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Bulletin of the World Health... 1994A randomized comparative trial of the pharmacokinetics and pharmacodynamics of oral doses of mefloquine and of mefloquine in combination with artesunate was carried out... (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
A randomized comparative trial of the pharmacokinetics and pharmacodynamics of oral doses of mefloquine and of mefloquine in combination with artesunate was carried out on 20 Thai male patients with acute, uncomplicated falciparum malaria. The patients were randomized to receive either mefloquine alone (8 patients; 1250 mg of mefloquine--initial dose, 750 mg; followed 6 hours later by 500 mg), or in combination with oral artesunate (12 patients--initial dose, 200 mg of artesunate; followed by 750 mg and 500 mg of mefloquine 6 hours and 12 hours later, respectively). The patients who received mefloquine alone all showed initially good responses to the treatment, with mean +/- SD values for the fever clearance time (FCT) and parasite clearance time (PCT) of 44.7 +/- 43.1 hours and 82.3 +/- 52.3 hours, respectively. Two patients had recrudescences on day 20 and day 31 (RI response). The cure rate was 75%, and one patient had Plasmodium vivax in his peripheral blood on day 52. The patients who received the combination treatment were clinically markedly improved, with a relatively shorter FCT (31.2 +/- 12.4 hours) and significantly shorter PCT (47.5 +/- 19.6 hours). Four had recrudescences on days 12, 18, 26 and 33; the cure rate was 66%. Artesunate caused three significant changes in mefloquine pharmacokinetics: a decrease in the maximum concentration (Cmax: 1623 ng.ml-1 versus 2212 ng.ml-1); an increase in the clearance rate (Cl/f:2.9 ml.min-1.kg-1 versus 1.1 ml.min-1.kg-1); and an expansion of the volume of distribution (Vdz/f: 31.8 l.kg-1 versus 25.0 l.kg-1).
Topics: Adolescent; Adult; Antimalarials; Artemisinins; Artesunate; Drug Therapy, Combination; Humans; Malaria, Falciparum; Male; Mefloquine; Middle Aged; Sesquiterpenes
PubMed: 8131255
DOI: No ID Found -
Malaria Journal Jul 2018A fixed-dose combination of mefloquine with artesunate was evaluated in cases of falciparum malaria in the Brazilian Amazon basin with acceptable efficacy, safety and...
BACKGROUND
A fixed-dose combination of mefloquine with artesunate was evaluated in cases of falciparum malaria in the Brazilian Amazon basin with acceptable efficacy, safety and tolerability. However, there are no data on the pharmacokinetics of mefloquine in this coformulation in Brazil, which is valuable to evaluate whether Plasmodium is exposed to an effective concentration of the drug.
METHODS
A prospective, single-arm study was conducted in male patients with slide-confirmed infection by Plasmodium falciparum using two tablets of a fixed-dose combination of artesunate (100 mg) and mefloquine base (200 mg) once daily and over 3 consecutive days. Serial blood samples were collected at admission and throughout 672 h post-administration of the drugs. Mefloquine was measured in each blood sample by high-performance liquid chromatography. The pharmacokinetic parameters were determined by non-compartmental analysis.
RESULTS
A total of 61 patients were enrolled in the study and 450 whole blood samples were collected for mefloquine measurement. The mefloquine half-life was 10.25 days, the maximum concentration (C) was 2.53 µg/ml, the area-under-the-curve (AUC) was 359 µgml h, the observed clearance (Cl/f) was 0.045 l/kg/h and the volume of distribution (V/f) was 14.6 l/kg. Mefloquine concentrations above 0.5 µg/ml were sustained for a mean time of 9.2 days.
CONCLUSION
The pharmacokinetic parameters of mefloquine determined in the study suggest an adequate exposure of parasite to mefloquine in the multiple oral dose regimen of the fixed dose combination of mefloquine and artesunate.
