Dose prediction of long-acting cabotegravir and rilpivirine in children and adolescents according to weight categorie

Back, D

Flexner, C

Owen, A

Rajoli, RKR

Rannard, S

Siccardi, M

University of Liverpool Repository

Long-acting injectable formulations for children and adolescents using PBPK modellingRajith KR Rajoli1, David J. Back1, Steve Rannard2, Caren Freel Meyers3, Charles Flexner4, Andrew Owen1, Marco Siccardi11Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK, 2Department of Chemistry, University of Liverpool, Liverpool, UK, 3Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore, USA, 4Johns Hopkins University School of Medicine and Bloomberg School of Public Health, Baltimore, USABackground• Current antiretroviral (ARV) formulations necessitate lifelong, daily dosing• Suboptimal adherence in the clinical setting leads to high risk of treatment failure and ranges from 50 to 70 % • Additional care and monitoring is necessary in special populations such as paediatric patients• Injectable long-acting nano-formulations could represent a pharmacological option• NIH funding call has been recently published to highlight the relevance of long-acting formulations in infants, children, young adults and pregnant womenSmriti Naswa, Y.S.M., Indian J Sex Transm Dis 32, 1-8 (2011). Chesney, M.A.,Clinical Infectious Diseases, 30(Supplement 2): p. S171-S176 (2000). Spreen, W.R., D.A. Margolis, and J.C.J. Pottage,. Curr. Opin. HIV AIDS. 8(6): p. 565-571 (2013). http://grants.nih.gov/grants/guide/notice-files/NOT-HD-16-022.htmlConventional vs NanoformulationExisting ARVsConventional tablets Long-actingNanoformulationsPaediatric patients• Current paediatric doses are scaled down based on weight from adult dose• Development of anatomy and physiology is not linear with agede Wildt, S., et al.,. Clin Pharmacokinet., 1999. 37(6): p. 485-505.Ginsberg, G., et al., Toxicological Sciences, 2002. 66(2): p. 185-200.Aims• Design and validate a paediatric physiologically based pharmacokinetic (PBPK) model• Identify the optimal doses for existing long-acting formulations of antiretrovirals according to weight categories of paediatric populationPBPK model• Physiologically based pharmacokinetic (PBPK) modelling was used to inform the optimal dose of ARVs in children and adolescents Mathematical description of absorption, distribution, metabolism and elimination processes defining pharmacokinetics  PBPK modelling integrates in vitro data to simulate drug distribution in virtual population HeightWeightBMIGenderEthnicityAgeOrgan volumeCardiac outputRegional blood flows% of body fat Liver sizeRenal functionsCytochrome P450 expressionPlasma proteinTransporter expressionParameter correlation3.107+(0.012*Weight^1.369))*60 (5-18 years)(0.004*Age^2+0.5348*Age+10.92) (7-18 years, male)(271.58+0.163*Age*365)/1000 (3-18 years, male & female) (1.51*BMI-0.7*Age-3.6+1.4)*Weight/100(7-18 years, male) Population variabilityVirtual populationVariabilityEssential PBPK ParametersVolume of distributionIntramuscular release rateMetabolic clearancePharmacokineticsStudy designValidationPredictionOptimization• Weights and blood flow rates of children/adolescents at different ages • Existing available IM formulations of cabotegravir and rilpivirine in adults• Release rates were kept similar to clinical formulations • Pharmacokinetics in children and adolescents according to WHO weight categories• Identify theoretical target dose for once monthly/quarterly administration such that the drug plasma concentrations are above the protein binding adjusted IC95 (PAIC95) or MEC valuesValidation against clinical formulations[1] Spreen, W., et al., Jaids, 2014. 67(5): p. 487-492.00.511.522.533.544.5584 100 116 132 148 164Concentration (µg/ml)Time (Days)Intramuscularly administered cabotegravir (800 mg)Mean Mean ± SD Clinical4* PAIC95 - 0.664 µg/mlAUC - 4,467 vs. 5,257 µg.h/mlCmax - 3.3 vs. 3.54 µg/mlCtrough - 1.1 vs. 1.2 µg/mlRelease rate – 0.00454 h-1[1]05010015020025030028 32 36 40 44 48 52 56Concentration (ng/ml)Time (Days)Intramuscularly administered rilpivirine (900 mg)Mean Mean ± SD ClinicalValidation against clinical formulationsAUC - 74,420 vs. 91,087 ng.h/mlCmax - 168 vs. 168.7 ng/mlCtrough - 79.1 vs. 78.3 ng/mlRelease rate – 0.0009 h-1[1] Spreen, W., et al., Jaids, 2014. 67(5): p. 487-492.[1]MEC – 80 ng/mlPrediction - SummaryWeight (kg) Rilpivirine (1st and 2nd dose in mg) Cabotegravir (mg)14 - 19.9 240, 180 960, 720 30 11020 - 24.9 250, 190 960, 720 30 13025 - 29.9 250, 190 970, 730 35 15030 - 34.9 270, 200 980, 740 35 16035 - 39.9 270, 200 1025, 770 45 17040 - 44.9 280, 210 1050, 790 45 18045 - 49.9 290, 220 1075, 810 50 19050 - 54.9 300, 230 1100, 830 50 20055 - 59.9 310, 230 1125, 840 55 21060 - 64.9 310, 230 1150, 860 55 22065 - 69.9 320, 240 1175, 880 60 240Duration 4 weeks 12 weeksCut-off limit (ng/ml) 20.3 (PAIC95) 80 (MEC) 166 (PAIC95) 664 (4*PAIC95)Limitations• The ontogeny and activity of transporters can affect distribution and elimination patterns• Drugs with high lipophilicity tend to diffuse through the lymphatic circulation rather than through blood• Physiological and metabolic variation of muscle composition in children compared to adults was not accountedDotan, R., et al. (2012). Pediatric exercise science 24(1): 2-21.Tegenge, M. and R. Mitkus (2013). J. Pharmacokinet. Pharmacodyn. 40(5): 545-556.Conclusion• This data could assist in dose optimisation of long-acting intramuscular antiretrovirals for paediatric patients improving adherence to therapy• PBPK modelling represents a predictive tool to improve dosing strategies for use in selective population thus potentially simplifying antiretroviral therapyAcknowledgements• Marco Siccardi • Prof. Andrew Owen• Prof. David Back• Prof. Saye Khoo• Prof. Steve Rannard• Paul Curley• James Hobson• Adeniyi Olagunju• Lee Tatham• José Moltó• Catia Marzolini• Neill Liptrott• Adny Henrique Silva• Christopher David• Darren Michael Moss• Owain Roberts• Sharon Murphy• Christina Chan• Louise Tidbury• Justin Chiong• Rohan Gurjar• Ana Jiminez-Valverde• Megan Neary• Rana Abutaima• Gini Joshua• Hannah Kinvig• Colleagues in the department of Molecular and Clinical Pharmacology

Long-acting injectable formulations for children and adolescents using PBPK modelling

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