Population pharmacokinetics of artesunate and amodiaquine in African children

<p>Abstract</p> <p>Background</p> <p>Pharmacokinetic (PK) data on amodiaquine (AQ) and artesunate (AS) are limited in children, an important risk group for malaria. The aim of this study was to evaluate the PK properties of a newly developed and registered fixed dose combination (FDC) of artesunate and amodiaquine.</p> <p>Methods</p> <p>A prospective population pharmacokinetic study of AS and AQ was conducted in children aged six months to five years. Participants were randomized to receive the new artesunate and amodiaquine FDC or the same drugs given in separate tablets. Children were divided into two groups of 70 (35 in each treatment arm) to evaluate the pharmacokinetic properties of AS and AQ, respectively. Population pharmacokinetic models for dihydroartemisinin (DHA) and desethylamodiaquine (DeAq), the principal pharmacologically active metabolites of AS and AQ, respectively, and total artemisinin anti-malarial activity, defined as the sum of the molar equivalent plasma concentrations of DHA and artesunate, were constructed using the non-linear mixed effects approach. Relative bioavailability between products was compared by estimating the ratios (and 95% CI) between the areas under the plasma concentration-time curves (AUC).</p> <p>Results</p> <p>The two regimens had similar PK properties in young children with acute malaria. The ratio of loose formulation to fixed co-formulation AUCs, was estimated as 1.043 (95% CI: 0.956 to 1.138) for DeAq. For DHA and total anti-malarial activity AUCs were estimated to be the same. Artesunate was rapidly absorbed, hydrolysed to DHA, and eliminated. Plasma concentrations were significantly higher following the first dose, when patients were acutely ill, than after subsequent doses when patients were usually afebrile and clinically improved. Amodiaquine was converted rapidly to DeAq, which was then eliminated with an estimated median (range) elimination half-life of 9 (7 to 12) days. Efficacy was similar in the two treatments groups, with cure rates of 0.946 (95% CI: 0.840–0.982) in the AS+AQ group and 0.892 (95% CI: 0.787 – 0.947) in the AS/AQ group. Four out of five patients with PCR confirmed recrudescences received AQ doses < 10 mg/kg. Both regimens were well tolerated. No child developed severe, post treatment neutropaenia (<1,000/μL). There was no evidence of AQ dose related hepatotoxicity, but one patient developed an asymptomatic rise in liver enzymes that was resolving by Day-28.</p> <p>Conclusion</p> <p>The bioavailability of the co-formulated AS-AQ FDC was similar to that of the separate tablets for desethylamodiaquine, DHA and the total anti-malarial activity. These data support the use this new AS-AQ FDC in children with acute uncomplicated falciparum malaria.</p

Optimizing the programmatic deployment of the anti-malarials artemether-lumefantrine and dihydroartemisinin-piperaquine using pharmacological modelling

Background: Successful programmatic use of anti-malarials faces challenges that are not covered by standard drug development processes. The development of appropriate pragmatic dosing regimens for low-resource settings or community-based use is not formally regulated, even though these may alter factors which can substantially affect individual patient and population level outcome, such as drug exposure, patient adherence and the spread of drug resistance and can affect a drug’s reputation and its eventual therapeutic lifespan. Methods: An in silico pharmacological model of anti-malarial drug treatment with the pharmacokinetic/ pharmacodynamic profiles of artemether-lumefantrine (AM-LF, Coartem®) and dihydroartemisinin-piperaquine (DHA-PPQ, Eurartesim®) was constructed to assess the potential impact of programmatic factors, including regionally optimized, age-based dosing regimens, poor patient adherence, food effects and drug resistance on treatment outcome at population level, and compared both drugs’ susceptibility to these factors. Results: Compared with DHA-PPQ, therapeutic effectiveness of AM-LF seems more robust to factors affecting drug exposure, such as age- instead of weight-based dosing or poor adherence. The model highlights the sub-optimally low ratio of DHA:PPQ which, in combination with the narrow therapeutic dose range of PPQ compared to DHA that drives the weight or age cut-offs, leaves DHA at a high risk of under-dosing. Conclusion: Pharmacological modelling of real-life scenarios can provide valuable supportive data and highlight modifiable determinants of therapeutic effectiveness that can help optimize the deployment of anti-malarials in control programmes

Population pharmacokinetics of Artemether and dihydroartemisinin in pregnant women with uncomplicated <it>Plasmodium falciparum</it> malaria in Uganda

<p>Abstract</p> <p>Background</p> <p>Malaria in pregnancy increases the risk of maternal anemia, abortion and low birth weight. Approximately 85.3 million pregnancies occur annually in areas with <it>Plasmodium falciparum</it> transmission. Pregnancy has been reported to alter the pharmacokinetic properties of many anti-malarial drugs. Reduced drug exposure increases the risk of treatment failure. The objective of this study was to evaluate the population pharmacokinetic properties of artemether and its active metabolite dihydroartemisinin in pregnant women with uncomplicated <it>P. falciparum</it> malaria in Uganda.</p> <p>Methods</p> <p>Twenty-one women with uncomplicated <it>P. falciparum</it> malaria in the second and third trimesters of pregnancy received the fixed oral combination of 80 mg artemether and 480 mg lumefantrine twice daily for three days. Artemether and dihydroartemisinin plasma concentrations after the last dose administration were quantified using liquid chromatography coupled to tandem mass-spectroscopy. A simultaneous drug-metabolite population pharmacokinetic model for artemether and dihydroartemisinin was developed taking into account different disposition, absorption, error and covariate models. A separate modeling approach and a non-compartmental analysis (NCA) were also performed to enable a comparison with literature values and different modeling strategies.</p> <p>Results</p> <p>The treatment was well tolerated and there were no cases of recurrent malaria. A flexible absorption model with sequential zero-order and transit-compartment absorption followed by a simultaneous one-compartment disposition model for both artemether and dihydroartemisinin provided the best fit to the data. Artemether and dihydroartemisinin exposure was lower than that reported in non-pregnant populations. An approximately four-fold higher apparent volume of distribution for dihydroartemisinin was obtained by non-compartmental analysis and separate modeling compared to that from simultaneous modeling of the drug and metabolite. This highlights a potential pitfall when analyzing drug/metabolite data with traditional approaches.</p> <p>Conclusion</p> <p>The population pharmacokinetic properties of artemether and dihydroartemisinin, in pregnant women with uncomplicated <it>P. falciparum</it> malaria in Uganda, were described satisfactorily by a simultaneous drug-metabolite model without covariates. Concentrations of artemether and its metabolite dihydroartemisinin were relatively low in pregnancy compared to literature data. However, this should be interpreted with caution considered the limited literature available. Further studies in larger series are urgently needed for this vulnerable group.</p