British Journal of Clinical Pharmacology

DOI:10.1111/bcp.12459

Maternal and fetal zidovudine pharmacokinetics during pregnancy and labour: too high dose infused at labour? Floris Fauchet,1,2 Jean-Marc Treluyer,1,2,3,4 Elodie Valade,1,2

Correspondence Dr Floris Fauchet PharmD, Unité de Recherche Clinique, AP-HP, Hôpital Tarnier 89 rue d’Assas, 75006 Paris, France. Tel.: +33 1 58 41 12 14 Fax: +33 1 58 41 11 83 E-mail: [email protected] -----------------------------------------------------------------------

*Saik Urien and Deborah Hirt contributed equally as last authors. -----------------------------------------------------------------------

Keywords HIV, intrapartum, population pharmacokinetics, prevention of mother to child transmission, zidovudine -----------------------------------------------------------------------

Sihem Benaboud,2,3,4 Emmanuelle Pannier,5 Ghislaine Firtion,5 Frantz Foissac,2 Naim Bouazza,2 Saik Urien1,2,4* & Déborah Hirt1,2,3,4* 1

EA 3620 Université Paris Descartes, Sorbonne Paris Cité, Paris, 2Unité de Recherche Clinique, AP-HP, Hôpital Tarnier, Paris, 3Service de Pharmacologie Clinique, AP-HP, Groupe Hospitalier Paris Centre, Paris, 4CIC-0901 Inserm, Cochin-Necker, Paris and 5Service de Gynécologie-Obstétrique, Maternité Port Royal, Groupe Hospitalier Paris Centre, Paris, France

Received 28 April 2014

Accepted 2 July 2014

Accepted Article Published Online 9 July 2014

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Since 1994, zidovudine infusions have been administered during labour to pregnant women for prevention of mother-to-child HIV transmission. • An important number of side effects with varying severity (anaemia, neutropenia, hyperlactataemia) have been observed in adults and infants receiving oral zidovudine. • Oral zidovudine pharmacokinetics have been previously described in adults and pregnant women.

WHAT THIS STUDY ADDS • Maternal zidovudine pharmacokinetics at labour and their impact on fetal exposure are described for the first time. • With the recommended infusions rates, neonates have exposures associated with higher risk of toxicity at delivery. • Decreasing infusions rates would maintain zidovudine efficacy and improve the safety in neonates.

AIMS The main goal of the study was to describe the pharmacokinetics of maternal zidovudine (ZDV) administration during pregnancy and labour and to evaluate their impact on fetal concentrations and exposures.

METHODS A total of 195 HIV-infected pregnant and non-pregnant women aged 16–59 years were included and 273 maternal and 79 cord blood ZDV concentrations were collected. A population pharmacokinetic model was developed to describe ZDV concentrations as a function of time in the mother and the fetus. Fetal exposures resulting from maternal oral administration and infusion were estimated and compared with therapeutic exposures (3–5 mg l−1 h) and to exposure providing higher risk of toxicity (>8.4 mg l−1 h). Different protocols for ZDV administration during labour were simulated.

RESULTS The median fetal exposure and the percentage of children with values above 8.4 mg l−1 h were 3.20 mg l−1 h and 0% after maternal oral administration, respectively, and 9.71 mg l−1 h and 51% after maternal infusion during labour. Two options were considered to reduce fetal exposure during labour: (i) maternal infusion rates could be 1 mg kg−1 h−1 during 1 h followed by 0.5 mg kg−1 h−1 and (ii) the mother could only take oral ZDV every 5 h from start of labour until delivery with her neonate having their first ZDV dose as soon as possible after birth.

CONCLUSIONS Zidovudine exposures are very important during labour and during the first days of a neonate’s life. Maternal ZDV dose should be reduced in addition to the neonate doses reduction already proposed.

