Pharmacokinetics Of Mefloquine Research Articles

Population pharmacokinetics of mefloquine given as a 3-day artesunate\u2013mefloquine in patients with acute uncomplicated Plasmodium falciparum malaria in a multidrug-resistant area along the Thai\u2013Myanmar border

BackgroundLow mefloquine exposure has been shown to contribute to treatment failure in patients with uncomplicated falciparum malaria following a 3-day artesunate–mefloquine combination. The present study aimed to develop a population pharmacokinetic model for mefloquine based on whole blood concentration–time profiles of this target population for further dose optimization.MethodsA total of 129 Burmese patients aged above 15 years who presented with typical symptoms of malaria and had a blood smear positive for Plasmodium falciparum were included in the study. All were treated with the standard 3-day combination regimen of artesunate and mefloquine consisting of mefloquine for 2 days and artesunate for 3 days. Blood samples were collected before and at different time points after drug administration from different sub-groups of patients. Mefloquine concentrations were quantified in whole blood using high-performance liquid chromatography. A non-linear mixed-effect modelling approach was applied for population pharmacokinetic analysis using the NONMEM v7.3 software. Covariates investigated (body weight, gender, admission parasitaemia, and molecular markers of mefloquine resistance) were investigated in a step-wise manner using the SCM functionality in Perl-Speaks-NONMEM.ResultsPopulation pharmacokinetic analysis of mefloquine was performed in all patients with a total of 653 samples. Whole blood mefloquine concentration–time profiles were described by a two-compartment disposition model. Of the covariates investigated, none was found to have a significant impact on the pharmacokinetics of mefloquine. Significant differences in maximum concentration (Cmax) and elimination half-life (t1/2) were found in patients who had treatment failure (36 cases) compared to patients with successful treatment (107 cases).ConclusionThe study successfully describes the pharmacokinetics of mefloquine following a 2-day treatment of mefloquine as a part of a 3-day artesunate–mefloquine in patients with uncomplicated falciparum malaria from Thailand. A model has been developed which adequately describes the pharmacokinetics of mefloquine. More extensive clinical studies including both adults and children are needed to fully characterize the pharmacokinetics of mefloquine.

Pharmacokinetics of mefloquine administered with artesunate in patients with uncomplicated falciparum malaria from the Brazilian Amazon basin

BackgroundA 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.MethodsA 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.ResultsA 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 (Cmax) was 2.53 µg/ml, the area-under-the-curve (AUC0–∞) was 359 µg/ml 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.ConclusionThe 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.

Pharmacokinetics of mefloquine and its effect on sulfamethoxazole and trimethoprim steady-state blood levels in intermittent preventive treatment (IPTp) of pregnant HIV-infected women in Kenya.

BackgroundIntermittent preventive treatment in pregnancy with sulfadoxine/pyrimethamine is contra-indicated in HIV-positive pregnant women receiving sulfamethoxazole/trimethoprim prophylaxis. Since mefloquine is being considered as a replacement for sulfadoxine/pyrimethamine in this vulnerable population, an investigation on the pharmacokinetic interactions of mefloquine, sulfamethoxazole and trimethoprim in pregnant, HIV-infected women was performed.MethodsA double-blinded, placebo-controlled study was conducted with 124 HIV-infected, pregnant women on a standard regimen of sulfamethoxazole/trimethoprim prophylaxis. Seventy-two subjects received three doses of mefloquine (15 mg/kg) at monthly intervals. Dried blood spots were collected from both placebo and mefloquine arms four to 672 h post-administration and on day 7 following a second monthly dose of mefloquine. A novel high-performance liquid chromatographic method was developed to simultaneously measure mefloquine, sulfamethoxazole and trimethoprim from each blood spot. Non-compartmental methods using a naïve-pooled data approach were used to determine mefloquine pharmacokinetic parameters.ResultsSulfamethoxazole/trimethoprim prophylaxis did not noticeably influence mefloquine pharmacokinetics relative to reported values. The mefloquine half-life, observed clearance (CL/f), and area-under-the-curve (AUC0→∞) were 12.0 days, 0.035 l/h/kg and 431 µg-h/ml, respectively. Although trimethoprim steady-state levels were not significantly different between arms, sulfamethoxazole levels showed a significant 53 % decrease after mefloquine administration relative to the placebo group and returning to pre-dose levels at 28 days.ConclusionsAlthough a transient decrease in sulfamethoxazole levels was observed, there was no change in hospital admissions due to secondary bacterial infections, implying that mefloquine may have provided antimicrobial protection.

