Jesmin Permala(1), Myat P. Kyaw(2), Myat H. Nyunt(2), Khin Chit(2), Moe M. Aye(2), Kyin H. Aye(2), Mats O. Karlsson(1), Martin Bergstrand(1), JoelTarning (3,4).
(1)Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden. (2) Department of Medical Research (Lower Myanmar), Yangon, The Republic of the Union of Myanmar. (3) Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand. (4) Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, UK.
Objectives: Malaria still kills almost 2,000 people each day, mainly children under the age of five. The artemisinin compounds are the most effective antimalarial drugs for uncomplicated and severe Plasmodium falciparum malaria. However, artemisinin resistance has been confirmed in the Mekong sub-region of Southeast Asia (1), threatining our ability to control and eliminate malaria. The aim of this work was to evaluate the PK/PD properties of artesunate (ARS) and its active metabolite, dihydroartemisinin (DHA), in patients with sensitive and resistant falciparum malaria infections to confirm the reach of artemisinin resistance to Southern Myanmar.
Methods: Fifty (50) subjects were recruited and received daily oral artesunate monotherapy (4 mg/kg) (2). Frequent plasma samples up to 8 hours post-dose and parasite microscopy counts every 12 hours until 2 consecutive negative readings were obtained. Data were evaluated using nonlinear mixed-effects modelling. Drug concentrations (PK) below the LOQ were characterized using the M3 method, whereas parasite counts (PD) below the LOQ were omitted.
Results: The absorption of artesunate was best characterized by a flexible transit-compartment (n=3) model, followed by one-compartment disposition models for artesunate and dihydroartemisinin. The only significant covariate effect was body weight, implemented as a fixed allometric function on clearance and volume parameters for both artesunate and dihydroartemisinin. Relative bioavailability was fixed to unity for the typical subject to allow between-subject variability in the same parameter. The population parameter estimates for both parent and metabolite (CI, %RSE), were CLARS/F 848 L/h (739-933, 6.4%), CLDHA/F 36.8 (32.6-40.8, 6.2%), VARS/F 640L (497-789, 12.6%), VDHA/F 49.5L (42-56.5, 8.1.
The drug-dependent parasite killing effect of dihydroartemisinin was implemented using an Emax function, with a mixture model discriminating between sensitive and resistant parasites. EC50 was fixed to 30 nM (prior information from a similar study) due to the inability to estimate this parameter reliably (3). Overall 70% of the studied population was estimated to have resistant infections. Inter-individual variability in Emax was estimated for the resistant population but not retained in the sensitive population
Conclusion: In conclusion, the PK/PD properties of artesunate and its active metabolite, dihydroartemisinin, were well characterized and a mixture model was successfully implemented to differentiate between drug sensitive and resistant parasites in this population.
References:
[1] World Health Organization. Guidelines for the treatment of Malaria. 2015;3rd Edition.
[2] Kyaw M.P., Nyunt M.H., Chit K., Aye M.M., Aye K.H., Aye M.M., Lindegardh N., Tarning J., Imwong M., Jacob C.G., Rasmussen C., Perin J., Ringwald P., Nyunt M.M. Reduced Susceptibility of Plasmodium falciparum to Artesunate in Southern Myanmar. PLoS One. 2013;8(3):e57689.
[3] Das J.P.L. Population Pharmacokinetic-Pharmacodynamic (PK/PD) Modelling of Emerging Artemisinin Resistance in Southeast Asia. Oral presentation. ICAAC. 2015.
Reference: PAGE 25 (2016) Abstr 5882 [www.page-meeting.org/?abstract=5882]
Poster: Drug/Disease modeling - Infection