© 2014 The British Pharmacological Society

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Introduction Administration of zidovudine (ZDV) to pregnant women has significantly decreased mother to child HIV transmission (MTCT). In 1994, the PACTG 076 trial reduced mother to child transmission by 67% (transmission rate of 25.5% with placebo compared with 8.3% with ZDV). The dosing regimen recommended was an oral administration during pregnancy (100 mg five times per day), continuous intravenous infusion during labour (2 mg kg−1 during the first hour followed by a rate of 1 mg kg−1 up to the end of delivery) and an oral administration (for 6 weeks) to the neonate after birth (2 mg kg−1 every 6 h) [1]. The dosing regimens recommended during pregnancy and at birth have been simplified later to 300 mg orally twice daily and 4 mg kg−1 every 12 h, respectively. This protocol has been widely applied for MTCT prophylaxis but new recommendations have been published by the World Health Organization (WHO). They suggested that intravenous ZDV could be avoided for HIV-infected pregnant women receiving a combination of three antiretroviral drugs with optimal control of HIV-1 viral load near delivery. Indeed, a recent study taking into account obstetric risk factors has reported no significant association between intravenous ZDV and transmission rate in women with low plasma viral load [2]. However, intravenous ZDV does remain an effective prophylactic measure to prevent MTCT in women with a high or unknown HIV viral load near delivery [2]. Although, ZDV toxicity has been established in neonates, the consequences of maternal dosing during pregnancy (oral) and labour (intravenous) have never been described in the fetus. Thus, a population pharmacokinetic approach was used to characterize ZDV pharmacokinetics (PK) in non-pregnant, pregnant and women in active labour. Fetal exposures due to the maternal administrations during pregnancy and labour were derived from the model and compared with both (i) effective and non-toxic exposures and (ii) post-partum neonate exposures.

Methods Patients The population included HIV infected women in active labour (WAL), HIV infected pregnant women (PW) and HIV infected non-pregnant women (NPW). The women in active labour and the pregnant women were enrolled at clinical sites of the ANRS-C01-French Perinatal Cohort (EPF). The mother and, when possible, the father of the child to be born provided signed informed consent. For the non-pregnant women, ethics committee approval and patient consent are not compulsory in France to use therapeutic drug monitoring data retrospectively and thus they were not obtained. Plasma concentrations were monitored on a routine basis and samples were measured in the pharmacology unit of Hospital Cochin (Paris, France). They 1388

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were collected from 2004 to 2013 during medical visits with therapeutic drug monitoring for WAL and PW and between 2004 and 2008 for NPW. Some women had available data from one, two or all of these groups.

Treatments Pregnant women and NPW received ZDV orally (250 mg or 300 mg) twice daily. Women in active labour were given an infusion of 2 mg kg−1 during the first hour at start of labour, and then the rate of flow was decreased to 1 mg kg−1 h−1 until delivery. Among WAL, some received ZDV orally during pregnancy whereas others had highly active antiretroviral therapy without zidovudine.

Sampling Blood samples were collected for therapeutic drug monitoring during a visit. Therefore the times elapsed between drug administration and sampling times were variable. Mother and cord blood samples were obtained at delivery. The doses, time of administration, time of sampling, infusion rate, last oral administration time before infusion, age, bodyweight (BW), co-treatments, trimester of pregnancy and gestational age were recorded.

Analytical method Plasma ZDV concentrations were determined by high performance liquid chromatography, as previously described [3]. The lower limit of quantification (LLOQ) was 0.02 mg l−1. Mean intra-assay and inter-assay precisions of the low, medium and high concentrations (0.02, 0.75, 2.5 mg l−1) of the quality controls for ZDV were 2.8 and 10%, 2.1 and 9.3% and 1.77 and 7.63%, respectively. The mean intra-assay and inter-assay accuracy (percent deviation from the expected value) of the same quality controls were 2.56 and 5.73%, 6.15 and 2.45% and 2.60 and 2.35%, respectively. Overall recovery from plasma was 83%.

