Background:  Plasma concentrations of some protease inhibitors are reduced in the third trimester of pregnancy relative to non-pregnant controls, presumably due to metabolic and physiologic changes associated with pregnancy. Data are limited on the pharmacokinetics and safety of atazanavir (ATV) in pregnancy. 

Methods:  BMS AI424182 is an ongoing, prospective study in HIV⁺ pregnant women to determine dosing of ATV/ritonavir (r) that achieves predefined AUC and C_min targets in the third trimester. A planned interim analysis was conducted when 12 subjects completed the third trimester (weeks 28 to 36) intensive pharmacokinetics. Subjects ³12 weeks’ gestation received ATV/r 300/100 mg once daily and zidovudine (ZDV)/lamivudine (3TC) 300/150 mg twice daily for ³2 weeks prior to intensive pharmacokinetic sampling in the third trimester and 4 weeks post partum. Protocol-defined exposures not requiring a dose adjustment were geometric mean AUCt ³30 µg·h/mL and ³10 of 12 C_min ³150 ng/mL. Safety assessments on mothers and infants included clinical examination and laboratory testing at each study visit. ATV and RTV were analyzed by liquid chromatography (LC)/mass spectrometry (MS)/MS. Descriptive statistics for third trimester and post-partum pharmacokinetic parameters were calculated and compared with historical data in HIV⁺ subjects as a reference; all available safety data are reported.

Results:  ATV geometric mean (%CV) AUC was 26.6 (43) µg·h/mL for the third trimester intensive pharmacokinetics (n = 12); all ATV C_min were ³150 ng/mL; C_min geometric mean (%CV) was 514 (48) ng/mL. Third trimester ATV AUC and C_min were approximately 40 and 21% lower, respectively, than historical data in HIV⁺ subjects (44 [51] µg·h/mL and 654 [76] ng/mL, respectively; n = 33). Post partum (n = 9) geometric mean (%CV) AUC (57 [41] µg·h/mL) and C_min (1192 [68] ng/mL) appear higher than historical data. Serious adverse effects unrelated to study drug occurred in 4 of 21 treated subjects. Grade 3 bilirubin occurred in 5 of 18 subjects with lab results. All 10 subjects reaching delivery achieved HIV RNA <50 copies/mL; all infants tested HIV-negative. All infant bilirubins were within normal limits through day 14; there was 1 grade 3 (4.5 mg/dL) at day 15.

Conclusions:  ATV/r 300/100 once daily did not meet the protocol-defined AUC criterion. Although the C_min criterion was met, these exposures may not be optimal for antiretroviral-experienced patients. A protocol-specified dose increase to ATV/r 400/100 once daily in the third trimester will be evaluated in a subsequent cohort. ATV exposures appear higher than historical data at 4 weeks post partum in HIV⁺ women likely due to ongoing physiologic changes. Study drugs were well tolerated. No unexpected safety events related to ATV/r occurred.