Topics: Adult; Aged; Antimalarials; Artesunate; Brazil; Chromatography, High Pressure Liquid; Drug Combinations; Humans; Malaria, Falciparum; Male; Mefloquine; Middle Aged; Plasmodium falciparum; Prospective Studies; Young Adult
PubMed: 30012152
DOI: 10.1186/s12936-018-2416-0 -
Transactions of the Royal Society of... 1994Mefloquine has an established place in the treatment of chloroquine-resistant falciparum malaria. To investigate mefloquine pharmacokinetics in pregnancy, 9 untreated...
Mefloquine has an established place in the treatment of chloroquine-resistant falciparum malaria. To investigate mefloquine pharmacokinetics in pregnancy, 9 untreated pregnant women aged 16-33 years and 8 non-pregnant females aged 16-38 years received an average of 15 (range 13-19) mg mefloquine/kg body-weight as single-dose treatment for uncomplicated falciparum malaria. Regular blood samples were taken during the subsequent 48 h and then intermittently for 3-26 d after treatment. Whole blood mefloquine concentrations were analysed by high-performance liquid chromatography and a one-compartment open pharmacokinetic model was fitted to the data. Peak mefloquine concentrations were significantly lower in the pregnant patients (median [range]; 1257 [650-1584] vs. 1617 [1051-3111] ng/mL) and the total apparent volume of distribution (Vd/f) was larger (10.8 [8.3-26.1] vs. 10.0 [4.8-13.9] L/kg; P < 0.05 in each case), consistent with an expanded circulating blood volume and increased tissue binding in pregnancy. There was no significant difference between the 2 groups in half-times of absorption or elimination (P > 0.1), and systemic clearance rates were also similar. These results suggest that pregnant patients need larger doses of mefloquine than non-pregnant women to achieve comparable blood levels, an important consideration in areas where multi-drug resistant falciparum malaria is emerging.
Topics: Adolescent; Adult; Drug Resistance; Female; Humans; Malaria, Falciparum; Mefloquine; Pregnancy; Pregnancy Complications, Parasitic
PubMed: 7974678
DOI: 10.1016/0035-9203(94)90101-5 -
Travel Medicine and Infectious Disease Sep 2007In this open randomized trial comparing 3-day oral quinine-clindamycin versus standard mefloquine regimen for uncomplicated imported falciparum malaria, mefloquine... (Comparative Study)
Comparative Study
In this open randomized trial comparing 3-day oral quinine-clindamycin versus standard mefloquine regimen for uncomplicated imported falciparum malaria, mefloquine treatment was associated with a higher risk of discontinuation of the treatment (RR=1.8, 95% CI [1.1-2.8]) related to mainly mild gastrointestinal adverse drug events. The poor tolerability of mefloquine sets a question mark against its use in outpatients.
Topics: Administration, Oral; Adult; Antimalarials; Clindamycin; Drug Therapy, Combination; Female; Humans; Malaria, Falciparum; Male; Mefloquine; Middle Aged; Quinine; Travel
PubMed: 17870636
DOI: 10.1016/j.tmaid.2007.07.001 -
British Journal of Clinical Pharmacology May 1991The pharmacokinetic properties of mefloquine hydrochloride (15 mg base kg -1) were studied in 12 Karen children (five girls, seven boys) aged between 5 and 10 years...
The pharmacokinetic properties of mefloquine hydrochloride (15 mg base kg -1) were studied in 12 Karen children (five girls, seven boys) aged between 5 and 10 years presenting with uncomplicated falciparum malaria. The drug was well tolerated. Mean (s.d.) peak blood drug concentrations of 2031 (831) ng ml-1 were reached in a median of 8 (range 6-24) h. Mean (s.d.) estimates for oral clearance and mean residence time were 0.52 (0.27) ml min -1 kg -1 and 15.3 (4.7) days, respectively. These values are similar to those reported previously in adults. In one child parasitaemia failed to clear despite whole blood mefloquine concentrations which peaked at 1744 ng ml -1; parasitaemia rose and fever recurred when blood drug concentrations had fallen to 442 ng ml -1. The prevalence of highly mefloquine resistant parasites such as this can be expected to increase under drug pressure in this area.