Population pharmacokinetic analysis and modelling Measured maternal plasma ZDV concentrations in PW, NPW, WAL and cord bloods were modelled using a nonlinear mixed effects model. The data were analyzed using NONMEM®, version 6.2, (ICON Development Solutions, Ellicott City, MD, USA) and the first order conditional estimation with interaction (FOCEI) method was applied [4]. Different analytical solutions were used to analyze the ZDV PK in (PW + NPW), WAL and the fetus. First, all the ZDV concentrations of the women were analyzed and maternal PK parameters were estimated. Then, these parameters were fixed in order to estimate fetal parameters. In the final step, all the parameters were estimated. One and two compartment models were tested to describe plasma ZDV concentrations in the mother. An effect compartment and one or two additional compartments linked to the maternal compartment were tested for the cord blood concentrations. The effect compart-

Maternal ZDV population pharmacokinetics

ment was modelled as a virtual compartment with a negligible volume and connected to the maternal compartment by one or two first order constants, which did not modify the compartmental model in the mother. After delivery, the fetal compartment is disconnected, the time is reset to zero and newborns have their own rate of absorption and elimination. Exponential between subject variabilities (BSVs) were assumed. Additive, proportional or mixed error models were tested to describe residual variability. The influence of each patient covariate was systematically tested. Indeed, they were evaluated via an upward-backward model building, as previously described [5]. A covariate was selected if (i) it produced a minimum decrease of 6.63 units (χ2 with 1d.f., P < 0.01) in the objective function value (OFV), (ii) it produced a reduction in the variability of the pharmacokinetic parameter(s), assessed by the associated BSV and (iii) its effect was physiologically plausible. The continuous covariates, age and bodyweight (BW), were tested according to the following equation, using CL, for example:

CL = θCL ×

(

BW medianBW

)

CL βBW

where θCL is the typical value of clearance for a patient with CL is the estimated influthe median covariate value and βBW ential factor for the continuous covariate. The median value from all of the other patients were set if a covariate was missing. Delivery (Del), co-treatments were considered as binary covariates and their influence was tested as follows: CL CL = θCL × (βDel )

Del

CL where Del = 1 for delivery and Del = 0 otherwise, and βDel is the estimated influential factor for delivery. Co-treatments were tested individually, i.e. the effect of lopinavir alone, or by pharmaceutical class, i.e. the effect of the protease inhibitors. The influence of pregnancy was investigated by splitting the clearance in different classes, first, second and third trimester of pregnancy. A continuous relation including gestational age was also tested as follows:

CL

β ⎡⎛ GA ⎞ GA ⎤ CL = θCL × ⎢⎜ ⎥ ⎟ ⎣⎝ median GA ⎠ ⎦

PREG

where PREG = 1 if pregnant and 0 if otherwise, and βCL GA is the estimated influential factor for pregnancy.

Evaluation Diagnostic graphics were used for a graphical evaluation of the goodness-of-fit. The stability of the model and accuracy of the parameters were assessed by a method

implemented in Wings for NONMEM (WfN, http://wfn .sourceforge.net/). ZDV concentration profiles were simulated and compared with the observed data using visual predictive check (VPCs) to evaluate the model. The final population model was used to simulate 1000 vectors of pharmacokinetic parameters from all the patients. The simulations were performed using NONMEM. The 5th, 50th and 95th percentiles of the simulated concentrations at each time were then overlaid on the observed concentrations using RfN (http://wfn.sourceforge.net/) and a visual inspection was performed. A 95% confidence interval was calculated on the percentage of data outside the 5th and the 95th percentile bounds of the simulated data. It must contain the value of 10% in order to validate the model.

Maternal exposure After ZDV administration to each woman and using to the model developed, maternal ZDV areas under the curve (AUC) were derived from the estimated individual PK parameters. The analytical solutions used in the model were integrated to estimate these exposures. Three maternal exposures were estimated: AUC(0, 24 h)tablet, exposure (0 up to 24 h) due to the oral administration in NPW, mAUC(0, 24 h)tablet exposure (0 up to 24 h) due to the maternal oral administration in PW and WAL and mAUC(0, 24 h)infusions, exposure due to the infusions (0 was the start of the first infusion up to 24 h after).

Fetal exposure Similarly, fetal exposures during pregnancy were calculated: fAUC(0, 24 h)tablet exposure (0 up to 24 h) due to the maternal oral administration and fAUC(0, 24 h)infusions exposure (from the start of the first infusion up to 24 h after) due to the maternal infusions on the day of delivery.

