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Antimicrobial Agents and Chemotherapy, March 2007, p. 1099-1101, Vol. 51, No. 3
0066-4804/07/$08.00+0     doi:10.1128/AAC.01253-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Assessment of the Effect of Mefloquine on Artesunate Pharmacokinetics in Healthy Male Volunteers{triangledown}

Timothy M. E. Davis,1* Michelle England,1 Anne-Marie Dunlop,1 Madhu Page-Sharp,1 Nathalie Cambon,2 Thomas G. Keller,2 János L. Heidecker,2 and Kenneth F. Ilett1,3

School of Medicine and Pharmacology, University of Western Australia, Crawley, Western Australia, Australia,1 Mepha Ltd., Pharmaceutical Research Development and Manufacture, Dornacherstrasse 114, 4147 Aesch, Switzerland,2 Clinical Pharmacology and Toxicology Laboratory, PathWest Laboratory Medicine, Nedlands, Western Australia, Australia3

Received 5 October 2006/ Returned for modification 12 November 2006/ Accepted 4 December 2006


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ABSTRACT
 
The effect of mefloquine on artesunate pharmacokinetics was assessed in 20 volunteers given artesunate for 3 days, followed ≥21 days later by combination therapy for 3 days. The areas under the concentration-time curve from 0 h to infinity for dihydroartemisinin, the active metabolite of artesunate, were similar on day 3 of the two dosing periods (P = 0.12), implying no interaction.


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TEXT
 
Mefloquine-artesunate was one of the first artemisinin combination therapies used clinically, and it remains an effective treatment for uncomplicated malaria (2, 9). While the influence of artesunate on the pharmacokinetics of mefloquine has been investigated (12, 16), with seemingly inconsistent results (11), the effect of mefloquine on artesunate disposition has not. The active metabolite of artesunate, dihydroartemisinin (DHA), is itself an antimalarial drug that has been partnered with mefloquine as a form of artemisinin combination therapy (2, 9). Mefloquine does not influence DHA pharmacokinetics in patients with falciparum malaria (13-15), but extrapolation of this finding to artesunate-mefloquine may be invalid. Artesunate and DHA have different chemical and pharmacologic properties (5), and between-subject variability and changes in drug disposition and metabolism during recovery from malaria complicate assessment of previously published parallel-group DHA-mefloquine patient studies. We have therefore evaluated the effects of mefloquine on artesunate and DHA pharmacokinetics in healthy males, using a crossover study design.

The study was approved by the South Metropolitan Health Service Human Research Ethics Committee, Western Australia, and all subjects provided informed consent. Twenty of the 25 volunteers recruited met eligibility criteria and provided complete valid data for analysis. Their mean age was 28.9 (range, 19.0 to 57.1) years and their mean body weight 77 (48 to 130) kg. Each subject received 200 mg artesunate (Mepha Ltd., Switzerland) by mouth after an overnight fast on three consecutive mornings (period 1). After a washout phase of ≥21 days, this schedule was repeated, but mefloquine (Mepha) at 250 mg daily was given at the same time as artesunate (period 2). On days 1 and 3 of each period, blood samples were drawn for drug assay under a predetermined schedule from immediately before (0 h) to 8 h postdose. Additional samples were taken for mefloquine assay on the mornings of days 2, 4, 5, and 6 during and after period 2.

Drug assays were by high-performance liquid chromatography. For mefloquine, extracted plasma (with clomipramine as an internal standard) was injected onto a RP Select B column (E. Merck, Darmstadt, Germany) run on a 1100 high-performance liquid chromatograph (Agilent Technologies, Waldbronn, Germany), using a mobile phase of 40% (vol/vol) acetonitrile in 45 mM KH2PO4 (pH 3) at 1.3 ml/min with UV detection at 225 nm. Within- and between-day relative standard deviations over 50 to 2,000 µg/liter were ≤9.4% and ≤8.8%, respectively. The lower limit of quantitation was 10 µg/liter. For artesunate and DHA, extracted plasma (with artemisinin as an internal standard) was chromatographed on an Intersil ODS2 C18 column (MZ-Analysentechnik GmbH, Mainz, Germany), using a mobile phase of CH3CN-H2O-30 mM ammonium formate buffer (pH 4.3)-CH3COOH (700:266:33:1) at 0.35 ml/min, with detection at m/z 402/267 (artesunate) and m/z 302/267 (DHA) using an API 2000 triple-quadrupole mass spectrometer (Applied Biosystems Inc., Foster City, CA). Within- and between-day relative standard deviations at 5 to 500 µg/liter for artesunate and 10 to 1,000 µg/liter for DHA were ≤7.4% and ≤8.2%, and lower limits of quantitation were 5 µg/liter and 10 µg/liter, respectively. Pharmacokinetic analysis was by noncompartmental methods (18). Nonnormally distributed variables were log transformed before statistical analysis, which was by general linear modeling for repeated measures.

