Here we describe the total and unbound pharmacokinetics of LPV in two cohorts of pregnant women: one cohort receiving the standard LPV/r SGC dose of 400/100 mg twice daily and the other receiving standard dosing of the LPV tablet (400/100 mg twice daily). Although LPV exposure was reduced during the third trimester in both cohorts, concentrations were adequate (>1,000 ng/ml) in the majority of women studied.
In cohort 1, none of the women had pharmacokinetic samples taken postpartum. Most received short-term ART (START) during pregnancy and therefore discontinued treatment shortly after delivery. Likewise, fewer patients underwent pharmacokinetic sampling in the second trimester, mainly due to late presentation and because early commencement of START in asymptomatic mothers was deemed to be necessary only in women with high baseline plasma pVLs.
In cohort 2, only five patients continued treatment and underwent PK sampling postpartum. As a result, the power of the study to show differences attributable to pregnancy was limited, since statistical techniques analyzing the data as antepartum-postpartum pairs (which exclude the effect of intersubject variability) could not be performed. Nonetheless, LPV antepartum and postpartum predose concentrations (0-h morning concentration, equivalent to a therapeutic drug monitoring [TDM] Ctrough
) were comparable to those in studies investigating LPV tablet pharmacokinetics in pregnant women undergoing routine TDM (20
). In the only other intensive pharmacokinetic study, Best and colleagues (3
) reported LPV pharmacokinetics in HIV-infected pregnant women receiving an increased tablet dose (600/150 mg twice daily) in the third trimester and standard dosing (400/100 mg twice daily) in the second trimester and at 2 weeks postpartum. The LPV AUC0–12
in the second trimester was significantly reduced (median, 72 μg · h/ml) compared with that in patients receiving an upward dose adjustment in the third trimester (median, 96 μg · h/ml), and both second and third trimester AUC0–12
s were significantly lower than the AUC0–12
postpartum (median, 133 μg · h/ml). The authors concluded that the higher tablet dose should be used in both the second and third trimesters, on the basis of the finding that subjects had LPV exposures in the third trimester similar to those of nonpregnant adults receiving the standard 400/100-mg tablet dose (~98 μg · h/ml) (3
). Interestingly, however, LPV exposures at 2 weeks postpartum were relatively high, despite the fact that subjects were reverted back to standard (400/100-mg twice daily) dosing postdelivery. This may have, in turn, accounted for the statistical differences between antepartum and postpartum pharmacokinetics reported in this study.
One limitation is that postpartum pharmacokinetics may not necessarily reflect true exposure in nonpregnant women, as, depending on the time of pharmacokinetic sampling postdelivery, the physiological changes associated with pregnancy that result in decreased plasma concentrations may not have fully resolved. On the basis of LPV/r (tablet) pharmacokinetic data from a study of Boffito et al. (6a
) performed in 16 (6 female) HIV-negative healthy volunteers, LPV postpartum pharmacokinetics in the current study were comparable to those of nonpregnant adults and may therefore provide a more reasonable estimation of reduced LPV exposure during pregnancy. Comparison of these data is justified since there are no reported differences in LPV pharmacokinetics between healthy volunteers and HIV-infected subjects (9
) or any known gender-related differences in LPV pharmacokinetics (27
Previous studies had found no significant difference in LPV trough concentrations between pregnant patients receiving standard doses of the SGC and patients receiving the tablet formulations (17
). Equally, we observed equivalent LPV trough concentrations in both cohorts; however, total LPV exposure and maximum concentrations were nonsignificantly higher in patients taking the tablet (cohort 2; n
= 11) than those receiving the SGC (cohort 1; n
= 6). We recognize that there are statistical limitations in comparing independent cohorts, especially given that the intersubject variability in protease inhibitor concentrations invariably exceeds the intrasubject variability. Nonetheless, the approximate 15% and 25% increases in LPV exposure and maximum concentrations, respectively, in cohort 2 were consistent with the reported 18% increase in oral bioavailability of the LPV/r tablet described in healthy volunteers (18
In addition, a relative 27% increase of the percent AUCunbound
LPV in the second trimester and 17% increase in the third trimester compared with that postpartum in patients receiving the LPV tablet (cohort 2) may compensate, to a certain extent, only for the overall decrease in total LPV exposure seen during pregnancy. These data are consistent with those reported by Aweeka and colleagues (1
). Previous evaluations by Lambert et al. (20
) also revealed no significant changes in the fraction of unbound LPV antepartum versus postpartum in patients receiving standard dosing of the LPV tablet. Interestingly, the percent unbound values reported were lower (first/second trimester = 1.01% [n
= 16]; third trimester = 0.83% [n
= 43]; postpartum = 0.96% [n
= 12]) than the percent AUCunbound
values described here. One explanation is that Lambert et al. (20
) measured only LPV trough concentrations, taken at approximately 12 to 14 h postdosing (roughly equivalent to a Cpredose
[0-h] sample) as part of routine TDM. Upon analysis of the pharmacokinetic profiles in the current study (cohort 2; b), it is apparent that LPV exhibits concentration-dependent binding, a phenomenon that has been observed previously (6
), in which unbound concentrations and the percentage of unbound LPV are higher during the absorptive and maximum phases of the dosing interval, thereby accounting for a higher overall percent AUCunbound
. These data highlight the importance of intensive pharmacokinetic studies, which provide a more meaningful representation of drug distribution over the course of an entire dosing interval.
