Maraviroc Pharmacokinetics in Blood Plasma, Genital Tract Fluid and Tissue in Healthy Female Volunteers Julie B. Dumond, Kristine B. Patterson, Allison Pecha, Rebecca E. Werner, Emma Andrews,* Bharat Damle,* Randy Tressler,* Jochen Worsley,* Kim A. Boggess, Angela D.M. Kashuba University of North Carolina, Chapel Hill, NC, USA *Pfizer, USA and UK
Background • There is large variability in ARV exposure in the female genital tract. (Dumond et al. AIDS, 2007; Min et al. JAIDS, 2004) • Discordance in exposure between the genital tract and blood plasma may lead to… -Resistant variants in the genital tract -Reseeding systemic compartment with resistant virus -On-going genital shedding of HIV-1 and secondary transmission • The concentration of ARV achieved in the genital tract is potentially important in developing strategies to prevent the sexual transmission of HIV. 2 Dumond J, et al. 15th CROI 2008 ; Presentation 135LB Dumond J, et al. 15th CROI 2008 ; Presentation 135LB
Maraviroc • CCR5 antagonist • Novel mechanism prevents cellular entry of R5 HIV-1 • The extent to which maraviroc penetrates into the female genital tract is not known 3 Dumond J, et al. 15th CROI 2008 ; Presentation 135LB
Objectives • Primary – To describe first dose (FD) and steady state (SS) PK of maraviroc (MVC) in cervicovaginal fluid (CVF) in HIV-negative women • Secondary – To evaluate SS vaginal tissue (VT) concentrations of MVC – To assess the protein binding of MVC in CVF – To describe the terminal elimination of MVC in CVF and BP 4 Dumond J, et al. 15th CROI 2008 ; Presentation 135LB
Methods • Healthy HIV-negative women – Comprehensive sexually transmitted infection evaluation • Single site, open-label trial • Days 1-6: MVC 300 mg BID Day 7: MVC 300 mg single dose • First dose administered within 7-10 days following onset of menses 5 Dumond J, et al. 15th CROI 2008 ; Presentation 135LB
Pharmacokinetic Sampling Blood Plasma (BP) Cervicovaginal Fluid (CVF) Vaginal Tissue (VT) 0 6 8 12 D2 D3 D4 D5 D6 0 6 8 12 24 48 72 First Dose Trough Steady State “Tail” 6 Dumond J, et al. 15th CROI 2008 ; Presentation 135LB
Analyses • Sample Analyses: – BP, CVF, and VT analyzed by validated methods using LC/MS/MS* – Quantitation range for maraviroc assay (LLQ-ULQ) • Plasma and CVF: 0.5 - 500 ng/mL • VT: 20 - 20,000 ng/g – Protein Binding determined by equilibrium dialysis on pooled samples • Data Analyses: – Non-compartmental PK analysis – Summary statistics *LC/MS/MS: Liquid chromatography with tandem mass spectrometry 7 Dumond J, et al. 15th CROI 2008 ; Presentation 135LB
Subject Demographics (mean, range) N = 12 Age (yrs) 26.9 (20-40) 4 (33%) African American 6 (50%) Caucasian Race/Ethnicity 1 (8%) Asian 1 (8%) Other Weight (kg) 63.0 (54.3-79.8) BMI (kg/m 2 ) 22.2 (18.7-25.3) * MVC-related AEs: nausea, fatigue and headache 8 Dumond J, et al. 15th CROI 2008 ; Presentation 135LB
