Abstract
BackgroundArtemisinins are the most effective anti-malarial drugs for uncomplicated and severe Plasmodium falciparum malaria. However, widespread artemisinin resistance in the Greater Mekong Region of Southeast Asia is threatening the possibility to control and eliminate malaria. This work aimed to evaluate the pharmacokinetic and pharmacodynamic properties of artesunate and its active metabolite, dihydroartemisinin, in patients with sensitive and resistant falciparum infections in Southern Myanmar. In addition, a simple nomogram previously developed to identify artemisinin resistant malaria infections was evaluated.MethodsFifty-three (n = 53) patients were recruited and received daily oral artesunate monotherapy (4 mg/kg) for 7 days. Frequent artesunate and dihydroartemisinin plasma concentration measurements and parasite microscopy counts were obtained and evaluated using nonlinear mixed-effects modelling.ResultsThe absorption of artesunate was best characterized by a transit-compartment (n = 3) model, followed by one-compartment disposition models for artesunate and dihydroartemisinin. The drug-dependent parasite killing effect of dihydroartemisinin was described using an Emax function, with a mixture model discriminating between artemisinin sensitive and resistant parasites. Overall, 56% of the studied population was predicted to have resistant malaria infections. Application of the proposed nomogram to identify artemisinin-resistant malaria infections demonstrated an overall sensitivity of 90% compared to 55% with the traditional day-3 positivity test.ConclusionThe pharmacokinetic-pharmacodynamic properties of artesunate and dihydroartemisinin were well-characterized with a mixture model to differentiate between drug sensitive and resistant infections in these patients. More than half of all patients recruited in this study had artemisinin-resistant infections. The relatively high sensitivity of the proposed nomogram highlights its potential clinical usefulness.
Highlights
Artemisinins are the most effective anti-malarial drugs for uncomplicated and severe Plasmodium falciparum malaria
The clearance of microscopy detectable parasites by 24–48 h after the first dose of Artemisinin-based combination therapy (ACT) is a typical indication of P. falciparum being fully susceptible to artemisinins [6], and parasite detection at 72 h after treatment initiation is interpreted as possible resistance [7]
Between subject variability (BSV) was maintained in all parameters and the eta shrinkages computed in the final pharmacokinetic model were moderate to low (CLARS = 36.6%, VARS = 14.8%, CLDHA = 38.6%, VDHA = 32.4%, MTT = 7.01% and F = 20.2%) while epsilon shrinkages were low (14.1% for ARS and 10.0% for DHA)
Summary
Artemisinins are the most effective anti-malarial drugs for uncomplicated and severe Plasmodium falciparum malaria. Widespread artemisinin resistance in the Greater Mekong Region of Southeast Asia is threatening the possibility to control and eliminate malaria. ACT is the most effective anti-malarial treatment today and consist of an artemisinin derivative and a partner drug [2]. The short-acting but potent artemisinin component eliminates the majority of parasites during the first 3 days of treatment and the slow acting and less potent partner drug removes residual parasites to prevent recrudescent infections. The clearance of microscopy detectable parasites by 24–48 h after the first dose of ACT is a typical indication of P. falciparum being fully susceptible to artemisinins [6], and parasite detection at 72 h after treatment initiation is interpreted as possible resistance [7]. High-grade resistance to both dihydroartemisinin and its partner drug, piperaquine, is seen in Cambodia, Thailand, Laos and Vietnam resulting in unacceptably high clinical failure rates [9,10,11]
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