Pregnancy-Related Effects on Tenofovir Pharmacokinetics: a Population Study with 186 Women

Abstract

According to the European AIDS Clinical Society, tenofovir disoproxil fumarate can be used in HIV-infected pregnant women if started prior to pregnancy, although no data are available on the pharmacokinetics of tenofovir (TFV) during pregnancy. The aim of this study was to describe TFV pharmacokinetics in HIV-infected women and to evaluate the effect of pregnancy on TFV disposition. Samples were collected according to a therapeutic drug monitoring in 186 women, including 46 pregnant women treated with TFV and retrospectively analyzed by a population approach. TFV pharmacokinetics were ascribed to an open two-compartment model with linear absorption and elimination. The mean population parameter estimates (between-subject variability) were as follows: absorption rate constant, 0.56 h ؊1 ; elimination clearance, 59.9 liters h ؊1 (0.436); central volume of distribution, 552 liters (1.96); intercompartmental clearance, 172 liters/h; and peripheral volume of distribution, 1,390 liters. Pregnant women had a 39% higher apparent clearance compared to nonpregnant women. Apparent clearance significantly decreased with age. In order to obtain an exposure similar to the known exposure in adults and guarantee similar trough concentrations (C min ) as observed in adults, an increase in the TFV dose should be considered for women from the second trimester to delivery. Because of the lack of data on the use of tenofovir disoproxil fumarate (TDF) in pregnancy and concerns over possible bone toxicity, U.S. guidelines recommend that TDF-based highly active antiretroviral therapy (HAART) should be used only after careful considerations of alternatives (8). However, for women who were already treated by TDF prior to pregnancy, European AIDS Clinical Society guidelines recommend to continue the TDF treatment during pregnancy. Thus, in these therapeutic drug monitoring data, some women were taking TDF during their pregnancy in the first, second, and third trimester.TDF is already taken during pregnancy at the same dose as in adults although physiological changes associated with pregnancy can lead to significant variations in pharmacokinetics (modified absorption, distribution, and elimination). No pharmacokinetic data on the use of TDF before the 38th week of pregnancy are available. Two studies restricted to late pregnancy and labor suggest that tenofovir (TFV) exposure is lower than nonpregnant adult exposure (9, 16).We performed here a population pharmacokinetic study of women during pregnancy, at delivery, and out of pregnancy in order to investigate TFV pharmacokinetics throughout pregnancy. MATERIALS AND METHODSPatients and treatments. The population included nonpregnant women, pregnant women, and women on the day of delivery receiving oral TFV for treatment of HIV infection and whose antiretroviral drug plasma concentrations were monitored on a routine basis. TFV was administered chronically using a 300-mg once-daily regimen. For each woman, the time elapsed between administration and sampling times, the time of dosing, the bod...

Population Pharmacokinetics of Tenofovir in HIV-1-Uninfected Members of Serodiscordant Couples and Effect of Dose Reporting Methods

“…Creatinine clearance was a significant covariate of clearance and is biologically meaningful because tenofovir is a renally cleared drug. The population pharmacokinetic parameters are in general agreement with those in previous reports (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16).…”

“…However, reliable dosing records and informative pharmacokinetic sampling are important for unbiased pharmacokinetic parameter estimation. Several population pharmacokinetic models for tenofovir have been reported (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16). However, all of them include data from HIV-1-infected subjects or a mix of healthy and HIV-infected subjects (7), except for our recent reports on a population of healthy women (15,16).…”

“…Population pharmacokinetics of tenofovir for HIV-infected patients have been described previously by several authors (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16), but none of them used electronic monitoring for adherence. We previously reported population pharmacokinetic models for tenofovir in plasma (15) and for tenofovir in plasma and intracellular tenofovir diphosphate in healthy women (16), with different methods of adherence correction utilizing superposition principles within the model framework.…”

Preventing Perinatal Transmission of HBV: An Australian Perspective

“…A study in lactating rhesus macaques showed that tenofovir concentrations in breast milk corresponded to 20 % of the serum values [46]. After maternal tenofovir injection, human breast milk concentrations of tenofovir are very low and it has been calculated that nursing infants would be exposed to less than 2 % of the oral infant therapeutic dose [47]. Overall these findings are very reassuring and should be discussed with a mother in the context of her wishes about breastfeeding and the plans to continue tenofovir post-partum.…”

11.0 References

“…Renal excretion of didanosine is increased in pregnancy, but dose alteration is probably not required [108]. Tenofovir concentrations in the third trimester were reported to be reduced by about 15% compared with postpartum, but trough levels are adequate [109] although in a population-based study of tenofovir use, pregnant women appear to have 39% more clearance than non-pregnant women [110]. Higher rates of treatment failure during pregnancy with tenofovir-containing combinations have not been reported.…”