HTB

Raltegravir pharmacokinetics in pregnancy and neonates

Polly Clayden, HIV i-Base

Two articles published ahead of print online in JAIDS describe raltegravir pharmacokinetics (PK) during pregnancy and in neonates following maternal dosing. [1,2] The data reported support previous smaller studies suggesting: a dose adjustment is not necessary in pregnancy; raltegravir could be a good option to provide pre-exposure prophylaxis to the foetus before and during delivery.

Raltegravir data from IMPAACT 1026 – an ongoing prospective study of antiretroviral PK during pregnancy and postpartum [3] – were first presented at the 50th ICAAC, 2010. [4,5]

The study compared the PK of raltegravir in the second and third trimesters of pregnancy with that postpartum among eligible women receiving standard dose (400 mg twice daily) in antiretroviral regimens before week 35 of gestation. Women who enrolled during the second trimester also had intensive raltegravir PK performed between 20 and 26 weeks gestation (repeated between 30 and 36 weeks). Women who enrolled in the third trimester had PK sampling between 30 and 36 weeks. All women had PK sampling between 6 and 12 weeks post partum.

The study enrolled 42 women. The majority was of African origin from the USA, with a median age of 30 years. Duration of raltegravir use was respectively 88 and 56 weeks for women who enrolled in the second and third trimesters. Half the women received raltegravir with two NRTIs – mainly as their first antiretroviral regimen. The other half received multiclass antiretroviral regimens (at least three classes), and these women were mostly drug-experienced with raltegravir added as an additional agent to prevent vertical transmission. Two women were receiving concomitant ritonavir-boosted atazanavir, which can increase raltegravir exposure.

The majority (>90%) of women had viral load <400 copies/mL by the third trimester. The infants had a median gestational age of 38.4 weeks (range 36.6-42.4) at delivery; at the time of reporting 34 were HIV negative and eight results were pending.

The PK parameters for raltegravir are shown in Table 1.

Table 1: Raltegravir median (range) PK parameters
Parameter 2nd trimester (2T) (n=16) 2T vs PP

p-value

3rd trimester (3T) (n=41) 3T vs PP p-value Postpartum (PP)

(n=38)

AUC0-12 (ug*hr/mL) 6.6 (2.1-18.5) 0.03 5.4 (1.4-35.6) 0.001 11.6 (1.6-39.9)
C12h (ug/mL) 0.06 (0.01-0.4) 0.02 0.06 (0.01-0.61) 0.3 0.08 (0.02-1.34)
Cmin (ug/mL) 0.05 (<0.01-0.16) 0.03 0.57 (<0.01-0.61) 0.66 0.05 (<0.01-0.9)
Cmax (ug/mL) 2.25 (0.37-5.96) 0.09 1.77 (0.32-7.82) 0.003 3.04 (0.31-12.6)
Tmin (hr) 12.0 (0-12.0) 0.91 12.0 (0-12.0) 0.67 12.0 (0-12.0)
Tmax (hr) 4.0 (1.0-8.0) ND 2.0 (0-12.0) ND 2.0 (0.8.0)
CL/F (L/hr) 60.6 (21.6-190.5) 0.36 74.8 (11.2-285.7) 0.21 34.8 (10.0-250.0)
Vd/F (hr) 264.1 (36.4-11228.5) 0.08 329.4 (71.8-10183.2) 0.61 238.8 (42.9-3032.4)
T1/2 (hr) 2.9 (1.2-85.6) 0.26 3.7 (1.1-211.7) 0.57 3.6 (1.1-30.5)
n (%) above C12h 10th percentile non-pregnant 11/16 (69%) 0.49 33/41 (80%) 1.0 30/38 (79%)

The investigators found that pregnancy reduced raltegravir exposure with median AUC of approximately 50% lower in both trimesters than postpartum. They noted that the C12h was below the target level in more than 10% of women at each sampling time (including post partum). During pregnancy, in about a third of the women, the raltegravir concentration continued to decline after dose, compared to about 10% in the post partum period. The investigators suggested this phenomenon indicated a lag in absorption. Overall the C12h was quite variable.

