 |
|
|
| |
Reyataz During Pregnancy
|
| |
| |
Patterns of neonatal bilirubin following atazanavir/ritonavir (ATV/r) treatment of mothers during pregnancy: clinical and pharmacogenetic factors identified in study AI424182 - (12/19/10)
10th Congress Drug Therapy HIV: Assessing the Risks of Birth Defects Associated With Atazanavir Exposure in Pregnancy - (12/22/10)
The Steady State Pharmacokinetics (PK) of Atazanavir/Ritonavir (ATV/RTV) During Pregnancy in HIV+ Women - (12/22/10)
Once-Daily 300/100-mg Atazanavir/Ritonavir During Pregnancy
1st International Workshop on HIV and Women, January 10-11, 2011, Washington, DC
Mark Mascolini
A once-daily atazanavir/ritonavir dose of 300/100 mg provided atazanavir minimum concentrations (Cmin) equivalent to those seen in nonpregnant historical controls and, with zidovudine/lamivudine, prevented transmission of HIV [1]. A dose of 400/100 mg once daily resulted in more frequent high bilirubin levels in this study by Bristol-Myers Squibb researchers.
This open-label trial recruited pregnant women in South Africa, Puerto Rico, and the United States and assigned 20 to take 300/100 mg of atazanavir/ritonavir once daily and 21 to take 400/100 mg once daily. All women also took 300/150 mg of zidovudine/lamivudine twice daily. Women enrolled between 12 and 32 weeks' gestation, and all had a CD4 count above 200. Researchers measured atazanavir concentrations in the second and third trimesters and after delivery, comparing those concentrations with levels in 23 HIV-positive nonpregnant historical controls taking 300/100 mg once daily. They also assessed atazanavir levels in infants and monitored both women and infants for possible side effects.
Women's ages averaged 29 in the 300/100-mg group and 28 in the 400/100-mg group. Thirty-six women (88%) were black, 4 were white, and 1 had another ethnicity. Three women in the 300/100 group and 2 in the 400/100 group stopped treatment; 1 in each group stopped because of adverse events. All but 1 woman maintained a viral load below 50 copies/mL. All infants were born without HIV infection.
Atazanavir Cmin concentrations during the second and third trimesters were equivalent to those in nonpregnant historical controls with the 300/100-mg dose and higher with 400/100 mg (see below). Postpartum Cmins measured 3 to 10 weeks after delivery were twice higher in the combined-dose group than in historical controls. Maximum concentrations (Cmax) were lower than those of historical controls in the second and third trimesters with either atazanavir/ritonavir dose and higher after delivery than in controls:
Cmin geometric mean ratio (and 90% confidence interval)
300/100 mg once daily, second trimester (n = 9): 1.00 (0.65 to 1.54)
300/100 mg once daily, third trimester (n = 20): 1.01 (0.73 to 1.40)
400/100 mg once daily, third trimester (n = 20): 1.39 (0.96 to 2.00)
300/100 mg once daily, 3 to 10 weeks after delivery (n = 35): 2.15 (1.65 to 2.80)
Cmax geometric mean ratio (and 90% confidence interval)
300/100 mg once daily, second trimester (n = 9): 0.83 (0.65 to 1.06)
300/100 mg once daily, third trimester (n = 20): 0.73 (0.56 to 0.96)
400/100 mg once daily, third trimester (n = 20): 0.94 (0.76 to 1.17)
300/100 mg once daily, 3 to 10 weeks after delivery (n = 35): 1.26 (1.10 to 1.46)
All Cmin values were more than 10 times the 90% effective concentration of atazanavir (14 ng/mL for wild-type virus). The lowest Cmin recorded, 196 ng/mL, was higher than the Cmin considered necessary for therapeutic efficacy, 150 ng/mL.
Seven women in the 300/100-mg group (35%) and 8 in the 400/100-mg group (38%) had a serious adverse event. Respective rates of all grade 2 to 4 treatment-related adverse events were 20% and 29%. Ten infants in the 300/100-mg group (50%) and 4 in the 400/100-mg group (20%) had a serious adverse event. Three infants in the 300/100-mg group had adverse events considered related to zidovudine: overdose, anemia, and restrictive cardiomyopathy.
Most infants had bilirubin elevations. Statistical analysis found no correlation between atazanavir cord blood levels at days 1, 3, or 5 and infant bilirubin. UGT1A1 function and genotype did correlate with grade of bilirubin elevation in mothers. In infants, average change in bilirubin at day 7 was higher in the 400/100-mg group than in the 300/100-mg group (2.92 versus 1.98 mg/dL). Total bilirubin elevations more than 2.5 times the upper limit of normal affected 13 mothers in the 400/100-mg group and 6 in the 300/100-mg group (62% versus 30%).
The Bristol-Myers Squibb investigators proposed that their findings "indicate that atazanavir/ritonavir 300/100 mg once-daily dosing can provide adequate atazanavir exposure throughout pregnancy and does not result in exacerbation of physiologic hyperbilirubinemia in newborn infants."
Reference
1. Hardy H, Eley T, Child M, et al. The safety, efficacy, and steady state pharmacokinetics of atazanavir/ritonavir during pregnancy: results of study AI424182. 1st International Workshop on HIV and Women. January 10-11, 2011. Washington, DC. Abstract P_18.
|
| |
|
|
|
|
|
