For AUC, the criterion was set at a geometric mean of 30 000 ng h/mL based on our rationale that a reduction of up to 30% in ATV AUC would not compromise outcome. The criteria for a dose increase within the current study were based on the assumption that, although exposures were likely to be lower in pregnant patients, the relationship between these AUC and Cmin values would be largely consistent with that in nonpregnant patients. Reductions of 20–30% in ATV AUC and Cmin were observed when ATV was given in combination with tenofovir, with no apparent loss of antiviral effect [35]. Indeed, the recent CASTLE study (AI424138) indicated that, even though tenofovir

lowered ATV exposures, the antiviral efficacy was very good and comparable to that for twice-daily lopinavir/RTV to

96 weeks [36]. In this study, the JNK inhibitor lowest observed AUC fell below the range of historical reference Ribociclib values, but the relationship between AUC and Cmin differed in this population, where Cmin values were higher than in nonpregnant patients at similar AUC values. At ATV/r 300/100 mg qd, the range of observed Cmin values in the third trimester was very comparable to the historical reference [interquartile range 455.5–986.0 ng/mL (current study) vs. 370–1035.3 ng/mL (historical)]. Furthermore, with data from 20 patients, the geometric mean AUC for 300/100 mg qd meets the predefined criterion for AUC. Although this result appears to conflict the interim analysis with 12 patients, considering the known variability in ATV pharmacokinetics, these two estimates of the population mean are not incompatible. On the basis of the pharmacokinetic data in this study, RVX-208 particularly Cmin,

a dose adjustment does not appear to be necessary during pregnancy. The seeming disconnect between the decision to study a second cohort at 400/100 mg qd and the recommendation of 300/100 mg qd is based in large part on the differing relationship between AUC and Cmin in this population. After reviewing the pharmacokinetic data as a whole, the dosing recommendation is rational despite this apparent contradiction within the study. Any consideration of a dose increase should also take relative safety profiles and ease of compliance with a new dosing regimen into account. For the latter consideration, switching from one 300 mg capsule to two 200 mg capsules of ATV at the beginning of the third trimester may lead to dosing errors and compliance problems. In this regard, not having to dose-adjust during pregnancy and complicate the ATV/r 300/100 mg treatment regimen could be viewed as a potential benefit. Regarding safety considerations, both ATV/r 300/100 mg and 400/100 mg were well tolerated with no unexpected, related adverse events; however, maternal grade 3–4 hyperbilirubinaemia occurred more frequently at the higher dose.