Effect of rifampin on plasma concentrations of mefloquine in healthy volunteers.

Mefloquine is a 4-quinolinemethanol compound structurally related to quinine. Quinine is mainly metabolized by the cytochrome P450 3A4 isozyme (CYP3A4), whereas rifampin, a potent inducer of CYP3A4, is known to markedly decrease plasma quinine concentration. Our aim was to study the effect of rifampin on the pharmacokinetics of mefloquine, and explore a possible role of CYP3A4 on mefloquine metabolism. In an open, two-phase crossover study, seven healthy Thai male volunteers received a single oral dose of 500 mg mefloquine alone, or 500 mg mefloquine plus a long-term administration of 600 mg rifampin. Blood samples were collected at specific time points over a 56-day period. Plasma mefloquine and its carboxylic acid metabolite were measured by HPLC for pharmacokinetic analysis. The results indicate that rifampin significantly decreased the area under the plasma concentration-time curve (AUC0 - infinity) of mefloquine by 68% (P < 0.01), maximum plasma concentration (Cmax) by 19% (P < 0.001), and elimination half-life (t1/2) by 63% (P < 0.01), whereas the time to reach Cmax (t(max)) of mefloquine was unaffected. The apparent oral clearance (CL) of mefloquine was significantly increased by 281% (P < 0.01). After administration of rifampin, the Cmax of the carboxylic acid metabolite of mefloquine was significantly increased by 47% (P < 0.05), whereas the t1/2 was significantly decreased by 39% (P < 0.01), and t(max) by 76% (P < 0.01). The AUC0 - infinity and CL of the mefloquine metabolite were increased by 30% and 25%, respectively, but were not significantly different from the control phase. The results indicate that rifampin reduces the plasma concentration of a single oral dose of 500 mg mefloquine by increasing metabolism of mefloquine in the liver and gut wall. The CYP3A4 isozyme most likely plays an important role in the enhanced metabolism of mefloquine. Simultaneous use of rifampin and mefloquine should be avoided to optimize the therapeutic efficacy of mefloquine and prevent the risk of Plasmodium falciparum resistance in malarial treatment.

Pharmacokinetics and Comparative Bioavailability of Artesunate and Mefloquine Administered Separately or as a Fixed Combination Product to Healthy Volunteers and Patients with Uncomplicated Plasmodium falciparum Malaria.

Purpose: The current World Health Organization recommendation for the treatment of uncomplicated Plasmodium falciparum malaria is with artemisinin-based combination therapy. Artesunate and mefloquine combination therapy has achieved consistently high efficacy rates and reduced malaria morbidity; however, the current standard treatment regimen is complex and may be difficult to comply with outside of a research setting. Consequently, an artesunate mefloquine fixed dose oral co-formulation has been developed and is now registered in Brazil. This study was conducted in order to assess the pharmacokinetics and comparative bioavailabilities of artesunate and mefloquine administered as separate products and the new co-formulated product. Methods: The pharmacokinetics of artesunate, dihydroartemisinin, the artesunate metabolite and predominant species and mefloquine were assessed in a single-dose, randomised, crossover design study in healthy volunteers and in a multiple-dose, randomised, parallel group study in patients with uncomplicated falciparum malaria. Results: For artesunate/dihydroartemisinin the lower bound of the 90% confidence intervals for the comparison between co-formulated and separate products extended below the 80% bioequivalence limit; area under the curve and Cmax values were 15-25% and 25-40% lower than those observed after administration of the separate products. The two formulations were bioequivalent in terms of mefloquine pharmacokinetics in uncomplicated falciparum malaria patients; the 90% confidence intervals for dose-normalised area under the curve (AUClast and AUCinf) and maximum observed concentration (Cmax) were within the 80 - 125% limits. In contrast, mefloquine area under the curve and Cmax values were 15% and 30% lower for the co-formulated products compared to the separate products in healthy volunteers. Conclusions: These differences in the exposure to artesunate, dihydroartemisinin and mefloquine are unlikely to be of clinical relevance based on in vitro and clinical data. However, the results of this study do emphasise the importance of evaluating the bioavailability and bioequivalence of new formulations, particularly in specific patient groups.