Neonatal exposure The exposure due to the first oral doses administered to the neonate (nAUC(0, 24 h)syrup) (0 was the start of the oral dose administered up to 24 h) was calculated according to the previous neonate ZDV model developed by the team [6]. As in this model, clearance was dependent of bodyweight and post-natal age, a mean neonate weight of 3 kg and 1 day post-natal age was assumed to compare nAUC(0, 24 h)syrup with fAUC(0, 24 h)infusions.

Placental transfer The placental transfer during pregnancy was estimated as the median fetal-to-maternal ratio exposure, due to maternal oral administration.

Safety and efficiency criteria A fetal concentration higher than 10 times the value of the half maximal inhibitory concentration (IC50) was chosen in the absence of any target relating ZDV concentration with protection against HIV transmission [7]. This first criterion was defined as transmission protective concentration. Br J Clin Pharmacol

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Time bounds keeping fetal concentrations higher than 0.05 mg l−1 (i.e. 10 × IC50) [8] were calculated for the fetus during pregnancy and for the neonate with the lower and higher concentrations at delivery. Two other criteria have been defined to interpret the different exposures calculated, the therapeutic range described in adults/children between 3 and 5 mg l−1 h [9–13] and the exposure associated with a higher risk of toxicity reported in children. Indeed, a mean exposure, from 0 to 24 h (AUC(0,24 h)), greater than 8.4 mg l−1 h was suggested to increase the risk of anaemia by 32% [14]. This exposure was considered as a threshold of high risk toxicity.

Oral forms

Infusions

Gut ka

k1F Maternal

Fetal kF1

ke

Simulations

Figure 1

Three continuous intravenous infusion rates were simulated for the mother: (i) 2 mg h−1 kg−1 during the first hour of labour followed by a rate of 1 mg h−1 kg−1 up to the end of delivery, (ii) 1.5 mg h−1 kg−1 followed by a rate of 0.75 mg h−1 kg−1 and (iii) 1 mg h−1 kg−1 followed by a rate of 0.5 mg h−1 kg−1. Maternal oral administration was also simulated during labour instead of maternal infusions. These simulations aimed to (i) decrease the percent of fetal exposures higher than 8.4 mg l−1 h, (ii) quickly reach fetal concentrations higher than 10 × IC50 (0.05 mg l−1) and (iii) keep fetal concentrations higher than 0.05 mg l−1 as long as possible after birth.

Population pharmacokinetic model of zidovudine concentrations in the mother and the fetus (cord blood). The parameters estimated were maternal bioavailability (F), absorption rate constant (ka), elimination rate constant (ke) equals to the ratio of elimination clearance on the volume of distribution (CL/V), maternal to fetal rate (k1F) and fetal to maternal rate (kF1)

Results Demographic data The population included 195 women, from 16 years to 59 years old (median 33 years). The median (range) value for bodyweight was 72 kg (41–110 kg). Three groups were defined and the first one included 74 HIV infected women in active labour with a median gestational age of 38 weeks. Among these women, 48 received ZDV during their pregnancy and 31 received another highly active antiretroviral therapy without zidovudine. The second group included 56 HIV infected pregnant women (median gestational age, 27 weeks) and the third included 89 HIV infected nonpregnant women. A total of 79 paired concentrations were obtained in WAL and their fetus (cord blood), 72 concentrations were obtained in PW (11 in the first trimester, 38 in the second, 23 in the third) and 122 in NPW. Regarding ZDV infusions during delivery, the median (range) time elapsed between the last oral administration and the start of the infusion (tVO) was 6.0 h (0.01–12), the median time of the first infusion (tF1) was 1 h (1–4.33), and the median dose received (DS1) during tF1 was 140 mg (100–780). The median time of the second infusion (tF2) was 4.9 h (0.45– 11) and the median dose received during tF2 was 300 mg (27–983).

