Background
Rapid maturation of metabolic/elimination pathways during the first month of life complicates using pediatric fixed-dose dispersible formulations in neonates. We previously reported that once daily administration of abacavir/lamivudine dispersible tablets (ABC/3TC-DT) to neonates gave high exposure during the first week of life. Administration of 5 mg dolutegravir (DTG) every 48 hours (q48) for the first 2 weeks of life, followed by 5 mg daily (q24) until Day 28 is under investigation in the PETITE-DTG study. Hence, we performed a pharmacokinetic (PK) modeling/simulation study to determine if less frequent (q48) administration of ABC/3TC-DT during the two weeks of life would align with DTG dosing to simplify treatment delivery in neonates.
Methods
The ‘PETITE’ study was a phase I/II, open-label, single arm, PK and safety trial of ABC/3TC-DT (120:60mg, double-scored) and lopinavir boosted with ritonavir (40:10 mg) granules in HIV-exposed term neonates in Tygerberg hospital, South Africa. Neonates received 30/15 mg of ABC/3TC-DT (¼ tablet) daily and 80/20 mg of LPV/r (2 sachets) twice daily through 28 days of life. PK blood samples were collected at visits during the neonatal period. Using single and multi-dose data, we developed population PK models for ABC and 3TC. Using the final models, we performed Monte Carlo simulation (n=5,600 virtual neonates) to predict plasma ABC and 3TC drug exposures using q48 dosing from birth to Day 14 and q24 from Day 15 to Day 28. Geometric mean (GM) ABC and 3TC target exposures (AUC0-24) were 6.3 to 50.4 and 6.3 to 26.5 mg.hr/L for ABC and 3TC, respectively.
Results
Twenty-four term neonates (14 girls) and 230 plasma ABC and 3TC concentrations were included. Median (range) body weight was 3,125 (2,270-3,995) g and postnatal age 8 (5-13) days of life at the 1st PK visit. ABC and 3TC plasma concentrations were best described by 1-comparments models. Both body weight and postnatal age influenced their oral clearance. Model-based simulations predicted the GM ABC AUC0-24 remaining within target exposures using q48 dosing compared to q24 dosing during the first 2 weeks of life (Figure 1a). For 3TC, the GM AUC0-24 also remained with the target with q48 dosing (Figure 1b).
Conclusions
Giving 30/15 mg of ABC/3TC every 48 hours for the first 14 days of life; then daily was predicted to maintained target drug exposures comparable to young children. This dosing schedule should align with the proposed DTG regimen in term neonates during the first month of life.
Table or Figure