As the women in this study had high rate of virologic suppression, a large variability of plasma concentrations is also seen in non-pregnant adults, and there does not appear to be a clear association between raltegravir concentrations and virologic effect, the investigators do not recommend a change in dosing from 400 mg twice daily.

The second article described raltegravir PK in neonates following the maternal dose from IMPAACT 1097 – early data from this evaluation were shown at the 13th PK workshop, 2012 and 20th CROI, 2013. [6,7,8,9]

IMPAACT 1097 looked at the washout PK and safety of in utero/intrapartum exposure to raltegravir in full-term neonates. [10] Mothers receiving raltegravir and their infants were enrolled in the study prior to delivery.

Neonatal plasma samples were collected at 1-5, 8-14 and 30-36 hours after birth in infants with birth weight >2 kg, gestational age >37 weeks who had not received medications that could induce UGT1A1. Dried blood spots were taken from infants to look at UGT1A1 polymorphisms.

Infants’ blood samples were also taken for total and direct bilirubin, liver transaminases and creatinine at 8-14, 30-36 hours and 1-2 weeks after birth and for complete blood counts at 8-14 hours and 1-2 weeks after birth. The infants were monitored until 20 weeks of age for raltegravir toxicity.

The study enrolled 22 mother/infant pairs, all of which were included in the safety analysis and 19 infants had complete evaluable data. Of 22 infants, 6 (27%) were girls, 13 (59%) were African American and 8 (36%) Hispanic. The median gestational age at delivery was 38 weeks (range 37-40) and birth weight was 3080 grams (range 2200-4100).

At delivery the median maternal raltegravir concentration was 540 ng/mL (range 12-5809), at a median of 4.6 hours after dosing (range 1.1-21.0). Median cord blood raltegravir concentration was 957 ng/mL (range 24-3974) and median cord blood to maternal delivery concentration was 1.48 (range 32-4.33).

Median infant concentrations and the time of collection after birth were: 671 ng/mL (range 13-2672) at 1.9 hours (0.9-4.4), 507 ng/mL (range <10-2280) at 9.3 hours (7.9-13.3), 481 ng/mL (range <10-2106) at 20.5 hours, and 291 ng/mL (<10 – 1402) at 33.8 (range 30.3-35.8).

Raltegravir concentrations increased in 9/19 (47%) of infants over the initial 12-24 hours after birth before declining. The investigators noted that raltegravir concentrations were above the IC95 (14ng/mL) through the last time point for all but one infant. Elimination T1/2 could not be determined for another. For the remaining 17 infants, median T1/2 elimination was 28.6 hours (range 9.3-184; IQR 22.0-69.2).

UGT1A1 genotyping was obtained for 17 infants, of whom 16 also had PK evaluations. Eight infants were (TA)6/(TA)6 homozygotes, 7 were (TA)6/(TA)7 heterozygotes, 1 was a (TA)5/(TA)6 heteozygote and 1 (TA)7/(TA)7 homozygote. The investigators found no differences in median raltegravir concentrations at any time point or in elimination when they compared the (TA)6/(TA)6 infants to the other three IGT1A1 genotypes. The investigators suggested that it is more likely the immaturity of neonatal UGT1A1 enzyme activity accounts for the variability in raltegravir PK than the infant genotype.

Five infants (22.7%) had grade 3 or 4 laboratory events (total bilirubin, creatinine, haemoglobin, neutrophil count and glucose), 2 had grade 3 or 4 signs or symptoms (fever and respiratory discomfort) and 1 grade 3 or 4 diagnosis (metabolic/endocrine disorder).

One infant was low birth weight (2200 grams) and there were no reported deaths or stillbirths. The investigators did not consider any of the adverse events to be related to maternal raltegravir. One infant received phototherapy for hyperbilirubinaemia. The infant was heterozygous (TA)6/(TA)7 with a raltegravir T12 of 75.4 hours. None of the infants received exchange transfusion therapy.

Comment

The BHIVA guidelines recommend raltegravir containing regimens for late presenting women and if viral load is unknown or >100,000 copies/mL.