Population pharmacokinetics A total of 273 maternal and 79 cord blood ZDV concentrations were used for pharmacokinetic analysis. All concen1390

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trations for PW and NPW were collected at steady-state and 12 (6.2%) concentrations were below the limit of quantification. They were replaced by the LOQ/2 value [15]. The best model that described the plasma ZDV concentrations of the women was a one compartment model with first order absorption and elimination. An effect compartment with two exchange rate constants represented satisfactorily the cord blood concentrations. A two compartment model or additional compartment linked to the mother compartment did not improve the fit for the mother or the cord blood concentrations. Since ZDV was given orally or by infusion, the maternal fraction of the absolute bioavailability could be estimated in the analytical solutions. As shown in Figure 1, the maternal model parameters were the bioavailability (FRAC), volume of distribution (V), absorption rate constant (ka), elimination clearance (CL), maternal to fetal rate (k1F) and fetal to maternal rate (kF1). Residual variabilities were best described by proportional error models and BSVs were estimated for CL and V. Our data did not allow the estimation of a ka value. Thus, fixing ka to previously reported values was tested [14, 16, 17]. The stability of the model was improved for a ka value fixed to 2.86 h−1. This value has been reported by Panhard et al. [16] and used in others studies [10, 11]. A covariance between CL and V significantly improved the model. Covariates were tested on CL and V in an upward procedure, but maternal BW, maternal age, delivery, gestational age or pregnancy had no significant effect either on ZDV CL or on V. An allometric model was tested but it did not significantly improve the results. Pregnant women in active labour and non-pregnant women had the same median population clearance. The final population pharmacokinetic estimates are summarized in Table 1.

Maternal ZDV population pharmacokinetics

Table 1 Population pharmacokinetic parameters of zidovudine from the final model

Parameter

Estimate

RSE %

95% CI

Structural model ka (h−1)

2.86a

CL (l h−1)

131

5.8

118, 147 156, 227





V (l)

188

10.1

FRAC (%)

56

9.2

k1F (h−1)

1.21

38.8

0.660, 13.5

0.946

41.9

0.484, 11.1

0.358 0.363 0.885 0.39 0.278

22.3 47.5 13.0 15.4 28.9

0.286, 0.216, 0.748, 0.335, 0.163,

kF1 (h−1) Statistical model ωCL ωV Corr (CL,V) σmaternal σfetal

47, 67

0.450 0.554 0.984 0.451 0.336

RSE is the standard error of the estimate divided by the estimate and multiplied by 100 (RSEs and 95% CI are derived from a bootstrap procedure); a, fixed value; ω, square root of between subject variance; Corr, correlation between two ω parameters; σ, residual variability (proportional model).

The following observations support the model developed. The median half-life value of ZDV (1 h) and the median tmax (0.65 h) were consistent with previous reports (between 0.75 and 2 h, and between 0.5 to 0.75 h respectively) [18–20]. The median CL (1.80 l h−1 kg−1) and the exposure due to an administration of 300 mg ZDV twice a day AUC(0,24 h) (2.85 mg l−1 h), were in agreement with previously reported values obtained from adults studies, with a CL from 1.2 to 3.2 l kg−1 h−1 and with an exposure from 2.2 to 3.2 mg l−1 h, respectively [12, 13, 21–23].

Evaluation The parameters and their associated BSV were accurately estimated, and the confidence intervals (CIs) derived from the bootstrap analysis were reasonably narrow and did not include zero (Table 1). The visual predictive checks (VPC) performed on the final model showed that the average prediction matched the observed concentration−time courses and that the variability was reasonably estimated for the maternal and fetal concentrations. The percentage of data out the 5th and the 95th percentiles of simulated data and its 95% CI were 9.79% (6.2, 14.9) for the pregnant and the non-pregnant women, 8.81% (4.9, 14.3) for the women in active labour and 6.25% (2.1, 14.0) for the fetus, Since women received different drug dosages, we normalized the observed and the predicted concentrations for a mean dose are shown in Figure 2.

Maternal exposure The maternal concentration−time courses after oral and intravenous administrations are depicted in Figure 3. The exposures obtained after maternal oral administration or infusions are summarized in Table 2 as well as median and

[minimum–maximum] values. The median exposure in non-pregnant women (AUC(0, 24 h)tablet = 2.77 mg l−1 h) was close to that resulting from oral administration during pregnancy (mAUC(0, 24 h)tablet = 2.50 mg l−1 h). These exposures were in the ranges (2.5 and 3 mg l−1 h) previously reported [12, 13]. The median maternal exposure due to infusions (mAUC(0, 24 h)infusions = 3.77 mg l−1 h) was higher than that resulting from oral administration (mAUC(0, 24 h)tablet) and 4% of these exposures were higher than 8.4 mg l−1 h.

