Pharmacokinetics of Atazanavir Boosted With Cobicistat in Pregnant and Postpartum Women With HIV

Jeremiah D. Momper, PharmD, PhD; Jiajia Wang, MS; Alice Stek, MD; David E. Shapiro, PhD; Kathleen M. Powis, MD; Mary E. Paul, MD; Martina L. Badell, MD; Renee Browning, RN, MSN; Nahida Chakhtoura, MD; Kayla Denson, PhD; Kittipong Rungruengthanakit, MD; Kathleen George, MPH; Edmund V. Capparelli, PharmD; Mark Mirochnick, MD; Brookie M. Best, PharmD, MAS

Disclosures

J Acquir Immune Defic Syndr. 2022;89(3):303-309. 

In This Article

Results

Participant Characteristics

Eleven pregnant women receiving atazanavir and cobicistat once daily enrolled in the study. Evaluable atazanavir pharmacokinetic data were available for 6, 8, and 9 participants in the second trimester, third trimester, and postpartum, respectively. Evaluable cobicistat pharmacokinetic data were available for 6, 9, and 9 participants in the second trimester, third trimester, and postpartum, respectively. All atazanavir concentrations in 1 participant in the third trimester period were below the limit of quantitation of the assay, consistent with lack of absorption. Third trimester atazanavir pharmacokinetic data from this participant were deemed nonevaluable and excluded from both third trimester summary statistics and from matched comparisons. Overall, evaluable paired pregnancy and postpartum atazanavir pharmacokinetic data were available for 5 of 6 participants who had second trimester visits and for 6 of 9 participants who had third trimester visits. Evaluable paired pregnancy and postpartum cobicistat pharmacokinetic data were available for 5 of 6 participants who had second trimester visits and for 7 of 9 participants who had third trimester visits. The median (range) duration of atazanavir/cobicistat before PK sampling was 16.6 weeks (4.1, 303.4, n = 6) in the second trimester and 23.4 weeks (7.0, 312.3, n = 9) in the third trimester. Clinical characteristics are listed in Table 1.

Atazanavir Pharmacokinetics

The median (IQR) atazanavir AUC0–24 in the second trimester, third trimester, and postpartum periods was 25.33 μg × h/mL (20.95–27.32), 18.85 (11.90–31.48), and 36.20 (24.09–46.14), respectively (Figure 1, Table 2). Compared with paired postpartum data, atazanavir AUC0–24 was 26% lower in the second trimester (n = 5, P = 0.1875, GMR = 0.739, 90% CI: 0.527 to 1.035) and 54% lower in the third trimester (n = 6, GMR = 0.459, P = 0.1563, 90% CI: 0.190 to 1.109). The median (IQR) 24-hour trough concentration was 0.21 μg/mL (0.16–0.28) in the second trimester, 0.21 μg/mL (0.11–0.56) in the third trimester, and 0.61 μg/mL (0.42–1.03) in postpartum. The frequency of participants meeting the atazanavir AUC0–24 target (28.4 μg × h/mL) was 1 of 6 (17%) in the second trimester, 2 of 9 (22%) in the third trimester, and 5 of 9 (56%) in postpartum. Atazanavir Cmin was 66% lower in the second trimester and 72% lower in the third trimester compared with paired postpartum data (P = 0.0625 and P = 0.0313, respectively).

Figure 1.

Atazanavir antepartum and postpartum median plasma concentration versus time profiles after once-daily dosing of 300/150 mg atazanavir/cobicistat. The shaded area displays the 10th to 90th percentile concentrations in nonpregnant patients with HIV receiving once-daily atazanavir and ritonavir.

Eight maternal plasma samples at delivery and 8 cord blood samples were available. Of these, 2 maternal plasma samples and 5 cord blood samples were below the lower limit of quantitation of the assay for atazanavir (0.039 μg/mL). The median (IQR) concentration of atazanavir in maternal plasma at delivery was 0.61 μg/mL (0.05–0.89, n = 8). The highest atazanavir concentration observed in cord blood was 0.13 μg/mL. Six sets of paired samples had quantifiable atazanavir concentrations in maternal plasma at delivery along with a cord blood sample (including cord blood samples below the limit of quantitation). Of these paired samples, the median (IQR) ratio of cord blood to maternal plasma was 0.07 (0.02–0.19).

A total of 38 washout samples were collected from 10 infants after birth. In 6 infants, all samples were below the quantitation limit for atazanavir (0.039 μg/mL). The remaining 4 infants provided 7 samples which had a quantifiable atazanavir concentration. Of these samples, the median (IQR) plasma atazanavir concentration was 0.10 μg/mL (0.07–0.26).

Cobicistat Pharmacokinetics

The median (IQR) cobicistat AUC0–24 in the second trimester, third trimester, and postpartum periods was 7.39 μg × h/mL (5.39–8.31), 4.89 μg × h/mL (2.98–6.89), and 9.38 μg × h/mL (8.57–10.28), respectively. Compared with paired postpartum data, cobicistat AUC0–24 was 35% lower in the second trimester (n = 5, P = 0.0625, GMR = 0.65, 90% CI: 0.49 to 0.86) and 52% lower in the third trimester (n = 7, P = 0.0156, GMR = 0.48, 90% CI: 0.30 to 0.77) (Figure 2, Table 3). Cobicistat concentrations at 24 hours postdose (C24) were below the quantitation limit in 3 of 6 (50%), 4 of 9 (44%), and 0 of 9 (0%) participants in the second trimester, third trimester, and postpartum, respectively.

Figure 2.

Cobicistat antepartum and postpartum median plasma concentration versus time profiles after once-daily dosing of 300/150 mg atazanavir/cobicistat.

A total of 8 maternal plasma samples at delivery and 8 cord blood samples were available. Of these, 2 maternal plasma samples and 4 cord blood samples were below the lower limit of quantitation of the assay for cobicistat (4.9 ng/mL). The median (IQR) concentration of cobicistat in maternal plasma at delivery was 47.95 ng/mL (12.16–219.25, n = 8). The highest cobicistat concentration observed in cord blood was 576.0 ng/mL. A total of 6 sets of paired samples had quantifiable cobicistat concentrations in maternal plasma at delivery along with a cord blood sample (including cord blood samples below the limit of quantitation). Of these paired samples, the median (IQR) ratio of cord blood to maternal plasma was 0.10 (0.10–0.16). Cobicistat was not quantifiable in any neonatal washout plasma samples after birth.

Clinical Outcomes

Five mothers had DAIDS grade 3 or higher adverse events. All maternal adverse events were considered unrelated to study drugs by site investigators and the study team except for elevated total bilirubin in 3 participants and gestational diabetes in 1 participant. The percentage of women with suppression of HIV replication (defined as HIV-1 RNA < 50 copies/mL) at the second trimester (n = 6), third trimester (n = 9), delivery (n = 11), and postpartum (n = 9) visits was 100%, 100%, 100%, and 77.8%, respectively.

Three infants had adverse events grade 3 or higher. All infant adverse events were considered unrelated to study drugs by site investigators and the study team except for the grade 2 hyperbilirubinemia in 1 infant. The only clinical abnormality observed at birth was a unilateral undescended testicle in 1 infant. Eight infants had sufficient virologic testing to be classified as uninfected, and 3 infants with incomplete virologic testing were classified as uninfected based on the best available data.

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