Mefloquine tolerability during chemoprophylaxis: focus on adverse event assessments, stereochemistry and compliance

Schlagenhauf, Patricia; Steffen, Robert; Lobel, Hans O.; Johnson, Richard F.; Letz, Richard; Tschopp, Alois; Vranješ, N.; Bergqvist, Yngve; Ericsson, Örjan; Hellgren, Urban; Rombo, Lars; Mannino, Salvatore; Handschin, J.; Stürchler, D

doi:10.1046/j.1365-3156.1996.d01-85.x

Cited by 69 publications

(46 citation statements)

References 17 publications

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“…These findings suggested that plasma tafenoquine concentrations are not the primary predictor of tafenoquine tolerability. This lack of an association between plasma drug concentrations and adverse events has also been seen with another antimalarial agent, mefloquine, which shares similar pharmacokinetic properties with tafenoquine (12) in that both are lipophilic, are slowly absorbed from the gastrointestinal tract, are extensively bound to tissues, and have elimination t 1/2 values of about 2 weeks (1, 2, 9, 14).…”

Section: Discussionmentioning

confidence: 81%

Population Pharmacokinetics of Tafenoquine during Malaria Prophylaxis in Healthy Subjects

Charles

Miller

Nasveld³

et al. 2007

Antimicrob Agents Chemother

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The population pharmacokinetics of tafenoquine were studied in Australian soldiers taking tafenoquine for malarial prophylaxis. The subjects (476 males and 14 females) received a loading dose of 200 mg tafenoquine base daily for 3 days, followed by a weekly dose of 200 mg tafenoquine for 6 months. Blood samples were collected from each subject after the last loading dose and then at weeks 4, 8, and 16. Plasma tafenoquine concentrations were determined by liquid chromatography-tandem mass spectrometry. Population modeling was performed with NONMEM, using a one-compartment model. Typical values of the first-order absorption rate constant (K a ), clearance (CL/F), and volume of distribution (V/F) were 0.243 h ؊1 , 0.056 liters/h/kg, and 23.7 liters/kg, respectively. The intersubject variability (coefficient of variation) in CL/F and V/F was 18% and 22%, respectively. The interoccasion variability in CL/F was 18%, and the mean elimination half-life was 12.7 days. A positive linear association between weight and both CL/F and V/F was found, but this had insufficient impact to warrant dosage adjustments. Model robustness was assessed by a nonparametric bootstrap (200 samples). A degenerate visual predictive check indicated that the raw data mirrored the postdose concentration-time profiles simulated (n ‫؍‬ 1,000) from the final model. Individual pharmacokinetic estimates for tafenoquine did not predict the prophylactic outcome with the drug for four subjects who relapsed with Plasmodium vivax malaria, as they had similar pharmacokinetics to those who were free of malaria infection. No obvious pattern existed between the plasma tafenoquine concentration and the pharmacokinetic parameter values for subjects with and without drug-associated moderate or severe adverse events. This validated population pharmacokinetic model satisfactorily describes the disposition and variability of tafenoquine used for long-term malaria prophylaxis in a large cohort of soldiers on military deployment.

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Section: Discussionmentioning

confidence: 81%

Population Pharmacokinetics of Tafenoquine during Malaria Prophylaxis in Healthy Subjects

Charles

Miller

Nasveld³

et al. 2007

Antimicrob Agents Chemother

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“…A modified version of this screen was used here. Female rats were selected since the neurological effects of mefloquine in humans are more often observed in women (18,19,36). This may be due to higher plasma concentrations or areas under the curve (19), but a gender bias cannot be ruled out.…”

mentioning

confidence: 99%

“…This may be due to higher plasma concentrations or areas under the curve (19), but a gender bias cannot be ruled out. We chose a 72-h observation window because neurological effects in humans are most often observed during this time frame (18,36). Finally, in an attempt to put any neurological findings observed into a clinical context, plasma mefloquine concentrations were determined in order to guide dose selection.…”

