Pharmacokinetics of halofantrine in healthy Thai volunteers [letter]

Karbwang, Juntra; Ward, SA; Milton, KA; Bangchang, Na K; Edwards, Glenn A.

doi:10.1111/j.1365-2125.1991.tb03968.x

Cited by 13 publications

(12 citation statements)

References 5 publications

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“…The recrudescences (or reinfection) observed in our patients were probably not due to poor absorption of the drug, since HPLC measurements indicated adequate levels of the drug in plasma. Results are in good agreement with those of pharmacokinetic studies (11,12,15,18). However, the micronized formulation did not improve the large interindividual variability of drug absorption (6).…”

Section: Discussionsupporting

confidence: 80%

“…Halofantrine has been used since 1988 in France and some West and Central African countries and was demonstrated to be effective in treating resistant falciparum malaria (5, 10, 17). However, a major drawback of halofantrine is its poor and variable absorption and bioavailability between subjects; these have been responsible for a number of treatment failures (3,11,12,15,18 greater, respectively. These doses correspond to one-half the normal dose for the standard formulation of halofantrine (25 mg/kg of body weight).…”

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confidence: 99%

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Efficacy of micronized halofantrine in semi-immune patients with acute uncomplicated falciparum malaria in Cameroon

Fadat

Louis

et al. 1993

Antimicrob Agents Chemother

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Fifty subjects with acute uncomplicated falciparum malaria were treated orally with a new micronized formulation of halofantrine. The dose given corresponded to one-half the normal dose for the standard formulation. Parasitemia cleared in all subjects within 78 h. There was recrudescence of falciparum malaria in seven subjects after day 14. The mean standard deviation clearance times of parasitemia and fever were 49.0 14.2 and 24.3 13.2 h, respectively. Other clinical symptoms related to malaria cleared within the first 3 days. Pruritus occurred in two subjects, back pain occurred in one subject, and diarrhea occurred in one subject; all of these symptoms were mild. Hematological and biochemical indices were not adversely affected by treatment except in five subjects in whom minor and transitory increases in aspartate aminotransferase and alanine aminotransferase were observed. Micronized halofantrine appears to be a safe, well-tolerated, and effective treatment for acute falciparum malaria in semiimmune patients.The spread of chloroquine-resistant Plasmodium falciparum to most countries in Africa has prompted the development of alternative drugs for the treatment of malaria. Halofantrine has been used since 1988 in France and some West and Central African countries and was demonstrated to be effective in treating resistant falciparum malaria (5, 10, 17). However, a major drawback of halofantrine is its poor and variable absorption and bioavailability between subjects; these have been responsible for a number of treatment failures (3,11,12,15,18 greater, respectively. These doses correspond to one-half the normal dose for the standard formulation of halofantrine (25 mg/kg of body weight). The drug was administered to patients without a specific food regimen. Patients were followed at home, and the intake of the doses was supervised. Investigations including clinical examination, temperature, symptom recording, and blood smears were performed twice daily for the first 4 days and on days 7, 14, 21, and 28 posttreatment. Parasite counts on blood smears were determined twice daily until two successive thick blood smears were negative.Routine blood examinations (hematocrit, hemoglobin, erythrocyte count, total leukocyte count, and platelet count) were performed before treatment and on days 3, 7, 14, 21, and 28 posttreatment.Aspartate aminotransferase (ASAT), alanine aminotransferase (ALAT), alkaline phosphatase, bilirubin, and creatinine were measured before treatment and on days 3, 7, and 28 posttreatment.In vitro antimalarial drug susceptibilities (chloroquine, quinine, and halofantrine) were assessed before treatment by an isotopic semimicrotest (13). Briefly, a suspension (700 ,ul per well) of parasitized erythrocytes (1.5% hematocrit, 0.2 to 0.5% initial parasitemia) in RPMI 1640 medium supplemented with 10% human serum and buffered with 25 mmol of N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES) per liter and 25 mmol of NaHCO3 per liter was distributed in predosed 24-well plates. The plates were incu...

