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.

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 (>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 >100%, nevirapine exposure was 53%, and lopinavir and ritonavir exposures were <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.

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. 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. Results-The Index termsAntiretroviral agents; Blood levels; Dosage; Drug interactions; Gastrointestinal drugs; HIV infections; Indinavir; Omeprazole; Pharmacokinetics; Ritonavir Protease inhibitors (PIs) exhibit a high degree of pharmacokinetic variability in patients infected with the human immunodeficiency virus (HIV). 1,2 Large interindividual differences in drug absorption and elimination in HIV-infected patients have been primarily attributed to constitutive or altered drug metabolizing enzymes, P-glycoprotein transporter activities, and poor drug solubility. 3 With the PIs indinavir and atazanavir, changes in gastric pH can alter drug absorption. 4,5 Specifically, when these PIs are administered with medications that Address correspondence to Dr. Kashuba at the School of Pharmacy, CB7360, University of North Carolina, Chapel Hill, NC 27599-7360 (akashuba@unc.edu increase gastric pH, such as histamine (H 2 )-receptor antagonists and proton-pump inhibitors (PPIs), bioavailability can decrease by up to 76%. 4,6 A survey of 200 HIV-infected patients was performed to assess their use of drugs that affect gastric acidity. 7 Fifty-six percent of HIV-infected patients who had recently begun highly active antiretroviral therapy (HAART) had taken nonprescription acid-reducing agents, and 39% had used both nonprescription and prescription products for acid reduction. Forty-six percent of patients on a PI-containing regimen had used PPIs or H 2 -receptor antagonists once they started HAART, and 35% had used them within the previous 12 months. This widespread use of acid-reducing agents among HIV-infected patients has implications for drug interactions with antiretrovirals and other medications that require an acidic environment for adequate dissolution and absorption.Ritonavir is a cytochrome P-450 (CYP) isoenzyme 3A and P-glycoprotein inhibitor which, when used in low doses, can increase the exposure of concomitantly administered PIs. The concomitant ad...