Mefloquine pharmacokinetics and mefloquine-artesunate effectiveness in Peruvian patients with uncomplicated Plasmodium falciparum malaria

BackgroundArtemisinin-based combination therapy (ACT) is recommended as a means of prolonging the effectiveness of first-line malaria treatment regimens. Different brands of mefloquine (MQ) have been reported to be non-bioequivalent; this could result in sub-therapeutic levels of mefloquine with decreased efficacy. In 2002, mefloquine-artesunate (MQ-AS) combination therapy was adopted as the first-line treatment for uncomplicated Plasmodium falciparum malaria in the Amazon region of Peru. Although MQ resistance has yet to be reported from the Peruvian Amazon, it has been reported from other countries in the Amazon Region. Therefore, continuous monitoring is warranted to ensure that the first-line therapy remains efficacious. This study examines the in vivo efficacy and pharmacokinetic parameters through Day 56 of three commercial formulations of MQ (Lariam®, Mephaquin®, and Mefloquina-AC® Farma) given in combination with artesunate.MethodsThirty-nine non-pregnant adults with P. falciparum mono-infection were randomly assigned to receive artesunate in combination with either (1) Lariam, (2) Mephaquin, or (3) Mefloquina AC. Patients were assessed on Day 0 (with blood samples for pharmacokinetics at 0, 2, 4, and 8 hours), 1, 2, 3, 7, and then weekly until day 56. Clinical and parasitological outcomes were based on the standardized WHO protocol.Whole blood mefloquine concentrations were determined by high-performance liquid chromatography and pharmacokinetic parameters were determined using non-compartmental analysis of concentration versus time data.ResultsBy day 3, all patients had cleared parasitaemia except for one patient in the AC Farma arm; this patient cleared by day 4. No recurrences of parasitaemia were seen in any of the 34 patients. All three MQ formulations had a terminal half-life of 14–15 days and time to maximum plasma concentration of 45–52 hours. The maximal concentration (Cmax) and interquartile range was 2,820 ng/ml (2,614–3,108) for Lariam, 2,500 ng/ml (2,363–2,713) for Mephaquin, and 2,750 ng/ml (2,550–3,000) for Mefloquina AC Farma. The pharmacokinetics of the three formulations were generally similar, with the exception of the Cmax of Mephaquin which was significantly different to that of Lariam (p = 0.04).ConclusionAll three formulations had similar pharmacokinetics; in addition, the pharmacokinetics seen in this Peruvian population were similar to reports from other ethnic groups. All patients rapidly cleared their parasitaemia with no evidence of recrudescence by Day 56. Continued surveillance is needed to ensure that patients continue to receive optimal therapy.

Population pharmacokinetics of mefloquine in military personnel for prophylaxis against malaria infection during field deployment