Topics: Animals; Child; Child, Preschool; Drug Resistance; Female; Humans; Malaria; Male; Mefloquine; Plasmodium falciparum
PubMed: 1888626
DOI: 10.1111/j.1365-2125.1991.tb05581.x -
Annals of Tropical Paediatrics Dec 1996In an area where multi-drug resistance in Plasmodium falciparum is a particular problem, more than 500 children under 5 years of age weighing > 5 kg were treated with... (Clinical Trial)
Clinical Trial
In an area where multi-drug resistance in Plasmodium falciparum is a particular problem, more than 500 children under 5 years of age weighing > 5 kg were treated with mefloquine, either alone or combined with an artemisinin derivative, and followed up for a minimum of 28 days. The principal adverse effect was vomiting and this was associated with reduced efficacy of treatment (even when treatment was repeated). Later adverse effects occurred less frequently than in adults. There was no serious toxicity and, in particular, there were no neuropsychiatric side-effects. The high dose of mefloquine (25 mg/kg) required in this area is well tolerated by young children. It should be given in a divided dose of 15 mg/kg initially, followed by 10 mg/kg > or = 12 hours later.
Topics: Administration, Oral; Adult; Child, Preschool; Drug Administration Schedule; Female; Humans; Infant; Malaria, Falciparum; Malaria, Vivax; Male; Mefloquine; Prospective Studies; Random Allocation; Vomiting
PubMed: 8985524
DOI: 10.1080/02724936.1996.11747839 -
The American Journal of Tropical... Aug 1996From June until October 1993, a battalion of Dutch marines was stationed in Cambodia for a United Nations deployment. In 73 volunteers who used mefloquine as malaria...
From June until October 1993, a battalion of Dutch marines was stationed in Cambodia for a United Nations deployment. In 73 volunteers who used mefloquine as malaria chemoprophylaxis, possible mefloquine-related adverse events were monitored with special emphasis on QT prolongation. All participants started mefloquine chemoprophylaxis with a loading dose (250 mg a day for three days) one week before departure, followed by a weekly dose (250 mg) for approximately 25 weeks. One month before (t - 1) and one (t + 1) and three (t + 3) months after mefloquine prophylaxis was started, an at rest electrocardiogram was made. Frequency, PR-, and QT-intervals were measured; blood samples for liver transaminases, total white blood cell count, and mefloquine concentration were obtained after one and three months. Adverse events such as dizziness, headache, coordination problems, and nausea were spontaneously reported in one (1.4%) and three (4.1%) persons at t + 1 and t + 3, respectively, while specific questioning revealed adverse events in nine (12.3%) and five (6.9%) persons, respectively, at the same time point. Three months after starting chemoprophylaxis, the heart rate at rest and total white blood cell count were lower (P < 0.05), while the QTc-interval was longer and levels of liver transaminases increased (P < 0.05), although both were still within the normal range. There was no extreme prolongation of the QTc-interval or increased levels of liver transaminases that resulted in a need to stop the chemoprophylaxis. No accumulation of mefloquine in the serum occurred, and no relationship was observed between the incidence of adverse events and serum mefloquine concentrations. The incidence of self reported mefloquine-related adverse events was low. In conclusion, mefloquine chemoprophylaxis was safe and well-tolerated in this group.
Topics: Adult; Antimalarials; Cambodia; Diarrhea; Dizziness; Electrocardiography; Heart; Humans; Leukocyte Count; Malaria, Falciparum; Male; Mefloquine; Middle Aged; Military Personnel; Netherlands; Psychomotor Performance
PubMed: 8780466
DOI: 10.4269/ajtmh.1996.55.230 -
Lancet (London, England) Jul 1991
Topics: Animals; Drug Combinations; Drug Resistance; Humans; Malaria; Mefloquine; Plasmodium falciparum; Pyrimethamine; Sulfadoxine
PubMed: 1676099
DOI: No ID Found -
Tropical Medicine & International... Aug 1996This longitudinal study of travellers to Africa taking mefloquine (MQ) chemoprophylaxis aimed to quantify and assess non-serious adverse events (AE) occurring during...
