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Transplacental transfer of raltegravir and delayed plasma clearance in preterm neonates

<p>Polly Clayden</p>


December 10, 2011

Preterm birth is common in infants born to HIV positive mothers and is associated with an increased risk of mother to child transmission. Oral drug absorption in infants is unpredictable due to the immaturity of the gastro intestinal tract at this age. Preloading the foetus with maternal nevirapine (NVP) is common in these cases.

Raltegravir (RAL) is pregnancy category C and data to guide its use in pregnancy are limited. However, it has been used to achieve a rapid reduction in viral load before delivery, for preloading the foetus where poor oral absorption is anticipated and in cases where there is resistance or intolerance to other antiretrovirals.

RAL is absorbed rapidly (with a Tmax of about three hours) it takes two days to reach steady state concentrations and has an elimination terminal half-life of 9 hours. It uses the UGT 1A1 metabolic pathway. About half of the oral dose is excreted unchanged in the stool and 30% in the urine (about a third of which is as unchanged RAL and the remainder as the metabolite). There is considerable inter patient variability in its metabolism.

In an oral presentation, Aseel Hegazi from St Georges University Hospital, London showed three maternal infant case studies in which pregnant mothers of preterm neonates received RAL as part of their prevention of mother to child transmission (PMTCT) regimens. [1] The investigators looked at transplacental transfer of the drug and plasma clearance in the infants.

The same group has previously described the use of RAL in PMTCT regimens in mothers of three term infants. In these cases they found good transplacental transfer with higher concentrations in the infants than the mothers approximately three hours after delivery. [2] They also reported persistence of neonatal concentrations at three days (although below the therapeutic range). They suggested that poor neonatal and foetal maturity of the UGT-dependent pathways could account for this. And that it is possible that increased activity of UGT1A1, associated with progesterone, observed in pregnant women contributed to the disparity.

In the three cases of RAL use in preterm delivery, paired blood samples were taken as close as possible to delivery and then post partum. Maternal and neonatal RAL plasma concentrations were measured using liquid chromatography and mass spectrometry. Table 1 summarises these cases.

Table 1. Three cases of maternal RAL use in preterm delivery
  Case 1Case 2Case 3
Background ART and clinical context NNRTI and 3TC resistance. Ritonavir intolerance. Poor adherence. Preeclampsia. Placenta praevia. Small for gestational age. Emergency Caesarean section. Poor adherence. Small for gestational age. Emergency Caesarean section. ART naïve. Started on ABC+AZT+3TC in 2nd trimester. Spontaneous rupture of membranes. Multiple fibroids. Emergency Caesarean section.
Time of RAL initiation 22 weeks gestation 14 hours pre-delivery. No repeat dose due to advanced labour and obstetric complications). 25.5 hours pre-delivery. Dose repeated 10.5 hours pre-delivery.
Viral load at RAL initiation (copies/mL) 5030 100 Undetectable
Background regimen TDF + ATV ATV/r + TDF + FTC (NVP + IV AZT at delivery) EFV + TDF + 3TC (NVP + IV AZT at delivery)
Gestation at delivery 33 weeks + 2 days 30 weeks + 3 days 29 weeks + 5 days
Infant birth weight 1510 g 920 g 1365 g
Viral load at delivery (copies/mL) Undetectable 55 Undetectable
Maternal RAL plasma concentrations (ng/mL) 2318 (6 hours post dose at delivery) 4870 (3.5 hours post dose, 11 hours pre-delivery)

64 (3 hours post dose, 1 hour post delivery)

300 (10.5 hours post dose at delivery)
Neonatal RAL plasma concentrations (ng/mL) 3781 (7 hours post maternal dose, 1 hour post delivery) 120 (16 hours post maternal dose, 2 hours post delivery)

67 (65 hours post maternal dose, 63 hours post delivery)

602 (11 hours post maternal dose, 0.5 hours post delivery)
Neonatal:maternal RAL plasma concentrations 1.6 1.9 2.0

Dr Hegazi concluded that therapeutic RAL plasma concentrations (> 15ng/mL) might be persistent for up to five days in preterm neonates. She noted that this is longer than that observed in term infants and is probably linked to immature UGT1A1 mediated gluronidation. She suggested that maternal RAL preloading might be a good alternative to NVP where oral absorption is unreliable (particularly with preterm infants) and maternal options are limited

Comment

These case studies are interesting and this use of RAL could prove important. RAL used this way is likely to be mentioned in the next BHIVA guidelines (although data is very sparse so evidence will be weak).

IMPAACT 1097 is a washout (passive) PK and safety study designed to investigate this phenomenon in neontates. It is the first clinical trial of an investigational drug to look at neonatal PK. It is recruiting mothers already receiving RAL in pregnancy and the infants will be sampled at intervals up to 30 to 36 hours after dosing.

After a review of PK and safety data from this and IMPAACT1060 – which is investigating this drug in children in de-escalated age bands with those below two years, receiving a granule formulation, now being studied – the company is planning a study of infants born to HIV positive mothers from immediately after birth until their status has been confirmed.

References:

  1. Hegazi A et al. Raltegravir in the prevention of mother to child transmission of HIV: effective transplacental transfer and delayed plasma clearance observed in preterm neonates. 13th EACS, 12–15 October 2011, Belgrade. Oral abstract PS 6/7.
  2. Mckeown D A et al. High neonatal concentrations of raltegravir following transplacental transfer in HIV-1 positive pregnant women AIDS. 24 September 2010. Volume 24. Issue 15. p 2416–2418.





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