PII-162 - APPLICATION OF PBPK TO SUPPLEMENT CLINICAL DATA AND INVESTIGATE THE IMPACT OF UGT1A1 PHENOTYPE ON DOLUTEGRAVIR EXPOSURE IN AFRICAN BREASTFED INFANTS

J. Ning¹, K. Rowland-Yeo¹, A. Pansari¹, C. WAITT², L. Almond³; ¹Certara UK, ²University of Liverpool, ³Certara UK (Simcyp).

Background: The WHO recommends dolutegravir-based HIV treatment as the first-line in all populations [1] and that mothers living with HIV should exclusively breastfeed their infants for the first 6 months of life [2]. Drug exposure in breastfed infants depends on factors including the infant daily dose (IDD, from milk) and the relevant enzyme ontogenies. Dolutegravir is metabolised by UGT1A1 with a minor role of CYP3A4. Higher plasma exposure has been reported in patients with UGT1A1 alleles with impaired activity [3].

Methods: Dolutegravir PBPK models (Simcyp V22) for the mother and breastfed infant were verified using clinical data in Ugandan/South African subjects. The models were then applied to assess the impact of maternal and infant UGT phenotype on exposure in milk and infants. The exposure in breastfed neonates and 6-month-olds who were UGT1A1 extensive (EMs) and poor metabolizers (PMs) was simulated assuming the predicted IDD was split across 6 equal feeds per day and accounting for developmental changes in physiology and enzyme maturation.

Results: Simulated dolutegravir in lactating women was within 1.6-fold of observed data. The simulated M/P of 0.023 (90% CI 0.023-0.024) was in line with observed 0.03 (N=17, 90% CI 0.03-0.04) [4] and 0.02 (N=1) [5]. Assuming a milk intake of 150ml/kg/day, the predicted relative infant dose (RID) and IDD were 1.51%, and 0.0078 mg/kg/day, respectively, using average milk concentrations. Simulated plasma profiles in neonates were in reasonable agreement with clinical data (Cmax was within 0.71-fold of that observed) [4]. The predicted exposure in breastfed neonates and infants was 1.28-and 2-fold higher in UGT1A1 PMs (with PM mothers) compared to EMs (EM mothers) but remained 51- and 108-fold lower than that observed in the lactating mothers, respectively.

Conclusion: Although predicted exposure in breastfed neonates was higher than in infants, the impact of UGT1A1 phenotype was less due to the differing enzyme ontogenies. PBPK modelling can be used to supplement clinical data to assess the interplay between covariates in populations that are difficult to study, such as breastfed infants and lactating mothers.

[1] WHO, 2018 WHO-CDS-HIV-18.51-eng.pdf
[2] WHO & unicef 2016 Updates on HIV and infant feeding.
[3] NDA204790
[4] PLoS Med. 2019 Sep 20;16(9):e1002895
[5] AIDS. 2016 Nov 13;30(17):2731-2733.