Single-dose kinetics of mefloquine in Brazilian male subjects

Bulletin of the World Health Organization, 65 (3): 353-356 (1987) i World Health Organization 1987 Single-dose kinetics of mefloquine in Brazilian male subjects J. M. DE SOUZA,1 P. HEIZMANN,2 & D. E. SCHWARTZ2 Ten male subjectsfrom a region of the state ofPard, Brazil, where malaria is endemic received a single oral dose of 1000 mg mefloquine. Theplasma levels of the drug and of its metabolite, 2,8-bis(trifluoromethyl)-4-quinolinecarboxylic acid, were determined densito- metrically on thin-layer chromatography plates. Thepharmacokineticparameters obtained fell well within the range of values reported previously for Africans and Caucasians. The study was conducted according to the guidelines laid out in the declaration of Helsinki and organized as part of a double-blind trial of mefloquine and sulfadoxine-pyrimethamine spon- sored by WHO at Barros Barreto Hospital, Belem, Pars State, Brazil. The clinical results obtained have already been reported (1). Here, we compare the pharmacokinetic parameters for mefloquine deter- mined in the Brazilian subjects from a malaria- endemic area with those previously reported for Caucasian and African volunteers (2). MATERIALS AND METHODS Subjects and administration of the drug Ten male subjects aged 19-50 years, who weighed between 50 and 68 kg, were drawn from the popu- 1 Adjunct Professor of Pharmacology, Health Sciences Centre, Federal University of Para, and Principal Investigator, Clinical Trial Centre, Barros Barreto Hospital, Bel6m, Para, Brazil. 2 Biological Pharmaceutical Research Department, F. Hoff- mann-La Roche & Co. Ltd., CH4002 Basle, Switzerland. Requests for reprints should be addressed to these authors. lation living in an area of the state of Para in the north of Brazil that is known to be endemic for malaria. Three of the subjects (MI, M4, and M14) were slide-positive for the trophozoites of Plas- modium falciparum on the first 2 days of the trial. These individuals, however, did not show acute symptoms of malaria, possibly because they were "semi-immune". In addition they were not suffering from other acute or debilitating diseases and had normal plasma albumin values (3). Furthermore, none of the participants had received any anti- malarial drug during the 4 weeks preceding the trial. Characteristics of the study are given in Table 1. Excluded from the trial were: -subjects suffering from a deficiency of glucose-6- phosphate dehydrogenase, haemoglobinopathy, mal- nutrition, gastrointestinal disorders, impaired liver or kidney functions, cardiovascular diseases, or any serious infections; and -alcoholics or drug addicts. Mefloquine, as the hydrochloride, was adminis- tered in tablet form. Each tablet contained an amount Table 1. Characteristics of the subjects in the trial Subject' Ml M2 M3 M4 M1o M11 M13 M14 M17 M22 Characteristic (C.S.B.) (R.B.C.) (F.C.A.) (J.C.C.) (O.F.C.) (F.P.) (J.C.A. ) (P. V.S.R. ) (F.A.G.R. ) (S.G.S. ) Age (years) 21.3 28.6 20.6 19.6 50.7 23.25 22.8 19.9 23.7 42.5 Weight (kg) 52.8 53.0 59.9 50.0 63.0 60.8 55.5 62.2 55.0 68.3 Height (m) 1.67 1.63 1.63 1.56 1.72 1.69 1.66 1.63 1.70 1.79 a The level of albumin in all patients was normal (3.5-4.6 g/lOO ml plasma) (2). 