Therapeutic drug monitoring of atazanavir/ritonavir in pregnancy

Abstract

ObjectivesPregnant 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). MethodsPregnant 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). ResultsFrom 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. ConclusionsThis 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.

Pharmacokinetics, Safety and Efficacy of Ritonavir-Boosted Atazanavir (300/100 mg Once Daily) in HIV-1-Infected Pregnant Women

“…This study is one of the largest cohorts of HIV-1-infected pregnant women, mostly from sub-Saharan Africa receiving ATV/r (300/100 mg once daily). Pharmacokinetic results were consistent with previous data [12][13][14]. We did not find that a higher dose of ATV/r (400/100 mg once daily) was required during the second and third trimesters of pregnancy, despite what was indicated in the product information.…”

“…We found a median fetal/maternal ratio of ATV of 0.19 (n=28), which is consistent with previous studies, showing a mean plasma fetal/maternal ATV ratio of 0.13 (95% CI 0.10, 0.16) [18] based on 14 mother-infant pairs and 0.21 (range 0-1.18) [19], based on 18 mother-infant pairs. This relatively limited diffusion could be related to the placental barrier, including action of transporters, and protein-binding ratio [12]. However, we did not assess the protein-binding ratio, because previous results did not find a significant variation in the ratio during pregnancy [13].…”

Pregnancy-Associated Changes in Pharmacokinetics: A Systematic Review

“…In the case of antiretrovirals, all studies had showed decreased drug exposure in pregnancy due to PK changes. While most of these studies reported adequate viral suppression and no mother-to-child HIV transmission [132,135,138], one study reported an increased viral load during pregnancy, with a few cases of neonatal transmission of the virus [150]. Conflicting clinical results were also reported for antimalarial drugs: while some studies reported equal parasite clearance time or no increase in treatment failure in spite of decreased exposure [182], others demonstrated a positive correlation between the decreased exposure and poor clinical outcome, reporting an increase in treatment failure or a decrease in post-treatment prophylactic effect [181,195].…”

“…This collection of PK data could prove to be a decision support base for future attempts to tailor medication prescription for pregnant women to achieve target serum concentrations; however, one must take into account that many studies often report undiminished drug efficacy despite the aforementioned pregnancy-associated PK changes [132,135,138,145,146,163,172,177]. …”

Pharmacokinetic Enhancement of HIV Antiretroviral Therapy During Pregnancy

“…28 Another study showed that lower atazanavir exposure during pregnancy was not associated with a lack of virologic suppression at delivery. 29 Therefore, the standard dose of 300 mg/100 mg is recommended for some patients (including treatment-naïve women), but careful monitoring is warranted. A dose adjustment of atazanavir to 400 mg should be considered for treatment-experienced patients, especially those taking tenofovir or medications that alter atazanavir bioavailability such as H 2 receptor blockers (eg, famotidine, ranitidine).…”