mentioning

confidence: 99%

Mefloquine Induces Dose-Related Neurological Effects in a Rat Model

Dow¹,

Bauman²,

Caridha³

et al. 2006

Antimicrob Agents Chemother

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Mefloquine is one of the drugs approved by the FDA for malaria chemoprophylaxis. Mefloquine is also approved for the treatment of malaria and is widely used for this purpose in combination with artesunate. However, the clinical utility of the compound has been compromised by reports of adverse neurological effects in some patients. In the present study, the potential neurological effects of mefloquine were investigated with six 7-week-old female rats given a single oral dose of the compound. Potential mefloquine-induced neurological effects were monitored using a standard functional observational battery, automated open field tests, automated spontaneous activity monitoring, a beam traverse task, and histopathology. Plasma mefloquine concentrations were determined 72 h after dosing by using liquid chromatography-mass spectrometry. Mefloquine induced dose-related changes in endpoints associated with spontaneous activity and impairment of motor function and caused degeneration of specific brain stem nuclei (nucleus gracilis). Increased spontaneous motor activity was observed only during the rats' normal sleeping phase, suggesting a correlate to mefloquine-induced sleep disorders. The threshold dose for many of these effects was 187 mg/kg of body weight. This dose yielded plasma mefloquine concentrations after 72 h that are similar to those observed in humans after the treatment dose. Collectively, these data suggest that there may be a biological basis for some of the clinical neurological effects associated with mefloquine.

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“…Some studies have shown that more women than men report neurological or psychiatric adverse events (WHO 1991;Phillips-Howard & ter Kuile 1995;ter Kuile et al 1995;Schlagenhauf et al 1996). Therefore, gender should also be taken into consideration.…”

Section: Discussionmentioning

confidence: 99%

“…Weinke et al (1991) estimated the incidence of neuropsychiatric adverse reactions during prophylaxis as 1:1300; by comparison a recent retrospective study found that disabling neuropsychiatric side-effects occurred in 1:140 of travellers taking mefloquine for prophylaxis (Barrett et al 1996). Another recent study showed that 7.9% (33:420) of travellers taking mefloquine reported minor neuropsychiatric adverse effects, but no serious adverse effects (Schlagenhauf et al 1996). In 1996 the Department of Drug Safety of F. Hoffmann-La Roche reported a total of 3827 adverse events, 87 for curative treatment.…”

Section: Discussionmentioning

confidence: 99%

Neuropsychiatric manifestations after mefloquine therapy for Plasmodium falciparum malaria: comparing a retrospective and a prospective study

Rønn

Rønne-Rasmussen

et al. 1998

Tropical Med Int Health

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Mefloquine has been increasingly used for treatment of chloroquine‐resistant malaria since its introduction in the late 1970s. In 1987 the first case of toxic encephalopathy was published, and in 1989 the WHO initiated reporting and investigation of neuropsychiatric adverse reactions of mefloquine. Neuropsychiatric adverse drug reactions are now well documented. We compared an open prospective 3 year study including all patients with P. falciparum treated with mefloquine with an earlier published, retrospective study on a comparable population from our department covering the period up to 1989.dollar;>In the retrospective study neuropsychiatric adverse effects were not specifically asked for, while in the prospective study possible adverse reactions were registered daily according to a specified questionnaire. No case of neuropsychiatric adverse reaction was registered in the retrospective study. In the prospective study, 28% had one or more neuropsychiatric adverse reactions, although severity was mostly mild to moderate. Other adverse reactions occurred in 96% in the retrospective study compared to 81% in the prospective study. In conclusion: one often finds only what one looks for, e.g adverse events may be overlooked for a decade, if relatively uncommon. This report also shows that retro‐ and prospective studies may give very different results.

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Mefloquine tolerability during chemoprophylaxis: focus on adverse event assessments, stereochemistry and compliance

Cited by 69 publications

References 17 publications

Population Pharmacokinetics of Tafenoquine during Malaria Prophylaxis in Healthy Subjects

Population Pharmacokinetics of Tafenoquine during Malaria Prophylaxis in Healthy Subjects

Mefloquine Induces Dose-Related Neurological Effects in a Rat Model

Neuropsychiatric manifestations after mefloquine therapy for Plasmodium falciparum malaria: comparing a retrospective and a prospective study

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