Lack of bioequivalence of a generic mefloquine tablet with the standard product

Weidekamm, E.; Rüsing, Guido; Caplain, H; Sörgel, Fritz; Crevoisier, C

doi:10.1007/s002280050523

Cited by 27 publications

(27 citation statements)

References 10 publications

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“…Direct comparison of these results with those from previous studies should also take into account that a different formulation of the drug was used. Previous studies have shown that the different products are not bioequivalent (10,18). Tolerability of this three-dose mefloquine regimen was good.…”

Section: Discussionmentioning

confidence: 81%

Population Pharmacokinetic Assessment of a New Regimen of Mefloquine Used in Combination Treatment of Uncomplicated Falciparum Malaria

Ashley

Stepniewska

Lindegårdh

et al. 2006

Antimicrob Agents Chemother

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A fixed artesunate-mefloquine combination, comprising three daily doses of 8 mg of mefloquine/kg of body weight and 4 mg of artesunate/kg, has been developed recently. This study was designed to construct a population pharmacokinetic model describing this new dosage regimen of mefloquine given as loose tablets together with artesunate. In two randomized trials in Thailand which evaluated the efficacy, safety, and tolerability of this new regimen, the members of a subgroup of 50 patients were randomized to have capillary blood sampling before treatment and at five randomly assigned time points during the 63-day follow-up period. Mefloquine levels in capillary whole blood were assayed by liquid chromatography with UV detection. A pharmacokinetic model for mefloquine was constructed using mixed-effects modeling. A one-compartment model with first-order absorption and elimination was selected to describe the kinetic properties of mefloquine. For capillary whole-blood mefloquine, the area under the concentration curve (AUC) was 40% higher than previous estimates for patients given the equivalent conventional-dose regimen (mefloquine given as 15 mg/kg and then 10 mg/kg on the second and third days of treatment). The half-life (t 1/2 ) of the carboxylic acid metabolite was estimated as 26 days, and the metabolite was eliminated more slowly than the parent drug (population t 1/2 estimate, 10.5 days). Splitting the 25 mg/kg dose of mefloquine into three doses of 8 mg/kg each resulted in improved oral bioavailability compared to the conventional split-dose regimen results. This new regimen is well tolerated and results in an equivalent therapeutic response.Mefloquine, a fluorinated 4-quinoline methanol compound, was developed by the Walter Reed Army Institute of Research over 35 years ago. Mefloquine has two asymmetric carbon atoms and is used as an oral treatment containing a racemic mixture of equal proportions. The pharmacokinetic properties are stereospecific. Mefloquine is moderately well absorbed orally and extensively distributed and is Ͼ98% bound to plasma proteins. The terminal elimination half-life is approximately 3 weeks for healthy subjects and 2 weeks for subjects with malaria (6). The main metabolite identified in man is 2-8-bis-trifluoromethyl-4-quinoline carboxylic acid (MMQ), which is inactive against Plasmodium falciparum.Mefloquine was introduced first as a single-dose therapy for falciparum malaria in Thailand in 1984, but initial high cure rates were not sustained (11). In a bid to halt the loss of antimalarial monotherapies to resistance in rapid succession, the strategy of artemisinin-based combination therapy with mefloquine was developed (19) and was adopted in Thailand in 1994.In cases of malaria, absorption of mefloquine is dose limited and is reduced in the acute phase of illness. Splitting the dose and delaying administration after the first dose of an artemisinin derivative increase mefloquine absorption (12,14). This is attributed partly to the rapid clinical and parasitological responses t...

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Section: Discussionmentioning

confidence: 81%

Population Pharmacokinetic Assessment of a New Regimen of Mefloquine Used in Combination Treatment of Uncomplicated Falciparum Malaria

Ashley

Stepniewska

Lindegårdh

et al. 2006

Antimicrob Agents Chemother

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“…The affinity of (+)-mefloquine for the [ 125 I]DOI binding site of recombinant h5-HT 2A receptors is similar to the affinity of DMT (Ki = 210 nM), a psychotomimetic, but DMT and mefloquine have much lower affinity than LSD and DOM at this receptor (Table 1). The K i value for mefloquine (341 nM), is below the minimum anti-plasmodial therapeutic concentration of the drug in blood (1.6 μM; see Schlagenhauf et al, 2011; C max = 1018 μg/L ≈ 2.6 μM, but varies by preparation, see Wiedekam et al, 1998). However, free concentrations of mefloquine in brain would be much smaller, as indicated above.…”

