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.
ObjectivesTo determine the impact of pregnancy on the pharmacokinetics (PK) of nevirapine (NVP) during chronic dosing in HIV-infected women and appropriate NVP dosing in this population. MethodsTwenty-six pregnant women participating in two open-label Pediatric AIDS Clinical Trials Group studies (P1022 and P1026S) were evaluated. Each patient received 200 mg NVP every 12 h and had PK evaluations during the second or third trimester; these evaluations were repeated postpartum. Paired maternal and cord blood NVP concentrations were collected at delivery in nine patients. Ante-and postpartum comparisons were made using paired t-tests and using a 'bioequivalence' approach to determine confidence interval (CI). ResultsThe average NVP Area Under the Curve (AUC) was 56 AE 13 mcg*h/mL antepartum and 61 AE 15 mcg*h/mL postpartum. The typical parameters AE standard error were apparent clearance (CL/F) 5 3.51 AE 0.18 L/h and apparent volume of distribution (Vd/F) 5 121 AE 19.8 L. There were no significant differences between antepartum and postpartum AUC or pre-dose concentrations. The AUC ratio was 0.90 with a 90% CI of the mean equal to 0.80-1.02. The median ( AE standard deviation) cord blood to maternal NVP concentration ratio was 0.91 AE 0.90. ConclusionsPregnancy does not alter NVP PK and the standard dose (200 mg every 12 h) is appropriate during pregnancy.Keywords: HIV, nevirapine, non-nucleoside reverse transcriptase, pharmacokinetics, pregnancy IntroductionMother-to-child transmission of HIV-1 can be greatly reduced if the maternal viral loads are below the limit of detection at delivery [1]. To achieve this target, combination antiretroviral (ARV) therapy, consisting of two nucleoside reverse transcriptase inhibitors (NRTIs) plus a protease inhibitor (PI) or a non-nucleoside reverse transcriptase inhibitor (NNRTI), is recommended. Although efavirenz (EFV) is the preferred NNRTI in the general population, it has been found to cause severe central nervous system defects when given to primates during the Physiological and hormonal changes associated with pregnancy can have profound effects on drug disposition, including increased plasma volume and reduced plasma protein concentration, increased renal blood flow and modified metabolic enzyme activity. Several ARVs have been studied in pregnancy, with some exhibiting significant alterations in pharmacokinetics (PK), requiring drug dose modifications or avoidance [5,6].The antiviral effects of NVP are rapid, with significant reduction in plasma virus. However, development of viral resistance to NVP can occur with a single mutation in the HIV-1 reverse transcriptase gene [7]. NVP is metabolized primarily in the liver by the cytochrome P450 (CYP) 2B6 and 3A family enzymes [8,9]. Low NVP concentrations have been associated with inadequate viral suppression [10] and may also contribute to NNRTI resistance [11]. The PK of single-dose NVP to mothers at delivery have been described [12,13], but welldesigned PK studies of continuous NVP therapy in pregnancy have not been pub...
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 ! ...
HIV-1 p24 antibody, HIV-1 RNA and CD4 cell percentage independently predict mortality amongst infected children. Whereas CD4 cell percentage provides an estimate of the general degree of immune suppression, HIV-1 p24 antibody could provide an easily obtained, inexpensive assessment of CD4 cell function and could augment prognostic information provided by CD4 cell count and viral load for clinical management of infected children.
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