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Section: Discussionsupporting

confidence: 80%

mentioning

confidence: 99%

Efficacy of micronized halofantrine in semi-immune patients with acute uncomplicated falciparum malaria in Cameroon

Fadat

Louis

et al. 1993

Antimicrob Agents Chemother

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“…Moreover, lipoprotein profiles concentrations are also affected by factors such as age, gender, and various pathological states including acute P. falciparum malaria. It is possible that altered lipoprotein profiles may contribute to the observed differences in Hf pharmacokinetics between malaria patients and healthy volunteers, 16,17 and to differences between ethnic groups. [16][17][18] In summary, the association of drugs with plasma lipoproteins is a relatively new and evolving area, and the mechanistic basis of drug lipoprotein interactions is not well understood.…”

Section: Resultsmentioning

confidence: 94%

“…It is possible that altered lipoprotein profiles may contribute to the observed differences in Hf pharmacokinetics between malaria patients and healthy volunteers, 16,17 and to differences between ethnic groups. [16][17][18] In summary, the association of drugs with plasma lipoproteins is a relatively new and evolving area, and the mechanistic basis of drug lipoprotein interactions is not well understood. The data presented here suggest that it may be prudent to routinely evaluate lipoprotein binding profiles of lipophilic drugs in the light of potential variations in clearance, disposition profiles, and toxicity that may result from variations in plasma lipoprotein profiles in response to food, age, and disease state.…”

Section: Resultsmentioning

confidence: 94%

Association of Halofantrine with Postprandially Derived Plasma Lipoproteins Decreases Its Clearance Relative To Administration in the Fasted State

Humberstone

Porter

Edwards

et al. 1998

Journal of Pharmaceutical Sciences

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The oral bioavailability of halofantrine (Hf), a highly lipophilic phenanthrenemethanol antimalarial, is significantly enhanced when ingested with food. Although food enhances the absorption of Hf, it also alters the intrinsic pharmacokinetics of Hf as the observed postprandial absolute bioavailability was greater than 100% (Humberstone et al., J. Pharm. Sci. 1996, 85, 525-529). In this study, the association of Hf with plasma lipoproteins and the effect of postprandial lipoproteins on the pharmacokinetics of Hf after intravenous administration was examined in beagles. In fasted dogs, approximately 50% of plasma Hf was associated with lipoproteins, with HDL accounting for 42-43%, LDL for 4-5%, and triglyceride rich lipoproteins (TRL) for 2-3%. At 0.5 and 2 h postdosing in the postprandial state, the proportion of Hf present in both TRL and LDL increased to 7-10%. Changes in Hf distribution between lipoprotein fractions reflected the respective postprandial changes in plasma triglyceride (TG) concentrations. In terms of pharmacokinetics, when an equivalent dose of Hf was administered intravenously in a crossover study to fed and fasted beagles, plasma Hf AUC values were significantly higher, and CL and Vss were significantly lower, in the fed state compared to the fasted state (p < 0.05). The mean postprandial increase in plasma AUC values was 19% (range 14-34%), with corresponding decreases in CL (15%) and Vss (21%). A broadly linear relationship between increased postprandial Hf concentrations at specific time points (fed vs fasted) and corresponding postprandial increases in TG concentrations suggested that the decreased postprandial clearance of Hf was a function of increased association with TG-rich plasma lipoproteins. This study confirms that the clearance of Hf is influenced by plasma lipoprotein profiles, and the findings have implications for the design and interpretation of fed/fasted bioavailability studies of lipophilic drugs and determination of their intrinsic pharmacokinetic parameters in subjects or patients with dyslipidemic profiles.

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“…It has been shown in Thai people that the elimination half-life of HF was greater in malaria patients in healthy volunteers, whereas that of ItFM was greater in healthy volunteers than in malaria patients [4]. For that reason, it would also be interesting to investigate any potential difference in stereosclectivity between healthy volunteers and malaria patients.…”

Section: Resultsmentioning

confidence: 99%

Plasma concentrations of the enantiomers of halofantrine and its main metabolite in malaria patients

Gimenez

Gillotin

Basco

et al. 1994

Eur J Clin Pharmacol

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The plasma concentrations of the enantiomers of halofantrine and its N-desbutyl metabolite in six patients with malaria were measured after oral administration of 3 x 750 mg doses of micronised, racemic halofantrine hydrochloride given at 6-hour intervals. Significant differences were observed between the plasma concentrations of the enantiomers both of halofantrine and its N-monodesbutyl metabolite. AUC(0)84h values were higher for (+)halofantrine (9917 micrograms.ml-1.h) than for (-)-halofantrine (6127 micrograms.ml-1.h). The clinical significance of these observations is not known. The isomers have equipotent activity in vitro but their relative toxicity has not yet been assessed.

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Pharmacokinetics of halofantrine in healthy Thai volunteers [letter]

Cited by 13 publications

References 5 publications

Efficacy of micronized halofantrine in semi-immune patients with acute uncomplicated falciparum malaria in Cameroon

Efficacy of micronized halofantrine in semi-immune patients with acute uncomplicated falciparum malaria in Cameroon

Association of Halofantrine with Postprandially Derived Plasma Lipoproteins Decreases Its Clearance Relative To Administration in the Fasted State

Plasma concentrations of the enantiomers of halofantrine and its main metabolite in malaria patients

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