The authors of the pregnancy study above also suggest that raltegravir might be an option for women receiving co-treatment for TB with a rifampicin-containing regimen.

The neonatal study reported above includes careful discussion on the elimination of transplacentally-acquired raltegravir in infants, particularly those born preterm. The authors note that once raltegravir concentrations started to decline, the rate of elimination was highly variable and most infants very had slow elimination, with the longest T1/2 of 184 hours.

They stress that excessive raltegravir concentrations must be avoided in neonates as high concentrations might increase the risk of bilirubin neurotoxicity. And sub-therapeutic concentrations, which could lead to development of raltegravir resistance, also need to be considered.

They caution that giving raltegravir to preterm infants is likely to pose a higher risk of central nervous system bilirubin toxicity and should be avoided until raltegravir has been well-studied in term and preterm infants.

Two IMPAACT studies are investigating the safety of raltegravir given directly to term infants and washout raltegravir PK in low birth weight infants.

IMPAACT P1110 is a dose-finding PK study to evaluate the safety and tolerability of raltegravir granules given to high-risk, HIV-exposed infants during the first 6 weeks of life with standard antiretroviral prophylaxis. P1110 will start with an initial cohort, receiving two single doses of raltegravir approximately one week apart, followed by a second cohort receiving daily dosing.

Version 2 of P1097 looks at raltegravir washout PK in low birth weight infants, and P1110 might also be expanded to include low birth weight infants.

Together the studies should provide the data necessary to develop raltegravir-containing regimens suitable for the first month of life for prevention and treatment (and possibly cure) of HIV in infants.

References:

  1. Watts H D et al. Raltegravir pharmacokinetics during pregnancy. JAIDS. Published ahead of print 26 August 2014.
    http://journals.lww.com/jaids/Abstract/publishahead/Raltegravir_Pharmacokinetics_during_Pregnancy_.97822.aspx
  2. Clarke DF et al. Raltegravir pharmacokinetics in neonates following maternal dosing. JAIDS. Published ahead of print 26 August 2014.
    http://journals.lww.com/jaids/Abstract/publishahead/Raltegravir_Pharmacokinetics_in_Neonates_Following.97823.aspx
  3. ClinicalTrials.gov. Pharmacokinetic study of antiretroviral drugs and related drugs during and after pregnancy.
    http://clinicaltrials.gov/show/NCT00042289
  4. Capparelli EV et al. Raltegravir pharmacokinetics during pregnancy. 50th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC).12-15 September 2010, Boston. Poster abstract H-1668a.
    http://www.abstractsonline.com/Plan/ViewAbstract.aspx?sKey=1496d8f3-434c-42ff-960b-ff213a2769a6&cKey=8897bf34-bf8d-46af-8011-09f3093246cf&mKey=%7b93AEED6A-54D4-4EF6-99BD-A9B3CE9FACD9%7d
  5. Clayden P. Raltegravir pharmacokinetics in pregnancy. HTB. October 2010.
    http://i-base.info/htb/14035
  6. Clarke DF et al. Raltegravir (RAL) pharmacokinetics (PK) and safety in neonates: washout PK of transplacental RAL (IMPAACT P1097). 13th International Workshop on Clinical Pharmacology of HIV Therapy. Barcelona, Spain.16 -18 March 2012. Oral Abstract: O_22.
  7. Clayden P. Washout pharmacokinetics of transplacental raltegravir in neonates. HTB, 1 June 2012.
    http://i-base.info/htb/16580
  8. Clarke D et al. Raltegravir pharmacokinetics and safety in neonates (IMPAACT P1097). 20th CROI, 3-6 March 2013, Atlanta, GA, USA. Poster abstract 974.
  9. Clayden P. Safety of transplacental raltegravir in neonates and washout pharmacokinetics. HTB. 1 April 2013.
    http://i-base.info/htb/21191
  10. ClinicalTrials.gov. Evaluating the safety and pharmacokinetics of raltegravir in infants.
    https://clinicaltrials.gov/ct2/show/NCT01828073

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