A combined population pharmacokinetic model of proguanil and its active metabolite cycloguanil in infants to adults with uncomplicated malaria
Christoph Pfaffendorf (1), Johannes Mischlinger (2,3), Michael Ramharter (2,3), Sebastian G. Wicha (1)
(1) Dept. of Clinical Pharmacy, Institute of Pharmacy, University of Hamburg, Germany, (2) Department of Tropical Medicine, Bernhard Nocht Institute for Tropical Medicine & I. Dep. of Medicine University Medical Center Hamburg-Eppendorf, Hamburg, Germany. (3) German Centre for Infection Research (DZIF), partner site Hamburg-Luebeck-Borstel, Hamburg, Germany.
Introduction: A rising concern in the treatment of malaria is the development of resistance to the artemisinin combination therapy (ACT), which is the WHO recommended first line treatment in all malaria-endemic countries [1]. In order to halt the emergence of resistance and increase cure rates, new combination therapies are needed. A proof-of-concept phase II clinical trial was conducted to test new combination therapies in children and adults with uncomplicated malaria in Ghana and Gabon. The objective of this analysis was to describe the population pharmacokinetics of proguanil and its active metabolite cycloguanil with this new combination.
Methods: a total of 40 patients aged between 6 months and 65 years were treated with the new combination therapy consisting of three doses of artesunate/pyronaridine and atovaquone/proguanil (dosed at 0 h, 24 h, 48 h). Proguanil doses were adjusted to weight (5-8 kg: 50 mg, 9-10 kg: 75 mg, 11-20 kg: 100 mg, 21-30 kg: 200 mg, 31-40 kg: 300 mg, >40 kg 400 mg). Samples were taken up to day 42 after treatment started with a dense sampling scheme after the first dose, which allowed to characterise the absorption phase of the drugs. For adults, samples were taken at 0, 15 min, 30 min, 45 min, 90 min, 3 h, 5 h, 8 h, 24 h, and 48 h, 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 on day 7, 14, 21, 35, and 42. Children below 20 kg were sampled at a reduced rate. The samples were analyzed using LC-MS, with a lower limit of quantification of 1 ng/mL for proguanil and 0.2 ng/mL for cycloguanil. Nonlinear-mixed-effects modeling was used for pharmacokinetic analysis using NONMEM® 7.5. Step-wise covariate modelling (SCM) was performed with structural modeling with alleviable covariate including height, weight, body temperature.
Results: A 2 compartment (proguanil) – 1 compartment (cycloguanil) model with linear elimination and a time-dependent Weibull absorption for proguanil and its active metabolite was found to best describe the data. The absorption of proguanil was described by the following equation: KA= KAMax * (1 – exp(-KA1*time)GAMA1). The final typical parameter values were as follows: proguanil clearance (CL_PG): 35.9 L/h, proguanil central volume of distribution (V2_PG): 422.0 L, proguanil peripheral volume of distribution (V3_PG): 361.0 L, proguanil intercompartmental clearance (Q_PG): 27.5, metabolite rate (KM): 0.462 1/h, clearance cycloguanil (CL_CG): 36.2 L/h, volume cycloguanil (V_CG): 95.8 L, KAMax: 0.0286 h-1, KA1: 0.576 and GAMA1: 4.52. In the SCM, we found that age was a covariate on V2_PG and KM. An allometric scaling approach was also tested, but it did not significantly improve the model. The data supported the estimation of interindividual variability (IIV) for all absorption parameters KAMax (18.1 %CV), KA1 (90.4 %CV), GAMA1 (48.1 %CV), KM (50.9 %CV), and bioavailability (36 %CV), as well as inter occasional variability on bioavailability (41.8 %CV). The residual error was modeled with a proportional error for proguanil (32.6 %CV) and a combination of proportional and additive error for cycloguanil (29.7 %CV, 0.105 ng/mL).
Discussion: The main driver of the variability between individuals was the absorption process, with high variability in the absorption parameters and bioavailability. The rate at which the active metabolite cycloguanil is formed was found to be affected by age. An examination of the effect of age on the exposure to cycloguanil is planned to determine if the dosing regimen leads to equivalent cycloguanil exposures in all age groups.
References:
[1] WHO Guidelines for malaria, 2021