Fetal exposure The fetal concentration–time courses obtained following maternal oral administration, maternal infusion and first neonatal administration are shown in Figure 3. Although the median fetal exposure due to maternal oral administration (fAUC(0, 24 h)tablet = 3.20 mg l−1 h) was higher than the maternal exposure (mAUC(0, 24 h)tablet = 2.50 mg l−1 h) during pregnancy, there was no fetal exposure greater than the toxic threshold (Table 2). Accordingly, the placental transfer during pregnancy was estimated at 128%. Also, the median fetal exposure resulting from maternal infusions, from the start of the infusions up to 24 h later, was much higher (fAUC(0, 24 h)infusions = 9.71 mg l−1 h) than the one resulting from oral administration and 51% of these exposures were above the toxic threshold. However, this exposure is three times lower than the 0–24 h exposure (nAUC(0, 24 h)syrup = 24.9 mg l−1 h) estimated in a neonate weighting 3 kg on the first day of life and receiving current WHO recommendations (15 mg twice daily). For a pregnant woman receiving only an oral administration (no infusion), fetal concentrations remained above 0.05 mg l−1 during at least 5 h (median = 6.5, range 5.2– 8.33 h). Following maternal infusions, fetal concentrations varied at delivery between 0.376 to 1.59 mg l−1. Thus, with this protocol and a bodyweight varying from 1 to 5 kg at birth, a protective fetal concentration could be observed during 13 to 180 h. So, following maternal infusions, no children should be below the protective concentration during the first 12 h of life.

Simulations To decrease fetal exposure while maintaining fetal concentrations above 10 × IC50 (0.05 mg l−1) during at least 12 h after birth, three different infusion rates according to different delivery times are shown in Figure 4. Fetal exposures higher than 8.4 mg l−1 h were reached following 3 h of infusion, protocol 1 (2 mg kg−1 h−1 followed by 1 mg kg−1 h−1 ), 9 h, protocol 2 (1.5 mg kg−1 h−1 followed by 0.75 mg kg−1 h−1) and more than 12 h, protocol 3 (1 mg kg−1 h−1 followed by 0.5 mg kg−1 h−1) (Figure 4B). For the three of them, fetal concentrations higher than 0.05 mg l−1 were reached in less than 0.6 h (0.38, 0.45 and 0.57 h, respectively) after the start of infusions (Figure 4C). If the infusion time was londer than 1 h, the fetal concentrations remained above 0.05 mg l−1 for at least 12 h after Br J Clin Pharmacol

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A 1.00 0.50 0.20 0.10 0.05 0.02 0.01 1

2

3

4

5

6

Time (h)

B 2.0 1.0 0.5 0.2 0.1 0.05 0.02 0.01 0.0

0.5

1.0

1.5

2.0

2.5

3.0

Fetal ZDV concentrations (mg l–1)

Maternal ZDV concentrations (mg l–1)

Maternal ZDV concentrations (mg l–1)

F. Fauchet et al.

C 2.0 1.0 0.5

0.2 0.1 –0.2

Time (h)

0.0

0.2

0.4

Time (h)

Figure 2

ZDV concentrations (mg l–1)

A 1.0 0.8

Birth Pregnancy Labour

Post-partum

0.6 0.4 0.2 0.0 0

5

10

15

20

25

30

Fetal ZDV concentrations (mg l–1)

Visual predictive check: comparison between the 5th (dashed line), 50th (solid line) and 95th (dashed line) percentiles obtained from 1000 simulations and the ZDV observed plasma concentrations (o) for (A) pregnant and non-pregnant women, (B), women after delivery and (C) cord blood at delivery time

B 1.5 Birth 1.0

Neonatal administration (2 mg kg–1)

Labour Pregnancy

0.5

10*IC50

0.0 0

10

Time (h)

20

30

40

50

60

Time (h)

