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

Discussion

In pregnant individuals living with HIV receiving atazanavir in combination with cobicistat, atazanavir exposure was lower during pregnancy compared with postpartum. Compared with paired postpartum data, atazanavir AUC0–24 was 26% lower in the second trimester and 54% lower in the third trimester. Atazanavir 24-hour trough concentrations were 74% lower in the second and third trimesters of pregnancy as compared with previously reported values in nonpregnant adult patients with HIV receiving once-daily dosing of 300/150 mg atazanavir/cobicistat.[12] Subtherapeutic antiretroviral exposure during pregnancy may increase the risk of virologic failure in the mother and of perinatal HIV transmission. In this study, the minimum AUC target for atazanavir (28.4 μg × h/mL) was the 10th percentile AUC0–24 in nonpregnant adults with HIV which was taken from published pharmacokinetic parameters.[18] Fewer participants met this minimum threshold during pregnancy (17% in second trimester and 22% in third trimester) compared with postpartum (56%).

In November 2019, the US Food and Drug Administration (FDA) revised drug labeling for cobicistat products with a recommendation that cobicistat should not be used during pregnancy to boost atazanavir, darunavir, and elvitegravir because of substantially lower exposures of darunavir and elvitegravir with cobicistat boosting in pregnant individuals.[15,16,19] The results of this study support the recommendation that cobicistat at the standard adult dose of 150 mg daily is an inadequate pharmacokinetic booster during pregnancy for antiretroviral drugs that are primarily eliminated by CYP3A-mediated hepatic metabolism, including atazanavir.

Atazanavir boosted with ritonavir has been studied in pregnancy. Among 18 pregnant women receiving atazanavir/ritonavir 300 mg/100 mg once daily, the atazanavir AUC was reduced by approximately 30% compared with postpartum data.[14] Despite the lower atazanavir exposure, atazanavir/ritonavir 300 mg/100 mg once daily is recommended in pregnant women with HIV.[13] The differences between ritonavir and cobicistat boosting in pregnancy may be due to low systemic cobicistat concentrations in pregnant women.

The atazanavir population estimated protein binding adjusted effective concentration at 90% (EC90) is 0.014 μg/mL.[20] In this study, 2 participants in the third trimester had predose trough concentrations below the lower limit of quantitation of the assay for atazanavir (0.039 μg/mL), suggesting that exposures in these participants may have fell below the EC90. However, no clear exposure–response relationship was observed. For example, although the percentage of participants with suppression of HIV replication (defined as HIV-1 RNA < 50 copies/mL) was lowest postpartum, atazanavir exposures were highest during this period. Previous studies in adults with HIV have shown only a weak correlation between atazanavir exposure and virologic response.[20,21]

Physiologic changes during pregnancy likely contribute to the observed altered pharmacokinetics of atazanavir and cobicistat. Pregnancy-related hormones may modify the expression and activity of gastrointestinal and hepatic drug metabolizing enzymes—including CYP3A—through activation of nuclear receptors, including the pregnane X receptor (PXR) and the constitutive androstane receptor (CAR).[22] Separately, increases in blood volume and total body water can have a dilutional effect on drug concentrations and plasma proteins.[23] The elimination of both atazanavir and cobicistat is primarily by CYP3A-mediated metabolism. Cobicistat is used as a pharmacokinetic booster to inhibit CYP3A-mediated metabolism of atazanavir, increasing atazanavir systemic exposure. In this study, cobicistat AUC0–24 was 35% lower during the second trimester and 52% lower during the third trimester relative to paired postpartum data. Reduced cobicistat exposure during pregnancy likely also plays a role in the decreased atazanavir exposure.

Atazanavir is 86%–89% bound to human serum proteins (albumin and alpha-1-acid glycoprotein). The concentrations of both albumin and alpha-1-acid glycoprotein are reduced during pregnancy.[23–25] In addition, atazanavir binding to serum proteins may potentially be displaced by increased hormone binding during pregnancy. Although the unbound atazanavir concentration is responsible for anti-HIV activity, unbound drug concentrations were not measured in this study. Although lower atazanavir exposure was observed during pregnancy, the therapeutic unbound free fraction during pregnancy is unknown.

This study assessed in utero transfer of atazanavir and cobicistat and the washout kinetics of these drugs transferred in utero across the placenta in infants born to mothers receiving atazanavir and cobicistat during pregnancy. For atazanavir, the median ratio of cord blood to maternal plasma was 0.07 (from 6 available paired sets of cord blood and maternal plasma at delivery). For cobicistat, the median ratio of cord blood to maternal plasma was 0.10 (from 6 available paired sets of cord blood and maternal plasma at delivery). A total of 38 washout plasma samples were collected from 10 infants during the first 9 days of life. Of these, only 7 samples (18%) were quantifiable for atazanavir (≥0.039 μg/mL), whereas cobicistat was not quantifiable in any neonatal washout samples. These data suggest that the placental transfer of both drugs is limited and infant washout elimination could not be assessed.

A limitation of this study is the opportunistic approach of only enrolling pregnant women receiving atazanavir and cobicistat as part of clinical care. This study design results in enrollment of pregnant women who respond virologically to the atazanavir/cobicistat combination without developing treatment-limiting toxicity because women who virologically fail or have severe toxicity will be switched to other antiretroviral regimens. This selection bias may overestimate positive outcomes and underestimate adverse outcomes, including inadequate virologic response and drug toxicity. In addition, our sample size of 11 is smaller than other IMPAACT 1026s study arms. This small sample size was due to fewer pregnant women receiving this combination compared with other cobicistat combinations for routine clinical care during pregnancy at study sites before the FDA labeling revisions. No additional participants were recruited once the FDA issued the revised labeling recommending against the use of cobicistat as pharmacologic booster during pregnancy.[19] Therefore, although the sample size is small, it is likely these data will represent the only clinical pharmacokinetic data on atazanavir boosted with cobicistat during pregnancy. Another limitation is that the infant washout analysis included wide sampling windows with sparse time points.

In conclusion, standard atazanavir/cobicistat dosing during pregnancy results in lower atazanavir exposure which may increase the risk of virologic failure and perinatal transmission, and this drug combination should be avoided during pregnancy. These results support the FDA recommendations in revised drug labeling.

processing....