Physiologically based pharmacokinetic modelling to support design of microarray patches delivering antiretroviral drugs to HIV positive children
Gianluca Selvaggio (1), Johanna Eriksson (1), Robert K.M. Choy (2), Jessica Mistilis (2), Priscilla Kwarteng (2), Courtney Jarrahian (2), Erik Sjögren (1), Marylore Chenel (1)
(1) Pharmetheus AB, Uppsala Science Park, Uppsala, Sweden (2) PATH, Seattle, USA
Introduction: Advancements in facilitating access to antiretroviral therapy (ARV) are evident, with 29.8 million out of 39 million HIV positive individuals currently receiving treatment globally. However, disparities persist, notably among children and adolescents, where 43% of the 1.5 million children living with HIV lack access to treatments, contributing to a higher mortality rate among this demographic [1]. Challenges in paediatric treatment adherence, dosage availability, and administration methods are evident, demanding alternative solutions that are specific to this population. Microarray patches (MAPs) are a novel method for administering ARV drugs to children in low- and middle-income countries that could address issues related to user compliance, refrigeration, and formulations appropriate for pediatric use.
Objectives: To inform islatravir (ISL) MAP design and dosing regimen needed to achieve a therapeutic target concentration of islatravir-triphosphate (ISL-TP) in HIV positive children, from neonates to adolescents, by developing a physiologically based pharmacokinetic (PBPK) model of ISL.
Methods: A rat PBPK model was developed describing the distribution and elimination of ISL in PK-Sim® after intravenous (IV) administration using physicochemical data, in vitro data, and internally established PBPK models for humans. After model optimization to rat IV data, the whole-body model was then extended with a dermal module in MoBi®, based on a previously published dermal model developed to evaluate MAP delivery [2]. The drug release rates from the MAP needles to the skin sub-layers (i.e., stratum corneum, viable epidermis, hair follicle, and dermis) were described according to an empirical double-Weibull function. The release function parameters were identified by optimizing parameters towards pre-clinical MAP data. The resulting rat PBPK model was then extrapolated to human children by scaling anatomical and physiological parameters and implementing an age dependency on the thickness of different skin layers [3].
Results: The paediatric PBPK model for ISL was used to simulate pharmacokinetic (PK) profiles after monthly administration of ISL-MAPs to human children of different weight groups, and the dose (i.e., number of MAPs) to achieve therapeutic target concentration was estimated. The ISL release profile required the definition of an onset day from which the whole-blood concentration of ISL-TP was above the therapeutic target (i.e., 0.0585 pmol/mL). In the first stage, different onset requirements (i.e., 1, 5, and 10 days) were tested to investigate the cost/benefits of delaying the onset. Results indicated that a 5-day onset had a superior trade-off between number of MAPs and time required to reach therapeutic concentration, leading to its selection for optimizing the MAP design. Moreover, simulations showed that repeated monthly dosing induces an accumulation of ISL, as the release was not completed within day 30. The accumulation ratio was calculated between the trough concentration at day 90 and day 30, indicating a 33% accumulation.
Conclusion: In summary, this analysis suggests that MAPs are a viable drug delivery system for ISL in HIV positive children that would improve both access and adherence to HIV treatment for this population.
References:
[1] Joint United Nations Programme on HIV/AIDS (UNAIDS). The path that ends AIDS: UNAIDS Global AIDS Update 2023. Geneva: UNAIDS; 2023. (UNAIDS/JC3082E)
[2] Rajoli RK, Flexner C, Chiong J, Owen A, Donnelly RF, Larrañeta E, et al. Modelling the intradermal delivery of microneedle array patches for long-acting antiretrovirals using PBPK. European Journal of Pharmaceutics and Biopharmaceutics. 2019;144:101-9.
[3] Yun YE, Calderon-Nieva D, Hamadeh A, Edginton AN. Development and Evaluation of an In Silico Dermal Absorption Model Relevant for Children. Pharmaceutics. 2022;14(1):172.