The purpose of this study was to determine the population pharmacokinetics of mefloquine in healthy military personnel during prophylaxis for malaria infections. The subjects were 1,111 Australian soldiers participating in two studies: a randomised double-blinded study (group A, 161 subjects) and an open-label study (group B, 950 subjects). Following a loading dose (250 mg mefloquine base daily, 3 days), subjects received an oral weekly maintenance dose of 250 mg over 6 months. Blood was collected after the last split loading dose then at weeks 4, 8 and 16 for group A, and at weeks 13 and 26 for group B. Plasma mefloquine concentrations were measured by high-performance liquid chromatography (HPLC). Pharmacokinetic modelling was performed using NONMEM. A two-compartment model with inter-occasion variability (IOV) for clearance satisfactorily described the pharmacokinetics. Typical values were clearance (CL/F, 2.09 l/h), central volume of distribution (V1/F, 528 l), absorption rate constant (KA, 0.24 h(-1)), inter-compartmental clearance (Q/F, 12.5 l/h), peripheral volume of distribution (V2/F, 483 l) and elimination half-life (t (1/2), 14.0 days). Weight had a positive influence on central volume but was insufficient to warrant dosage adjustments. The inter-individual variability (coefficient of variation, CV%) for CL/F and V1/F was 24.4% and 29.6%, respectively. The IOV for CL/F was 17.8%. The proportional residual error (CV%) for groups A and B was 11.5% and 19.5%, respectively, and the additive error standard deviation (SD) was 57 ng/ml and 149 ng/ml, respectively. The typical parameter values were comparable with those estimated in much smaller cohorts of healthy subjects and in malaria patients treated with single-dose mefloquine. The lower unexplained variability in the blinded study suggested these subjects may have been more compliant in taking their medication than soldiers in the open-label study.

ARTESUNATE WITH MEFLOQUINE AT VARIOUS INTERVALS FOR NON-SEVERE PLASMODIUM FALCIPARUM MALARIA

To study the efficacy, tolerance, population pharmacokinetics and pharmacodynamics of artesunate followed by mefloquine at various intervals, 360 patients with Plasmodium falciparum malaria received 4 mg/kg of artesunate and thereafter 15 mg/kg of mefloquine simultaneously (group A), after 8 hours (after group B), and after 24 hours (group C). Three dosages were completed with placebo. Follow-up was 28 days. All patients recovered rapidly except one case of failure within the first 24 hours. Mefloquine pharmacokinetics was similar in the three regimens. Parasites reappeared in 26%, 26%, and 33% of the patients in groups A, B, and C, respectively. Early recrudescence was associated with high initial parasite density, slow parasite clearance, and rapid mefloquine clearance and low plasma concentrations at day 28. Mefloquine plasma concentrations all reached therapeutic ranges, suggesting reduced parasite sensitivity. In conclusion, there is no interaction between artesunate and mefloquine with respect to tolerance, efficacy, and pharmacokinetics. Single-dose combination therapy with artemisinin drugs and 15 mg/kg of mefloquine does not completely prevent parasite recurrence and may not prevent mefloquine resistance.

Pharmacokinetic interaction between mefloquine and ritonavir in healthy volunteers

To evaluate the pharmacokinetic interaction between ritonavir and mefloquine. 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. 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%. 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.

Mefloquine pharmacokinetics in healthy subjects and in peptic ulcer patients after cimetidine administration.

The pharmacokinetics of orally administered mefloquine were determined in six healthy male subjects and in six ulcer patients before and after a 3-day course of cimetidine (400 mg morning and evening). Peak plasma concentrations Cmax and AUC0-infinity were similarly and significantly (P < 0.05) increased after cimetidine pretreatement in both healthy subjects and peptic ulcer patients Cmax was increased by 42.4% and 20.5% while AUC0-infinity was increased by 37.5% in healthy and peptic ulcer subjects respectively. The values of t1/2ab absorption and t1/2 beta elimination, total crearance CLT/F and volume of distribution were altered to varying levels after cimetidine treatment but the changes were not statistically significant in both healthy and peptic ulcer subjects. The established long t1/2 beta and this apparent interaction between mefloquine and cimetidine which resulted in increased mefloquine plasma concentration might be of clinical significant in patients with neurological/psychiatric history.

