Randomized Clinical Trial Comparing the Pharmacokinetics of Standard- and Increased-Dosage Lopinavir-Ritonavir Coformulation Tablets in HIV-Positive Pregnant Women

Abstract

A lopinavir-ritonavir (LPV/r)-based regimen is recommended during pregnancy to reduce the risk of HIV mother-to-child transmission, but the appropriate dose is controversial. We compared the pharmacokinetics of standard and increased LPV/r doses during pregnancy. This randomized, open-label prospective study enrolled 60 pregnant women between gestational weeks 14 and 30. The participants received either the standard dose (400/100 mg twice a day [BID]) or increased dose (600/150 mg BID) of LPV/r tablets during pregnancy and the standard dose for 6 weeks after childbirth. Pharmacokinetics analysis was performed using a high-performance liquid chromatography-tandem mass spectrometry method. Adherent participants who received the standard dose presented minimum LPV concentrations of 4.4, 4.3, and 6.1 g/ml in the second and third trimesters and postpartum, respectively. The increased-dose group exhibited values of 7.9, 6.9, and 9.2 g/ml at the same three time points. Although LPV exposure was significantly higher in the increased-dose group, the standard dose produced therapeutic levels of LPV against wild-type virus in all adherent participants, except one patient in the third trimester; 50%, 37.5%, and 25%, and 0%, 15%, and 0% of the participants in the standard-and increased-dose groups failed to achieve therapeutic levels against resistant viruses during the second and third trimesters and after childbirth, respectively. After 12 weeks of treatment and after childbirth, all adherent participants achieved undetectable HIV viral loads, and their babies (49/54) were uninfected. No serious drug-related adverse events were observed. We conclude that the standard dose is appropriate for use during pregnancy and that an increased dose may be necessary for women harboring resistant HIV. (This study has been registered at ClinicalTrials.gov under registration no. NCT00605098.)

Population Approach To Analyze the Pharmacokinetics of Free and Total Lopinavir in HIV-Infected Pregnant Women and Consequences for Dose Adjustment

“…A one-compartment model with linear absorption and elimination satisfactorily describes the unbound (unbound model) and total (MFLA model) LPV concentrations in pregnant women. The following observations supported the models developed: the mean half-life value of LPV (5.5 h) and the median CL (5.72 liters/h) were consistent with previous reports (between 5.5 and 5.9 h and between 4.9 to 9 liters/h, respectively) (15)(16)(17)38). The unbound fraction (F u ) was estimated by using the trough concentration; in pregnant women, the median F u was 1.5%.…”

No Need for Lopinavir Dose Adjustment during Pregnancy: a Population Pharmacokinetic and Exposure-Response Analysis in Pregnant and Nonpregnant HIV-Infected Subjects

“…Conflicting reports on the fraction of LPV unbound during pregnancy have been reported. One study demonstrated no change in the fraction of LPV unbound, and four studies reported an increase in the fraction of LPV unbound (16,20,28,47,48). An increase in the fraction unbound may potentially offset at least part of the increase of the LPV clearance during pregnancy.…”

“…Table 1 summarizes the clinical studies used in this analysis and their dosing and pharmacokinetic sampling schemes. Study 1 was a randomized, open-label prospective study that enrolled 53 HIV-infected pregnant women between 14 and 30 weeks of gestation (20). Subjects were randomized in a 1:1 ratio to receive LPV/r tablets either at 400/100 mg BID or 600/150 mg BID during pregnancy; all participants then received LPV/r at 400/100 mg BID for at least 6 weeks postpartum.…”

“…Several clinical studies have demonstrated LPV/r efficacy in achieving virologic suppression in mothers during pregnancy and preventing HIV transmission to their children (9)(10)(11)(12)(13)(14)(15)(16). Reports of higher LPV clearance during pregnancy have prompted some investigators to propose the use of a higher dose during the third trimester, while others advocated no adjustment to the standard 400/100-mg twice-daily (BID) regimen (17)(18)(19)(20). As an important component of cART given during pregnancy, further assessment of LPV/r dosing during pregnancy would support its appropriate use in this population.…”

Adverse drug reactions associated with antiretroviral therapy during pregnancy

“…The protective effect of maternal ART on HIV transmission to infants was demonstrated in retrospective and prospective observational studies, randomized clinical trials, systematic reviews and meta-analyses [49,50,47,[51][52][53][54][55][56] . The other benefits of ART during pregnancy are delayed disease progression in the women [50] and reduced risk of HIV transmission to HIV-serodiscordant partners [57].…”