Population pharmacokinetic model of atovaquone in infants to adults
Christoph Pfaffendorf (1,2), Johannes Mischlinger (2), Michael Ramharter (2,3), Sebastian G. Wicha (1)
(1) Dept. of Clinical Pharmacy, Institute of Pharmacy, University of Hamburg, Germany , (2) Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany ,(3) University Medical Center Hamburg-Eppendorf, Department of Medicine, Hamburg, Germany
Introduction: The development of resistance to the artemisinin combination therapy (ACT), which is the WHO recommended first line treatment in all malaria endemic countries [1], has been a rising concern. A declining efficacy of the ACT has been observed in the last decade in the Greater Mekong Region in South East Asia (SAE). Epidemiological genomic studies confirmed that artemisinin resistance had developed. [2]. At the same time resistance to the partner drugs developed causing a decline in cure rates of the ACT in SAE [3]. New combination therapies are needed to halt the emergences of resistance and increase the curing rates. In a proof of concept Phase II trial new combination therapies were tested in Children and Adults with uncomplicated Malaria in Ghana and Gabon. In this analysis our aim was to describe the pharmacokinetics of atovaquone with this new combination.
Methods: 40 patients between 6 month and 65 years were given the new combination therapy consisting of three doses of artesunate/pyronaridine and atovaquone/proguanil (0 h,24 h,48 h). The atovaquone doses were adjusted to weight (5-8 kg :125 mg, 9-10 kg: 187.5 mg, 11-20 kg 250 mg, 21-30 kg: 500 mg, 31-40 kg: 750 mg, >40 kg 1000 mg) Samples were taken up to day 42 after treatment start with a dense sampling scheme after the first dose allowing to identify the absorption phase of the drugs. For adults, samples were taken at 0, 15 min, 30 min, 45 min, 90 min, 3h, 5h, 8h, 24h, and 48h, and for children at 1 h, 3 h, 5 h, 8 h, 24 h, and 48 h. At later time points sparse samples were taken at Day 7, 14, 21, 35, 42. For children below 20 kg the sampling scheme was reduced. The samples were analyzed using LC-MS with a lower limit of quantification of 25 ng/mL. Pharmacokinetic analysis was performed using nonlinear-mixed-effects modeling in NONMEM® 7.5.
Results: We found a 1-compartment model with linear-elimination to be the most suitable model. The absorption was modeled with a transit compartment estimating the mean transit time (MTT) and number of compartments (N) as described by Savic et.al. [4]. The final typical population values were as follows: clearance (CL): 6.87 L/h, volume of distribution (V): 618 L, absorption constant (KA): 0.473 h-1, MTT: 1.13 h and N: 8.81. Allometric scaling was used on clearance and volume of distribution [V]. The data supported estimation of interindividual variability (IIV) on CL, bioavailability and KA. A maturation function was tested on CL, but it didn´t improve the model.
Discussion: The model adequately described the PK of atovaquone. We found the absorption process to be the main driver for IIV, with a high IIV on KA and bioavailability. In a next step we plan on analyzing the exposure in the different age groups of the study population. With the use of clinical trial simulations, we will assess if the doses given to children reach comparable exposures to adults. Finally, we will add pharmacodynamic data (parasite density) to the model to explore the exposure response relationship of atovaquone.
References:
[1] WHO Guidelines for malaria, 2021
[2] Miotto, O., Amato, R., Ashley, E. A., MacInnis, B., Almagro-Garcia, J., Amaratunga, C., et al. (2015). Genetic architecture of artemisinin-resistant Plasmodium falciparum. Nature Publishing Group, 47(3), 226–234. http://doi.org/10.1038/ng.3189
[3] Amato, R., Lim, P., Miotto, O., Amaratunga, C., Dek, D., Pearson, R. D., et al. (2017). Genetic markers associated with dihydroartemisinin-piperaquine failure in Plasmodium falciparum malaria in Cambodia: a genotype-phenotype association study. The Lancet Infectious Diseases, 17(2), 164–173. http://doi.org/10.1016/S1473-3099(16)30409-1
[4] Savic, R.M., Jonker, D.M., Kerbusch, T. et al. Implementation of a transit compartment model for describing drug absorption in pharmacokinetic studies. J Pharmacokinet Pharmacodyn 34, 711–726 (2007). https://doi.org/10.1007/s10928-007-9066-0
