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No age-related difference in dolutegravir metabolic glucuronidation ratio in children between 3 months and 18 years old in the ODYSSEY trial

Title
No age-related difference in dolutegravir metabolic glucuronidation ratio in children between 3 months and 18 years old in the ODYSSEY trial
Presenter
Tom G Jacobs
Authors
T.G Jacobs * (1), A. Colbers (1), H. Waalewijn (1), P. Amuge (2), D. Bbuye (2), E. Kaudha (3), A. Nanduudu (3), S. Makumbi (4), L. Atwine (4), S. Mudzingwa (5), K. Nathoo (5), J. Hakim (5), A. Liberty (6), A.J. Van Rensburg (7), M. Archary (8,9), D.M Gibb (10), D. Ford (10), A. Turkova (10), D.M Burger (1), ODYSSEY trial team
Institutions
(1) Radboud University Medical Centre, Pharmacy, Nijmegen, Netherlands, (2) Baylor College of Medicine, Children's Foundation, Kampala, Uganda, (3) Joint Clinical Research Centre (JCRC), Kampala, Uganda, (4) Joint Clinical Research Centre (JCRC), Mbarara, Uganda, (5) University of Zimbabwe Clinical Research Centre (UZCRC), Harare, Zimbabwe, (6) University of the Witwatersrand, Perinatal HIV Research Unit, Johannesburg, South Africa, (7) Stellenbosch University, Family Center for Research with Ubuntu, Department of Paediatrics & Child Health, Tygerberg, South Africa, (8) University of KwaZulu- Natal, Durban, South Africa, (9) Enhancing Care Foundation, Durban International Clinical Research Site, Durban, South Africa, (10) University College London, Institute of Clinical Trials & Methodology, London, United Kingdom

BACKGROUND: ODYSSEY and IMPAACT-P1093 found lower and more variable dolutegravir (DTG) exposure in children compared to adults based on mg/kg dose. Investigating the main metabolic pathway (UGT1A1) for DTG could help to explain these findings. Estimates of DTG glucuronide/DTG molar metabolic ratio (DTG-MR) are 0.05-0.08 in adults but this has not been studied in children.
METHODS: A subset of children was selected from PK substudies within the ODYSSEY trial, including all children aged <2 years and a random sample of older children receiving DTG film-coated tablets (FCT; >=20kg) or dispersible tablets (DT; 3-<25kg). DTG and DTG-glucuronide concentrations were measured with a validated UPLC-MS/MS assay and geometric mean (GM) DTG-MR was determined using 3 plasma samples per PK curve (t=2, 6 and 24h). We assessed correlation between DTG-MR and DTG clearance in children, as clearance adjusted for formulation is independent of DTG dose, and it is associated with DTG exposure. Pearson's correlation coefficient was used on log-transformed data to assess the relationships between DTG-MR and DTG clearance/kg (corrected for higher bioavailability of DT), and DTG-MR and age (not log-transformed).
RESULTS: In total, 37 children (age 3 months ' 18 years) were included in this study. There was positive relationship between DTG-MR and DTG clearance/kg in children (r(37)=0.64, p<.001) (Figure). No association was found between DTG-MR and age (r(37)=-0.12, p=0.50). GM(CV%) DTG-MR in children was 0.051(66%), in line with adult values.
CONCLUSIONS: Intersubject variability in DTG-MR was high in children and as the ratio correlates with clearance, this may explain high variability of DTG exposure between children. DTG-MR was similar to adult values and did not change with age, hence increased glucuronidation does not appear to explain the relatively low DTG exposure observed in children aged >3 months. Further studies are needed to assess the role other factors contributing to differences in DTG exposure in children.