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Population Pharmacokinetics of Nevirapine in HIV-1-Infected Pregnant Women and Their Neonates - published pdf attached
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Antimicrobial Agents and Chemotherapy, January 2011
Sihem Benaboud,1,2 Didier K. Ekouevi,3 Saik Urien,1,2 Elisabeth Rey,4 Elise Arrive,5 Stephane Blanche,6 Glenda Gray,7 Kruy Leang Sim,8 Divine Avit,3 James McIntyre,7 Eric Nerrienet,9 Francois Dabis,5 Jean-Marc Treluyer,1,2,4 Deborah Hirt,* and the TEmAA ANRS 12109 Study Group,1,2
* Corresponding author. Mailing address: Unite de Recherche Clinique, Hopital Tarnier, 89 rue d'Assas, 75006 Paris, France. Phone: 33 15 8412884. Fax: 33 15 8411183. E-mail: deborah.hirt@parisdescartes.f
EA3620, Universite Paris-Descartes, Paris, France,1 Unite de Recherche Clinique, AP-HP, Hopital Tarnier, Paris, France,2 Programme PAC-CI, ANRS Abidjan, Cote d'Ivoire,3 Service de Pharmacologie Clinique, AP-HP, Hopital Cochin-Saint-Vincent-de-Paul, Universite Paris-Descartes, Paris, France,4 INSERM U897, ISPED, Universite Victor Segalen, Bordeaux, France,5 Service d'Immunologie et Hematologie Pediatrique, Hopital Necker Enfants Malades, Universite Paris-Descartes, Paris, France,6 Perinatal HIV Research Unit (PHRU), University of the Witwatersrand, Chris Hani Baragwanath Hospital, Johannesburg, South Africa,7 Service Gynecologie-Obstetrique de l'Hopital Calmette, Phnom Penh, Cambodia,8 Institut Pasteur du Cambodge, Phnom Penh, Cambodia9
ABSTRACT
The aim of the present study was to describe the nevirapine (NVP) pharmacokinetics (PK) in pregnant women and their neonates and to evaluate the transplacental drug transfer and administration scheme for the prevention of mother-to-child transmission. Thirty-eight HIV-1-infected pregnant women were administered one tablet of NVP (200 mg) and two tablets of tenofovir-emtricitabine (Truvada) at the initiation of labor. Children were given NVP syrup (2 mg/kg of body weight) as a single dose (sdNVP) on the first day of life. By pair, NVP concentrations were measured in 11 maternal, 1 cord blood, and 2 neonatal plasma samples and analyzed by a population approach. A one-compartment model was used for mothers and neonates; the absorption rate constants for mothers and neonates were 0.95 h-1 (intersubject variability, 111%) and 0.39 h-1, respectively; the apparent elimination clearances were 1.42 liter·h-1 (intersubject variability, 22%) and 0.035 liter·h-1, respectively; and apparent volumes of distribution were 87.3 liters (intersubject variability, 25%) and 5.65 liters, respectively. An effect compartment was linked to maternal circulation by mother-to-cord and cord-to-mother rate constants of 1.10 h-1 and 1.43 h-1, respectively. Placental transfer, expressed as the fetal-to-maternal area under the curve ratio, was 75%. Neonates had a very long half-lives (110 h) compared to adults. In the 38 mothers, the simulated median individual predicted time during which the NVP concentration remained above the half-maximal inhibitory concentration (IC50) was 13.2 days (range, 12 to 19.2 days). Thus, the administration of tenofovir-emtricitabine for at least 3 weeks after delivery should be considered to prevent the emergence of resistant viruses. The neonate must receive sdNVP immediately after birth when the infant is born less than 30 min after maternal drug intake to keep NVP concentrations above the IC50.
INTRODUCTION
Mother-to-child transmission (MTCT) accounts for 20% of all new HIV infections in sub-Saharan Africa (http://data.unaids.org/pub/Report/2009/2009_epidemic_update_en.pdf.). To prevent MTCT of HIV at about the time of delivery, a single dose of nevirapine (sdNVP) is administered at the start of labor and is the most common antiretroviral regimen used in resource-limited settings, as recommended by the World Health Organization (http://www.who.int/hiv/pub/mtct/en/arvdrugswomenguidelinesfinal.pdf).
However, the use of sdNVP results in resistance mutations in 15 to 70% of women at 4 to 6 weeks postpartum (2, 10, 14), compromising the success of subsequent treatments with NVP in mother and child (7, 19, 15). The results of a recent clinical trial suggest that adding a single dose of tenofovir (TDF) and emtricitabine (FTC) at delivery may reduce those resistance rates by half (6).
Nevirapine is characterized by rapid and nearly complete absorption, rapid distribution throughout the body, metabolism by the hepatic cytochrome P450 (CYP) 3A4 (CYP 3A4) enzyme (with autoinduction during the first 2 weeks of treatment), and prolonged elimination (8, 22). Emtricitabine and tenofovir are predominantly eliminated by the kidney, and no drug-drug interactions between NVP and tenofovir-emtricitabine (Truvada) are expected.