4789 -353- J. M. DE SOUZA ET AL. equivalent to 250 mg drug base and was given early in the morning after a light breakfast. Each subject received four tablets (a dose equivalent to 1000 mg mefloquine base), which were taken with a glass of water. Collection of blood samples Blood samples (10 ml) were collected from each subject before administering the drug, and subse- quently 1, 2, 3, 4, 5, 6, 7, 14, 21, 28, 35, 42, 49, 56, and 63 days thereafter. Samples were collected in tubes containing a mixture of ammonium and potassium oxalate, and were inverted ten times to ensure thorough mixing. The tubes were centrifuged for 15 minutes at 1000 g within 1 hour of sample collection and the plasma was transferred to clean glass tubes. Samples of plasma thus obtained were stored at - 20 °C until analysed. Analysis Plasma specimens were thawed at room tempera- ture, heated for 10 minutes in a water-bath at 37 OC, while the tubes were inverted several times by hand, and extracted as previously described (4). Extracts were analysed by thin-layer chromatography (TLC) (silica gel 60 F254 precoated TLC plates' activated for 15 minutes at 140 IC; mobile phase: dichloro- methane-methanol-acetic acid, 80:10:10 v/v) and the plates were scanned at X= 300 nm for absorption in the UV. The method has a sensitivity limit of 50 ng mefloquine per ml and its reproducibility is better than ± 5% for mefloquine and its major metabolite, 2,8-bis(trifluoromethyl)-4-quinolinecarboxylic acid, over the concentration range 200-600 ng/ml and 600-1800 ng/ml, respectively. Pharmacokinetic evaluation Data were generally evaluated pharmacokinetically using "topfit" programs (5). RESULTS AND DISCUSSION Plasma level profiles for mefloquine and its metabolite for subject M17 are shown in Fig. 1 and 2, respectively, while the corresponding pharmaco- kinetic parameters are given in Table 2 for all 10 subjects. Values for half-lives and the area under the plasma concentration-time curves were determined using two-compartment model kinetics with weighting of individual data points. The average weight of the Brazilian subjects was a Merck 5715. 11.0 * o0.1 8 *r 0.01 0.00110 5.6 11.2 16.8 22.4 28 33.6 39.2 44.8 60.4 56 61.6 67.2 Timw (daYS) Fig. 1. Plasma level profile of mefloquine (subject Ml17). 10 kg less than that of the collective African and Caucasian volunteers examined previously (2). In spite of this difference in average weight, the mean pharmacokinetic parameters for the Brazilian subjects fall well within the range of those reported for the volunteers in (1) for the same dose and form of mefloquine (data for Brazilian subjects are given first): area under the plasma concentration-time curve (587±164 itg*mlP'*hour versus 608± 137 1&g.mlP'.hour); systemic clearance (31.1 ±6.4 ml*hour-'.kg'1 versus 27.8 ±6.5 ml*hour 1.kg'1); terminal elimination half-life (21.6 ± 5.1 days versus 22.0 ±5.4 days). A slightly larger volume of distribution (23.2 ±7.6 I.kg-' versus 19.4 ±5.0 1-kg'1) and a somewhat greater metabolite: mefloquine ratio (4.2 ±1.4 versus 3.3±1.0) was observed for the Brazilian subjects. The metabolite, 2,8-bis(trifluoromethyl)-4-quinolinecarboxylic acid, was eliminated from plasma (estimated average half- life, 20.2 ± 4.1 days) at a rate that is similar to that of mefloquine. However, since mefloquine itself has a long half-life, that of the metabolite may be limited by its rate of formation (flip-flop model). 