Pharmacokinetic interaction trial between co-artemether and mefloquine

Forty-two healthy subjects were randomized in a parallel three-group design trial to investigate potential electrocardiographic and pharmacokinetic interactions between the new antimalarial co-artemether, a combination of artemether and lumefantrine (both of which are predominantly metabolized through CYP3A4), and mefloquine, another antimalarial described as a substrate (and possible inhibitor) of CYP3A4. Subjects were assigned to one of the three possible treatment groups (i.e., co-artemether alone or mefloquine alone or the combination of both). The dosage was 1000 mg mefloquine (divided into three doses over 12 h) followed 12 h later by six applications of co-artemether (40 mg artemether+480 mg lumefantrine each) over 60 h. The study medications were generally well tolerated after all treatments. Concomitant administration with mefloquine caused statistically significant lower (around 30–40%) plasma concentrations of lumefantrine than when co-artemether was administered alone. Even if important, this decrease in lumefantrine exposure was considered unlikely to impact clinical efficacy given the wide therapeutic index of co-artemether and the usual high variability in lumefantrine plasma levels, mostly and more importantly influenced by food intake. However, patients should be encouraged to eat at dosing times to compensate for this decreased bioavailability. The pharmacokinetics of artemether, DHA or mefloquine were not affected. Artemether concentrations significantly decreased over doses, independently of mefloquine co-administration, while DHA concentrations slightly (not significantly) increased. Therefore, no clinically relevant risks due to pharmacokinetic drug–drug interaction are expected at the enzymatic level following co-administration of co-artemether with CYP3A4 substrates with similar affinity to that of mefloquine.

Population pharmacokinetics of mefloquine in patients with acute falciparum malaria.

To construct a population pharmacokinetic model for mefloquine in the treatment of falciparum malaria. Mefloquine is the treatment of choice for multidrug-resistant falciparum malaria. The factors that influence the pharmacokinetic properties of mefloquine in acute malaria are not well characterized. The pharmacokinetic properties of mefloquine were evaluated in 257 patients with acute falciparum malaria by use of nonlinear mixed-effects modeling. Two different oral dose regimens were used: (1) a split dose of 15 mg base/kg initially followed by 10 mg/kg 24 hours later (n = 159) and (2) a single dose of 25 mg/kg (n = 98). Mefloquine was combined with artesunate in 105 (41%) patients (74 received a split dose and 31 received a single dose). Splitting the mefloquine dose increased the area under the concentration-time curve [AUC(0-infinity)] by 50% (95% confidence interval [CI], 36% to 65%) for monotherapy and by 20% (95% CI, 3% to 40%) for combined therapy. The apparent volume of distribution (V/F) was significantly lower in patients receiving split doses of mefloquine monotherapy (mean, 8.14 L/kg; 95% CI, 7.49 to 8.86 L/kg) compared with a single dose (mean, 20.37 L/kg; 95% CI, 16.26 to 25.51 L/kg). Patients who received mefloquine monotherapy and cleared parasitemia in less than 48 hours had a significantly higher AUC(0-infinity) independent of any confounders, compared with patients with slower parasite clearance (geometric mean [95% CI], 50,373 ng/mL x day [46,121 to 55,017 ng/mL x day] versus 45,583 ng/mL x day [42,306 to 49,125 ng/mL x day]). The pharmacokinetic properties of mefloquine in malaria were relatively unaffected by demographic variables (other than body weight) or disease severity. If it is assumed that apparent clearance and volume of distribution are unaffected by dose regimen, then splitting the 25 mg/kg mefloquine dose improves oral bioavailability and the therapeutic response in the treatment of acute falciparum malaria.

Mefloquine pharmacokinetics when combined with artesunate in children with acute falciparium malaria

Mefloquine pharmacokinetics when combined with artesunate in children with acute falciparium malaria

Mefloquine for malaria chemoprophylaxis 1992-1998: a review.

