Objective We evaluated the pharmacokinetics (pk) of raltegravir in HIV-infected women during pregnancy and postpartum. Methods IMPAACT 1026s is an on-going prospective study of antiretroviral pk during pregnancy (NCT00042289). Women receiving 400 mg raltegravir twice daily in combination antiretroviral therapy had intensive steady state 12-hour pk profiles performed during pregnancy and at 6–12 weeks postpartum. Targets were trough concentration above 0.035 µg/mL, the estimated tenth percentile in non-pregnant historical controls. Results Median raltegravir AUC was 6.6 µg*hr/mL for second trimester (n= 16), 5.4 µg*hr/mL for third trimester (n=41), and 11.6 µg*hr/mL postpartum (n= 38) (p=0.03 pp vs 2nd trimester, p=0.001 pp vs third trimester). Trough concentrations were above the target in 69%, 80%, and 79% of second trimester, third trimester and postpartum subjects respectively, with wide variability (<0.010–0.917 µg/mL), and no significant difference between third trimester and postpartum trough concentrations was detected. The median ratio of cord blood/maternal raltegravir concentrations was 1.5. HIV RNA levels were < 400 copies/mL in 92% of women at delivery. Adverse events included elevated liver transaminases in one woman and vomiting in one. All infants with known status are HIV-uninfected. Conclusions Median raltegravir AUC was reduced by approximately 50% during pregnancy; trough concentrations were frequently below target both during late pregnancy and postpartum. Raltegravir readily crossed the placenta. High rates of viral suppression at delivery and the lack of a clear relationship between raltegravir concentration and virologic effect in nonpregnant adults suggest that despite the decreased exposure during pregnancy, a higher dose is not necessary.

Objectives The aim of the study was to describe emtricitabine pharmacokinetics during pregnancy and postpartum. Methods The International Maternal Pediatric and Adolescent AIDS Clinical Trials (IMPAACT), formerly Pediatric AIDS Clinical Trials Group (PACTG), study P1026s is a prospective pharmacokinetic study of HIV-infected pregnant women taking antiretrovirals for clinical indications, including a cohort taking emtricitabine 200 mg once daily. Intensive steady-state 24-hour emtricitabine pharmacokinetic profiles were performed during the third trimester and 6–12 weeks postpartum, and on maternal and umbilical cord blood samples collected at delivery. Emtricitabine was measured by liquid chromatography–mass spectrometry with a quantification limit of 0.0118 mg/L. The target emtricitabine area under the concentration versus time curve, from time 0 to 24 hours post dose (AUC0-24), was ≥7 mg h/L (≤30% reduction from the typical AUC of 10 mg h/L in nonpregnant historical controls). Third-trimester and postpartum pharmacokinetics were compared within subjects. Results Twenty-six women had pharmacokinetics assessed during the third trimester (median 35 weeks of gestation) and 22 postpartum (median 8 weeks postpartum). Mean [90% confidence interval (CI)] emtricitabine pharmacokinetic parameters during the third trimester vs. postpartum were, respectively: AUC: 8.0 (7.1–8.9) vs. 9.7 (8.6–10.9) mg h/L (P = 0.072); apparent clearance (CL/F): 25.0 (22.6–28.3) vs. 20.6 (18.4–23.2) L/h (P = 0.025); 24 hour post dose concentration (C24): 0.058 (0.037–0.063) vs. 0.085 (0.070–0.010) mg/L (P = 0.006). The mean cord:maternal ratio was 1.2 (90% CI 1.0–1.5). The viral load was <400 HIV-1 RNA copies/mL in 24 of 26 women in the third trimester, in 24 of 26 at delivery, and in 15 of 19 postpartum. Within-subject comparisons demonstrated significantly higher CL/F and significantly lower C24 during pregnancy; however, the C24 was well above the inhibitory concentration 50%, or drug concentration that suppresses viral replication by half (IC50) in all subjects. Conclusions While we found higher emtricitabine CL/F and lower C24 and AUC during pregnancy compared with postpartum, these changes were not sufficiently large to warrant dose adjustment during pregnancy. Umbilical cord blood concentrations were similar to maternal concentrations.

ObjectivesOur objective was to evaluate the pharmacokinetics of nelfinavir (NFV) (625 mg tablets) 1250 mg twice daily during pregnancy and postpartum. MethodsThe participants were HIV-1-infected pregnant women enrolled in P1026s and receiving NFV (625 mg tablets) 1250 mg twice daily as part of routine clinical care. Intensive steady-state 12-h NFV pharmacokinetic profiles were performed during pregnancy and postpartum. The target NFV area under the plasma concentration-time curve (AUC 0-12 ) was ! 10th percentile NFV AUC 0-12 in non-pregnant historical controls (18.5 mg h/mL). ResultsOf 27 patients receiving NFV, pharmacokinetic data were available for four (second trimester), 27 (third trimester) and 22 (postpartum) patients. The NFV maximum concentration (C max ), 12-h post-dose concentration (C 12 ) and AUC 0-12 were significantly lower during the third trimester compared to postpartum (P 0.03). The metabolite hydroxyl-tert-butylamide (M8) AUC 0-12 and the M8/NFV AUC ratio were lower during the third trimester compared to postpartum (Po0.01). The NFV AUC 0-12 exceeded the AUC 0-12 target for 15/27 (56%) and 21/22 (95%) of third trimester and postpartum patients, respectively. The minimum concentration (C min ) was above the suggested minimum trough concentration (0.8 mg/mL) in 15% (third trimester) and 18% (postpartum). The plasma viral load was o400 HIV-1 RNA copies/mL in 81% of patients at delivery. ConclusionsThese results suggest that higher doses of NFV should be considered during pregnancy.Keywords: HIV, nelfinavir, pharmacokinetics, pregnancy IntroductionMany HIV-infected pregnant women receive nelfinavir (NFV) as part of their antiretroviral (ARV) regimens, whether for treatment or as a component of combination ARV regimens for the prevention of mother-to-child transmission of HIV. During pregnancy, physiological changes can result in changes in the absorption, distribution, metabolism and elimination of drugs. Previous data indicated that NFV exposure was inadequate in most pregnant women receiving NFV as 250 mg tablets at a dose of 750 mg orally three times daily [1]. Subsequent studies suggested that NFV exposure remained inadequate with 1250 mg taken orally twice daily [2][3][4].More recently, a new formulation of NFV as 625 mg tablets has been approved for use. In non-pregnant adults, the bioavailability of NFV is increased following Patients and methodsP1026s is an ongoing, multi-centre, prospective study of ARV pharmacokinetics among HIV-infected pregnant women receiving ARVs for routine clinical care. The current analyses address only those women using NFV. P1026s is a sub-study of P1025, a prospective cohort study of HIV-infected pregnant women receiving care at PACTG sites. Institutional review boards approved both P1025 and P1026s at all participating sites. All participants provided written informed consent prior to participation in these studies. Participants were eligible for inclusion in the NFV arm of P1026s if they met the following criteria: they were HIVinfected pregnant women ! ...

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