A compartmental pharmacokinetic evaluation of long-acting rilpivirine in HIV-negative volunteers for pre-exposure prophylaxis.

Rilpivirine long-acting (RPV-LA) is a parenteral formulation enabling prolonged plasma exposure. We explored its multiple-compartment pharmacokinetics (PK) after a single dose, for pre-exposure prophylaxis. Sixty-six HIV-negative volunteers were enrolled: women received an intramuscular dose of 300, 600, or 1,200 mg, with plasma and genital levels measured to 84 days postdose; men receiving 600 mg had similar PK determined in plasma and rectum. Ex vivo antiviral activity of cervicovaginal lavage (CVL) was also assessed. After a single dose, RPV concentrations peaked at days 6-8 and were present in plasma and genital-tract fluid to day 84. Vaginal and male rectal tissue levels matched those in plasma. At the 1,200 mg dose, CVL showed greater antiviral activity, above baseline, at days 28 and 56. All doses were well tolerated. All doses gave prolonged plasma and genital-tract rilpivirine exposure. PK and viral inhibition of repeated doses will be important in further dose selection.

Therapeutic drug monitoring of atazanavir/ritonavir in pregnancy.

OBJECTIVES: Pregnant women experience physiological changes during pregnancy that can have a significant impact on antiretroviral pharmacokinetics. Ensuring optimal plasma concentrations of antiretrovirals is essential for maternal health and to minimize the risk of vertical transmission. Here we describe atazanavir/ritonavir (ATV/r) plasma concentrations in a cohort of pregnant women undergoing routine therapeutic drug monitoring (TDM). METHODS: Pregnant HIV-positive women received ATV/r as part of their routine pre-natal care. Demographic and clinical data were collected. ATV plasma concentrations ([ATV]) were determined in the first (T1), second (T2) and third (T3) trimesters and at postpartum (PP) using liquid chromatography-tandem mass spectrometry (LC-MS/MS). RESULTS: From January 2007, 44 women (37 black African) were enrolled in the study. All received ATV/r at a dose of 300/100 mg once a day. Twenty-four had received antiretroviral therapy (ART) prior to pregnancy, and 20 initiated ATV/r in pregnancy. At the time nearest to delivery, 36 patients had undetectable plasma viral loads. [ATV] values were determined in 11 (T1), 25 (T2), 34 (T3) and 28 (PP) patients. [ATV] at 24 hours post-dose (C24) values significantly lower at T2/T3 relative to PP. CONCLUSIONS: This study was carried out in one of the larger cohorts of women undergoing TDM for ATV in pregnancy. Lower [ATV] values were seen in T2/T3 compared with T1/PP. However, [ATV] were not associated with a lack of virologic suppression at delivery. Nonetheless, careful monitoring of women in pregnancy is required, and dose adjustment of ATV to 400 mg may be an option.

Improved oral bioavailability of lopinavir in melt-extruded tablet formulation reduces impact of third trimester on lopinavir plasma concentrations.

Lopinavir exposure was reduced during the third trimester in pregnant women receiving standard dosing of the soft-gel capsule (SGC; 400/100 mg twice daily [b.i.d.]). Pharmacokinetic data on the lopinavir tablet in pregnancy are limited. On the basis of the tablet's improved bioavailability, standard dosing (400/100 mg b.i.d.) may provide adequate lopinavir exposure in pregnancy without a need for dose adjustment. Here we compared the total and unbound lopinavir pharmacokinetics throughout pregnancy in the second and third trimesters in HIV-infected women receiving standard dosing of the lopinavir SGC or tablet. Postpartum sampling was also performed in patients continuing therapy postdelivery. Blood samples were collected at 0 to 12 h postdosing, and lopinavir concentrations were determined by high-pressure liquid chromatography-tandem mass spectrometry. Nineteen patients were included: 8 received the SGC (cohort 1) and 11 received the tablet (cohort 2). Total lopinavir exposures in the third trimester were lower than those in the second trimester (35 and 28% for cohorts 1 and 2, respectively) and postpartum (35% for cohort 2). In the third trimester, the area under the concentration-time curve (AUC) from 0 to 12 h (AUC(0-12)) and maximum concentration were ∼15% and 25% higher, respectively, for the lopinavir tablet than the SGC. One SGC patient had lopinavir concentrations of <1,000 ng/ml; all patients on the tablet had concentrations of >1,000 ng/ml. In cohort 2, the percentage of the AUC that was unbound was higher (nonsignificantly) in the second (1.28%) and third (1.18%) trimesters than postpartum (1.01%). Seventeen of 19 patients had an undetectable viral load at delivery. There were no HIV transmissions. Although lopinavir (tablet) exposures were reduced during the third trimester, the higher total and unbound concentrations achieved in women receiving the tablet than in women receiving the SGC suggest that the tablet's improved oral bioavailability may partly compensate for the reduction in lopinavir exposure during the later stages of pregnancy.

Therapeutic drug monitoring of lopinavir/ritonavir in pregnancy.

OBJECTIVES: The aim of the study was to determine total and unbound lopinavir (LPV) plasma concentrations in HIV-infected pregnant women receiving lopinavir/ritonavir (LPV/r tablet) undergoing therapeutic drug monitoring (TDM) during pregnancy and postpartum. METHODS: Women were enrolled in the study who were receiving the LPV/r tablet as part of their routine prenatal care. Demographic and clinical data were collected and LPV plasma (total) and ultrafiltrate (unbound) concentrations were determined in the first, second and third trimesters using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Postpartum sampling was performed where applicable. Antepartum and postpartum trough concentrations (C(trough) ) were compared independently [using analysis of variance (anova)] and on a longitudinal basis (using a paired t-test). RESULTS: Forty-six women were enrolled in the study (38 Black African). Forty women initiated LPV/r treatment in pregnancy. Median (range) gestation at initiation was 25 (15-36) weeks and median (range) baseline CD4 count and viral load were 346 (14-836) cells/µL and 8724 (<50-267408) HIV-1 RNA copies/mL, respectively. Forty women (87%) had LPV concentrations above the accepted minimum effective concentration for wild-type virus (MEC; 1000 ng/mL). Geometric mean (95% confidence interval [CI]) total LPV concentrations in the first/second [3525 (2823-4227) ng/mL; n=16] and third [3346 (2813-3880) ng/mL; n=43] trimesters were significantly lower relative to postpartum [5136 (3693-6579) ng/mL; n=12] (P=0.006). In a paired analysis (n=12), LPV concentrations were reduced in the third trimester [3657 (2851-4463) ng/mL] vs. postpartum (P=0.021). No significant differences were observed in the LPV fraction unbound (fu%). Conclusions The above target concentrations achieved in the majority of women and similarities in the fu% suggest standard dosing of the LPV/r tablet is appropriate during pregnancy. However, reduced LPV concentrations in the second/third trimesters and potentially compromised adherence highlight the need for TDM-guided dose adjustment in certain cases.