Effect of Pregnancy on Emtricitabine Pharmacokinetics
This is the first study describing intensive steady-state emtricitabine pharmacokinetics in pregnant women. The pharmacokinetic results show that, while overall exposure to emtricitabine on standard doses is reduced in pregnant women compared with nonpregnant adults, this reduction is not of sufficient magnitude to warrant a dosing adjustment. Fifty-eight per cent of women achieved third-trimester AUCs above the target (≤ 30% reduction from the typical nonpregnant adult AUC), derived from AUC data reported in the medical literature. Postpartum AUC (9.7 mg h/L) and CL/F (20.6 L/h) in this cohort were consistent with AUC (10.0 mg h/L) and CL/F (18.1 L/h) from published studies of this dose in nonpregnant adults. The antepartum and postpartum Cmax values for emtricitabine were also within the reported limits of 1.8 ± 0.7 mg/L, being 1.4 mg/L at both time-points. The variability of AUC noted in this group of pregnant subjects was greater than that in nonpregnant adults after a single dose.
Along with the comparison to historical controls, this study also compared third-trimester emtricitabine pharmacokinetics to pharmacokinetics for the nonpregnant, postpartum state in these same subjects. The within-subject comparisons demonstrated no difference in emtricitabine Vd/F and Cmax during pregnancy and postpartum. However, these women had a slightly lower AUC and a slightly higher CL/F during pregnancy. Physiological changes during pregnancy can increase excretion of drugs and their metabolites by the kidney. Pregnancy is associated with a 25–50% increase in renal plasma flow and a 50% increase in glomerular filtration rate, which results in an increase in clearance of drugs eliminated predominantly by renal clearance. A lower C24 was observed in this study, 0.058 mg/L antepartum vs. 0.085 mg/L postpartum, which also supports the conclusion that emtricitabine is cleared at a faster rate and has lower drug exposure during pregnancy. Pregnancy is associated with increased plasma progesterone, decreased intestinal motility, increased gastric emptying time and increased intestinal transit time. While these physiological changes would be expected to result in delayed drug absorption and reduced peak maternal blood concentrations, the absorption of emtricitabine among pregnant women enrolled in this study was not affected. All four of the instances of pre-dose levels below the detection limit occurred postpartum. These were probably attributable to nonadherence, even though the subjects reported taking their prior dose. Only one C24 was below the detection limit; this was in the third trimester and we surmise that it was a result of the increased clearance. Adherence to antiretrovirals is often poorer during the postpartum period than during pregnancy. In our study, four of 19 women with viral load measured at the postpartum pharmacokinetic visit had viral loads >400 copies/mL, which we attribute to decreased antiretroviral adherence.
This study also evaluated placental drug transport of emtricitabine by comparing maternal and cord blood emtricitabine concentrations at delivery. Paired umbilical cord/maternal samples showed excellent foetal emtricitabine concentrations, with a geometric mean ratio of 1.2. Transfer of emtricitabine through the placenta appears to be mainly via simple passive diffusion. No data are available regarding active transport. The only previous data describing cord and maternal blood emtricitabine concentrations found a ratio of 80% following single 400 mg emtricitabine doses administered during labour. Equivalent exposure between mother and foetus at delivery has been noted for other nucleoside and nonnucleoside reverse transcriptase inhibitors, including zidovudine, lamivudine, abacavir, stavudine and nevirapine. The concentration of emtricitabine in umbilical cord blood samples in this study (0.23 mg/L) was well above the mean in vitro IC50 and IC90 for wild-type HIV-1 viral replication: 0.004 and 0.051 mg/L, respectively. This cord concentration was also above the minimum adult concentration, 0.077 mg/L, reported in previous studies, optimizing protection for the foetus against HIV-1 transmission.
