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Dolutegravir pharmacokinetics in pregnant and postpartum women living with HIV
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AIDS Jan 13 2018 - Mulligan, Nikkia; Best, Brookie M.a; Wang, Jiajiab; Capparelli, Edmund V.a; Stek, Alicec; Barr, Emilyd; Buschur, Shelley L.e; Acosta, Edward P.f; Smith, Elizabethg; Chakhtoura, Nahidah; Burchett, Sandrai; Mirochnick, Markjfor the IMPAACT P1026s Protocol Team
Objective: To evaluate dolutegravir pharmacokinetics during pregnancy compared to postpartum and in infant washout samples after delivery.
Design: Ongoing, nonrandomized, open-label, parallel-group, multicenter phase-IV prospective study of antiretroviral pharmacokinetics in HIV-infected pregnant women and infants.
Methods: Intensive steady-state 24 h pharmacokinetic profiles after dolutegravir 50 mg once-daily were performed during the second trimester (2T), third trimester (3T) and postpartum (PP). Infant samples were collected after birth. Dolutegravir was measured by validated LC-MS/MS; quantitation limit was 0.005mcg/mL. A two-tailed Wilcoxon signed-rank test (α = 0.10) was employed for paired within-subject comparisons.
Results: Twenty-nine enrolled participants had a median age of 32 years (range 21-42). Pharmacokinetic data were available for 15 (2T), 28 (3T) and 23 (PP) women. Median dolutegravir AUC0-24, Cmax and C24 were 25-51% lower in the 2T and 3T compared to PP. The median cord blood/maternal plasma concentration ratio was 1.25 (n = 18). In 21 infants, median elimination half-life was 32.8 h after in utero exposure. Viral load at delivery was <50 copies/mL for 27/29 women (93%). Twenty-nine infants were HIV-negative. Renal abnormalities noted on ultrasound in two infants were deemed possibly related to dolutegravir.
Conclusions: Dolutegravir exposure is lower in pregnancy compared to postpartum in the same women on once-daily dosing. Median AUC0-24 during pregnancy was similar to, while trough concentrations were lower than, those seen in nonpregnant adults. Trough concentrations in pregnancy were well above dolutegravir EC90 (0.064mcg/mL). Dolutegravir readily crosses the placenta. Infant elimination is prolonged, with half-life over twice that of historical adult controls.
DISCUSSION
Increasing use of INSTIs as first-line treatment regimens among adults living with HIV will lead to more pregnancies occurring in women on dolutegravir-containing regimens. This study is the first to analyze the pharmacokinetics of dolutegravir 50mg once-daily dosing in a large population of pregnant women. Paired data demonstrated a 29% decrease in dolutegravirAUC0-24 in the third trimester compared to postpartum. Second trimester AUC0-24 was also lower than postpartum. Both second and third trimester Cmaxand C24were significantly lower than paired postpartum data by 25-51%.The general risk of decreased antiretroviral exposure is failure to suppress viral replication. This study designated sub-therapeutic exposure less than the 10thpercentile dolutegravirAUC0-24(37.5mcg*hr/mL) of non-pregnant adults. Significantly fewer participants met this minimum threshold during pregnancy (60% in second trimester, 71% in third trimester) compared to postpartum (100% postpartum). Although all women had HIV-1 RNA less than 50 copies/mL at the time of the second and third trimester pharmacokinetic sampling, two women had detectable viral loads at delivery. One of these women had a lower but still detectable viral load postpartum, while the other woman had an undetectable viral load postpartum.
Even though exposure was lower during pregnancy compared to postpartum, median AUC during pregnancy in this study (47-49mcg*hr/mL) were similar to the reported values in non-pregnant adults (53.6mcg*hr/mL)[14].Also, postpartum AUC and maximum concentrations in this study were higher than reported values in non-pregnant adults; the significant differences seen between pregnancy and postpartum were in part due to the higher than expected dolutegravir exposures postpartum. This increased exposure postpartum has been noted with other antiretrovirals[15,21-22]. The postpartum visits were a median of 10 weeks after delivery.
