Dose-response relationship between tissue concentrations of UC781 and explant infectibility with HIV type 1 in the RMP-01 rectal safety study.
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).
Alpha StatConsult LLC, Damascus, Maryland 20872, USA. nicola@alphastatconsult.com
Nicola
N
Richardson-Harman
Christine
C
Mauck
Ian
I
McGowan
Peter
P
Anton
D000285:Administration, Rectal; D000704:Analysis of Variance; D000813:Anilides / Q000494:pharmacology*; D000890:Anti-Infective Agents / Q000494:pharmacology*; D000891:Anti-Infective Agents, Local / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004724:Endoscopy; D005260:Female; D005663:Furans / Q000494:pharmacology*; D005782:Gels; D015658:HIV Infections / Q000188:drug therapy* / Q000473:pathology; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D016015:Logistic Models; D008297:Male; D012007:Rectum / Q000187:drug effects* / Q000473:pathology* / Q000821:virology; D015203:Reproducibility of Results; D012189:Retrospective Studies; D013854:Thioamides; D013997:Time Factors; D046509:Tissue Culture Techniques
D000813:Anilides; D000890:Anti-Infective Agents; D000891:Anti-Infective Agents, Local; D005663:Furans; D005782:Gels; D013854:Thioamides; C100668:UC-781