Fixed-dose chloroquine and sulfadoxine/pyrimethamine treatment of malaria : outcome and pharmacokinetic aspects
Background: A pre-packaged fixed-dose formulation of chloroquine (CQ) and sulfadoxine/pyrimethamine (SIP) combination (Homapak) is widely used for the treatment of falciparum malaria in the Home Based Management of Fevers program for Ugandan children. Until the present study, the efficacy, pharmacokinetics and drug interactions of the dose regimen of the product were not known.
Aims: To explore treatment outcome and the pharmacokinetics with fixed-dose CQ+SP combination in uncomplicated falciparum malaria in Uganda.
Materials and methods: In a classical pharmacokinetic study, possible pharmacokinetic interactions between CQ and SIP during co-administration as Homapak were explored and the bioequivalence was determined in healthy volunteers (n=32). Multiple blood samples were obtained on day 0 and up to day 21. Plasma drug levels were assayed using HPLC and classical pharmacokinetic calculations were pursued (I). The efficacy of the fixed-dose CQ+SP (Homapak) compared with AQ+SP combination was determined during a clinical trial in children with uncomplicated falciparum malaria (n= 18 3) (II). The effects of nutritional status and other host factors at recruitment together with the attained CQ and S concentrations on the treatment outcomes in the children were determined by statistical predictions using regression analyses (III). Blood samples collected on filter paper in children (n=83) treated with the fixeddose CQ+SP were modeled in a population approach using the NONMEM software to determine the exposure (AUC) that predicts cure, from which a proposal for dose modification was made for the treatment of uncomplicated falciparum malaria (IV).
Results: Sulfadoxine absorption was more rapid in Homapak (ka = 0.55 h-1) than when given as Fansidar + CQ (ka = 0.27 h-, p=0.004), but similar when Fansidar was given alone (ka = 0.32 h-1, p=0.03). Other pharmacokinetic parameters of S, P and CQ were similar when given together or separately, demonstrating bioequivalence of Homapak to reference formulations (I). Efficacy of Homapak was tested, and based on the day 14 adequate clinical and parasitological response, CQ+SP (Homapak) had poorer efficacy at 70.9% compared to 97.4% for AQ+SP (p<0.001). In those given Homapak, treatment failure rates were much higher (48.2%) for the younger age group given halfstrength (HS), than in the older children (18.2%, p=0.004) given the fullstrength (FS) Homapak. (II). Among the children given Homapak, stunting was more common (27.7%) compared to underweight (19.3%) and wasting (9.6%), with the mean given doses of CQ and S (mg/kg) and concentrations higher in the FS than HS dose groups. Overall the significant explanatory covariates for cure were day 1 S concentration (p=0.004), day 3 CQ concentration (p=0.037), and stunting (p=0.046) (III). By applying a population approach to the response and pharmacokinetics in these children using twocompartmental models the drug exposure (especially AUC0-336) was found to be predictive of response, with the HS dose group having lower AUCO-336 values, the majority being below the level predicted for cure. A simulated modified dose, with all children in the age range 6 - 60 months given the same higher fixed-dose CQ+SP would greatly improve the possibility of achieving AUC necessary for cure in at least 95% of the children (IV).
Conclusions: The fixed-dose CQ+SP formulation (Homapak) is of good quality. It is however inferior in efficacy compared with AQ+SP combination. AQ could therefore be used as a replacement in combination with SP in the treatment of falciparum malaria where sensitivity patterns permit. To improve response with the fixed-dose CQ+SP a dose modification is proposed by giving all children 6 - 60 months the same higher dose of the formulation.
List of scientific papers
I. Obua C, Ntale M, Lundblad MS, Mahindi M, Gustafsson LL, Ogwal-Okeng JW, Anokbonggo WW, Hellgren U (2006). Pharmacokinetic interactions between chloroquine, sulfadoxine and pyrimethamine and their bioequivalence in a generic fixed-dose combination in healthy volunteers in Uganda. Afr Health Sci. 6(2): 86-92
https://pubmed.ncbi.nlm.nih.gov/16916298
II. Obua C, Gustafsson LL, Aguttu C, Anokbonggo WW, Ogwal-Okeng JW, Chiria J, Hellgren U (2006). Improved efficacy with amodiaquine instead of chloroquine in sulfadoxine/pyrimethamine combination treatment of falciparum malaria in Uganda: experience with fixed-dose formulation. Acta Trop. 100(1-2): 142-50. Epub 2006 Nov 20
https://pubmed.ncbi.nlm.nih.gov/17113554
III. Obua C, Ntale M, Ogwal-Okeng JW, Gustafsson LL, Hellgren U, Petzold MG (2007). The importance of drug concentrations and nutritional status for the outcome of malaria treatment with chloroquine. [Submitted]
IV. Obua C, Hellgren U, Ntale M, Gustafsson LL, Ogwal-Okeng JW, Gordi T, Jerling M (2007). Population pharmakokinetics of chloroquine and sulfadoxine and treatment response in children with malaria: suggestions for an improved dose regimen. [Manuscript]
History
Defence date
2007-04-27Department
- Department of Laboratory Medicine
Publication year
2007Thesis type
- Doctoral thesis
ISBN
978-91-7357-144-9Number of supporting papers
4Language
- eng