Pharmacokinetics of chloroquine and primaquine in healthy volunteers

Abstract

Background Vivax malaria is a neglected disease. There is an irrefutable need for better treatments with higher acceptability and efficacy. The treatment efficacy is influenced by many factors, including bioavailability. Hence, a straightforward strategy to improve vivax malaria treatment efficacy is the deployment of good quality formulations of primaquine and chloroquine. As these treatments were developed more than 70 years ago, many of the available data on blood levels of both drugs are based on obsolete analytical methodologies or pharmaceutical formulations, which are not available anymore. Herein, the results of three bioequivalence studies are presented, providing individual pharmacokinetic data on chloroquine and primaquine of more than a hundred healthy volunteers and using up-to-date analytical methods. Methods Three trials were designed as a single centre, randomized, single dose, open label, fasting, crossover bioequivalence studies comparing a new coated chloroquine tablet to the uncoated tablet, and 5 and 15 mg primaquine formulations to either an international reference product or the currently distributed tablets. Plasma concentrations of chloroquine and primaquine were measured using a validated HPLC–MS/MS method in accordance with current international regulatory requirements for bio-analytical methods. Results In total, a hundred eleven healthy volunteers of both genders were included in the three studies (n = 32; 30 and 56 respectively). No serious adverse events occurred. Drugs levels were measured in 5,520 blood samples. The estimated ratio of the geometric means of Cmax, AUC0-t and AUC0-inf of test and reference drugs and their 90% CI for chloroquine 150 mg, primaquine 15 mg and primaquine 5 mg were: 95.33% (89.18; 101.90), 86. 85% (82.61; 91.31), and 84.45% (76.95; 92.67); 93.28% (81.76; 106.41), 94.52% (86.13; 103.73) and 93.93% (85.83; 102.79); 97.44% (90.60; 104.78), 93.70% (87.04; 100.87) and 91.36% (85.27; 97.89), respectively. As Cmax and AUC0-t 90% CI were within the acceptance interval of 80–125% in all cases, the formulations tested were bioequivalent. Conclusions In conclusion, the three studies provided detailed chloroquine and primaquine pharmacokinetic data in accordance with current regulatory standards. Together with other open data initiatives, this individual data may increase the accuracy of pharmacokinetic models guiding best dose, new combinations, regimens and formulations to optimize the current chloroquine and primaquine treatments for vivax malaria. The data presented here may support the deployment of high-quality drugs and evidence-based public health policies.

Bioequivalence of a new coated 15 mg primaquine formulation for malaria elimination

“…This could be related to the increased sensitivity of mass spectrometry in the current analysis. Other key PK parameters, notably, the median/mean T max , t 1/2 , CL/ F , and Vz/F of both formulations were also consistent with studies dating as far back as the 1980s [ 5 – 7 , 15 , 19 – 22 ]. Taken together, these previously published data support the validity of our PK findings.…”

“…Following 15, 30 and 45 mg of PQ to the same 5 healthy adult volunteers, the measured mean C max values were 53, 104, and 176 ng/mL, respectively, and the corresponding mean AUC 0–24 values were 0.5, 1.0, and 1.6 µg × h/mL [ 6 ]. Consistent findings are also reported by Khan et al [ 14 ] who documented a doubling of C max and AUC 0–24 following the administration of 15–30 or 22.5–45 mg of (+)- S enantiomer and racemic PQ, as well as Daher et al [ 15 ] who recorded geometric mean C max values in Brazilian adults of 65.33 and 21.73 ng/mL, following 15 and 5 mg tablets, respectively. Food enhances PQ absorption and, in one study, two buttered bread rolls, providing 28 g of fat, increased the C max by 26% and AUC 0–∞ by 14% in 20 healthy Vietnamese males (n = 10) and females (n = 10) [ 16 ].…”

“…The bioanalysis used a validated method that Cliantha developed and the PK parameters obtained are consistent with those reported previously from a range of studies. The GM C max of 62 ng/mL (≈ 66 ng/mL) is very close to the 65 ng/mL in Brazilian adults [ 15 ], broadly similar to the 53 ng/mL in 5 adult volunteers [ 6 ] and the 56 ng/mL in vivax-infected, Thai adults given 15 mg of PQ after chloroquine [ 21 ], as well as being around half of the median C max reported in three studies of Thai adult volunteers given 30 mg of PQ: 122 [ 22 ], 128 [ 19 ] and 139 ng/mL [ 20 ].…”