Pharmacokinetics of tenofovir during pregnancy and postpartum.

OBJECTIVES: Tenofovir disoproxil fumarate (TDF) is increasingly used in the highly active antiretroviral therapy (HAART) regimens of pregnant women, but limited data exist on the pregnancy pharmacokinetics of chronically dosed TDF. This study described tenofovir pharmacokinetics during pregnancy and postpartum. METHODS: International Maternal Pediatric and Adolescent AIDS Clinical Trials (IMPAACT) P1026s is a prospective, nonblinded pharmacokinetic study of HIV-infected pregnant women that included a cohort receiving 300 mg TDF once daily. Steady-state 24-hour pharmacokinetic profiles were measured at the second and third trimesters, postpartum, and in maternal and umbilical cord samples collected at delivery. Tenofovir was measured by liquid chromatography-mass spectrometry (LC-MS). The target area under the concentration versus time curve from time 0 to 24 h post dose (AUC) was ≥ 1.99 µg h/mL (nonpregnant historical control 10th percentile). RESULTS: The median tenofovir AUC was decreased during the second (1.9 µg h/mL) and third (2.4 µg h/mL; P = 0.005) trimesters versus postpartum (3.0 µg h/mL). Tenofovir AUC exceeded the target for two of four women (50%) in the second trimester, 27 of 37 women [73%; 95% confidence interval (CI) 56%, 86%] in the third trimester, and 27 of 32 women (84%; 95% CI 67%, 95%) postpartum (P > 0.05). Median second/third-trimester troughs were lower (39/54 ng/mL) than postpartum (61 ng/mL). Median third-trimester weight was greater for subjects below the target AUC versus those above the target (97.9 versus 74.2 kg, respectively; P = 0.006). The median ratio of cord blood to maternal concentrations was 0.88. No infants were HIV infected. CONCLUSIONS: This study found lower tenofovir AUC and troughs during pregnancy. Transplacental passage with chronic TDF use during pregnancy was high. Standard TDF doses appear to be appropriate for most HIV-infected pregnant women but therapeutic drug monitoring with dose adjustment should be considered in pregnant women with high weight (> 90 kg) or inadequate HIV RNA response.

Alteration in cytochrome P450 3A4 activity as measured by a urine cortisol assay in HIV-1-infected pregnant women and relationship to antiretroviral pharmacokinetics.

OBJECTIVES: Pregnancy results in physiological changes altering the pharmacokinetics of drugs metabolized by cytochrome P450 3A4 (CYP3A4). The urinary ratio of 6-ß hydroxycortisol to cortisol (6ßHF : F) is a marker of CYP3A4 induction. We sought to evaluate its change in antiretroviral (ARV)-treated HIV-1-infected women and to relate this change to ARV pharmacokinetics. METHODS: Women receiving various ARVs had pharmacokinetic evaluations during the third trimester of pregnancy (>30 weeks) and postpartum with determination of 6ßHF : F carried out on the same days. The Wilcoxon signed rank test was used to compare the ratio antepartum to postpartum. The relationship between the change in ratio and the change in pharmacokinetics was analysed using Kendall's tau. RESULTS: 6ßHF : F ratios were available for 107 women antepartum, with 54 having postpartum values. The ratio was higher antepartum (P=0.033) (median comparison 1.35; 95% confidence interval 1.01, 1.81). For 71 women taking a protease inhibitor (PI), the antepartum vs. postpartum 6ßHF : F comparison was marginally significant (P=0.058). When the change in the 6ßHF : F ratio was related to the change in the dose-adjusted ARV area under the plasma concentration vs. time curve (AUC) between antepartum and postpartum, the 35 subjects in the lopinavir/ritonavir (LPV/r) arms demonstrated an inverse relationship (P=0.125), albeit this correlation did not reach statistical significance. CONCLUSIONS: A 35% increase in the urinary 6ßHF : F ratio was measured during late pregnancy compared with postpartum, indicating that CYP3A induction occurs during pregnancy. The trend towards an inverse relationship between the change in the 6ßHF : F ratio and the change in the LPV AUC antepartum vs. postpartum suggests that CYP3A induction may be one mechanism behind altered LPV exposure during pregnancy.

Effect of pregnancy on emtricitabine pharmacokinetics.

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 (AUC(0-24) ), 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 (C(24) ): 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 C(24) during pregnancy; however, the C(24) was well above the inhibitory concentration 50%, or drug concentration that suppresses viral replication by half (IC(50) ) in all subjects. CONCLUSIONS: While we found higher emtricitabine CL/F and lower C(24) 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.

Lopinavir protein binding in HIV-1-infected pregnant women.

BACKGROUND: Pregnancy may alter protein binding (PB) of highly bound protease inhibitors due to changes in plasma concentrations of albumin and alpha-1 acid glycoprotein (AAG). Small changes in PB can greatly impact the fraction of drug unbound (FU) exerting pharmacological effect. We report lopinavir (LPV) PB during third trimester (antepartum, AP) compared to > or =1.7 weeks postpartum (PP) to determine if FU changes compensate for reduced total concentrations reported previously. METHODS: P1026s enrolled women receiving LPV/ritonavir, soft gel capsules 400/100 mg or 533/133 mg twice daily. LPV FU, albumin and AAG were determined AP and PP. RESULTS: AP/PP samples were available from 29/25 women respectively with all but one woman receiving the same dose AP/PP. LPV FU was increased 18% AP vs. PP (mean 0.96+/-0.16% AP vs. 0.82+/-0.21% PP, P=0.001). Mean protein concentrations were reduced AP (AAG=477 mg/L; albumin=3.28 mg/dL) vs. PP (AAG=1007 mg/L; albumin=3.85 mg/dL) (P<0.0001 for each comparison). AAG concentration correlated with LPV binding. Total LPV concentration did not correlate with LPV FU AP or PP. However, higher LPV concentration PP was associated with reduced PB and higher FU after adjustment for AAG. CONCLUSIONS: LPV FU was higher and AAG lower AP vs. PP. The 18% increase in LPV FU AP is smaller than the reduction in total LPV concentration reported previously and is not of sufficient magnitude to eliminate the need for an increased dose during pregnancy.

Should antiretroviral therapy for HIV infection be tailored for intracerebral penetration?

The continuous replication of HIV-1 in the central nervous system, in particular the brain, and its potential long-term deleterious effect is the focus of this review. Cognitive deficits are observed in a significant percentage of HIV-1-infected patients. That may occur despite successful peripheral suppression of the HIV-1 replication. Compartmentalisation of HIV-1 in the brain, genetic mutation of HIV-1, age, HCV coinfection and poor intracerebral penetration, as well as possibly a direct toxic effect of antiretroviral drugs, are factors that may account for potential creeping damage of the brain after many years of treatment. Patients with neurological symptoms or cognitive deficits may require another approach to the treatment of their HIV infection.

Pharmacokinetics of new 625 mg nelfinavir formulation during pregnancy and postpartum.

OBJECTIVES: Our objective was to evaluate the pharmacokinetics of nelfinavir (NFV) (625 mg tablets) 1250 mg twice daily during pregnancy and postpartum. METHODS: The 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 >or=10th percentile NFV AUC(0-12) in non-pregnant historical controls (18.5 microg h/mL). RESULTS: Of 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