Mefloquine is an orally administered blood schizontocide for the chemoprophylaxis of malaria in nonimmune travelers. New pharmacokinetic data has shown that food increases the bioavailability of mefloquine. Steady-state pharmacokinetics of weekly prophylaxis in long term travelers have shown that toxic accumulation does not occur and that weekly dosing is associated with protective levels of the drug. The pharmacokinetics of mefloquine are highly stereospecific and all pharmacokinetic parameters, except tmax are significantly different for the (+) and (-) enantiomers. Mefloquine and its metabolite are not appreciably removed by hemodialysis. Steady-state levels of mefloquine can be attained in a reduced time frame of 4 days compared to 7-9 weeks using a loading dose strategy of 250 mg mefloquine daily for 3 days followed thereafter by weekly mefloquine dosage. This strategy, is however, associated with a higher incidence of an adverse event (AE). Cumulative evidence suggests a high protective efficacy of mefloquine (>91%) in nonimmune travelers to areas of chloroquine resistant Plasmodium falciparum (CRPF) except for clearly defined regions of multi-drug resistance. Reports from sub-Saharan Africa indicate a low but increasing level of resistance to this drug. Mefloquine resistance is associated with halofantrine and quinine resistance but not with chloroquine resistance. Penfluridol has been shown to reverse P. falciparum mefloquine resistance in vitro. There is some controversy regarding the tolerabilty of mefloquine for malaria chemoprophylaxis. A review of the studies conducted during 1992-1998 shows that in the reporting of any AE the incidence lies in the range (12-90%) and where there is a comparator, is equivalent to the incidence reported for almost all alternative regimens. When some measure of subjective severity is applied to the rating of AE, it appears that 11-17% of travelers are, to some extent, incapacitated by AE. Major studies and worldwide monitoring have shown that serious events are rare. A recent meta-analysis showed that rates of withdrawal and overall incidence of AE with mefloquine were not significantly higher than those observed with comparator regimens except that mefloquine was more likely to cause insomnia and fatigue. Withdrawals in mefloquine arms were higher than in placebo arms. No performance deficit or functional impairment was observed in five clinical toxicity studies of mefloquine prophylaxis, including a study of driving performance. There is limited data regarding use of mefloquine in pregnancy. Early animal studies have documented teratogenic and embryotoxic effects associated with the use of high dose mefloquine. Two studies have shown a relatively high incidence of spontaneous abortions in mefloquine users. Cumulative evidence, however, is reassuring and has led the World Health Organization (WHO) and the Centers for Disease Control and Prevention (CDC) to sanction the use of mefloquine in pregnant women during the second and third trimesters. In conclusion, mefloquine prophylaxis is recommended for travelers to high risk areas of chloroquine resistant Plasmodium falciparum. The risk of malarial infection and the proven efficacy of mefloquine to prevent malaria should be weighed against the risk of drug associated adverse events.

ECG pharmacodynamics and pharmacokinetics of halofantrine and mefloquine.

ECG pharmacodynamics and pharmacokinetics of halofantrine and mefloquine.

Clinical application of mefloquine pharmacokinetics in the treatment of P falciparum malaria.

Malaria remains a major public health problem in large areas of the world. One of the major factors responsible for the resurgence is the emergence of Plasmodium falciparum, resistant to available antimalarials. An antimalarial, mefloquine, has been considered since its introduction as a promising alternative antimalarial drug to overcome the situation of widespread multidrug resistant P falciparum. Pharmacokinetic studies of mefloquine have been investigated in several groups of subjects either as mefloquine alone or as combined regimens. The oral absorption of mefloquine is relatively rapid, reaching peak concentrations within 24 hours. Metabolism takes place in the liver, with carboxymefloquine as a major metabolite. Mefloquine has a large apparent volume of distribution of 200 L and is highly bound (98%) to plasma proteins. The elimination is slow; the terminal half-life is 13 10 to 14 days in Thai patients with falciparum malaria. Vomiting within 1 hour of drug administration has an influence on blood concentrations of mefloquine and this may result in treatment failure. The whole blood concentrations of mefloquine on the first two days of treatment are important determinants of parasitological response. There appear to be no pharmacokinetic interactions between mefloquine and the other two components of Fansimef in patients with uncomplicated falciparum malaria. The advantage of this combination over mefloquine alone in multidrug resistant P falciparum is still debatable. However, recent data seem to support the higher efficacy of Fansimef over mefloquine alone. Concurrent administration of antibiotics, ie ampicillin and tetracycline with mefloquine results in a significant increase in maximum concentration, reduction of the apparent volume of distribution and shortening of the terminal elimination half-life of mefloquine. An antiemetic drug metoclopramide accelerates the absorption of mefloquine and increases the maximum concentration. In contrast, mefloquine concentrations are decreased in the presence of an antimalarial, artesunate. Primaquine has no effect on the pharmacokinetics of mefloquine when given concurrently.

