Abstract Body

Antiretroviral treatment (ART) from birth in neonates (<28 days of age) at high risk of HIV acquisition can provide both enhanced HIV prophylaxis and early treatment. Although abacavir (ABC) is a recommended component of 1st line ART in children, pharmacokinetic (PK) data and dosing information are limited for neonates. ABC is licensed for children >3 months of age (8 mg/kg, BID), while the WHO recommends weight band dosing for children ?4 weeks weighing ?3 to <5.9 kg (60 mg or ~ 10 – 20 mg/kg, BID). We performed a PK analysis using ABC plasma concentrations from neonates and young infants to determine ABC dosing for term neonates.

Data were pooled from 3 studies administering ABC liquid: (1) PACTG 321 (2) a Tygerberg cohort and (3) IMPAACT P1106. Studies 1 and 2 performed intensive PK sampling in term neonates receiving ABC for HIV prophylaxis. Study 3 performed sparse PK sampling on term and low birth weight (LBW; <2500g) infants with HIV initiating ABC based ART after 1 month of life. ABC PK parameters were estimated using a population approach. Monte Carlo simulations were run for virtual term neonates to achieve ABC exposures (AUC0-12) within the expected range based on WHO weight band dosing (3.2 to 25.2 mcg.hr/mL).

Forty-five infants contributed 308 ABC concentrations; 21 term neonates <15 days of life undergoing intensive PK sampling. LBW infants were older at first PK assessment with a median (range) postnatal age (PNA) of 78 (41–190) days and weight of 3.6 (2.4–5.8) kg. ABC plasma concentrations were described by a 1-compartment model. ABC CL/F was allometrically scaled according to infant body weight and PNA described maturation in a non-linear manner. At birth, term neonates demonstrated a low ABC CL/F of 0.15 L/hr/kg reaching 0.71 L/hr/kg by 6 months of age (~five-fold increase). ABC CL/F in LBW infants at 6 weeks PNA was similar to term infants of a similar chronological age. Simulations predicted that an ABC dose of 2 mg/kg BID in term neonates and then 4 mg/kg BID from 4–12 weeks of age, achieved an AUC0-12 in the expected range (Fig 1).

ABC elimination is greatly reduced at birth but rapidly increases over the first weeks of life. Our proposed mg/kg dosing for ABC from birth to 3 months of life provides exposures within the expected range, but data on LBW infants are needed. Using the WHO weight band dose of 60 mg for children ?4 weeks and weighing ?3 to <5.9 kg would lead to higher exposures, but no safety concerns have been reported.