Rajith KR Rajoli (1), Charles Flexner (2), Andrew Owen (1), Marco Siccardi (1)
(1) University of Liverpool, UK, (2) Johns Hopkins University School of Medicine, USA
Background: Malaria remains a global health threat despite the improvement in controlling the spread of this disease. Although effective treatment and chemoprophylactic regimens are available, sub-optimal adherence to oral regimens results in sub-therapeutic plasma concentrations increasing the risk of failure (1). Atovaquone is a commonly used antimalarial for treatment and prophylaxis as part of a combination with proguanil, and target plasma concentrations for treatment and prevention have been identified (2). Recent application of long-acting injectable (LAI) drug delivery in other therapeutic areas such as schizophrenia, contraception and HIV has opened opportunities to simplify therapy, reduce drug costs and tackle adherence issues (3).
Objective: The aim of this study was to simulate the pharmacokinetics (PK) of a theoretical parenteral atovaquone LAI using physiologically-based pharmacokinetic (PBPK) modelling. Atovaquone PK was simulated across doses and release rates to achieve PK targets for treatment and prophylaxis as 4-weekly LAI administration.
Methods: Simulations were conducted in 100 healthy individuals (50% women, 18-60 years, 77 ± 19 kg (40-120 kg)) (4) using published anthropometric equations (5). A validated whole-body PBPK model for parenteral delivery was used in this study (6) and the PBPK model was constructed using Simbiology v 5.8 (MATLAB 2018a). The PBPK model was constructed using physicochemical and drug-specific parameters available from the literature. Initially, atovaquone simulations were qualified against observed data from a single oral dose in healthy adults (7). The PBPK model was assumed to be qualified if the mean simulated values i.e. the AUC, Cmax and the plasma concentration time curve were within ± 50% from the mean observed values. Atovaquone LAI PK were simulated across a range of doses and release rates. For atovaquone LAI treatment and prophylaxis, target concentrations of 1.83 mg/L (2) and 0.2 mg/L (8) were considered as adequate target concentrations at the end of the 4-weekly dosing interval to identify the minimum dose and optimal release rate.
Results: The PK parameters of atovaquone oral PBPK model qualification were within the acceptable range, with the mean simulated vs. observed AUClast (mg.h/L) – 351 ± 95 vs. 430 ± 103 (difference of -18.4%) and Cmax (mg/L) – 3.7 ± 1.1 vs. 5.3 ± 1.59 (difference of -30.2%) values comparable. For a 4-weekly LAI, the administration of a LAI dose of 1500 mg with the release rate constants from 1.5 × 10-3 to 2.5 × 10-3 h-1 for treatment and a minimum dose of 200 mg with release rate constants from 1 × 10-3 to 3 × 10-3 h-1 for prophylaxis, was predicted to result in plasma concentrations above the defined target concentrations.
Conclusions: The PBPK model identified minimum dose and release characteristics for atovaquone, supporting rational development and streamlining the optimisation of future LAI formulations. Dosing suspensions containing over 300 mg/mL have been developed for other indications meaning that higher doses and longer exposures may be possible for atovaquone. Ultimately, the duration of achievable exposure will be dependent upon achievable drug loading and whether intramuscular or subcutaneous administration is preferred.
References:
[1] Angelo KM, Libman M, Caumes E, Hamer DH, Kain KC, Leder K, et al. Malaria after international travel: a GeoSentinel analysis, 2003–2016. Malaria Journal. 2017;16(1):293.
[2] Shone AE, Moss DM, Lalloo DG, Nixon GL, Fisher N, Ward SA, et al. Antimalarial pharmacology and therapeutics of atovaquone. Journal of Antimicrobial Chemotherapy. 2013;68(5):977-85.
[3] Owen A, Rannard S. Strengths, weaknesses, opportunities and challenges for long acting injectable therapies: Insights for applications in HIV therapy. Advanced Drug Delivery Reviews. 2016;103:144-56.
[4] Centers for Disease Control and Prevention. CDC growth charts: United States. 2000 May 30, 2000. Report No. Available from: http://www.cdc.gov/growthcharts/.
[5] Bosgra S, Eijkeren Jv, Bos P, Zeilmaker M, Slob W. An improved model to predict physiologically based model parameters and their inter-individual variability from anthropometry. Crit Rev Toxicol. 2012;42(9):751-67.
[6] Rajoli RKR, Back DJ, Rannard S, Freel Meyers CL, Flexner C, Owen A, et al. Physiologically Based Pharmacokinetic Modelling to Inform Development of Intramuscular Long-Acting Nanoformulations for HIV. Clin Pharmacokinet. 2015;54(6):639-50.
[7] Rolan PE, Mercer AJ, Tate E, Benjamin I, Posner J. Disposition of atovaquone in humans. Antimicrobial Agents and Chemotherapy. 1997;41(6):1319-21.
[8] Bakshi RP, Tatham LM, Savage AC, Tripathi AK, Mlambo G, Ippolito MM, et al. Long-acting injectable atovaquone nanomedicines for malaria prophylaxis. Nature Communications. 2018;9(1):315.
Reference: PAGE 28 (2019) Abstr 8865 [www.page-meeting.org/?abstract=8865]
Poster: Drug/Disease Modelling - Absorption & PBPK