Kesara Na Bangchang

Clinical Pharmacokinetics of Halofantrine

SummaryHalofantrine is a phenanthrenemethanol antimalarial that is effective against asexual forms of multidrug-resistant Plasmodium falciparum malaria. It has no action on gametocytes or hypnozoites in the liver. The drug is administered as a racemic mixture but the (+)- and (−)-enantiomers show no difference in activity in vitro. Three formulations for oral administration are available for human use, i.e. tablets, capsules and suspension. Toxicity studies in animals suggest that halofantrine has very low toxicity both in short term and long term animal studies, and there has been no evidence of mutagenicity in these studies.Phase I, II and III clinical trials of halofantrine conducted in several tropical countries found the drug to be well tolerated and effective against multidrug-resistant P. falciparum malaria when 500mg was administered every 6 hours for 3 doses. The majority of clinical adverse effects reported, including nausea, vomiting, abdominal pain, diarrhoea, orthostatic hypotension, prolongation of QTc interval, pruritus and rash, have been mild and transient.There is wide interindividual variation in halofantrine absorption. The maximal plasma concentration (Cmax) is achieved approximately 6 hours after oral administration. Bioavailability is not dose-proportional for doses over 500mg, but there is a dose-proportional increase in Cmax and area under the plasma concentration-time curve (AUC) for doses between 250 and 500mg. In patients with malaria the bioavailability of halofantrine is decreased. The mean half-life of absorption is 4 hours and Cmax is significantly lower than that obtained in healthy individuals. Furthermore, halofantrine absorption is enhanced when the drug is taken with fatty food. Therefore, halofantrine should be taken with food to ensure optimal absorption in patients with malaria. The terminal elimination half-life is 5 days in patients with malaria.Halofantrine is biotransformed in the liver to its major metabolite N-debutylhalofantrine. Plasma concentrations of this metabolite are observed soon after administration of halofantrine, but in much lower concentrations. The elimination half-life is similar to that of halofantrine.There have been increasing reports of halofantrine treatment failure, particularly in the eastern part of Thailand. The majority of treatment failures have been associated with incomplete drug absorption. The dose-dependent cardiotoxic effects (e.g. cardiac arrhythmia) are a major concern, particularly when the bioavailability of the drug cannot be predicted. Ongoing and future studies should aim at developing more appropriate drug formulation(s) and/or optimising dosage regimens. This will allow therapeutic concentrations to be achieved with minimum adverse effects, particularly cardiotoxicity.

High dose of primaquine in primaquine resistant vivax malaria

The efficacy of low dose chloroquine, characteristic pattern of relapse and the relapse rate in vivax malaria after high dose primaquine were investigated in 167 Thai patients. 87 patients were allocated at random to receive 300 mg, and 80 received 450 mg of chloroquine on the first day of admission. All patients in both groups showed a rapid response with comparable fever clearance times (27.3 vs. 26.1 h) and parasite clearance times (67.1 vs. 58.1 h). After recovery and clearance of parasitaemia, the patients were allocated at random (double blind) to receive 2 dosage regimens of primaquine, a daily dose of 15 mg or 22.5 mg for 14 d. Relapses in both groups occurred within 6 months; no patient relapsed beyond that period. The relapse rate in the primaquine 15 mg group was significantly higher than that in the 22.5 mg group (17.5% vs. 2.4%).

Pharmacokinetics of primaquine in G6PD deficient and G6PD normal patients with vivax malaria

The pharmacokinetics of primaquine have been studied in 13 G6PD normal and 13 G6PD deficient Thai male patients with Plasmodium vivax malaria who were given daily doses of 15 mg of primaquine over 14 d, following a full course of chloroquine. After the first dose (15 mg), primaquine underwent rapid absorption. Mean values (SD in parentheses) of maximum plasma concentration of 57.7 (7.7) vs. 55.7 (7.4) ng/mL were reached at 2.2 (0.6) vs. 2.2 (0.6) h, for the G6PD deficient and G6PD normal groups, respectively. Thereafter, drug levels declined rapidly and monoexponentially with a t1/2 lambda of 6.4 (1.9) vs. 6.3 (2.7) h. The respective mean values (SD in parentheses) for MRT, AUC0-varies; is directly proportional to Cl/f, and Vz/f were 6.8 (0.4) vs. 6.8 (0.5) h, 0.547 (0.070) vs. 0.521 (0.090) micrograms/h/mL, 8.54 (0.37) vs. 8.97 (1.46) mL/min/kg and 4.8 (1.7) vs. 5.1 (1.2) L/kg. There was no difference in the plasma concentrations or pharmacokinetics of primaquine between patients with normal G6PD and G6PD deficiency. In the G6PD deficient group, no relationship between the severity of haemolysis (< 20% or > 20% haemolysis) and the concentrations/pharmacokinetics of primaquine was observed.

