Physiologically based pharmacokinetic (PBPK) modelling of cabotegravir (CAB) to support design of microarray patches (MAPs) for the treatment of HIV positive children
Johanna Eriksson (1), Erik Sjogren (1), Moriah Pellowe (1), Robert K.M. Choy (2), Jessica Mistilis (2), Courtney Jarrahian (2), Darin Zehrung (2), Lalit K. Vora (3), Fabiana Volpe-Zanutto (3), Ismaiel A. Tekko (3), Ryan F. Donnelly (3), Marylore Chenel (1)
(1) Pharmetheus, Sweden, (2) PATH, USA, (3) Queen’s University Belfast, UK
Administration of antiretroviral (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 patch size based on body weight, MAPs can be tuneable for growing children and deposit a depot of medication to limit the frequency of administration.
CAB is an ARV drug, administered orally or intramuscularly, which is inactivated in the body by direct glucuronidation, by UGT1A1 and UGT1A9. CAB is a Biopharmaceutics Classification System class II drug, with incomplete oral bioavailability [1,2].
PBPK modeling allows the integration of age-dependent anatomy, physiology, and enzyme ontogeny together with MAP release kinetics and CAB disposition.
Objectives: The aim of this analysis was to support CAB MAP design and dosage to achieve therapeutic target concentrations in plasma for HIV-positive pediatrics from neonates to adolescents.
Methods: A stepwise approach was used to develop CAB PBPK model using PK-Sim® (v9) : 1- development of a model describing the disposition in adults, 2- scaling of the model to pediatrics, 3- simulation of plasma concentrations in pediatrics after administration of CAB with MAPs, and finally 4- determination of patch sizes and weight-based dosages for HIV positive pediatrics to achieve therapeutic target concentrations.
Physicochemical properties, in vitro data, and clinical observations were used to inform the CAB PBPK model in terms of absorption, distribution, and elimination. The elimination of CAB 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 CAB PBPK model was applied to simulate plasma concentrations in pediatric populations, from neonates to adolescents, after administration of CAB MAPs. Systemic drug input, i.e., drug release from MAPs and absorption from the 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, 25 to <35 kg and >=35 kg). The creation of the different pediatric populations was performed by adopting age-dependent changes in anatomy, physiology, and enzyme ontogeny. MAPs 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 (Ctrough) > 4 x protein adjusted IC90, which corresponds to 664 ng/ml [4,5]. The patch sizes were calculated based on the estimated effective dose needed to achieve the therapeutic target, and the drug delivered into porcine skin from prototype MAPs.
A PBPK model of CAB was established that could describe the available clinical data in adults.
Metabolism was modeled to occur via UGT1A1 and UGT1A9, where the in vitro measured capacity of recombinant UGT1A1 and UGT1A9 to metabolize CAB was used to inform the model on the fraction metabolized by each enzyme. In addition, observed clinical data after multiple dosing suggested autoinhibition of metabolizing enzyme, thus this mechanism was included in the final PBPK model.
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 Cmax and 1.08 for AUC.
The PBPK model was used to estimate MAP sizes for pediatric populations in different weight bands by adopting age-dependent changes in anatomy, physiology, and enzyme ontogeny. The estimated sizes of the drug-loaded area of the MAP ranged from 14 to 88 cm2, under the assumption that the drug release follows zero-order kinetics.
Conclusions: A PBPK model was developed and qualified for CAB with the aim to estimate the patch size 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.
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