Genital tract, cord blood, and amniotic fluid exposures of seven antiretroviral drugs during and after pregnancy in human immunodeficiency virus type 1-infected women.

The objective of the study was to measure antiretroviral exposures in four physiological compartments during pregnancy, delivery, and postpartum. This prospective, open-label, longitudinal study collected paired blood plasma (BP) and genital tract (GT) aspirates antepartum, at delivery, and up to 12 weeks postpartum. Antiretroviral cord BP and amniotic fluid concentrations were also measured. Drug concentrations were analyzed by validated high-performance liquid chromatography/UV and liquid chromatography/tandem mass spectrometry methods, with secondary compartment concentrations presented as the percentage of BP. Fourteen women taking lamivudine plus zidovudine and either lopinavir-ritonavir (n = 7), nelfinavir (n = 6), or nevirapine (n = 1) were enrolled; four also received tenofovir. GT penetration relative to BP was highest for the nucleoside reverse transcriptase inhibitors compared to the protease inhibitors and nevirapine. Only antepartum nelfinavir GT penetration was significantly higher than in the second trimester (geometric mean ratio [GMR], 179.3) or third trimester (GMR, 41.9). Compared to nonpregnant historical controls, antepartum GT penetration was significantly lower (P < 0.05) for zidovudine (GMR, 0.25) and lopinavir (GMR, 0.03); postpartum lopinavir GT penetration continued to be significantly lower (GMR, 0.27). Cord BP exposures were highest for lamivudine and tenofovir (> or = 100%), with cord BP levels of the remaining drugs ranging from 49 to 86% of that of the respective BP level. Amniotic exposures for lamivudine, zidovudine, tenofovir, and nelfinavir were > or = 100%, nevirapine exposure was 53%, and lopinavir and ritonavir exposures were < or = 6% that of BP. We conclude that GT, cord BP, and amniotic fluid exposures vary within and between antiretroviral drug classes and biologic sites. Measurement of antiretroviral exposure in maternal genital secretions, cord BP, and amniotic fluid may be needed to identify signals of subtherapeutic or supratherapeutic drug exposure.

Effect of omeprazole on the plasma concentrations of indinavir when administered alone and in combination with ritonavir.

PURPOSE: The effects of omeprazole on indinavir when administered alone or in combination with ritonavir were evaluated. METHODS: Fourteen men and women age 18-55 years not infected with human immunodeficiency virus who met study qualifications were randomized to receive placebo, 20 mg of omeprazole, or 40 mg of omeprazole daily. After seven days, the single-dose pharmacokinetic profile of an 800-mg dose of indinavir alone or in combination with 200 mg of ritonavir was evaluated. Study participants received each of four study regimens in one of four randomly assigned orders. Blood samples were collected, and plasma indinavir and ritonavir concentrations were analyzed using high-performance liquid chromatography. RESULTS: The coadministration of 20 or 40 mg of omeprazole with indinavir significantly reduced the mean indinavir area under the concentration-versus-time curve (AUC) from 30.0 mg x hr/L (95% confidence interval [CI], 21.9-41.1 mg x hr/L) to 19.7 mg x hr/L (95% CI, 14.6-26.8 mg x hr/L) or 16.0 mg x hr/L (95% CI, 11.8-21.7 mg x hr/L), respectively (p < 0.002). The addition of 200 mg of ritonavir to 800 mg of indinavir in combination with 40 mg of omeprazole significantly increased the mean indinavir AUC from 30.0 mg x hr/L (95% CI, 21.9-41.1 mg x hr/L) to 46.6 mg x hr/L (95% CI, 34.0-63.8 mg x hr/L), but it did not significantly affect mean omeprazole concentrations (p < or = 0.02). CONCLUSION: The AUC of indinavir was substantially decreased in healthy volunteers who received omeprazole 20 or 40 mg daily for seven days before the administration of a single 800-mg dose of indinavir. Concomitant administration of ritonavir 200 mg with indinavir in participants receiving omeprazole led to a significant increase in the AUC of indinavir.

The pharmacokinetics and viral activity of tenofovir in the male genital tract.

OBJECTIVE: To measure tenofovir (TFV) concentrations in the male genital tract (GT) after single and multiple doses of tenofovir disoproxil fumarate (TDF) and evaluate the HIV-1 RNA response to monotherapy. DESIGN AND METHODS: A pharmacokinetic study of blood plasma (BP) and GT TFV concentrations in 9 men was conducted after 1 and > or =14 doses of TDF. TFV concentrations were measured by validated high-performance liquid chromatography-ultraviolet or tandem mass spectrometry methods, and HIV-1 RNA was measured using Roche (Roche Molecular Systems, Branchburg, NJ) or bioMerieux (bioMerieux, Durham, NC) kits. RESULTS: TFV GT concentrations were 4.4-fold +/- 5.1-fold higher than BP after dose 1 and 5.1-fold +/- 6.8-fold higher than BP after dose 14. Intracellular GT TFV-diphosphate concentrations were 9.4-fold higher than BP after dose 1 and 17.5-fold +/- 22.6-fold higher after dose 7. After 14 days ofTDF monotherapy, HIV-1 RNA decreased by 0.9 log10 copies/mL in blood and 1.0 log10 copies/mL in the GT. CONCLUSIONS: High TFV concentrations were achieved rapidly in the GT of all subjects after single and multiple doses and potently reduced BP and GT HIV-1 RNA levels.