Primaquine metabolism by human liver microsomes: effect of other antimalarial drugs

A number of drugs have been studied for their effect on the metabolism of the antimalarial drug primaquine by human liver microsomes (N = 4) in vitro. The only metabolite generated was identified as carboxyprimaquine by co-chromatography with the authentic standard. Ketoconazole, a known inhibitor of cytochrome P450 isozymes, caused marked inhibition of carboxyprimaquine formation with IC50 and K(i) values of 15 and 6.7 microM, respectively. This finding and the dependency of metabolite formation on NADPH indicates that cytochrome P450 isozyme(s) catalysed metabolite production. Of compounds actually or likely to be coadministered with primaquine to malaria patients, only mefloquine produced any inhibition (K(i) = 52.5 microM). Quinine, artemether, artesunate, halofantrine and chloroquine did not significantly inhibit metabolite formation. It seems unlikely that the concurrent administration of mefloquine, or other antimalarials, with primaquine will lead to appreciably altered disposition.

Whole blood concentrations of mefloquine enantiomers in healthy Thai volunteers

We studied the pharmacokinetics of the enantiomers of mefloquine in whole blood in healthy Thai volunteers after administration of a single oral dose of 750 mg of the racemic mixture.Mefloquine pharmacokinetics were stereoselective. The peak concentrations and areas under the curve of the (−) enantiomer were significantly higher than those of its antipode (0.79 versus 0.46 μg · ml-1 and 402 versus 94 μg · h · ml-1). The half-lives of (−)MQ were significantly longer than those of (+)MQ (531 versus 206 h). No stereoselectivity was observed for tmax values.

Pharmacokinetics of Zidovudine Phosphorylation in Human Immunodeficiency Virus-Positive Thai Patients and Healthy Volunteers

ABSTRACT We assessed the pharmacokinetics of zidovudine (ZDV) in plasma and intracellular ZDV phosphate anabolites in peripheral blood mononuclear cells in Thai human immunodeficiency virus (HIV) type 1-infected patients and healthy volunteers. The plasma ZDV area under the concentration-time curve from 0 to 6 h (AUC0–6) was similar in patients and healthy volunteers (32.77 and 22.77 μmol/liter · h, respectively; confidence interval, −3.37 to 19.92). Although the concentration of ZDV triphosphate (ZDVTP) was similar in the two groups, the ZDV monophosphate (ZDVMP) AUC0–6 was significantly greater in HIV patients (1.12 pmol/106 cells) than in healthy volunteers (0.15 pmol/106 cells). In agreement with previously published data obtained with Caucasians, the significant difference in intracellular phosphorylation in Thai volunteers and HIV patients is primarily due to ZDVMP. Comparing the data from this study with the data obtained with Caucasians suggests no marked ethnic differences in ZDV phosphorylation.

Chiral chromatographic method to determine the enantiomers of halofantrine and its main chiral desbutyl metabolite in erythrocytes

We describe a direct liquid chromatographic method with spectrofluorimetric detection to quantify the two enantiomers of halofantrine and the two enantiomers of its main chiral N-monodesbutylated metabolite in erythrocyte pellets. The method involves a Chiralpak AD column and a rapid one-step extraction procedure with acetonitrile. The method was validated for the four enantiomers within the range 0-1000 ng/ml. The absence of stereoconversion was studied in samples stored frozen for up to eight months. The optical rotation of the halofantrine and metabolite enantiomers was determined after separation on a semi-preparative Chiralcel OD column with polarimetric detection.