Pharmacokinetics of chloroquine in Thais: plasma and red‐cell concentrations following an intravenous infusion to healthy subjects and patients with Plasmodium vivax malaria.

Abstract

1 Chloroquine diphosphate (15 mg base kg-") was given by constant rate intravenous infusion to two groups of Thai subjects. Eleven were patients with malaria (10 with Plasmodium vivax and one case with Plasmodium malariae) and 10 were healthy normal volunteers. 2 Plasma and packed red-cell concentrations of chloroquine, electrocardiographic intervals, arterial blood pressure and pulse were measured at frequent intervals.3 Peak plasma concentrations at the end of the infusion ranged from 979 to 2,900 ng ml-' in the malaria patients. In the group of healthy subjects the range was 550-2,200 ng ml-'.Values for terminal elimination rate constant, (X,) plasma clearance (CL), initial volume of distribution (V1) and volume of distribution at steady state (Vss) were calculated. For the healthy subjects, mean estimates of these parameters were X, = 0.062 ± 0.030 day-1, CL = 597 ± 238 ml min-, V1 = 0.66 ± 0.71 1 kg-" and Vss = 132 ± 50 1 kg-1For the group of malaria patients, the corresponding values were A, = 0.055 ± 0.032 day-1, CL = 535 ± 246 ml min-1, V1 = 0.74 ± 0.75 1 kg-1 and Vss = 136 ± 64 1 kg-1There was no statistically significant difference in the estimates for any parameter between groups (P -0.05). 4 Chloroquine concentrations in packed red blood cells consistently exceeded those in plasma and showed no consistent change with time throughout the period of study in either group. The median value for the red cell to plasma ratio was between 3 and 4 in each group. Peak red-cell concentrations were significantly higher than the equivalent plasma concentration in both groups. In the malaria patients the range of concentration was 1829-11052 ng ml-'. In the healthy volunteers, the range was 2410-4570 ng ml-'. were not statistically significant. There was no significant difference in the area under the sacked red-cell concentration vs time curve between the malaria patients (151637 + 85737 ng m-1' h) and healthy volunteers (100053 ± 42536 ng ml-1 h), when measured to infinite time.5 Various subjective side effects were reported in all participants. A small but significant fall from baseline systolic blood pressure 105 ± 6 mmHg was recorded, 2 h into the infusion (99 ± 9 mmHg), but baseline values had been regained by the end of the infusion (101 ± 10 mmHg). There was no significant rise in heart rate. However the minimum measured blood pressure and maximum recorded pulse in each subject were significantly different from the resting values. 6 Coincident with changes in blood pressure, there was, in both groups, a significant prolongation of the PR interval, QRS interval (88 ± 13 ms to 101 ± 17 ms) and an increase in T wave height (44 ± 13%). 7 These findings suggest that there are no major differences in the pharmacokinetics of chloroquine between the group of patients with vivax malaria studied here and a matched group of healthy volunteers. The cardiovascular effects of the drug are common to both groups, suggesting that the relationships between the pharmacokinetics of chloroquine are governed principally by the ...

A review of clinical pharmacokinetics of chloroquine and primaquine and their application in malaria treatment in Thai population

“…This multiexponential decline in blood concentrations of both CQ and DECQ were in consistency with previous reports (Gustafsson et al, 1983;Aderounmu et al, 1986;Karunajeewa et al, 2008;Obua et al, 2008). The mean transit time of absorption (MTT: 0.773 h), peripheral volume of distribution (Vp: 1,600 l), and elimination halflife (t 1/2 : 10.7 days) of CQ were similar to the previously reported values in other populations, but systemic clearance (CL: 6.13 l/h) was relatively lower (FriskHolmberg et al, 1984;Aderounmu et al, 1986;Gustafsson et al, 1987;Tett et al, 1987;Edwards et al, 1988;Titus et al, 1989;Vries et al, 1994;Lee et al, 2008;Karunajeewa et al, 2008;Obua et al, 2008;Karunajeewa et al, 2010;Wetsteyn et al, 2012;Zhao et al, 2014). For DECQ on the other hand, Vp (566,257 l) and CL (2.04 l/h) were relatively lower than the previously reported values.…”

“…The absorption and systemic availability of CQ were higher in patients with P. vivax infection compared with healthy subjects as supported by a significantly higher maximal plasma concentration (C max ) and area under plasma concentration-time curve from time 0 to 28 days of drug administration (AUC 0 -28 days ) of CQ, and in addition, the AUC 0 -28 days of DECQ (Table 1). The author concluded that the increase in systemic exposure of CQ and DECQ after oral dosing in patients with malaria could reflect the change in CQ absorption during the acute phase infection since no such change was observed after intravenous dosing (Edwards et al, 1988). This improvement in systemic exposure of CQ/DECQ should benefit treatment of patients, particularly in the light of accumulating reports on increasing level of CQ resistant P. vivax.…”

“…Previous studies of CQ and DECQ pharmacokinetics involved small number of subjects and in some cases, with limitation of sensitivity of analytical methods and pharmacokinetic analysis approach (Gustafsson et al, 1987;Tett and Cutler, 1987;Edwards et al, 1988;Titus et al, 1989;Lee et al, 2008;Zhao et al, 2014). In addition, a wide range of inter-individual variability in the estimated pharmacokinetic parameters hurdles optimization of dose regimens of CQ particularly in patients infected with P. vivax.…”

“…The first two studies investigated the relationship between CQ blood concentrations and cardiovascular adverse effects, as well as the possibility of enhancement of toxicity during acute phase malaria infection due to alteration of pharmacokinetics of CQ/DECQ (Looareesuwan et al, 1986;Edwards et al, 1988). The report on significant impact of acute phase malaria infection on quinine pharmacokienetics (White et al, 1982) stimulated great concern for clinical use of CQ in patients with malaria.…”

Effect of Khat ( Catha edulis ) Use on the Bioavailability, Plasma Levels and Antimalarial Activity of Chloroquine

“…Edwards et al reported that CQ blood concentrations and AUC were significantly higher in malaria patients receiving oral CQ treatment than in healthy subjects, suggesting that malaria induces absorption changes and increases systemic exposure to CQ. 27 In the current study, reduction in the plasma CQ levels among khat-chewing malaria patients could be related to impaired gastrointestinal absorption due to the effect of khat on CQ absorption.…”