1.0 0.1 0.01 1121.224 A1 L JL L 5.6 33.668224 28 M 39.2 44.8 50.4 56 61.6 67.2 Time (days) Fig. 2. Plasma level profile of mefloquine metabolite 2,8- bis(trifluoromethyl)-4-quinolinecarboxylic acid (subject Ml17). SINGLE-DOSE KINETICS OF MEFLOQUINE E + _ ~ O CD N ) c C:co g~~~~~~~MCO -H -H+ iv ~~ _P . X 0X Lo 04 Co Q C _~~( CD (l.N CD o CCC) 4r- c ) CCAcoN o (N Nsg CD) 0~~~~~~~~~0 E° (C)o . N CD X. _ oC) 0 V- co 0 C_o CO CO Co .0 2 ~ 0 'i) 1- DL CC) oO C') (C) cn E r b X ,5 CTC *:o co0r- oi (6 C-4 CE C co C c( S-87 ~ ow - ao (N) 3.E 0 0~~~~ cn~~~~~~0 ( i0~~~~~~C .Q~~~~~~~( .6 0 CY06 PI o .0 0 o a-0 .' CE)_-U) > rV C5W c~j 6 o6 co CC) cr 0co CD4 75 ~ 0 04r .00 0 oc 0v_: Co r.:co CD Co & C ~~~~~~~~N 0 00 C; ~ ~~~CC ai m' c'i C~~~~~~~~~~~~~~~~~~~~~~~~C C~~~~~~~~~C cr ~~~0 0 6; 06 C6 c'i cl '~~~~~- (C -'0 0 ~~~~0 0 C4~~~~~~~~C Co 0~~~~~~~~C C')0 co co) CO Co (IC0i- W ;Z 7 -o = E- !a C m 4) X Lu cx "lx 03~~~~~~~~~~~~~4 cc 355 356 J. M. DE SOUZA ET AL. ACKNOWLEDGEMENTS The valuable technical assistance of Miss Schwittay and Mrs K. Zinapold is gratefully acknowledged. The work was supported financially by the UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases. RtSUMt CINETIQUE D'UNE DOSE UNIQUE DE MEFLOQUINE CHEZ DES BRESILIENS DE SEXE MASCULIN Dix adultes de sexe masculin, habitant une region de l'Etat de Para (Bresil), ou le paludisme est endemique, ont requ une dose orale unique de 1000 mg de mefloquine. Les concentrations plasmatiques du medicament et de son metabolite, I'acide bis(trifluorom6thyl)-2,8 quinoline-4 carboxylique, ont ete determinees par densitometrie apres separation par chromatographie sur couche mince et les parametres pharmacocinetiques ci-apres ont ete obtenus. Mefloquine Aire sous la courbe de concentration plasmatique en fonction du temps (AUCo): 410-913 ,g.mlF'.h(moyenne = 587 jg.ml' .h); volume apparent de distri- bution (VT, 0): 16,0-41,6 1.kg-' (moyenne=23,2 I.kg-'); clairance generale (Cls): 18,3-38,7 ml.h-'.kg'l (moyenne=31,1 ml.h '.kg-1; temps de demi-elimination finale A partir du plasma (ti ): 16,7-31,0 jours (moyenne = 21,6 jours). Me6tabolite Temps de demi-elimination A partir du plasma (tQ,): 13,9-27,6 jours (moyenne = 20,2 jours). Le rapport entre les concentrations du metabolite et de la mefloquine, calcule A partir des aires sous les courbes de concentration en fonction du temps, du jour zero au jour 63, etait compris entre 2,6 et 6,1, avec une moyenne de 4,2. Ces r6sultats montrent que les parametres pharmaco- cinetiques de la mefloquine chez des sujets bresiliens semi-immuns s'inscrivent dans les fourchettes etablies precedemment pour des sujets africains et caucasiens. REFERENCES 1. DE SOUZA, J. M. A phase I clinical trial of mefloquine in Brazilian male subjects. Bulletin ofthe World Health Organization, 61: 809-814 (1983). 2. SCHWARTZ, D. E. ET AL. Single dose kinetics of mefloquine in man: plasma levels of the unchanged drug and one of its metabolites. Chemotherapy, 28: 70-84 (1982). 3. DIEM, K. Scientific tables, Documenta Geigy, 6th edition, Basle, J. R. Geigy, 1962, p. 553. 4. SCHWARTZ, D. E. Quantitative determination of the antimalarial drug mefloquine and of its main metabolite in plasma by direct densitometric measure- ment on TLC-plates. In: Frigerio, A. & McCamish, M., ed. Recent developments in chemotherapy and electro- phoresis, vol. 10. Amsterdam, Elsevier, 1980, pp. 69-74. 5. HEINZEL, G. Topfit programs-salient features of topfit programs package in pharmacokinetics during drug development. In: Bozler, G. & Rossum, J. M., ed. Data analysis and evaluation techniques. Stuttgart, Fischer, 1980.