Access to artesunate-amodiaquine, quinine and other anti-malarials: policy and markets in Burundi by Amuasi JH, Diap G, Blay-Nguah S, Boakye I, Karikari PE, Dismas B, Karenzo J, Nsabiyumva L, Louie KS, Kiechel J. Malaria Journal 2011, 10:34 (10 February 2011) doi:10.1186/1475-2875-10-34

Conclusions: AS-AQ was widely available and affordable in the public and NGO markets of hard-to-reach post-conflict communities in Burundi. However greater accessibility and affordability of policy recommended anti-malarials in the private market sector is needed to improve country-wide policy uptake.

Anti-malarial market and policy surveys in sub-Saharan Africa by Diap G, Amuasi J, Boakye I, Sevcsik A-M, and Pecoul B. Malaria Journal Supplement, BioMed Central 2010 April, 9(1):S1

Following the development by DNDi and the FACT partners of the ASAQ fixed-dose combination, according to WHO recommendations (easy to use, affordable, field adapted and non-patented), and despite the fact that ASAQ fixed-dose combination is registered and available in more than 25 African endemic countries and eligible for Global Fund and other international funding, general access to ACTs for patients is still inadequate.

At the recent meeting (Sept 18, 2009) on public and private market and policy survey: ‘Antimalarial market and policy surveys in sub-Saharan Africa’, a validated methodology for these surveys in two countries (Sierra Leone and Burundi) was discussed. Real-life data were presented in a highly interactive brainstorming session among key stakeholders, in a time when market issues for malaria are at the top of the international agendas.

Amodiaquine (AQ) is an antimalarial drug that was frequently combined with artesunate (AS) for the treatment of uncomplicated malaria due to Plasmodium falciparum and is now available as a fixed dose combination. Despite its widespread use, the simultaneous  pharmacokinetics of AQ and its active metabolite, desethylamodiaquine (DAQ) were not characterized to date in patients. The pharmacokinetics of AQ and DAQ were therefore investigated in 54 adult patients receiving the AS/AQ combination by the use of a population approach. AQ followed a 1-compartment model with first-order absorption and elimination as well as a first-order and irreversible transformation  into DAQ, which in turn followed a 2-compartment model with first-order elimination from its central compartment. Mean AQ apparent clearance and distribution volume were 3410 L/h and 39200 L respectively. Mean terminal elimination half-life of DAQ was 211 h. Bodyweight was found to explain the interindividual variability of the apparent volume of distribution of AQ and the elimination rate constant of DAQ. A new dosage form consisting in a fixed dose combination of AS and AQ was found to have no effect on the pharmacokinetic parameters of AQ and DAQ. All patients achieved parasite clearance within 4 days following the initiation of the treatment, which prevented the investigation of the possible relationship between DAQ exposure and treatment outcome. This study provided the first simultaneous pharmacokinetic model for AQ and DAQ.

Efficacy of artesunate-amodiaquine for treating uncomplicated P. falciparum malaria in Sub-Saharan Africa: a multi-centre analysis by Zwang J, Olliaro P, Barennes H, Bonnet M, Brasseur P, Bukirwa H, Cohuet S, D'Alessandro U, Djimde A, Martensson A, Yeka A, Karema C, Guthmann J-P, Hamour S, Ndiaye J-L, Rwagacondo C, Sagara I, Same-Ekobo A, Sirima S, van den Broek I, Taylor W, Dorsey G, Randrianarivelojosia M. Malaria Journal 2009 Aug 23; 8:203.

This multi-centre analysis led by Julien Zwang at the Shoklo Malaria Research Unit addresses the efficacy of artesunate-amodiaquine, a very important candidate for the treatment of uncomplicated malaria globally. The analysis of patient-level data examining the efficacy of AS&AQ compared with local standard therapy, makes a strong case for the use of AS&AQ in all transmission settings. The analysis, sponsored by DNDi, has pooled data from 26 drug studies in a majority of paediatric malaria cases in sub-Saharan Africa identified through a systematic search and has focused on efficacy as safety will be reported separately. While not without limitations, this analysis contributes to the evidence base as to the proper use of ACTs, particularly the AS&AQ combination, and has provided results consistent with the recently published Cochrane systematic review and meta-analysis on ACTs (including AS&AQ.)

Population pharmacokinetics of artesunate and amodiaquine in African children by Stepniewska K, Taylor W, Sirima S.B, Ouedraogo E.B, Ouedraogo A, Gansane A, Simpson J.A, Morgan C.C, White N.J, Kiechel J-R. Malaria Journal 2009 Aug 20, 8:200.

