(M1130-11-63) Physiologically Based Pharmacokinetic (PBPK) Modelling of Cabotegravir to Evaluate the Feasibility of Drug Delivery via Microarray Patches for the Treatment of HIV in Children

Purpose: Administration of anti-retroviral (ARV) drugs via MAPs has the potential to increase compliance and acceptability of HIV treatment for children. MAPs are easy to apply to the skin and may be more acceptable than oral dosing in young children. By adjusting the size based on weight, MAPs can be tuneable for growing children and deposit a depot of medication to limit the frequency of administration. Cabotegravir is an ARV drug, that is administered orally or as a long-acting injectable. Cabotegravir is metabolized in the body by UGT1A1 and UGT1A9. The plasma protein binding is very high ( >99%) and the systemic half-life is 41 hours after oral administration and 5.6 to 11.5 weeks after administration of a long-acting injectable [1]. PBPK modelling allows the integration of age-dependant anatomy, physiology, and enzyme ontogeny together with MAP release kinetics and cabotegravir disposition. Thus, PBPK modelling is suitable to assess the patch size and dosing regimen for MAPs needed to achieve therapeutics target to treat HIV positive children. The objective of this study was to evaluate if delivery of cabotegravir via microarray patches (MAPs) is feasible with regards to patch size and dosing regimen, to achieve therapeutics target concentrations in plasma for HIV positive children in ages from neonates to adolescents.

Methods: A stepwise approach was used to develop a PBPK model for cabotegravir using PK-Sim^® (v9) [2]: 1) develop a model describing the disposition in adults, 2) scale the model to pediatrics, 3) simulate plasma concentrations in pediatric populations after administration of cabotegravir via MAPs, and finally 4) determine patch sizes and weight-based dosing regimens for HIV positive children to achieve therapeutic target concentrations. Physicochemical properties, in vitro data and clinical observations were used to inform the cabotegravir PBPK model in terms of absorption, distribution, and elimination. The elimination of cabotegravir was attributed to UGT1A1 and UGT1A9 metabolism. Ontogeny and expression of UGT1A1 and UGT1A9 were obtained from the RT-PCR database available in PK-Sim^®. Simulations with virtual populations were performed for all external datasets used for model development and qualification. Model performance was evaluated by comparing simulated with observed PK profiles and parameters. The final cabotegravir PBPK model was applied to simulate plasma concentrations in pediatric populations, from neonates to adolescents, after administration of cabotegravir MAPs. Systemic drug input, i.e., drug release from MAPs and absorption from administration site, was described with zero-order kinetics. The simulations were performed using populations consisting of 200 virtual children for each weight group (3 to < 6 kg, 6 to < 10 kg, 10 to < 14 kg, 14 to < 20 kg, 20 to < 25kg and 25 to < 35 kg). Creation of the different pediatric populations was performed by adopting age-dependent changes in anatomy, physiology, and enzyme ontogeny. MAP dosing regimens were established for a dosing interval of 1 month to achieve therapeutic target concentrations for 90% of the pediatric population in each weight group. The therapeutic target was total plasma trough concentration (C_trough) > 4 x protein adjusted IC₉₀, which corresponds to 664 ng/ml [3,4]. The patch sizes and loaded doses were calculated based on the estimated effective doses needed to achieve therapeutic target, the drug delivered into porcine skin from MAPs (0.305mg/0.5cm²) and the drug loaded into MAPs (1.08mg/0.5cm²).

Results: A PBPK model of cabotegravir was established that could describe the available clinical data after oral administration of different doses in adults (Figure 1) [5,6]. Comparison of simulated and observed PK parameters for the model qualification data set demonstrated acceptable performance of the model as simulated-to-observed absolute average fold error was 1.23 for C_max and 1.08 for AUC. The estimated sizes of the drug-loaded area of the MAPs for pediatric patients ranged from 14 to 88 cm² (Table 1). The patch sizes were estimated under the assumptions of zero-order release rate from the MAP and complete bioavailability, as experimental release rates from MAPs and bioavailability have not yet been obtained from in vitro or in vivo studies. Thus, the estimated patch sizes should be regarded as a best-case scenario.

Conclusion: A PBPK model was developed and qualified for cabotegravir with the aim to estimate patch sizes for monthly therapeutic delivery to HIV positive children. Reducing the estimated patch sizes by shifting to weekly administration may be necessary for acceptability and manufacturing feasibility for most pediatric age groups, except for neonates.

References: [1] European Medicines Agency, 2021, Vocabria:EPAR – Product information. 5 January 2021.
[2] Jörg Lippert et al. 2019, Open Systems Pharmacology Community—An Open Access, Open Source, Open Science Approach to Modeling and Simulation in Pharmaceutical Sciences. CPT Pharmacometrics Syst Pharmacol. 8(12): 878–882.
[3] Trezza C, Ford S, Spreen W, Pan R and Piscitelli S, 2015, Formulation and pharmacology of long-acting cabotegravir. Current Opinion in Hiv and Aids vol. 10(4): 239–245.
[4] Spreen W, Min S, Ford S, Chen S, Lou Y, Bomar M, St Clair M, Piscitelli S and Fujiwara T, 2013, Pharmacokinetics, safety, and monotherapy antiviral activity of GSK1265744, an HIV integrase strand transfer inhibitor. HIV clinical trials vol. 14(5): 192–203.
[5] Min S, DeJesus E, McCurdy L, Richmond G, Torres J, Ford S, Chen S, Lou Y, Bomar M, Cyr T
and Fujiwara T, 2009, Pharmacokinetics (PK) and safety in healthy and HIV-infected subjects and short-term antiviral efficacy of S/GSK1265744, a next generation once daily HIV integrase inhibitor.
The Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco
[6] Parasrampuria R, Ford S, Lou Y, Fu C, Bakshi K, Tenorio A, Trezza C, Spreen W and Patel P, 2019, A phase I study to evaluate the pharmacokinetics and safety of cabotegravir in adults with severe renal impairment and healthy matched control participants. Clinical pharmacology in drug development vol. 8(5): 674–681

Acknowledgements: MAPs for Peds: Development of a Microarray Patch for Delivery of Long-Acting Antiretrovirals for Treatment of Pediatric HIV Infection was funded by the Eunice Kennedy Shriver National Institute Of Child Health & Human Development and the National Institute Of Allergy And Infectious Diseases (NIAID) under NIAID grant number 1R61AI149642-01


Figure 1. Cabotegravir plasma concentration-time profiles after oral dosing for model development dataset (blue) and model qualification dataset (green). Observations are represented by dots [5,6]. Solid line and shaded area represent the simulated geometric mean and the 5-95% quantiles of the PBPK model for a virtual population (n=100).


Table 1. Estimated patch sizes, effective and loaded doses for cabotegravir MAP for children in different weight bands