Physiological changes caused by pregnancy and labor can modify NVP pharmacokinetics at each step. Furthermore, pharmacokinetics in the neonate are different from those in adults; e.g., the low level of expression of the CYP 3A4 enzyme may reduce metabolism.
Placental transfer of NVP has been described by the ratio between the cord blood concentration and the maternal concentration at delivery, and this ratio is highly variable: from 71.9% to 122.8% in the study of Mirochnick et al. (20) and from 57.6% to 93.0% in the study of Musoke et al. (21). A more representative measure of this transfer is proposed in this article.
The objective of this analysis was (i) to describe the pharmacokinetics of NVP after a single dose in the mother, fetus, and neonate, (ii) to estimate the placental transfer of NVP with an exposure ratio, and (iii) to evaluate the actual recommendations of the administration scheme.
DISCUSSION
In the present study, NVP mother and child pharmacokinetics were satisfactorily described by the proposed compartmental model. The following observations support the validity of this model: the population predicted maternal, cord blood, and neonatal concentrations were well correlated with the observed concentrations. The population model was validated by the visual predictive check method and the fact that the values of the typical pharmacokinetic parameters were consistent with those from prior pharmacokinetic studies: for CL/F, 1.42 liters/h in the present study versus 1.40 liters/h in the study of Kunz et al. (17), and for the volume of distribution, 87.3 liters in the present study versus 104.3 liters in the study of Kunz et al. (17).
The elimination of the sdNVP in parturient women is close to the elimination of sdNVP in nonpregnant women. Because CYP 3A4 is upregulated during pregnancy (1, 23), we could expect a more rapid elimination in the women in our study. One explanation for no difference could be that upregulation of CYPs is rapidly reversed after delivery, which is in agreement with recently published data on lopinavir (5), where much higher levels are already found a few days after delivery. Therefore, NVP elimination is mainly determined after delivery instead of during pregnancy.
The long elimination half-life of NVP leads to a long period of decreasing plasma levels. This persistence of NVP predisposes the individual to resistance mutation development (9). Although the minimum concentrations needed to select for the development of resistance is not known, concentrations near the IC50 were supposed to be sufficient. According to our simulations, these concentrations remain above the IC50 for almost 3 weeks in some women, which is in agreement with the findings of the studies of Cressey et al. (9) and Kunz et al. (17). These results suggest that longer treatment with tenofovir-emtricitabine postpartum should be evaluated to prevent the appearance of resistance. These suggestions were based on the plasma concentrations. However, due to a long intracellular half-life, its activity may be much longer and the associated inhibition of viral replication still prevents development of NVP resistance. However, WHO recommends that zidovudine plus lamivudine and not tenofovir-emtricitabine be given for 7 days postpartum (http://www.who.int/hiv/pub/mtct/en/arvdrugswomenguidelinesfinal.pdf.). Longer treatment with these drugs should also be considered.
Few data on NVP placental transfer were reported. In this study, from one sample for each mother-cord pair obtained at delivery (and at various times after drug administration), we were able to assess maternal and cord blood concentrations over time. Placental transfer was estimated as the ratio of the fetal exposure-to-maternal exposure to the drug. We found a relatively constant AUC ratio of 75%, while in other studies, the placental transfer is described by a simple cord blood concentration-to-maternal concentration ratio, which is highly variable: from 71.9 to 122% in the study of Mirochnick et al. (20) and from 57.6% to 93.0% in the study of Musoke et al. (21).
Elimination from the neonate was very slow compared to that from their mothers and to that from older children. This low clearance is in agreement with the developmental pattern of the activity of CYP 3A4, the main enzyme responsible for NVP biotransformation. CYP 3A4 activity appears to be low in newborns, increases to adult levels by 6 to 12 months of age, exceeds adult levels during years 1 to 4, and then declines to adult levels by the end of puberty (18). In contrast, CYP 3A7 activity is high in utero and low during postnatal life. Little is known about the development of CYP 2B6 activity.
In order to keep neonatal concentrations above the IC50, according to our simulations and in agreement with the nevirapine (Viramune) labeling (http://www.pmtctdonations.org/ftp/Guidelines%20use%20of%20VIRAMUNE-EN.pdf.), the newborns have to be dosed (i) within 48 to 72 h of life if the child is born more than 2 h after the mother's intake and (ii) immediately after birth if the child is born less than 30 min after the mother's intake. Contrary to the nevirapine labeling (which recommends administration immediately after birth), our simulations suggested that if the child is born between 30 min and 2 h after the mother's intake, the administration to the newborn is still possible within 48 to 72 h of life.