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 microgram.ml-1 and 402 versus 94 micrograms.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.

Clinical pharmacokinetics in the treatment of tropical diseases. Some applications and limitations.

In recent years major advances have been made in the clinical pharmacology of many drugs used for the treatment of tropical diseases, particularly in the design and development of dosage regimens for the treatment of severe malaria. For example, by careful manipulation of its rate of administration, chloroquine has been shown to be well tolerated when used for treatment of severe disease caused by susceptible parasites. Similarly, important advances have been made in the rational design of quinine dosage regimens for patients in South East Asia and Africa. Investigation of the pharmacokinetics of mefloquine has drawn attention to the problems associated with its administration as combination therapy with pyrimethamine and sulfadoxine in Thailand. Similarly, evaluation of the pharmacokinetic properties of halofantrine has led to the demonstration that poor and erratic absorption could be just as likely to explain therapeutic failure as resistance of the parasite to effects of this drug. Disposition of the antimalarial biguanides has highlighted the role of host-related effects in the determination of drug response. For example, a small percentage of individuals are unable to convert proguanil (chloroguanide) to its active triazine metabolite, cycloguanil. Finally, agents that reverse chloroquine resistance are currently under development for the treatment of malaria. The importance of assessing the clinical pharmacokinetic properties of potential resistance reversers must be recognised. While limited success has been achieved in antifilarial chemotherapy, other parasitic diseases have been largely neglected with advances in the laboratory still awaiting full recognition of their clinical application. For example, clinical pharmacokinetic concepts may be used to improve the therapy of human hydatid disease. We believe that clinical management of tropical diseases can be improved by the application of clinical pharmacokinetic principles. However, this may not be universally advantageous. For example, the artemisinin (qinghaosu) derivatives are among the most recently developed antimalarials that have great therapeutic promise. Recent evidence suggests that pharmacokinetic data would be of limited value in the design and optimisation of dosage regimens because of its chemical reactivity and the unusual mechanism by which these drugs kill parasites. Similar limitations may apply to the microfilaricidal drug, ivermectin.

Stereoselective Pharmacokinetics of Mefloquine in Healthy Caucasians after Multiple Doses

Mefloquine (MQ) is a chiral antimalarial agent effective against chloroquine‐resistantPlasmodium falciparum.It is commercially available as a racemic mixture of the (+) and (−) enantiomers for oral administration. The pharmacokinetics of the (+) and (−) enantiomers of MQ were studied in eight healthy volunteers after administration of a first oral dose of 250 mg of racemic MQ and at steady state after 13 repeated doses of 250 mg given at 1‐week intervals. Plasma samples were collected, and concentrations of each enantiomer were determined using a previously described achiralchiral double column‐switching liquid chromatographic method. At each time point, higher plasma concentrations values were found for the (−) enantiomer (p< 0.001). At steady state,Cmaxvalues of (−)‐MQ were higher than those of (+)‐MQ (1.42 ± 0.19 versus 0.26 ± 0.05 mg/L;p< 0.001). Similarly, the plasma concentrations 7 days after the final dose were higher for (−)‐MQ (1.01± 0.26 versus 0.11 ± 0.04 mg/L;p< 0.001). AUC values at steady state were also higher for (−)‐MQ (197.3 ± 36.7 versus 30.1 ± 8.9 mg/L·h;p< 0.001). The terminal half‐life values (T1/2β) were longer for (−)‐MQ (430.4 ± 225.2 versus 172.8 ± 56.5 h;p< 0.001). This study shows that the pharmacokinetics of MQ is highly stereoselective.

Mefloquine pharmacokinetics in pregnant women with acute falciparum malaria

Mefloquine has an established place in the treatment of chloroquine-resistant falciparum malaria. To investigate mefloquine pharmocokinetics 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 ( V d 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.