The pharmacokinetics of a number of other antiretroviral agents have been described during pregnancy. Of the nucleoside/tide reverse transcriptase inhibitors, exposure to zidovudine, abacavir, didanosine, stavudine and tenofovir is reduced during pregnancy but not to a degree that requires dosing adjustment. Exposure to the nonnucleoside reverse transcriptase inhibitor nevirapine has been shown to be reduced by 10–20% during pregnancy. Of the protease inhibitors, lopinavir/ritonavir, nelfinavir, atazanavir and indinavir demonstrated decreased exposure antepartum compared with historical nonpregnant adult controls, whereas the exposure of saquinavir boosted with ritonavir in pregnancy appeared comparable to nonpregnant exposure, although the ritonavir exposure in this same study was decreased during pregnancy. Recommendations for the use of increased doses of lopinavir/ritonavir, nelfinavir and atazanavir during pregnancy have been made. Changes in protease inhibitor exposure during pregnancy may be attributable to changes in absorption, distribution and/or metabolism/elimination associated with pregnancy. Increased plasma progesterone during pregnancy causes induction of metabolism by cytochrome P450 enzymes and may play a role in increasing protease inhibitor metabolism during pregnancy. As emtricitabine is metabolized by oxidation of the thiol moiety and conjugation with glucuronic acid, the cytochrome P450 system does not play a role. However, emtricitabine is renally eliminated by both glomerular filtration and active tubular secretion, which are both increased during pregnancy and could explain the observations in this study.
Historically, pharmacokinetic studies of antiretrovirals during pregnancy using traditional Phase I designs have accrued slowly. The current study incorporated several design elements that facilitated enrolment. As antiretrovirals are generally widely used in pregnant women before Phase I studies can be conducted during pregnancy, we enrolled pregnant women who were already receiving emtricitabine as part of their routine clinical care. We assayed all samples in real time and reported the results back to the subjects' physicians within 2 weeks of sample arrival in the laboratory. By incorporating early stopping rules based on published information in nonpregnant populations, therapeutic drug monitoring (providing real-time feedback to clinicians), and the opportunity to consult with pharmacologists and the study team when trying to interpret this information clinically, the risks to the mother and foetus were minimized and enrolment was encouraged. Our study design incorporated opportunistic enrolment of pregnant women already receiving the drug of interest and real-time drug assays and pharmacokinetic interpretation, and can serve as a practical and efficient model for studying pharmacokinetics during pregnancy.
One limitation of this study was the incomplete collection of maternal plasma and cord plasma samples at the time of delivery. However, 16 women were evaluated to provide adequate and crucial data for analysis. Postpartum evaluation was incomplete for four subjects who self-discontinued emtricitabine before completing the postpartum pharmacokinetic evaluation. Nevertheless, 22 women completed both intensive evaluations, providing adequate data for comparisons. Another limitation of this study is that we measured plasma but not intracellular emtricitabine concentrations. Intracellular emtricitabine triphosphate, the active drug moiety, has a much longer half-life than plasma emtricitabine. Concentrations of intracellular emtricitabine triphosphate are more useful in evaluating pharmacokinetic–pharmacodynamic relationships and in deriving a dose selection strategy. Measurement of intracellular concentrations is primarily limited by the available resources. Despite these limitations, this study serves as an initial description of the pharmacokinetic parameters of emtricitabine in HIV-infected pregnant women.
In summary, lower emtricitabine AUC and C24 and higher emtricitabine clearance were found during pregnancy when compared with postpartum. However, the magnitude of the AUC decrease during pregnancy was less than 20% and C24 exceeded the IC50 in all subjects. Therefore, dosing adjustment during pregnancy does not appear to be necessary. Emtricitabine crosses the placenta well and provides antiretroviral concentrations in the newborn at birth that help provide neonatal protection against HIV transmission if mothers have been taking emtricitabine on a chronic basis. However, the decrease in C24 and in AUC during pregnancy together with the increase in oral clearance in our population demonstrates the effect pregnancy may have on antiretroviral pharmacokinetics and the need for pharmacokinetic evaluations during pregnancy of all antiretrovirals used in pregnant women.
