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Predicting Utility of Long-Acting Injectables in Paediatric Patients With PBPK Models
Rajith Kumar Reddy Rajoli; David J. Back; Steve Rannard; Andrew Owen; Marco Siccardi
Univ of Liverpool, Liverpool, UK
The use of long-acting (LA) ARVs in children and adolescents could be a valuable pharmacological option to simplify regimens, reduce drug costs and improve adherence. Dose optimisation in paediatric patients is complex and physiologically-based pharmacokinetic (PBPK) modelling represents a predictive tool to identify promising dosing strategies. The aim of this study was to simulate the pharmacokinetics (PK) of LA ARVs in children and adolescents and to identify optimal doses using PBPK modelling.
In vitro PK data for cabotegravir (CBV) and rilpivirine (RPV) were integrated into PBPK models using MATLAB, R2013b. The models were validated against available clinical data (800 mg CBV and 900 mg RPV) for the LA formulations in adults. Paediatric patients were simulated using a mathematical description of covariance between demographics and tissue size, expression of metabolic enzymes and processes regulating drug distribution. The weight band categories were selected according to the World Health Organisation recommendations. ARV PK was simulated for 200 paediatric patients for each weight band following IM administration of LA CBV and RPV. LA doses were optimised to obtain Ctrough values above the protein-binding-corrected IC95 (PBIC95) or clinical cut-offs.
The simulated PK parameters for a long-acting CBV and RPV in adults were in agreement with previously published clinical data. The mean values of AUC were 4467 vs. 5257 µg.h/ml, Cmax 3.3 vs. 3.54 µg/ml and Ctrough 1.1 vs. 1.2 µg/ml for 800 mg CBV quarterly intramuscular administration. The mean values of AUC for 900 mg IM RPV monthly administration were 74,420 vs. 91,087 ng.h/ml, Cmax 168 vs. 168.7 ng/ml and Ctrough 79.1 vs. 78.3 ng/ml. The models predicted optimal ARV doses resulting in at least 95% of the patients achieving Ctrough over the cut-off values for quarterly or monthly administration of CBV or RPV, respectively (table 1).
These data suggest that existing LA nanoformulations may potentially be used in children and adolescents by adjusting the dose based on weight, thus broadening the usage of LA ARVs and providing alternative strategies for treatment simplification.