Back, D

Owen, A

Rajoli, RKR

Rannard, S

Siccardi, M

University of Liverpool Repository

Rajith KR Rajoli1, David Back1, Steve Rannard2, Andrew Owen1, Marco Siccardi1.1 - Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK 2- Department of Chemistry, University of Liverpool, UKMethods• In vitro PK data for rilpivirine (RPV) and cabotegravir(CBV) was 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 formulationsin adults. Drug release rate from the site of injection forRPV and CBV was derived from the clinical data inadults during the validation process.• The anatomy and physiology of children aged between3-18 years was also validated against data available inliterature [2-4].• The weight band categories were selected according tothe World Health Organisation recommendations [5].• ARV PK was simulated for 200 paediatric patients foreach weight band following IM administration of LACBV and RPV.Results• Weights and blood flow rates of children/adolescents at different ageswere validated against available anthropometric and anatomical data.[2]. Parameters of existing available adult IM formulations ofcabotegravir and rilpivirine were validated against available clinicaldata [3].• The mean values of AUC were 4467 vs. 5257 µg.h/ml, Cmax 3.3 vs. 3.54µg/ml and Ctrough 1.1 vs. 1.2 µg/ml for 800 mg CBV quarterlyintramuscular administration (Figure 2b) [5,6].• The mean values of AUC for 900 mg IM RPV monthly administrationwere 74,420 vs. 91,087 ng.h/ml, Cmax 168 vs. 168.7 ng/ml and Ctrough79.1 vs. 78.3 ng/ml (Figure 2a) [3].• The summary of the predicted doses for CBV and RPV for all weightcategories (according to WHO guidelines) are shown in Table 2.• Optimal ARV doses resulting in at least 95 % of the patientsachieving Ctrough over the cut-off values for quarterly or monthlyadministration of CBV or RPV were predicted.Predicting Utility of Long-Acting Injectables in Paediatric Patients With PBPK ModelsReferences1. Baert, L., et al., Eur J Pharm Biopharm. 2009. 72(3): p. 502-508.2. Bjorkman, S., Br J Clin Pharmacol, 2005. 59(6): p. 691-704.3. Spreen, W., et al., Jaids, 2014. 67(5): p. 487-492.4. Valentin J., Annals of the ICRP: 2003.5. WHO. http://www.who.int/hiv/pub/paediatric/paediatric_arv_dosing.pdf6. Trezza, C., et al., Current Opinion in hiv and Aids, 2015. 10(4): p. 239-245.Rajith Kumar Reddy Rajolirrajoli@liverpool.ac.uk T +44 151 794 5565F +44 151 794 5656Conclusion• The validated PBPK models predicted the in vivopharmacokinetics of CBV and RPV in children andadolescents.• This data could assist in the dose optimisation ofLA IM ARVs for paediatric patients.•Modelling approach could be an innovative wayto optimise dose requirements in specialpopulation, broadening usage in ARV therapy.•Role of transporters, immune system, drugdiffusion through the lymphatic system duringlong term therapy represent potentiallimitations which have not been considered inthese PBPK models.•PBPK model represents a predictive tool toimprove dosing strategies thus potentiallysimplifying antiretroviral therapy.Cabotegravir RilpivirinelogP 2.2 4.32pKa 4.14 3.26Fu 0.007 0.003B/P 0.441 0.67Vss (L) - -Clint CYP3A4 (µL/min/pmol)- 2.04Clint UGT1A1 (µL/min/pmol)4.5 -Clint UGT1A9 (µL/min/pmol)2.2 -IM Release rate (h-1) 0.000454 0.009Figure 2. Validation of PBPK model againstagainst available clinical data a) 800 mg CBV and 900 mg RPV for the LA formulations in adults [3] Table 2. Optimised doses of Rilpivirine and Cabotegravir long-acting formulations for various weights categories of children and adolescentsa)b)Table 1. Physicochemical and metabolic characteristics of simulated drugs# 442Overview• Long-acting (LA) sustained release ARVs inchildren and adolescents could represent avaluable pharmacological option, to simplifyregimens, reduce drug costs and improveadherence for treatment and PrEP [1].• Dose optimisation in paediatric patients iscomplicated due to the differences inanatomical and physiological process comparedto adults [2].• Physiologically-based pharmacokinetic (PBPK)modelling represents a mathematical approachto predict pharmacokinetics, through thedescription of molecular and physiologicalprocesses defining drug distribution.• The aim of this study was to simulate thepharmacokinetics (PK) of LA intramuscular (IM)ARVs in children and adolescents and toidentify optimal doses using PBPK modelling.Figure 1. Variability in in vitro data and mathematical equations defining the physiology of an individual yield pharmacokinetics of a population

Predicting Utility of Long-Acting Injectables in Paediatric Patients With PBPK Models

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