4.7 Article

Population Pharmacokinetics of Tenofovir in Pregnant and Postpartum Women Using Tenofovir Disoproxil Fumarate

期刊

出版社

AMER SOC MICROBIOLOGY
DOI: 10.1128/AAC.02168-20

关键词

HIV; AIDS; TDF; population pharmacokinetics; postpartum; pregnancy; tenofovir; tenofovir disoproxil fumarate

资金

  1. National Center for Advancing Translational Sciences of the National Institutes of Health [UL1TR000423]
  2. National Center for Advancing Translational Sciences through UCLA CTSI [UL1TR000124]
  3. NIH/NCATS Colorado CTSI [UL1 TR000154]
  4. University of Maryland Clinical Translational Science Institute
  5. University of Maryland General Clinical Research Center
  6. National Institute of Allergy and Infectious Diseases (NIAID)
  7. Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), components of the National Institutes of Health (NIH) [UM1AI068632, UM1AI068616, UM1AI106716]
  8. National Institute of Mental Health (NIMH), components of the National Institutes of Health (NIH) [UM1AI068632, UM1AI068616, UM1AI106716]
  9. NICHD [HHSN275201800001I]

向作者/读者索取更多资源

The pharmacokinetics of tenofovir in pregnant and postpartum women were affected by changes in apparent oral clearance and volume of distribution at steady state. These changes were primarily associated with increased body weight and enhanced renal function during pregnancy, leading to higher clearance rates compared to postpartum values. Dose adjustment of tenofovir disoproxil fumarate during pregnancy is generally not necessary, but any modifications should be made based on considerations of weight and renal function.
Pharmacokinetics of drugs can be affected by physiologic changes during pregnancy. Our aim was to assess the influence of covariates on tenofovir (TFV) pharmacokinetics in pregnant and postpartum women receiving tenofovir disoproxil fumarate (TDF). Population pharmacokinetic parameter estimates and the influence of covariates were assessed using nonlinear mixed-effects modeling (NONMEM 7.4). Forty-six women had intensive pharmacokinetic evaluations during the second and third trimesters of pregnancy, with another evaluation postpartum. A two-compartment pharmacokinetic model with allometric scaling for body weight and first-order absorption best described the tenofovir plasma concentration data. Apparent oral clearance (CUF) and volume of distribution at steady state (V-ss/F) were increased during pregnancy. Weight, serum creatinine (SCr), pregnancy, albumin, and age were associated with TFV CUF during univariate assessment, but in the multivariate analysis, changes in CUF and V-ss/F were only associated with increased body weight and enhanced renal function. Due to greater weight and lower SCr during pregnancy, CU F was 28% higher during pregnancy than postpartum. In the final model, CUF (liters per hour) was described as 2.07 x (SCr/0.6)(0.65) x weight(0.)(75), with a low between-subject variability (BSV) of 24%. The probability of target attainment (proportion exceeding area under the concentration-time curve of >1.99 mu g.h/ml, the 10th percentile of average TFV exposure for nonpregnant historical controls) was 68%, 80%, 87%, and 93% above the target with 300 mg, 350 mg, 400 mg, and 450 mg of TDF, respectively, during pregnancy and 88%, 92%, 96%, and 98% above the target with same doses in postpartum women. Dose adjustment of TDF during pregnancy is not generally warranted, but any modification should be based on weight and renal function.

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