Pharmacokinetic (PK) data on amodiaquine (AQ) and artesunate (AS) are limited in children, an important risk group for malaria. The aim of this prospective population pharmacokinetic study of AS and AQ was to evaluate the PK properties of “ASAQ”, a newly developed and registered fixed dose combination (FDC) of AS and AQ in African children. Conducted in 70 children aged six months to five years, the study utilized population PK models for dihydroartemisinin (DHA) and desethylamodiaquine (DeAq), the principal pharmacologically active metabolites of AS and AQ, respectively, and total artemisinin anti-malarial activity. Relative bioavailability between products was compared by estimating the ratios (and 95% CI) between the areas under the plasma concentration-time curves (AUC). 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.

Randomized, multicentre assessment of the efficacy and safety of ASAQ – a fixed-dose artesunate-amodiaquine combination therapy in the treatment of uncomplicated Plasmodium falciparum malaria by Ndiaye J-L, Randrianarivelojosia M, Sagara I, Brasseur P, Ndiaye I, Faye B, Randrianasolo L, Ratsimbasoa, Forlemu D, Moor V A, Traore A, Dicko Y, Dara N, Lameyre V, Diallo M, Djimde A, Same-Ekobo A, Gaye O. Malaria Journal 2009 Jun 8; 8:125.

Due to limited pharmacokinetic data available for the combination artesunate + amodiaquine, which is used widely to treat uncomplicated malaria, this study examined the bioavailability and tolerability of a fixed and loose combination of artesunate + amodiaquine with a 2×2 cross-over design in 24 healthy volunteers. The authours concluded that both combinations were well tolerated and had comparable pharmacokinetic profiles, and that differences are unlikely to be clinically relevant.

With the expanded use of the combination of artesunate (AS) and amodiaquine (AQ) for the treatment of falciparum malaria and the abundance of products on the market, comes the need for rapid and reliable bioanalytical methods for the determination of the parent compounds and their metabolites. While the existing methods were developed for the determination of either AS or AQ in biological fluids, the current validated method allows simultaneous extraction and determination of AS and AQ in human plasma. The method is sensitive, selective, accurate, reproducible and suited particularly for pharmacokinetic study of AS–AQ drug combination and can also be used to compare the bioavailability of different formulations, including a fixed-dose AS–AQ co-formulation.

Several products of artesunate plus amodiaquine (AS + AQ) are being deployed in malaria-endemic countries for treating uncomplicated falciparum malaria but dosing accuracy and consequential effects on efficacy and tolerability have not been examined. Patients were treated and followed by research teams or local health centre staff in Casamance, Senegal. AS + AQ was given as: (i) loose combination (AS 50 mg, AQ 200 mg), dosed on body weight, or (ii) co-blistered product (AS 50 mg, AQ 153 mg) dosed by weight or age. It was concluded that Artesunate is easier to dose than AQ. Currently available age-dosed, co-blistered AS + AQ tends to overdose AQ and is less well tolerated than loose tablets.

ASAQ, the new fixed-dose combination of artesunate (AS) and amodiaquine (AQ), is now available to treat malaria throughout sub-Saharan Africa. It is the first drug developed by the FACT (fixed-dose, artemisinin-based combination therapy) partners, and its development can serve as a model for future drug development to treat neglected diseases. The article describes the rationale and the process behind the development; the partners involved in the development, production and promoting availability; and the steps taken in the registration and postregistration phases to ensure that ASAQ reaches the populations who can most benefit from it.

Artesunate plus amodiaquine (AS+AQ) was used to treat slide-proven Plasmodium falciparum-infected patients of all ages in the Oussouye district, Casamance, Senegal, over a period of six years (2000 to 2005). AS+AQ in combination was highly efficacious and well-tolerated in this area and justifies the decision to use it as first line treatment. Long-term monitoring of safety and efficacy should continue.

Artesunate plus amodiaquine (AS+AQ) was used to treat slide-proven Plasmodium falciparum-infected patients of all ages in the Oussouye district, Casamance, Senegal, over a period of six years (2000 to 2005). AS+AQ in combination was highly efficacious and well-tolerated in this area and justifies the decision to use it as first line treatment. Long-term monitoring of safety and efficacy should continue.

Without an effective vaccine for the prevention of malaria, a fundamental component of the strategy for the control of this disease is based on prompt and effective treatment. An important step is the recent registration in Morocco (the country where the drug is manufactured) of a fixed combination of artesunate plus amodiaquine by the Drugs for Neglected Diseases initiative with sanofi-aventis as the industrial partner.

This editorial (in French) presents ASAQ, a fixed-dose combination of artesunate and amodiaquine launched in March 2007 by Drugs for Neglected Diseases initiative (DNDi) and sanofi-aventis. The combination is aimed for treating uncomplicated falciparum malaria in malaria-endemic countries in Africa.