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A multi-compartment, single and multiple dose pharmacokinetic study of the candidate vaginal microbicide 1% tenofovir gel
J. Schwartz1, R. Rountree2, A. Kashuba3, V. Brache4, M. Creinin5, A. Poindexter6, B. Kearney7
1CONRAD/Eastern Virginia Medical School, Arlington, United States, 2Family Health International, Durham, United States, 3University of North Carolina, School of Pharmacy, Chapel Hill, United States, 4PROFAMILIA, Santo Domingo, Dominican Republic, 5University of Pittsburgh, Pittsburgh, United States, 6Advances in Health, Inc., Houston, United States, 7Gilead Sciences, Foster City, United States
Background: Although tenofovir (TFV) gel is being evaluated as a pericoital and once daily microbicide, data on absorption and genital tract (GT) concentrations are lacking.
Methods: This multi-center study recruited 49 women for single (SD) and multiple (MD) 4mL gel dosing once (QD) or twice (BID) daily for two weeks. GT specimens (cervicovaginal fluid (CVF), endocervical cells (ECC), and vaginal biopsies) were collected at 0.5, 1, 2, 4, 6, 8, or 24 hr after a SD and 4, 8 or 24 hr after MD. After both SD and MD, 7 peripheral blood plasma (PB) samples were collected according to the SD strategy above. Using LC-MS/MS, TFV concentrations were measured in BP and CVF and are being analyzed in tissues. The TFV active metabolite [TFVdiphosphate (DP)] was measured in ECC and is being analyzed in tissues.
Results: Forty-five participants, mean age of 34, completed the study. There were minimal PK differences between QD and BID dosing. The following median (IQR) pharmacokinetic parameters were determined:
| Analyte, Matrix, Dose Frequency | Cmax (ng/mL) | Tmax (hr) | AUC24h (hr*ng/mL) | C24h(ng/mL) | | TNF BP SD | 4.0 (1.5-9.1) | 4 (2-6) | 36.4 (13.5-69.6) | 0.3 (0.3-0.5) | | TNF BP MD | 3.4 (2.4-6.1) | 4 (2-6) | 37.2 (24.6-62.6) | 0.3 (0.3-0.6) | | TNF CVF SD1 | 1.9 x 106 | 4 | 18.6 x 106 | 0.1 x 106 | | TNF CVF MD1 | 1.4 x 106 | 4 | 18.2 x 106 | 0.6 x 106 | | TFV-DP ECC SD1,2 | 33.6 x 104 | 4 | 259.9 x 104 | 3.5 x 104 | | TFV-DP ECC MD 1,2 | 16.2 x 104 | 8 | 205.1 x 104 | 3.1 x 104 | 1 Estimated from 4, 8 & 24 hour samples.
2 Cmax and C24h in fmol/106 cells; AUC24h in hr*fmol/106 cells. |
Conclusions: TFV exposure was low in BP and high in CVF up to 24 hrs after vaginal application. TVF-DP concentrations were high in ECC. Results show that SD and MD TFV gel exposure leads to high GT drug levels up to 24 hrs post-dose and support further study of pericoital and once-daily dosing of TFV gel.
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