In conclusion, our model accurately describes the NVP pharmacokinetics in mother, cord, and neonatal blood after the intrapartum and neonatal single dose. We estimated the placental transfer of NVP using an exposure ratio of 75%. NVP concentrations remained above the IC50 for 2 to 3 weeks, and administration of tenofovir-emtricitabine (or the recommended zidovudine plus lamivudine) for at least 3 weeks after delivery could improve the prevention of the emergence of resistant viruses. This hypothesis should be tested, and the efficacy of longer postpartum treatments covering the entire NVP tail needs to be determined. To keep NVP concentrations above the IC50, newborns have to be dosed (i) within 48 to 72 h of life if the child is born more than 30 min after the mother's intake and (ii) immediately after birth if the child is born less than 30 min after the mother's intake. These assumptions should be further evaluated.
RESULTS
Demographic data.
Data from the 38 enrolled women and 30 of their neonates were available for NVP pharmacokinetic evaluation. Table 1 summarizes the patients' characteristics.
Population pharmacokinetics.
A total of 405 maternal, 36 cord blood, and 55 neonatal NVP concentrations were used for pharmacokinetic analysis of NVP. Twenty-nine maternal concentrations, two cord blood concentrations, and one neonatal concentration were lower than the LOQ. The M3 method did not improve the estimation of the parameters, so the M6 method was kept: the first LOQ for concentration was set equal to half of the LOQ (3), and the following ones were excluded. Two maternal concentrations and one neonatal con- centration were excluded because previous concentrations in these mothers and this neonate were already under the LOQ. A one-compartment model with first-order absorption and elimination best described the maternal data. The autoinduc- tion model did not improve the fit. The effect compartment was kept for cord blood concentrations. Parameters of the model were the maternal absorption rate constant (ka), mater- nal elimination CL, maternal volume of distribution (V), moth- er-to-fetus rate constant (k1F), fetus-to-mother rate constant (kF1), neonatal absorption rate constant (kaN), neonatal elim- ination rate constant (keN), and neonatal volume of distribution (VN). Since NVP was orally administered, only ka, CL/F (where F is the unknown bioavailability), V/F, k1F, kF1, kaN, VN/F, and keN were identifiable. Analytical equations were used in a $PRED section in NONMEM to estimate these pharmacokinetic parameters. The available data were not sufficient to estimate intersubject variability for k1F, kF1, kaN, keN, and VN/F; and fixing the variance of these random effects to zero had no influence on the OFVs. Variabilities were thus estimated for ka, CL/F, and V/F. All residual variabilities were best described by a proportional error model. No significant correlation between maternal and cord blood residual variabilities was found. The effects of maternal body weight, type of delivery, and ethnicity were tested on CL/F, and none of these effects was significant.
Figure 2 displays the observed and predicted NVP plasma concentrations as a function of time for the mother, the cord, and the neonate. To better visualize the neonatal concentra- tions, cord blood concentrations were reported on the graph at time zero. Table 2 summarizes the final population pharmacokinetic estimates. Final model performance was appreciated by comparing population predicted and individual predicted plasma concentrations to observed plasma concentrations and population weighted residuals versus predicted concentrations and versus time for NVP (data not shown).
Validation. A visual predictive check of the final population pharmacokinetic model (Fig. 3) showed the predicted 5th, 50th, and 95th percentiles from the 1,000 simulations and the observed concentrations of nevirapine. The visual predictive check confirmed that the average prediction matched the ob- served concentrations. The variability was reasonably estimated.
Maternal and neonatal concentrations after 200 mg NVP administration to the mother at delivery and placental transfer.
The median delay between administration of NVP to the mothers and delivery was 5.1 h (minimum [min] and maximum [max], 0.92 and 20 h). At delivery, the median observed neonatal and maternal concentrations were 1.35 mg/liter (min and max, 0.125 and 2.95) and 1.70 mg/liter (min and max, 0.44 and 3.33), respectively. The median observed cord blood concen- tration-to-maternal concentration ratio was 71% (min and max, 13 and 140%). This wide range of concentration ratio at delivery suggests that placental transfer depends on the delay between maternal drug intake and delivery and could not be given as a simple percentage. A more representative measure of placental transfer would be the ratio between fetal NVP AUC and maternal NVP AUC for 24 h (12, 13). The predicted fetal AUC0-24-to-maternal AUC0-24 (where AUC0-24 is the AUCfrom0to24h)was75%.
Persistence of NVP in plasma of mothers.
In the 38 mothers, the simulated median individual predicted time during which the NVP concentration remained above IC50 was 13.2 days (range, 12.0 to 19.9 days) (Fig. 4).
Concentration in newborns before administration of sdNVP.
Figure 5 represents the simulated neonatal concentrations for 72 h in children if delivery occurred (i) 30 min, (ii) 2 h, (iii) 5 h, and (iv) 8 h after the administration of the sdNVP to the mother. Figure 5 suggests that the shorter that the delay be- tween the administration to the mother and delivery is, the earlier the dose should be given to the neonates. Neonates had a very long half-life, 110 h, compared to adults. If the neonate was born at least 30 min after maternal drug administration, the neonatal nevirapine concentration remained above the IC50 for at least 72 h for all children. If the neonate was born at least 2 h after maternal drug administration, the neonatal nevirapine concentration remained above 10 times the IC50 for at least 72 h for all children.
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