Figure 3 Evolution of maternal (blue line) and fetal (red line) concentrations vs. time (A). Three successive events are included in the time scale, time started after the last maternal oral administration, followed by the delivery time and finished by the post-partum phase. Evolution of fetal concentrations due to maternal infusion during labour (dark red line) or maternal oral administration during labour (dark orange line) vs. time (B). Three successive events were included in the time scale, time started after the last maternal oral administration, followed by the delivery time and finished by the first hours of the neonate life and their first ZDV administration. The French ZDV recommended doses were used (2 mg kg−1) and the protective concentration (0.05 mg l−1) defined is , mother; , fetus; , represented by the green line. The exposures were estimated by the integration of the analytical solutions used in the model. protocol with maternal infusions during labour; , protocol with maternal tablets during labour

the end of infusion (Figure 4D). Thus, protocol 3 should be preferred to the other protocols. Regarding oral administration to the mother during labour instead of infusions, fetal exposures will never be higher than 8.4 mg l−1 h (i.e. median 0–5 h fetal exposure = 1.44 mg l−1 h). Fetal concentrations higher than 0.05 mg l−1 would be reached in 0.2 h and remained above the limit during 5 h after maternal administration. Thus, if ZDV is given orally during labour, it should be administered at the start of labour and every 5 h until delivery. Moreover, ZDV 1392

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should be administered as soon as possible to the neonate after birth.

Discussion This is the first time that a population approach has been used to describe the ZDV PK in pregnant women and women in active labour. Bootstrap and VPC procedures gave a good evaluation of the model. In the present study,

Maternal ZDV population pharmacokinetics

Table 2 Results of the different maternal and fetal exposures

Exposure

Non-pregnant AUC(0, 24 h)tablet

mAUC(0, 24 h)tablet

Sample size Median

n = 122 2.77

n = 151 2.50

Minimum–Maximum (mg l−1 h) Percent of AUC > 8.4 mg l−1 h

1.49–4.51 0

1.33–5.67 0

Maternal mAUC(0, 24 h)infusions

15

10

fAUC(0, 24 h)infusions

n = 79 3.77

n = 79 3.20

n = 79 9.71

0.87–11.33 4%

1.8–6.6 0

5.37–25.84 51%

B Fetal exposure (mg l–1)

Maternal exposure (mg l–1)

A

Anemia

5

0 0

2

4

6

8

10

15

10

Anemia

5

0 0

12

2

4

C 1.2 1.0 0.8 0.6 0.4 0.2

10*IC50

0.0 0

2

4

6

8

10

6

8

10

12

Time of delivery (h)

12

14

Time of delivery (h)

Fetal concentration (mg l–1)

Time of delivery (h) Fetal concentration (mg l–1)

Fetal fAUC(0, 24 h)tablet

D 0.8 0.6 0.4 0.2 10*IC50 0.0 0

5

10

15

20

Time of delivery (h)

Figure 4 Evolution of maternal exposures as a function of delivery time are represented in (A). Evolutions of fetal exposure as a function of delivery time are represented in (B). Evolution of fetal concentrations as a function of delivery time are represented in (C). Evolution of fetal concentrations, according to protocol 3, as a function of delivery time are represented by the solid line (D). Three infusion rates, in decreasing order, are represented by solid lines in A, B and C. The exposure associated with a higher risk of toxicity (8.4 mg l−1 h) is represented by the long dashed line in A and B. The range of therapeutic exposures is represented by the two dashed lines (3–5 mg l−1 h) in B. The fetal protective concentration (0.05 mg l−1) is represented by the long dashed line , 2 mg kg−1 and 1 mg kg−1 h−1; , 1.5 mg kg−1 and 0.75 mg kg−1 h−1; , in C and D. Three different delivery times are represented by dotted lines in D. −1 −1 −1 1 mg kg and 0.5 mg kg h ; , delivery time of 1 h; , delivery time of 3 h; , delivery time of 12 h

no covariate was found to influence the ZDV PK. Pregnant women and non-pregnant women had similar ZDV PK. This is consistent with previous studies which suggested that the PK parameters were similar between pregnant and non-pregnant women [19, 24]. However, a 40% decrease in ZDV exposure has also been described during pregnancy [18, 20], but, these two studies were conducted on a limited number of patients (n ≤ 10) and a noncompartmental analysis was used.