As found previously (5), artesunate was measurable transiently and in low concentrations relative to DHA (Fig. 1), and we restricted artesunate pharmacokinetic analysis to estimation of the maximum concentration in plasma (Cmax) and time to Cmax (Tmax) as a result (Table 1). There was no difference between mean log-transformed values of these parameters by time of study. For DHA, there were similarly no differences between ln(Cmax) and ln(Tmax) and also elimination half-life and volume of distribution and clearance relative to bioavailability (Table 1). Since artesunate is metabolized stoichiometrically to DHA (8), we selected the logarithm of the area under the DHA concentration-time curve from 0 h to infinity [ln(DHA AUC0-{infty})] as the primary outcome variable. There was no significant difference between the mean values (Table 1). With the DHA AUC0-{infty} for day 3 of period 1 as reference (R) and that of day 3 of period 2 as test (T), the mean percent T/R was 102% (90% confidence interval, 87 to 117%). This interval lies within the accepted 80 to 125% boundaries for bioequivalence (19).


Figure 1
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  		FIG. 1. Mean plasma dihydroartemisinin and artesunate concentrations during days 1 and 3 of periods 1 and 2 in healthy male volunteers.


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  		TABLE 1. Pharmacokinetic parameters for artesunate and dihydroartemisinin on days 1 and 3 of periods 1 and 2

Although we did not sample for long enough to characterize the pharmacokinetics of mefloquine, the Cmax following a total mean dose of 9.7 mg/kg during period 2 was 1,058 ± 383 µg/liter. Since, in two previous healthy-volunteer studies, single-dose mefloquine given as means of 19.6 (10) and 27.5 (6) mg/kg produced proportionately lower Cmax values of 1,220 ± 360 and 1,440 ± 740 µg/liter, respectively, we assume that there is dose-dependent bioavailability. Consistent with this hypothesis, dividing the dose in patients with falciparum malaria increases bioavailability (1, 17).

None of the 25 recruits withdrew from the study because of drug-related adverse events, and there were no significant changes in routine hematologic and biochemical tests in any subject over the 4-week study period. Artesunate was well tolerated, with no changes in supine and erect blood pressure, rate-corrected electrocardiographic QT interval, or plasma glucose during period 1 (data not shown). Three subjects (12%) experienced mild neurological symptoms, which lasted a day in each case and required no medical intervention. There were similarly no changes in postural blood pressure, rate-corrected electrocardiographic QT interval, or glycemia during period 2 (data not shown). However, nine subjects (43%) experienced neurological symptoms (mainly insomnia, dizziness, or vivid dreams), which started after the second dose of artesunate-mefloquine and lasted a median of 3 days. None of these events led to withdrawal from the study or medical intervention. A further six subjects (30%) reported mild self-limited gastrointestinal symptoms during period 2. Because of (i) these data, (ii) previous volunteer studies involving single mefloquine treatment doses with relatively high rates of adverse events (6), and (iii) the present study and other studies with volunteers (6, 10) and patients (1, 17) indicating that dividing the dose increases concentrations in plasma, care should be taken in designing dose regimens in future mefloquine volunteer studies.

We conclude that mefloquine does not alter the pharmacokinetics of artesunate when the drugs are coadministered. In contrast to the case for artemisinin (3, 4), and as would be predicted from the short-term artesunate-DHA exposure in our study and from the literature on autoinduction by artemisinin drugs (7), we observed no significant time-dependent changes in artesunate-DHA pharmacokinetics.


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ACKNOWLEDGMENTS
 
We are grateful to Mepha Pharmaceuticals for financial support.

We thank A. Prestel and H. Bozler from BiochemA GmbH, Germany, for artesunate and DHA assays; N. Kamber for valuable assistance with clinical procedures; and W. Davis for help with statistical analysis.


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FOOTNOTES
 
* Corresponding author. Mailing address: University of Western Australia, School of Medicine and Pharmacology, Fremantle Hospital, P.O. Box 480, Fremantle, Western Australia 6959, Australia. Phone: (618) 9431 3229. Fax: (618) 9431 2977. E-mail: tdavis{at}cyllene.uwa.edu.au. Back

{triangledown} Published ahead of print on 18 December 2006. Back


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Antimicrobial Agents and Chemotherapy, March 2007, p. 1099-1101, Vol. 51, No. 3
0066-4804/07/$08.00+0     doi:10.1128/AAC.01253-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.




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