Pharmacokinetic Results First Dose AUC CVF:BP mean (SD) 10000 10 Plasma 9 CVF Maraviroc Concentration (ng/mL) 8 1000 Maraviroc CVF:BP AUC Ratio 7 6 100 5 4 3 10 2 1 protein-free IC90 = 0.5 ng/mL 1 0 0 2 4 6 8 10 12 N=12 First Dose Time (hr) AUC BP : 1,991 (518) ng*hr/mL CVF:BP AUC Ratio mean = 2.6 AUC CVF : 4,655 (3,661) ng*hr/mL 9 Dumond J, et al. 15th CROI 2008 ; Presentation 135LB
Pharmacokinetic Results Steady State mean (SD) Steady State D2-6 Trough 12 10000 10000 11 Plasm a Plasm a CVF CVF 10 Maraviroc Concentration (ng/mL) Maraviroc Concentration (ng/mL) Maraviroc CVF:BP AUC Ratio 9 1000 1000 8 7 100 6 100 5 4 10 10 3 2 1 protein-free IC 90 = 0.5 ng/mL 1 1 0 2 3 4 5 6 7 0 2 4 6 8 10 12 N=12 N=12 Steady State Study Day Tim e (hr) AUC BP : 2,648 (798) ng*hr/mL AUC CVF : 9,629 (7,819) ng*hr/mL CVF:BP AUC Ratio mean = 4.1 10 Dumond J, et al. 15th CROI 2008 ; Presentation 135LB
Pharmacokinetic Results Terminal Elimination Plasma 1000 CVF Maraviroc Concentration (ng/mL) 100 10 protein-free IC 90 = 0.5ng/mL 1 0 12 24 36 48 60 72 N=12 N=12 Time (hr) 11 Dumond J, et al. 15th CROI 2008 ; Presentation 135LB
Pharmacokinetic Results Vaginal Tissue Concentration CVF Protein Binding* (mean, range) 10000 Plasma 7.6 % (3.7-13.6%) CVF Maraviroc Concentration (ng/mL) vaginal tissue BP Protein Binding ~ 76% 1000 *4 pooled samples 100 protein-free IC90 = 0.5ng/mL 10 0 2 4 6 8 10 12 N=12 Time (hr) AUC VT : 4,992 ng*hr/mL VT:BP AUC Ratio mean = 1.9 AUC BP : 2,648 (798) ng*hr/mL CVF:BP AUC Ratio mean = 4.1 AUC CVF : 9,629 (7819) ng*hr/mL 12 Dumond J, et al. 15th CROI 2008 ; Presentation 135LB
Kashuba, ADM, CROI 2008 Cervicovaginal Fluid Exposure Cervicovaginal Fluid Exposure (mean percent of blood plasma) 600% NNRTI PI Entry Inhibitors N(t)RTIs 500% MVC (410%) 3TC (400%) 400% FTC (375%) 300% 200% IDV (200%) ZDV (235%) GT AUC : BP AUC TDF (110%) 100% NVP (80%) 75% 50% APV (50%) RTV (26%) 25% ddI (21%) DLV (20%) ATV (18%) ABC (8%) Min et al. JAIDS 2005 LPV (8%) 0% Dumond et al. AIDS 2007 EFV (0.4%) d4T (5%) Dumond et al. CROI 2008 SQV (ND) 13 Dumond J, et al. 15th CROI 2008 ; Presentation 135LB
Conclusions • Maraviroc concentrations in the female genital tract were 10-fold higher than IC 90 in all subjects by 2hrs • Maraviroc exposure in the female genital tract: – 2 (FD) and 4-fold (SS) higher AUC in CVF than BP – 72 hours after dosing CVF concentrations were similar to BP 12 hours post dose – Vaginal tissue (SS) ~2-fold higher than BP – Protein-binding in CVF 10-fold lower than BP • First time terminal elimination, VT concentrations and protein binding has been measured in FGT Maraviroc achieves one of the highest female genital tract exposure relative to BP of all ARVs evaluated to date. Additional work is needed to fully understand the implications of this finding. 14 Dumond J, et al. 15th CROI 2008 ; Presentation 135LB
Acknowledgements Funded by Pfizer The clinical, laboratory and research staff from University of North Carolina Volunteers UNC General Clinical Research Center (RR00046) UNC Center for AIDS Research (AI50410) AI54980, AI77355, Building Research Careers in Women’s Health (HD001441) 15 Dumond J, et al. 15th CROI 2008 ; Presentation 135LB
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