Using the model developed, we could estimate the placental transfer during pregnancy. Usually, a cord-tomaternal blood concentration ratio is used to describe ZDV placental transfer. However, this ratio is mostly depending on duration of infusion and on sampling times [25, 26]. Maternal and fetal (cord blood) sampling time are rarely simultaneous and actually they are very variable between subjects (before or after delivery, in both cases). The values reported previously varied from 86% to 225% Br J Clin Pharmacol

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[20, 25, 27–30]. In the present study, the ratio estimated (128%) was higher than the unique value estimated ex vivo (82%), using human term placenta perfused during 14 h by Boal et al. [26]. The maternal interindividual variability and some limits of the ex vivo study (limited number of placenta (n = 4), perfusion during 14 h, doses perfused very different) can explain this discrepancy. At the end, fetal concentrations are close to those in pregnant women. Adverse effects have been observed in an important number of infants who were exposed to ZDV. Anaemia and neutropenia have been significantly correlated with ZDV blood concentrations [14, 31]. Indeed, ZDV crosses the placenta by passive diffusion [32] and maternal doses administered by infusions can be considerable. In our study, the median fetal exposure following maternal infusion (fAUC(0, 24 h)infusions) was higher than the median fetal exposure following the maternal oral administration (∼3 fold fAUC(0, 24 h)tablet), and 51% of these fetal exposures were higher than the exposure being at toxicity risk. Thus, different options have been considered in order to decrease fetal exposure. As shown in Figure 4, the first option was to decrease the recommended infusion rate during delivery. Protocol 3 (1 mg kg−1 h−1 for 1 h followed by 0.5 mg kg−1 h−1 for the following hours) was the most convincing. It allowed a decrease in fetal exposure below 8.4 mg l−1 h even for very delayed labour. It maintained fetal concentrations above 0.05 mg l−1 for at least 12 h after birth for a birth occurring more than 1 h after the start of infusion (Figure 4D). The second option considered was to continue maternal oral administration during labour, instead of maternal infusions. The 300 mg maternal doses should be administered at the start of labour and every 5 h during labour and the neonate oral dose should be administered quickly after birth to obtain a protective concentration. This option has the benefit to produce fetal exposures much lower than previous infusion protocols while maintaining a fetal concentration higher than 10 × IC50. The context for decreasing the ZDV dose is global. The suggestions of decreasing doses support the already recommended decrease in neonatal ZDV doses. In the new French recommendations published in 2013 (2 mg kg−1 twice daily), doses have been reduced by half to decrease neonatal exposure [33, 34]. Moreover, even in this context of prevention of mother-to-child-transmission, the targets for ZDV concentrations have always been therapeutic concentrations whereas for nevirapine, target concentrations are only preventive (i.e. 10 × IC50 = 0.5 mg l−1; therapeutic>3 mg l−1) [8]. ZDV is metabolized intracellularly to its active metabolite (ZDV-TP). A limit of this study is that only plasma ZDV concentrations were collected. Active intracellular ZDV-TP could not be measured. Thus, further studies are required to evaluate the fetal and neonatal PK of ZDV-TP. To conclude, maternal ZDV infusions are not recommended when the plasma viral load is undetectable near 1394

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delivery, but they are still an efficient prophylactic measure to prevent MTCT in women with a high or unknown HIV viral load near delivery. By suppressing the ZDV infusion at delivery, the neonate would be at risk of having concentrations below the protective target. By maintaining the present protocol, neonates have exposures at higher risk of toxicity. Thus, either maternal infusion rate could be decreased to 1 mg kg−1 h−1 for the first hour and followed by 0.5 mg kg−1 h−1 or the mother could take oral ZDV every 5 h from start of labour until delivery and the neonate should have their first ZDV dose as soon as possible after birth. These conclusions should be prospectively confirmed.

Competing Interests All authors have completed the Unified Competing Interest form at http://www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare no support from any organization for the submitted work, no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years and no other relationships or activities that could appear to have influenced the submitted work.

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Maternal and fetal zidovudine pharmacokinetics during pregnancy and labour: too high dose infused at labour?

The main goal of the study was to describe the pharmacokinetics of maternal zidovudine (ZDV) administration during pregnancy and labour and to evaluat...
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