Dose-response relationship between tissue concentrations of UC781 and explant infectibility with HIV type 1 in the RMP-01 rectal safety study

Abstract

A retrospective correlational analysis of UC781 (0.1, 0.25%) gel pharmacokinetics (PK) and pharmacodynamics (PD) was undertaken using data generated in the RMP-01/MTN-006 Phase 1 rectal safety study of the UC781 microbicide gel, where strong UC781-related inhibition of ex vivo biopsy infectibility (PD) was seen. Precision analysis, linear and logistical correlational methods were applied to model the dose-response relationship. Four analyses of explant virus growth were compared to determine tissue concentrations of UC781 needed to maintain ex vivo virus growth below a range of cut-points. SOFT, a cross-sectional index from a growth curve, and cumulative p24 endpoints were the most precise measurement of ex vivo HIV infection and significantly (p<0.01) correlated with rectal tissue UC781 concentrations. Cut-points reflecting infectibility, ranging from 200 to 1300 p24 pg/ml, provided EC(50,90,95) tissue levels of UC781. A cut-point of 200 p24 pg/ml provided an EC(50) of 2148 UC781 ng/g tissue; a cut-point of 1100 p24 predicted a lower EC(50) of 101 UC781 ng/g. A 30- to 170-fold EC(90):EC(50) ratio was found. Higher p24 cut-points provided more predictive models. Tissue UC781 levels and ex vivo infectibility data were correlated to model dose-response drug efficacy in this small Phase 1 trial. Logistic regression analyses showed EC(50,90,95) values were inversely related to p24 cut-point levels, providing clinically relevant insights into tissue drug concentration necessary for ex vivo suppression of HIV tissue infectibility. This first PK-PD assessment of topical microbicides demonstrates feasibility in Phase 1 trials, enabling comparisons of microbicide efficacy (i.e., EC(50,90,95)) between formulations, compartments, and application methods. (ClinicalTrials.gov; #NCT00408538).

Trial registration: ClinicalTrials.gov NCT00408538 NCT00984971.

Figures

FIG. 1.

UC781 rectal tissue drug concentrations. Visit 3 (a), after single application of rectal microbicide gel and Visit 5 (b), after seven daily doses of rectal microbicide gel. The mean is displayed as a horizontal solid line. The horizontal dashed line indicates the lower limit of quantification for this assay (5 ng/g). Embedded tables show the probability values for the main effects of treatment (placebo, 0.1% and 0.25% UC781) and biopsy location (10, 30 cm) in the headers and the Tukey pairwise comparisons between each drug treated groups (0.1 and 0.25% UC781) and the placebo (treatment vs. placebo) and the effect of location (treatment at 10 cm vs. 30 cm) on log transformed UC781 tissue drug concentrations in the table. The treatment×location interaction for visits 3 and 5 are given as footnotes below each embedded table.

FIG. 2.

Linear relationships between UC781 tissue concentrations and p24 biopsy infection yields. Significant correlations between UC781 tissue concentrations and degree of virus suppression for (a) AUC, (b) CUM, (c) SLOPE, and (d) SOFT. All subjects' samples exposed to 104 TCID50 HIVBaL were included. Data were pooled for the 10 and 30 cm biopsy locations for tissue biopsy results >5 ng/g (LOQ). Embedded table reports on the intercept, slope, probability of 0 slope (“Probability”), and the correlation coefficient (r2) for the linear least squares fit.

FIG. 3.

Logistic regression results where rectal tissue (PK) UC781 concentrations predicted infected/noninfected (PD) status of HIV-1-infected rectal tissue explants. The data presented include only those rectal biopsies infected with 104 TCID50 HIV and with detectable UC781 levels. The infected/noninfected categorization was based on p24 (pg/ml) levels at the soft endpoint (SOFT), where an explant assay with a p24 SOFT greater than or equal to the p24 cut-point was classified as “infected” and an explant assay with a p24 SOFT lower than the p24 cut-off was “noninfected.” A range of p24 cut-point levels was tested (200–1300 p24 pg/ml). (a) Shows that for each cut-point p24 level there is a calculated EC50 (dashed line), which is the concentration of UC781 predicted to result in a 50% HIV inhibition (noninfected) rate, and a calculated EC90 (gray line) and EC95 (black line), which are the concentrations of UC781 predicted to result in a 90% and 95% explant HIV inhibition (noninfected) rate. (b) Identifies the area under the receiver operator characteristic (ROC) curve (“C”: dotted line). C is a measure of the goodness of fit of each logistic regression model where a value of 1 indicates a perfectly predicting logistic curve (i.e., zero false positives and negatives).

FIG. 4.

Nonlinear mixed effect model of UC781 gel concentration and rectal tissue (PK) UC781 concentrations at V3 (10 cm location). Open circles represent UC781 tissue concentrations and the solid line represents a nonlinear mixed effect model [y=max • x/(m+x)+s] where y=tissue UC781 concentration, x=gel UC781 concentration, max=maximum drug tissue concentration, m=gel concentration necessary to reach the half maximal drug tissue concentration, and s=subject error term,±95% confidence interval (dashed lines).