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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&lt;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).

Dose-Response Relationship Between Tissue Concentrations of UC781 and Explant Infectibility with HIV Type 1 in the RMP-01 Rectal Safety Study