Pharmacokinetics and Bioavailability of chloroquine in different dosage forms

Abstract

The pharmacokinetic parameters and bioavailability of oral chloroquine (syrup and tablet dosage forms) were estimated and compared to that of intramuscular formulation. This study was carried out in six healthy adult male volunteers after fully understood the purpose of the study and gave their approval ina written consent form. Four-way crossover trials were performed using a single dose of chloroquine (600 mg base) on an empty stomach preceded by an overnight fast. Blood samples were collected at specified time intervals following drug administration. Volunteers were allowed to take only pure water until 3 hrs after medication. A standard breakfast was then served. A 21 days washout period was allowed between trials. The blood samples were kept at -20 o C till analysis. Samples were analyzed by HPLC system using hydroxychloroquine as an internal standard. Non-compartmental pharmacokineticanalysis was performed on the blood concentration-time data. The pharmacokinetic parameters (Mean ± SD), Cmax, Tmax, AUC0→240, AUC0→∞, T½,Ke, MRT, Vd/F and Cl/F determined following the administration of 600 mg chloroquine syrup were found to be 1.54 ± 0.32 µg/ml, 2.5 ± 0.84 hr, 57.68 ± 30.23 µg.hrs/ml, 67.18 ± 31.13 µg.hrs/ml, 48.35 ± 7.33 hrs, 0.01 ± 0.0 h -1 , 81.47 ± 19.92 hrs, 739.89 ± 331.78 L and 10.98 ± 5.64 L/hr, respectively. On the other hand, the same parameters following the administration of 600 mg chloroquine tablets (A) formulation were estimated as 1.70 ± 0.54 µg/ml, 2.60 ± 1.14 hr, 53.22 ± 15.71 µg.hrs/ml, 59.58 ± 13.21 µg.hrs/ml, 36.99 ± 4.80 hrs, 0.02 ± 0.0 h -1 , 84.88 ± 17.99 hrs, 577.13 ± 231.32 L and 10.59 ± 2.96 L/hr, respectively. Statistically significant differences were observed in pharmacokinetics of tablets (B) in comparison with other formulations. The pharmacokinetic parameters after the ingestion of tablets (B) were as follows: Cmax 0.52 ± 0.31 µg/ml, Tmax 5.50 ± 2.17 hr, AUC0→240 25.11 ± 20.32 µg.hrs/ml, AUC0→∞ 30.54 ± 21.58 µg.hrs/ml, T½ 44.79 ± 13.59 hrs, Ke 0.02 ± 0.0 h -1 , MRT 78.96 ± 28.42 hrs, Vd/F 1888.3 ± 1373.8 L, Cl/F 32.25 ± 26.34 L/hr. For the intramuscular preparation, the pharmacokinetic parameters calculated were: Cmax 2.21 ± 1.32 µg/ml, Tmax 1.50 ± 0.84 hr, AUC0→24054.50 ± 28.89 µg.hrs/ml, AUC0→∞ 65.66 ± 30.12 µg.hrs/ml, T½ 49.16 ± 12.98 hrs, ke 0.01 ± 0.0 h -1 , MRT 86.63 ± 34.83 hrs, Vd/F 792.62 ± 398.51 L, Cl/F12.11 ± 8.37 L/hr. Statistical analysis using student′s t-test showed that there are no statistically significant differences in all pharmacokinetic parameters between syrup and tablets (A) comparedto the intramuscular formulation. Interestingly, the study showed that there are statistically significant differences (p < 0.05) in pharmacokinetic parameters; Cmax, Tmax, (AUC0→240), (AUC0→∞) and Vd/F of tablets (B) when compared to the intramuscular dosage form. Other pharmacokinetic parameters of tablets (B), i.e MRT, T½ and Cl/Fshowed no statistically significant differences. The relative bioavailabilities of syrup, tablets (A) and tablets (B) in comparison with the intramuscular formulation were 102 %, 92 % and 47%, respectively. The study concluded that tablets (A) and the syrup dosage forms are bioequivalent to the intramuscular standard formulation, whereas tablets (B) is bioinequivalent. Bioequivalence studies were recommended to be performed for all oral dosage forms locally marketed and manufactured before issuing their Certificate of Registration.