Pharmacokinetic Investigations of Oral Amodiaquine in Ghanaian Children: A Case Study of Suntreso Government Hospital, Kumasi.

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With the emergence or development of resistance to anti – malarial drugs, the World Health Organization (W.H.O.) now recommends treatment with one of several artimisinin based combination therapies (ACT’s) which includes artesunate plus amodiaquine. To date at least fifteen African countries including Ghana have adopted this treatment policy for uncomplicated malaria. Despite the extensive use of amodiaquine, (as combination therapy) in the treatment of uncomplicated malaria, its pharmacokinetic data, especially in the Sub-Saharan African region is limited. Therefore for optimization of its use in the country there is the urgent need for a clear understanding of its pharmacokinetics. This study therefore seeks to investigate the pharmacokinetics of oral amodiaquine, following administration of the suspension form of the drug to Ghanaian children with uncomplicated malaria. The analysis was based only on urine data. Fifteen Ghanaian children with uncomplicated malaria, but without any history of liver or kidney diseases and of ages between 8 and 12 years, were made to participate in the study. These subjects or patients who were selected from the Suntreso Government Hospital, were given oral doses of amodiaquine suspension, 10 mg/kg body weight in a single dose study. Urine samples were serially collected via a non-invasive approach for a period of 30 hrs. Urine concentrations of the drug, in the unmetabolized form were determined. The urine amodiaquine concentration was determined by liquid – liquid extraction (L.L.E.), followed by ultraviolet (U.V) Spectroscopy analysis. The Pharmacokinetic parameters of the drug which were investigated include, fe, kel, t 1/2, ke, km, ka, and t 1/2a. Statistically, the Pharmacokinetic parameter values were estimated at a probability level of p = 0.05. Extremely low fe values were obtained with a range of between 0.0035 and 0.0083; mean, (0.0059 +/- 0.0011). The estimated overall elimination rate constant kel, ranged from 0.1283 to 0.1823 hr -1; mean, (0.1553 +/- 0.0126 hr -1). The corresponding elimination half – life (t 1/2) range was between 4.0845 and 5.6647 hrs; mean, (4.8746 +/- 0.3691 hrs.).The metabolic rate constant km, ranged from 0.1280 to 0.1816 hr -1; mean, (0.1548 +/- 0.0125 hr -1.), with a corresponding excretion rate constant ke, range of between 0.0004 and 0.0012 hr -1; mean, (0.0008 +/- 0.0002 hr -1.). An absorption rate constant ka, range values of between 0.3586 and 0.5418 hr -1; mean, ( 0.4502 +/- 0.0428 hr -1.) were obtained. The corresponding absorption half-life (t ½ a) values estimated were; range 1.4129 to 2.0271hrs.; mean, (1.7200 +/- 0.1435 hrs). The study confirms orally administered amodiaquine’s rapid absorption as well as extensive hepatic first- pass metabolic effect as published in literature. Statistically, the pharmacokinetic parameters estimated were similar to those published in literature in healthy Caucasian adults as there was no significant difference between the two data. It appears from this observation that, age does not seem to exert any influence on the pharmacokinetics of oral amodiaquine. However, further statistical analyses revealed high significant differences in the pharmacokinetics of the drug between the study data of Ghanaian children and Zambian adults. The mean half life value and thereby the average plasma concentration at steady state of the drug was significantly higher in the Ghanaian children sub population than in the Zambian adults. This implies, perhaps, the need for separate dosing regimen of oral amodiaquine in these two sub populations. The currently available dosing regimen of the drug in the country, (which is based on pharmacokinetic studies in East African subjects) upon recommendations from the World Health Organization may thereby be inappropriate. Therefore to optimize oral amodiaquine therapy in the country there may be the need for its dosage regimen adjustment, probably in the downward trend. However, further pharmacokinetic studies based on both urine and plasma data as well as larger study sample sizes across board in Ghanaians, are needed to effect optimization of the dosage regimen of amodiaquine.
A thesis submitted to the Department of Pharmaceutics,Kwame Nkrumah University of Science and Technology in partial fulfillment of the requirements for the degree of MASTER OF PHARMACOLOGY (PHARMACEUTICS).