Discussion
This is the first study describing intensive steady-state emtricitabine pharmacokinetics in pregnant women. The pharmacokinetic results show that, while overall exposure to emtricitabine on standard doses is reduced in pregnant women compared with nonpregnant adults, this reduction is not of sufficient magnitude to warrant a dosing adjustment. Fifty-eight per cent of women achieved third-trimester AUCs above the target (≤ 30% reduction from the typical nonpregnant adult AUC), derived from AUC data reported in the medical literature. Postpartum AUC (9.7 mg h/L) and CL/F (20.6 L/h) in this cohort were consistent with AUC (10.0 mg h/L) and CL/F (18.1 L/h) from published studies of this dose in nonpregnant adults. The antepartum and postpartum Cmax values for emtricitabine were also within the reported limits of 1.8 ± 0.7 mg/L, being 1.4 mg/L at both time-points. The variability of AUC noted in this group of pregnant subjects was greater than that in nonpregnant adults after a single dose.
Along with the comparison to historical controls, this study also compared third-trimester emtricitabine pharmacokinetics to pharmacokinetics for the nonpregnant, postpartum state in these same subjects. The within-subject comparisons demonstrated no difference in emtricitabine Vd/F and Cmax during pregnancy and postpartum. However, these women had a slightly lower AUC and a slightly higher CL/F during pregnancy. Physiological changes during pregnancy can increase excretion of drugs and their metabolites by the kidney. Pregnancy is associated with a 25–50% increase in renal plasma flow and a 50% increase in glomerular filtration rate, which results in an increase in clearance of drugs eliminated predominantly by renal clearance. A lower C24 was observed in this study, 0.058 mg/L antepartum vs. 0.085 mg/L postpartum, which also supports the conclusion that emtricitabine is cleared at a faster rate and has lower drug exposure during pregnancy. Pregnancy is associated with increased plasma progesterone, decreased intestinal motility, increased gastric emptying time and increased intestinal transit time. While these physiological changes would be expected to result in delayed drug absorption and reduced peak maternal blood concentrations, the absorption of emtricitabine among pregnant women enrolled in this study was not affected. All four of the instances of pre-dose levels below the detection limit occurred postpartum. These were probably attributable to nonadherence, even though the subjects reported taking their prior dose. Only one C24 was below the detection limit; this was in the third trimester and we surmise that it was a result of the increased clearance. Adherence to antiretrovirals is often poorer during the postpartum period than during pregnancy. In our study, four of 19 women with viral load measured at the postpartum pharmacokinetic visit had viral loads >400 copies/mL, which we attribute to decreased antiretroviral adherence.
This study also evaluated placental drug transport of emtricitabine by comparing maternal and cord blood emtricitabine concentrations at delivery. Paired umbilical cord/maternal samples showed excellent foetal emtricitabine concentrations, with a geometric mean ratio of 1.2. Transfer of emtricitabine through the placenta appears to be mainly via simple passive diffusion. No data are available regarding active transport. The only previous data describing cord and maternal blood emtricitabine concentrations found a ratio of 80% following single 400 mg emtricitabine doses administered during labour. Equivalent exposure between mother and foetus at delivery has been noted for other nucleoside and nonnucleoside reverse transcriptase inhibitors, including zidovudine, lamivudine, abacavir, stavudine and nevirapine. The concentration of emtricitabine in umbilical cord blood samples in this study (0.23 mg/L) was well above the mean in vitro IC50 and IC90 for wild-type HIV-1 viral replication: 0.004 and 0.051 mg/L, respectively. This cord concentration was also above the minimum adult concentration, 0.077 mg/L, reported in previous studies, optimizing protection for the foetus against HIV-1 transmission.