Section: Discussionmentioning

confidence: 97%

Mefloquine and psychotomimetics share neurotransmitter receptor and transporter interactions in vitro

et al. 2014

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Rationale Mefloquine is used for the prevention and treatment of chloroquine-resistant malaria, but its use is associated with nightmares, hallucinations, and exacerbation of symptoms of post-traumatic stress disorder. We hypothesized that potential mechanisms of action for the adverse psychotropic effects of mefloquine resemble those of other known psychotomimetics. Objectives Using in vitro radioligand binding and functional assays, we examined the interaction of (+)- and (−)-mefloquine enantiomers, the non-psychotomimetic anti-malarial agent, chloroquine, and several hallucinogens and psychostimulants with recombinant human neurotransmitter receptors and transporters. Results Hallucinogens and mefloquine bound stereoselectively and with relatively high affinity (Ki = 0.71–341 nM) to serotonin (5-HT) 2A but not 5-HT1A or 5-HT2C receptors. Mefloquine but not chloroquine was a partial 5-HT2A agonist and a full 5-HT2C agonist, stimulating inositol phosphate accumulation, with similar potency and efficacy as the hallucinogen dimethyltryptamine (DMT). 5-HT receptor antagonists blocked mefloquine’s effects. Mefloquine had low or no affinity for dopamine D1, D2, D3, and D4.4 receptors, or dopamine and norepinephrine transporters. However, mefloquine was a very low potency antagonist at the D3 receptor and mefloquine but not chloroquine or hallucinogens blocked [3H]5-HT uptake by the 5-HT transporter. Conclusions Mefloquine but not chloroquine shares an in vitro receptor interaction profile with some hallucinogens and this neurochemistry may be relevant to the adverse neuropsychiatric effects associated with mefloquine use by a small percentage of patients. Additionally, evaluating interactions with this panel of receptors and transporters may be useful for characterizing effects of other psychotropic drugs and for avoiding psychotomimetic effects for new pharmacotherapies, including antimalarial quinolines.

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“…12 Different commercial preparations of MQ are known to vary in terms of their bioavailability. 13 A recent study in Thailand comparing Lariam ® (F. Hoffmann La Roche, Basel, Switzerland) with two other commercial preparations, Mephaquin ® and Eloquine ® (Medochemie, Ltd., Limassol, Cyprus) showed that blood levels and the area under the curve with Mephaquin ® were 50% lower that those with Lariam ® .…”

Section: Figure 2 Geometric Mean Parasite Density Of Patients Treatementioning

confidence: 99%

Efficacy of Mefloquine and a Mefloquine-Artesunate Combination Therapy for the Treatment of Uncomplicated Plasmodium Falciparum Malaria in the Amazon Basin of Peru

Marquiño

Huilca

Calampa

et al. 2003

The American Journal of Tropical Medicine and Hygiene

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Abstract. In the Amazon Basin of Peru, more than 50% of patients with uncomplicated Plasmodium falciparum malaria fail to respond to treatment with chloroquine or sulfadoxine-pyrimethamine. To assist the National Malaria Control Program in identifying an alternative first-line therapy for this region, we conducted a trial of the safety and efficacy of mefloquine (MQ) compared with mefloquine-artesunate (MQ-AS) combination therapy. Patients with uncomplicated P. falciparum infections between the ages of 5 and 50 years were randomly assigned to be treated with either MQ (15 mg/kg in a single oral dose) or MQ (15 mg/kg) plus AS (4 mg/kg/day for three days). A total of 98 patients were enrolled and followed for 28 days. None of the 47 patients who received MQ alone or the 51 patients who received MQ-AS combination therapy had recurrences of parasitemia during the 28-day follow-up period. Asexual parasite densities decreased significantly more rapidly and the proportion of patients with gametocytes was significantly lower on days 3−21 in the MQ-AS group than in patients treated with MQ alone. All patients tolerated the medication well. Based on the results of this study and with the objective of slowing the development of resistance, the Peruvian Ministry of Health has decided to revise its malaria treatment policy and recommend combination therapy with MQ-AS as the new first-line treatment of uncomplicated P. falciparum malaria in the Amazon region.

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Lack of bioequivalence of a generic mefloquine tablet with the standard product

Cited by 27 publications

References 10 publications

Population Pharmacokinetic Assessment of a New Regimen of Mefloquine Used in Combination Treatment of Uncomplicated Falciparum Malaria

Population Pharmacokinetic Assessment of a New Regimen of Mefloquine Used in Combination Treatment of Uncomplicated Falciparum Malaria

Mefloquine and psychotomimetics share neurotransmitter receptor and transporter interactions in vitro

Efficacy of Mefloquine and a Mefloquine-Artesunate Combination Therapy for the Treatment of Uncomplicated Plasmodium Falciparum Malaria in the Amazon Basin of Peru

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