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Atazanavir Levels Indicate Need for Higher Dose During Pregnancy
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12th International Workshop on Clinical Pharmacology of HIV Therapy, April 13-15, 2011, Miami
Mark Mascolini
An atazanavir/ritonavir dose of 400/100 mg daily during the third trimester of pregnancy yielded concentrations equivalent to concentrations with 300/100 mg daily after delivery in women taking the protease inhibitors (PIs) with or without tenofovir [1]. IMPAACT P1026s investigators recommended 400/100 mg for the third trimester, regardless of tenofovir use, and suggested it should also be considered for the second trimester.
Previous work by the IMPAACT team found that plasma exposure of ritonavir-boosted atazanavir decreased by about 30% during pregnancy and by an additional 30% when tenofovir was part of the regimen [2]. Those findings led the researchers to propose raising the atazanavir/ritonavir dose from 300/100 mg to 400/100 mg during pregnancy. The new study assessed the impact of the higher dose.
This study is part of IMPAACT P1026s, an ongoing nonblinded trial of antiretroviral pharmacokinetics in HIV-positive pregnant women that includes women taking atazanavir/ritonavir. With or without tenofovir as part of their regimen, these women took 300/100 mg of atazanavir/ritonavir once daily during the second trimester, 400/100 mg once daily during the third trimester, and 300/100 mg from delivery through 2 weeks postpartum. The IMPAACT investigators conducted intensive 24-hour sampling at steady state during the second and third trimester and postpartum.
Atazanavir pharmacokinetic targets were the estimated 10th percentile area under the concentration-time curve (AUC) of 29.4 mcg * h/mL in nonpregnant adults and a 24-hour concentration of 0.15 mcg/mL. The researchers also collected maternal and umbilical cord blood samples at delivery and measured infant bilirubin concentrations 24 to 48 hours and 4 to 6 days after birth.
Of the 59 study participants, 31 took atazanavir/ritonavir with tenofovir and 28 without tenofovir. Twenty-three women were Hispanic, 16 black, 16 Asian, 3 white, and 1 with unrecorded race. Median age and weight at delivery were 29.7 years and 71.4 kg. Median gestational age was 38 weeks and median birth weight 3088 grams.
Among women taking atazanavir/ritonavir with or without tenofovir, median AUC and trough concentrations, and numbers of women who met AUC and trough targets in each trimester showed better exposure with the 400/100-mg dose than with 300/100 mg during pregnancy:
Median (range) atazanavir AUC without tenofovir:
Second trimester (300/100 mg): 24.6 (9.2 to 93.8) mcg * h/mL
Third trimester (400/100 mg): 46.6 (11.0 to 88.3) mcg * h/mL
Postpartum (300/100 mg): 55.1 (9.9 to 99.5) mcg * h/mL
Women who met target atazanavir AUC without tenofovir:
Second trimester (300/100 mg): 3 of 6 (50%)
Third trimester (400/100 mg): 22 of 28 (79%)
Postpartum (300/100 mg): 17 of 27 (63%)
Median (range) atazanavir AUC with tenofovir:
Second trimester (300/100 mg): 26.2 (6.8 to 60.9) mcg * h/mL (P < 0.05 versus postpartum)
Third trimester (400/100 mg): 37.9 (9.3 to 88.2) mcg * h/mL (P < 0.05 versus postpartum)
Postpartum (300/100 mg): 58.2 (7.5 to 134.9) mcg * h/mL
Women who met target atazanavir AUC with tenofovir:
Second trimester (300/100 mg): 7 of 17 (41%)
Third trimester (400/100 mg): 23 of 31 (74%)
Postpartum (300/100 mg): 27 of 29 (93%)
Median (range) atazanavir 24-hour concentration without tenofovir:
Second trimester (300/100 mg): 0.31 (0.09 to 2.82) mcg/mL
Third trimester (400/100 mg): 0.74 (0.14 to 2.09) mcg/mL
Postpartum (300/100 mg): 0.88 (below quantitation to 2.73) mcg/mL
Women who met target 24-hour atazanavir concentration without tenofovir:
Second trimester (300/100 mg): 5 of 6 (83%)
Third trimester (400/100 mg): 27 of 28 (96%)
Postpartum (300/100 mg): 17 of 22 (77%)
Median (range) atazanavir 24-hour concentration with tenofovir:
Second trimester (300/100 mg): 0.44 (0.12 to 1.06) mcg/mL (P < 0.05 versus postpartum)
Third trimester (400/100 mg): 0.59 (0.17 to 2.06) mcg/mL (P < 0.05 versus postpartum)
Postpartum (300/100 mg): 1.24 (0.24 to 3.65) mcg/mL
Women who met target 24-hour atazanavir concentration with tenofovir:
Second trimester (300/100 mg): 16 of 17 (94%)
Third trimester (400/100 mg): 31 of 31 (100%)
Postpartum (300/100 mg): 29 of 29 (100%)
Median atazanavir cord blood concentration measured 0.15 mcg/mL (range below detection to 1.33), and median ratio of cord blood to maternal delivery concentration was 0.18 (range 0.03 to 4.08). Among 48 women with a detectable atazanavir concentration at delivery, median atazanavir concentration stood at 1.38 mcg/mL (range 0.18 to 5.63). Median ratio of cord blood/maternal atazanavir was 0.14 (range 0.02 to 4.08).
The researchers recorded 37 grade 3 or 4 maternal adverse events, including 23 elevated bilirubin values. All bilirubin levels in infants were normal.
The IMPAACT investigators concluded that atazanavir clearance is increased during the second and third trimesters. Atazanavir exposure improved from the second to the third trimester, when the dose rose from 300/100 mg to 400/100 mg once daily. After delivery, atazanavir concentrations with the 300/100-mg dose equaled or exceeded concentrations with the higher dose in the third trimester.
The researchers proposed that 400/100 mg of atazanavir/ritonavir provides adequate atazanavir exposure during the third trimester "and should be considered during the second trimester as well."
References
1. Mirochnick M, Stek A, Capparelli EV, et al. Pharmacokinetics of increased dose atazanavir with and without tenofovir during pregnancy. 12th International Workshop on Clinical Pharmacology of HIV Therapy, April 13-15, 2011, Miami. Abstract O_10.
2. Mirochnick M, Best BM, Stek AM, et al. Atazanavir pharmacokinetics with and without tenofovir during pregnancy. JAIDS. 2011;56:412-419. journals.lww.com/jaids/Fulltext/2011/04150/Atazanavir_Pharmacokinetics_With_and_Without.5.aspx.
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