This time frame post-delivery may not represent "non-pregnant adults", as physiologic changes that could affect pharmacokinetics of medications may happen abruptly or slowly postpartum and can variably rebound in the opposite direction of pregnancy changes. For example, cardiac output takes 6-12 weeks to return to non-pregnant levels, and kidneys usually take 2-3 months (sometimes up to 4 months) to return to normal, non-pregnant function[23].
Trough concentrations in this study during pregnancy (0.73 and 0.93mcg/mL) were somewhat lower than those reported in non-pregnant adults (1.11mcg/mL).However, even these lower values are still approximately 11-14times higher than the reported dolutegravir in vitro protein-adjusted 90% effective concentrations (EC90) of 0.064 mcg/mL[24].Notably, the Phase I and Phase II studies of dolutegravir found similar high efficacy rates with doses ranging from 10mg to 50mg[24,25]. Geometric mean trough concentrations with 10mg once-daily dosing for 10 - 14 days are approximately 0.2-0.3 mcg/mL[24,25]. The troughs seen in this study during pregnancy were still about 4 times higher than those with 10mg daily doses that have shown similar efficacy to the 50mg dose in prior clinical studies. During pregnancy, none of the women in this study had dolutegravir concentrations below the quantitative limit of the assay, 0.005mcg/mL, and no infants acquired HIV infection from their mothers.
Dolutegravir metabolism is primarily dictated by UGT1A1 activity with minor CYP3A contributions[14]. UGT1A1 enzymes can be found in the liver, lungs, intestine mucosa, brain, uterus and placenta [26]. Progesterone-induced UGT1A1 expression and the resulting net increase in metabolism, along with increased CYP 3A activity, may explain decreased dolutegravir concentrations during pregnancy[27][28]. This study found significantly shorter half-lives and decreased trough dolutegravir concentrations during pregnancy compared to postpartum, consistent with significantly increased clearance. However, half-lives are difficult to accurately estimate in a multiple-dose study with sampling in the elimination phase over less than two half-lives. Dolutegravir is highly bound to plasma proteins[14] but may be displaced by increased hormone binding to these proteins in pregnancy or may have higher unbound concentrations due to lower albumin concentrations in pregnancy. The fraction of unbound dolutegravir mediates the therapeutic action of this antiretroviral, but unbound concentrations were not measured in this study. Though this study observed lower total concentrations in pregnancy compared to postpartum, the therapeutic free fraction of dolutegravir may be increased, stable or decreased during pregnancy.
This study determined the washout kinetics of dolutegravir transferred in utero across the placenta in these infants born to mothers receiving dolutegravir during pregnancy. The median ratio of the dolutegravir concentration in cord blood/maternal plasma at delivery was 1.25, suggesting high placental transfer of dolutegravir consistent with another small study[29]. Elimination of dolutegravir in these newborns was prolonged, with a median elimination half-life in 16 infants of 33 hours compared to amedian maternal postpartum elimination half-life of 13.5 hours. These findings are consistent with a case report of dolutegravir pharmacokinetics in a pregnant woman that described a four-fold increase in elimination half-life in the infant compared to the mother[17].
In neonates, although UGT1A1 is found in equal concentrations to adults, its activity is low at birth and only reaches adult levels at 3.8 months[30]. Furthermore, UGT1A1 metabolism in adults and neonates is highly variable. Raltegravir, another INSTI metabolized by UGT1A1, had highly variable and extremely prolonged elimination in nineteen infants[31]. A common indicator of UGT1A1 activity is bilirubin. For instance, infants with UGT1A1 polymorphisms that decrease enzyme activity are at higher risk of hyperbilirubinemia which can lead to kernicterus[32]. This study did not measure bilirubin in infants so the correlation between dolutegravir elimination and UGT1A1 activity cannot be assessed this way. Metabolism of dolutegravir by CYP3A may not play a major role in extended dolutegravirelimination half-lives in infants. Neonatal CYP3A7 activity is high at birth and slowly decreases as adult CYP3A4 activity increases;CYP3A5 remains stable throughout development. This may result in stable CYP3A metabolism in infants compared to adults[33].
