Evaluation of pharmacokinetic and bioequivalence of brands of sulphadoxine-pyrimethamine tablets used in intermittent preventive therapy for pregnant women in Nigeria

摘要

Objectives: The aim of this study is to investigate the pharmacokinetic and relative bioavailability of three tablet formulation containing sulphadoxine pyrimethamine (SP) used for intermittent preventive therapy in pregnant women in Nigeria to see whether there is need for dose adjustment. Methods: Twelve healthy volunteers(pregnant women at their fourth month of pregnancy) attending antenatal clinic (ANC)were randomised to receive a single oral dose of three SP tablets each containing 500mg sulphadoxine (XD)and 25mg pyrimethamine (PY) in form of A (innovator product) and B,C(locally manufactured SP tablet formulation),after an overnight fasting. Several blood samples (100μl) were collected from a finger prick in duplicates up to ten days and dried on a Whatman? filter paper. The samples were analysed for DX and PY using the High Performance Liquid Chromatography (HPLC) method. The pharmacokinetic parameters assessed were maximum plasma concentration (Cmax), area under curve (AUC), elimination half life (t1/2), time to attain maximum concentration (tmax) and relative bioavailability using the single compartment model. Results: Sample formulation B was significantly lower than samples A and C (p<0.1) in mean plasma concentration (Cmax), area under curve (AUC). Conclusion: The difference shows in vivo inequivalence between the products, and calls for caution in using these products, however the pharmacokinetic results shows that there is no need for dose adjustment of SP in pregnancy since they attain therapeutic concentration in vivo, indicating that their kinetics is not altered in pregnancy. Introduction Malaria is a public health problem of global concern because of its high economic burden on the nation, high mortality in children, pregnant women and non immune individuals. It is a major cause of morbidity and mortality in Nigeria where it is holoendemic. Resistance of anti-malaria drug by plasmodium species has continued to create a burden in the management of malaria in endemic areas; the major causative factor in Sub-Saharan African is treatment with poor-quality drug preparation causing suboptimal dosing (1).The World Health Organization (WHO) designated intermittent Preventive Treatment (IPT) as the preferred approach to reduce the number of malaria parasites in pregnant women during the critical period of greatest fetal gain(2). IPT during pregnancy provides significant protection against low birth weight, maternal anemia, preterm delivery and maternal mortality (3, 4, 5, 6, 7, 8). WHO has recommended the use of Sulphadoxine-Pyrimethamine (SP) for intermittent preventive Therapy in pregnant women living in endemic area (irrespective of their peripheral parasite status) (2)Full treatment dose is given to all women at specified interval during the 2nd and 3rd trimester of their pregnancy. Poor in-vitro quality in over 50% of generic SP marketed in Nigeria have been reported (9).Over 80% of approximately 10,000 prescription drugs available in 1990 were obtained from more than one source, and variable clinical responses to these dosage forms supplied by two or more drug manufacturers is documented (10).These variable responses may be due to formulation ingredients employed, method of binding, packaging and storage and even the rigors of in-process quality control, thus the need to determine their therapeutic equivalence in order to ensure interchangeability. SP pharmacokinetic has been investigated widely in non-pregnant population (11, 12, 13, 14). There is no published data for SP pharmacokinetics in pregnant population in most part of Sub-Saharan Africa including Nigeria. There is evidence that the pharmacokinetics of several antimalaria drugs (chloroquine, mefloquine and artesunate) is altered in pregnancy and doses used in non pregnant population are not adequate in pregnancy (15, 16,17). Pregnancy comes with many physiological changes which may have some effect on metabolism and pharmacokinetics of drugs (19)This s