Pharmacokinetics of an increased atazanavir dose with and without tenofovir during the third trimester of pregnancy

Abstract

Background: Reduced atazanavir exposure has been demonstrated during pregnancy with standard atazanavir/ritonavir dosing. We studied an increased dose during the third trimester of pregnancy.

Methods: International Maternal Pediatric Adolescent AIDS Clinical Trials Group 1026s is a prospective, nonblinded, pharmacokinetic study of HIV-infected pregnant women taking antiretrovirals for clinical indications, including 2 cohorts (with or without tenofovir) receiving atazanavir/ritonavir 300/100 mg once daily during the second trimester, 400/100 mg during the third trimester, and 300/100 mg postpartum (PP). Intensive steady-state 24-hour pharmacokinetic profiles were performed. Atazanavir concentrations were measured by high-performance liquid chromatography. Pharmacokinetic targets were the 10th percentile atazanavir area under the concentration versus time curve (AUC) (29.4 μg·hr·mL·) in nonpregnant adults on standard dose and 0.15 μg/mL, minimum trough concentration.

Results: Atazanavir pharmacokinetic data were available for 37 women without tenofovir, 35 with tenofovir; median (range) pharmacokinetic parameters are presented for second trimester, third trimester, and PP and number who met target/total. ATAZANAVIR WITHOUT TENOFOVIR: AUC 30.5 (9.19-93.8), 45.7 (11-88.3), and 48.8 (9.9-112.2) μg·hr·mL, and 8/14, 29/37, and 27/34 met target. C24 h was 0.49 (0.09-4.09), 0.71 (0.14-2.09), and 0.90 (0.05-2.73) μg/mL; 13/14, 36/37, and 29/34 met target. ATAZANAVIR WITH TENOFOVIR: AUC 26.2 (6.8-60.9) (P < 0.05 compared with PP), 37.7 (0.72-88.2) (P < 0.05 compared with PP), and 58.6 (6-149) μg·hr·mL, and 7/17, 23/32, and 27/29 met target. C24 h was 0.44 (0.12-1.06) (P < 0.05 compared with PP), 0.57 (0.02-2.06) (P < 0.05 compared with PP), and 1.26 (0.09-5.43) μg/mL; 7/17, 23/32, and 27/29 met target. Atazanavir/ritonavir was well tolerated with no unanticipated adverse events.

Conclusions: Atazanavir/ritonavir increased to 400/100 mg provides adequate atazanavir exposure during the third trimester and should be considered during the second trimester.

Trial registration: ClinicalTrials.gov NCT00042289.

Conflict of interest statement

Conflicts of Interest:

No competing financial interests exist.

Figures

FIGURE 1

Median Atazanavir concentration–time curves for atazanavir without tenofovir subjects (top graph) and atazanavir with tenofovir subjects (lower graph), during second trimester, third trimester and postpartum The solid line represents the expected (50th percentile) concentration–time profile in non-pregnant adults.

FIGURE 2

Changes in area under the concentration–time curves (AUC) for atazanavir without tenofovir subjects (top graph) and atazanavir with tenofovir subjects (lower graph) during the second trimester, third trimester, and postpartum.