Bilirubin elevation of any grade occurred in 14 of 40 infants (35%). No difference in the time course of bilirubin elevation occurred between infants whose mothers received the

300/100 mg and 400/100 mg doses of ATV/r in the third trimester. Among infants who had elevated bilirubin in the first 14 days, none was elevated to grade 1 because thresholds for grade 1 bilirubins are higher in the first 2 weeks of life to account for normal, physiological bilirubin elevations [21]. Six infants underwent phototherapy (at ages ranging from 3 to 6 days); four infants had 2 days of phototherapy, one had 3 days, and one had 4 days; bilirubin levels associated with these SCH727965 price events ranged from 8.1 to 13 mg/dL. The total bilirubin level was <4 mg/dL in all infants by week 12.

All grade 3–4 bilirubins occurred after day 14; however, levels were decreasing by day 14 in all cases. The infants’ total bilirubin levels on delivery day correlated weakly with the mothers’ total bilirubin levels at delivery (Fig. 3a). When the infants’ total bilirubin levels were compared with the mothers’ bilirubin levels over the last 4 weeks of pregnancy, an PD0332991 in vivo even weaker correlation was observed (Fig. 3b). ATV/r 300/100 mg qd dosing had a lower AUCτ and Cmax in the third trimester of pregnancy compared with the AUCτ and Cmax in nonpregnant adults; however, Cmin values were similar. Increasing the dose of ATV/r to 400/100 mg achieved AUCτ and Cmax values similar to those in nonpregnant adults

and higher Cmin values. ATV concentrations were elevated in the postpartum period. This observation has been made for other protease inhibitors [22–24]. ATV concentrations appear to normalize by week 7 postpartum [18]. The ratio of maternal to cord blood ATV indicates Carnitine palmitoyltransferase II that, as with other protease inhibitors [25], ATV does not freely cross the placenta; however, in this study, plasma protein binding in cord blood was lower than in maternal blood, indicating that free drug concentrations in the fetus were approximately twice as high as in the mothers at a similar total (bound and unbound or ‘free’) ATV plasma concentration [26], suggesting that the levels achieved in the cord blood may provide some antiviral protection to the fetus [18]. A theoretical concern with ATV use during pregnancy is an increase in bilirubin in newborns [1]. This could occur either by passive back-diffusion of infant bilirubin across the placenta, as a result of saturation of protein binding of bilirubin in mothers with elevated maternal bilirubin, or theoretically through the effect of UGT1A1 inhibition in the fetus as a result of ATV crossing the placenta. The placenta normally only allows unidirectional flow of bilirubin from the fetus to the mother, and not from the mother to the fetus.