This longitudinal study of travellers to Africa taking mefloquine (MQ) chemoprophylaxis aimed to quantify and assess non-serious adverse events (AE) occurring during short-term prophylaxis and relate these to concentrations of racemic MQ, its enantiomers and metabolite. A total of 420 volunteers (52% F) participated. AEs with some impact on activities were reported by 11.2% of participants including 7.9% of neurological/psychiatric symptoms. Women were more likely to report AEs (P = 0.02). The standardized questionnaires used showed more pathological indicators in travellers who reported subjective AE with significantly more dizziness, distress, sleep disturbances and a high total mood disturbance (TMD) in the AE group. There was, however, no significant performance deficit in computerized psychomotor tests in those experiencing AE. Furthermore, no significant differences were observed in enantiomer ratios, metabolite concentrations, or racemic MQ levels in participants with or without AEs suggesting that these factors are not the main predictors of mefloquine intolerability.
Topics: Adolescent; Adult; Africa; Drug Tolerance; Female; Humans; Longitudinal Studies; Malaria, Falciparum; Male; Mefloquine; Middle Aged; Patient Compliance; Sex Factors; Stereoisomerism; Surveys and Questionnaires; Travel
PubMed: 8765456
DOI: 10.1046/j.1365-3156.1996.d01-85.x -
British Journal of Clinical Pharmacology Jun 2001To evaluate the pharmacokinetic interaction between ritonavir and mefloquine. (Clinical Trial)
Clinical Trial
AIMS
To evaluate the pharmacokinetic interaction between ritonavir and mefloquine.
METHODS
Healthy volunteers participated in two separate, nonfasted, three-treatment, three-period, longitudinal pharmacokinetic studies. Study 1 (12 completed): ritonavir 200 mg twice daily for 7 days, 7 day washout, mefloquine 250 mg once daily for 3 days then once weekly for 4 weeks, ritonavir restarted for 7 days simultaneously with the last mefloquine dose. Study 2 (11 completed): ritonavir 200 mg single dose, mefloquine 250 mg once daily for 3 days then once weekly for 2 weeks, ritonavir single dose repeated 2 days after the last mefloquine dose. Erythromycin breath test (ERMBT) was administered with and without drug treatments in study 2.
RESULTS
Study 1: Ritonavir caused less than 7% changes with high precision (90% CIs: -12% to 11%) in overall plasma exposure (AUC(0,168 h)) and peak concentration (Cmax) of mefloquine, its two enantiomers, and carboxylic acid metabolite, and in the metabolite/mefloquine and enantiomeric AUC ratios. Mefloquine significantly decreased steady-state ritonavir plasma AUC(0,12 h) by 31%, Cmax by 36%, and predose levels by 43%, and did not affect ritonavir binding to plasma proteins. Study 2: Mefloquine did not alter single-dose ritonavir pharmacokinetics. Less than 8% changes in AUC and Cmax were observed with high variability (90%CIs: -26% to 45%). Mefloquine had no effect on the ERMBT whereas ritonavir decreased activity by 98%.
CONCLUSIONS
Ritonavir minimally affected mefloquine pharmacokinetics despite strong inhibition of CYP3A4 activity from a single 200 mg dose. Mefloquine had variable effects on ritonavir pharmacokinetics that were not explained by hepatic CYP3A4 activity or ritonavir protein binding.
Topics: Administration, Oral; Adolescent; Adult; Antimalarials; Area Under Curve; Breath Tests; Chromatography, High Pressure Liquid; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Drug Interactions; Female; HIV Protease Inhibitors; Humans; Male; Mefloquine; Metabolic Clearance Rate; Middle Aged; Mixed Function Oxygenases; Models, Biological; Ritonavir; Time Factors
PubMed: 11422019
DOI: 10.1046/j.1365-2125.2001.01393.x