The pharmacokinetics of a number of other antiretroviral agents have been described during pregnancy. Of the nucleoside/tide reverse transcriptase inhibitors, exposure to zidovudine, abacavir, didanosine, stavudine and tenofovir is reduced during pregnancy but not to a degree that requires dosing adjustment. Exposure to the nonnucleoside reverse transcriptase inhibitor nevirapine has been shown to be reduced by 10–20% during pregnancy. Of the protease inhibitors, lopinavir/ritonavir, nelfinavir, atazanavir and indinavir demonstrated decreased exposure antepartum compared with historical nonpregnant adult controls, whereas the exposure of saquinavir boosted with ritonavir in pregnancy appeared comparable to nonpregnant exposure, although the ritonavir exposure in this same study was decreased during pregnancy. Recommendations for the use of increased doses of lopinavir/ritonavir, nelfinavir and atazanavir during pregnancy have been made. Changes in protease inhibitor exposure during pregnancy may be attributable to changes in absorption, distribution and/or metabolism/elimination associated with pregnancy. Increased plasma progesterone during pregnancy causes induction of metabolism by cytochrome P450 enzymes and may play a role in increasing protease inhibitor metabolism during pregnancy. As emtricitabine is metabolized by oxidation of the thiol moiety and conjugation with glucuronic acid, the cytochrome P450 system does not play a role. However, emtricitabine is renally eliminated by both glomerular filtration and active tubular secretion, which are both increased during pregnancy and could explain the observations in this study.
Historically, pharmacokinetic studies of antiretrovirals during pregnancy using traditional Phase I designs have accrued slowly. The current study incorporated several design elements that facilitated enrolment. As antiretrovirals are generally widely used in pregnant women before Phase I studies can be conducted during pregnancy, we enrolled pregnant women who were already receiving emtricitabine as part of their routine clinical care. We assayed all samples in real time and reported the results back to the subjects' physicians within 2 weeks of sample arrival in the laboratory. By incorporating early stopping rules based on published information in nonpregnant populations, therapeutic drug monitoring (providing real-time feedback to clinicians), and the opportunity to consult with pharmacologists and the study team when trying to interpret this information clinically, the risks to the mother and foetus were minimized and enrolment was encouraged. Our study design incorporated opportunistic enrolment of pregnant women already receiving the drug of interest and real-time drug assays and pharmacokinetic interpretation, and can serve as a practical and efficient model for studying pharmacokinetics during pregnancy.
One limitation of this study was the incomplete collection of maternal plasma and cord plasma samples at the time of delivery. However, 16 women were evaluated to provide adequate and crucial data for analysis. Postpartum evaluation was incomplete for four subjects who self-discontinued emtricitabine before completing the postpartum pharmacokinetic evaluation. Nevertheless, 22 women completed both intensive evaluations, providing adequate data for comparisons. Another limitation of this study is that we measured plasma but not intracellular emtricitabine concentrations. Intracellular emtricitabine triphosphate, the active drug moiety, has a much longer half-life than plasma emtricitabine. Concentrations of intracellular emtricitabine triphosphate are more useful in evaluating pharmacokinetic–pharmacodynamic relationships and in deriving a dose selection strategy. Measurement of intracellular concentrations is primarily limited by the available resources. Despite these limitations, this study serves as an initial description of the pharmacokinetic parameters of emtricitabine in HIV-infected pregnant women.
In summary, lower emtricitabine AUC and C24 and higher emtricitabine clearance were found during pregnancy when compared with postpartum. However, the magnitude of the AUC decrease during pregnancy was less than 20% and C24 exceeded the IC50 in all subjects. Therefore, dosing adjustment during pregnancy does not appear to be necessary. Emtricitabine crosses the placenta well and provides antiretroviral concentrations in the newborn at birth that help provide neonatal protection against HIV transmission if mothers have been taking emtricitabine on a chronic basis. However, the decrease in C24 and in AUC during pregnancy together with the increase in oral clearance in our population demonstrates the effect pregnancy may have on antiretroviral pharmacokinetics and the need for pharmacokinetic evaluations during pregnancy of all antiretrovirals used in pregnant women.
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