Although clinical abnormalities at birth were noted in seven infants, these findings were thought to be unrelated to dolutegravir exposure in five infants. Findings in three infants were considered normal variants. The mother of the infant with total anomalous pulmonary venous return did not start dolutegravir until week 16 of gestation, after cardiac development was complete, and so the cardiac anomaly was judged unrelated to fetal dolutegravir exposure. Renal abnormalities were found on ultrasound in two infants whose mothers began dolutegravir at the end of the first trimester, and these were the only birth abnormalities considered possibly related to dolutegravir exposure. The infant with the multicystic dysplastic kidney was also diagnosed with cystic fibrosis and had several other adverse events thought to be unrelated to dolutegravir exposure because they were consequences of cystic fibrosis. All of the other adverse events were judged not related to in utero dolutegravir exposure because they were either common newborn events (hypoglycemia), associated with maternal opiate use during pregnancy (neonatal abstinence syndrome) or was a genetic trait (sickle cell trait).Although our sample size is small for assessing adverse fetal effects from in utero drug exposure, our data are consistent with the lack of adverse fetal effects seen in preclinical reproductive toxicology studies of dolutegravir[14].Our data are also consistent with the 83 prospective cases of dolutegravir exposure during pregnancy reported so far to the Antiretroviral Pregnancy Registry, which includes two reports of birth defects in 41 infants with first trimester dolutegravirexposure and one report of a birth defect in 42 infants with second trimester exposure[34].
One limitation of this study is that opportunistic recruitment of women already taking dolutegravir generally means that these women are responding to and not experiencing adverse effects from this regimen. This selection bias may overestimate positive outcomes and underestimate adverse events. This study was also limited to subjects taking dolutegravir 50mg once-daily, indicated for treatment-naïve or INSTI-naïve patients. Dolutegravir 50mg is taken twice-daily for patients with specific INSTI-associated resistance mutations or use of a potent inducer of UGT1A1 or CYP3A metabolism. Once-daily and twice-dailydolutegravirhave a nonlinear dose-concentration relationship among non-pregnant adults[14]. Therefore, these findings cannot be applied to patients on a twice-dailydolutegravirregimen. Additionally, dolutegravir was taken regardless of food to align with FDA label recommendations. However, low fat meals increase dolutegravirAUC0-24by 33%, moderate fat meals increase AUC0-24 by 41%, and high fat meals increase AUC0-24 by 66%[35]. Therefore, dolutegravir dosing in relation to meals may have added greater variabilityto the pharmacokinetic data and statistical comparisons in this study.
Study limitations in our infant washout analysis included wide sampling windows, sparse pharmacokinetic time points and lack of correlation with bilirubin concentrations. Also, these results cannot be extrapolated to breastfeeding populations. Prior raltegravir studies identified a lag in elimination with raltegravir concentrations first increasing prior to decreasing in newly born infants[31]. Our sampling windows were too wide to capture this effect, so it is not known if dolutegravir also follows this pattern.
To conclude, exposure in pregnancy is decreased compared to postpartum, but standard once daily dosing during pregnancy provides exposure well above that needed to suppress viral replication. Women in this study experienced few adverse events and 93% had <50 copies/mL of HIV-RNA at delivery. Dolutegravir crosses the placenta easily,resulting in infant concentrations comparable to maternal plasma concentrations. Low UGT1A1 activity at birth may account for the greater than two-fold increase in dolutegravir elimination half-life in infants as compared to postpartum women. Of the clinical abnormalities observed at birth, only two infants with renal abnormalities, exposed to dolutegravir at the end of the first trimester, were considered possibly related to dolutegravir exposure. Additional data are needed on the use of dolutegravir in pregnant women to assess infant safety or to assess twice daily dosing.In summary, dolutegravir exposure is decreased in pregnancy compared to postpartum, but remains at therapeutic concentrations during pregnancy with standard once daily dosing.
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