exposure prophylaxis adherence and reduce HIV infection risk. In this study, we report the first-in-human evaluation of such a gel containing 1% IQP-0528, an investigational antiretroviral. Seven HIV-1-negative participants received one 10 mL rectal dose of radiolabeled 1% IQP-0528 gel. We assessed safety; IQP-0528 pharmacokinetics in plasma, and rectal and vaginal tissue; ex vivo local pharmacodynamics (PD); and colorectal distribution. The 1% gel was determined to be safe with one mild event attributed to study product and no effects on rectal tissue histology. All concentrations measured in plasma and vaginal tissue were below the limit of quantitation. Median IQP-0528 concentrations in rectal tissue exceeded the in vitro EC95 against HIV-1 (0.07 ng/mg) by 3-5 h of dosing and remained above this concentration for at least 24 h, despite a 3-log reduction in concentration over this duration of time. Rectal tissue PD-assessed by ex vivo HIV challenge-demonstrated significant p24 antigen reduction 3-5 h postdose compared with baseline (p = .05), but not 24-26 h postdose (p = .75). Single-photon emission computed tomography/computed tomography imaging revealed that product distribution was localized to the rectosigmoid. The IQP-0528 gel possesses desirable features for a topical microbicide including: local safety with no systemic absorption, delivery of locally high IQP-0528 concentrations, and significant reductions in ex vivo HIV infectivity. However, the gel is limited by its rapid clearance and inability to penetrate vaginal tissues following rectal dosing. Clinical Trial Registration number: NCT03082690.

Keywords: HIV; clinical trials; pharmacokinetics; pharmacology; pre-exposure prophylaxis; rectal microbicide.

Conflict of interest statement

R.W.B., Jr., is an officer in ImQuest (licensee of IQP-0528). R.W.B., Jr., K.W.B., and A.S.H. are all shareholders in ImQuest. E.J.F. serves on the scientific advisory board for Lubrinovation, a subsidiary of ImQuest Life Sciences, Inc. C.W.H. serves on the scientific advisory boards for Gilead, Merck, and ViiV/GSK. A.A.-K., E.S., M.A.M., R.P.B., P.H., J.B., E.D.W., H.C., and B.S.C. have nothing to disclose.

Figures

FIG. 1.

CONSORT diagram detailing movement of participants through study procedures. *This participant completed all other study procedures and was excluded only from pharmacokinetics, pharmacodynamics, and histological analysis of colorectal tissue.

FIG. 2.

Spatial distribution of IQP-0528 gel in the rectal lumen estimated via SPECT/CT imaging of 99mTc-labeled microbicide surrogate 1–2 h after rectal dosing. (A) SPECT image of radiolabel distribution in a male participant with distal and proximal labels for directional reference. (B) Data resampling (gray-shaded region) with estimated centerline in red following application of our curve-fitting algorithm. (C) Concentration–distance curve with labeled parameters estimated using noncompartmental analysis of the centerline. Distance set to 0 cm across SPECT/CT scans is consistent with anatomic location of the anal verge; the distance indicated on a flexible sigmoidoscope would be roughly 4 cm greater due to the full distance of the anal canal. Note: predicted concentration indicates relative changes in luminal signal intensity and not necessarily an absolute concentration value. CT, computed tomography; SPECT, single-photon emission computed tomography.

FIG. 3.

Median (IQR) weight-adjusted cumulative p24 measured from ex vivo explant challenge assays versus time (A), and versus IQP-0528 concentration (B) in rectal tissue. Colored points represent median (IQR, vertical error bars) of cumulative biopsy weight-adjusted p24 for each biopsy of four (baseline) or six (postdosing) replicates at a given sample time for each individual participant. Cumulative p24 values below the LLOQ were set as the median biopsy weight-adjusted LLOQ/2 (0.09–0.19 pg/mg; range represented by the gray-shaded regions). (A) Values at 0 h represent baseline measurements. Black symbol with error bars represents the overall bidimensional median and IQR, respectively, for values at each nominal time. (B) Predose IQP-0528 concentrations are imputed as 0.01 ng/mg to enable graphic comparison to postdose samples on the log scale. *Indicates p < .05 by the Wilcoxon signed rank test. IQR, interquartile range; LLOQ, lower limits of quantitation.