The implication of lower LPV exposure during pregnancy and the drug's limited placental transfer in terms of both the maternal virologic response and the risk of intrapartum MTCT remains undefined. A degree of assurance can be gained from the low rates of virologic failure and vertical HIV transmission among pregnant women stable on LPV/r-based regimens, with many achieving full viral suppression at the time of delivery and in certain cases being able to deliver vaginally. It is also likely that a substantial prophylactic benefit to the fetus occurs through coadministered nucleoside analogues, which are known to achieve high concentrations in the placenta (8
) and female genital tract (11
). In the current study (with ~63% treatment-naive patients), despite a reduction in LPV exposure during the third trimester in both cohorts, LPV concentrations were adequate (>1,000 ng/ml) in the majority of women studied. However, this proposed efficacy target relates only to naive patients without PI mutations. The impact of low protease inhibitor concentrations upon viral resistance (systemic and compartmentalized) and response in treatment-experienced patients remains a concern, especially as lower LPV concentrations have been associated with the development of resistance in experienced subjects (7
). For protease inhibitor-experienced patients, an efficacy target of 4,000 ng/ml has been proposed, as this was shown to be associated with achieving and maintaining an undetectable viral load in this population (7
). In cohort 1 (SGC), 33% and 83% of patients had LPV plasma concentrations below 4,000 ng/ml in the second and third trimesters, respectively. In cohort 2 (tablet), 33%, 91%, and 20% had LPV plasma concentrations below this target in the second and third trimesters and postpartum, respectively.
In previous cohorts, rates of detectable viral loads at delivery ranged from 6 to 16%; however, most present only isolated cases of detectable viremia or virologic failure specifically associated with subtherapeutic LPV concentrations during pregnancy (17
); in certain cases, these may have been due to poor treatment compliance (20
). However, Peytavin et al. found in a large patient cohort (n
= 101) that LPV trough concentrations in the second and third trimesters were statistically correlated with pVL at delivery (29
). It is worth noting that an inability to achieve viral suppression at delivery may be more closely associated with a patient's pretreatment viral load and/or the timing of short-course ART initiation in naive subjects than a reflection of LPV/r efficacy or pharmacokinetics per se
. For instance, Read et al. found that in patients with high baseline pVLs (>100,000), early initiation of treatment (<20 weeks) increased the likelihood of achieving an undetectable viral load at delivery (31
On the other hand, unnecessary upward dose adjustments of the tablet formulation could result in excessive exposure of the fetus to the drug, which may have implications upon fetal organogenesis, growth, and development. Indeed, despite the obvious benefits of ART in preventing MTCT, concerns remain over an association between PI-containing ART and the prevalence of preterm delivery, low birth weight, and fetal abnormalities. While LPV/r is classified in pregnancy category C by the Food and Drug Administration (28
), the European Medicines Agency-approved label rightly highlights the lack of any teratogenicity signal in more than 600 prospective reports to the Antiretroviral Pregnancy Register (APR). The potential association of protease inhibitor-based ART use at conception and during early pregnancy with the risk of other adverse pregnancy outcomes remains controversial, with many studies yielding discordant results. In collated data from all LPV/r-exposed pregnancies enrolled with the APR from September 2000 to July 2007, 13.4% of infants were born prematurely (<37 weeks gestation) and infants exposed in the first trimester had an increased likelihood of PTD and low birth weight than infants whose earliest exposure occurred later in the second/third trimester (32
); other studies have reported similar findings (4
). However, this has not been consistently proven, with some authors reporting no differences in PTD risk between women initiating ART later in pregnancy and those already receiving ART preconception (35
). Discrepancies between studies may be linked to patient and practice heterogeneity, as HIV disease stage, HIV-1 RNA load, and CD4 count are all potential confounders of timing of ART initiation in pregnancy and adverse pregnancy outcomes. For instance, women with advanced HIV infection are more likely to deliver prematurely and to receive ART early during pregnancy (38
). In the current study, there were six (32%) preterm deliveries, which is consistent with other reports (23
). Three mothers were treatment naive and commenced LPV/r treatment in the late second or early third trimester. Interestingly, recent data have suggested that RTV-boosted PI, compared with nonboosted PI, was associated with an increased incidence of complications during pregnancy and induced premature births (33
). It is unclear whether such an association, if confirmed, would be driven by RTV per se
or by higher concurrent PI concentrations; nonetheless, caution should be exercised, particularly with upward dose adjustments of the LPV/r tablet, given that the RTV boosting dose will also be increased. More studies specifically powered to evaluate a possible association between LPV (and low-dose RTV) pharmacokinetics following early and late LPV exposures during pregnancy and risk of PTD (as well as other adverse pregnancy outcomes) in HIV-infected mothers receiving LPV/r based ART are needed.
In conclusion, despite a significant reduction in LPV exposure during the later stages of pregnancy, all women receiving the tablet formulation achieved adequate LPV concentrations (>1,000 ng/ml), suggesting that standard (400/100-mg twice daily) dosing of the LPV/r tablet, in combination with nucleoside analogues, is a suitable induction or maintenance strategy for use in treatment-naive patients during pregnancy. Furthermore, the higher total and unbound LPV exposures achieved in women receiving the tablet than in those receiving the SGC suggests that the improved oral bioavailability of the tablet may compensate for the reduction in LPV exposure during the later stages of pregnancy and, in turn, reduce the concern surrounding the need to adjust the dose in naive patients during the third trimester. Nonetheless, the concern over poor treatment compliance or subtherapeutic (<4,000 ng/ml) LPV concentrations and associated viral resistance in treatment-experienced patients justifies TDM and adjustment of the LPV/r dose accordingly. We await pharmacokinetic data from patients receiving the LPV/r tablet at a dosage of 500/125 mg twice daily by substitution of a pediatric LPV/r 100/25-mg tablet, which may provide a viable alternative for certain cases.