Pharmacokinetics and pharmacodynamics of mefloquine in Thai patients with acute falciparum malaria.

Pharmacokinetics and pharmacodynamics of mefloquine in Thai patients with acute falciparum malaria* J. Karbwang,1 K. Na Bangchang,2 D. Bunnag,3 & T. Harinasuta4 A double-blind randomized comparative study of the pharmacokinetics and pharmacodynamics of a single oral dose of 750 mg or 1250 mg of mefloquine was carried out on 20 Thai male patients with acute uncomplicated falciparum malaria. In the 750-mg group, one patient exhibited an RII response, while the others responded to the treatment with a mean fever clearance time of 50.2 ± 28.2 hours and a mean parasite clearance time of 70.2 ± 17.3 hours. The main adverse effects were dizziness, nausea, vomiting, abdominal pain, and diarrhoea. Electrocardiogram monitoring detected sinus bradycardia in three patients and sinus arrhythmia in three others. In the 1250-mg group, one patient exhibited an RII response, while the others responded to the treatment with a mean fever clearance time of 43.4 ± 36.6 hours and a mean parasite clearance time of 73.4 ± 25.2 hours. However, during the follow-up period, two patients recrudesced on day 23 and on day 31 (RI response). Dizziness, nausea, vomiting, abdominal pain, and diarrhoea were the major adverse effects, with dizziness being more frequent compared with the 750-mg group. Sinus bradycardia occurred in four patients and sinus arrhythmia in four others. The pharmacokinetics of the two regimens were similar, with the absorption of mefloquine increasing linearly with the dose; however, vomiting within an hour of taking the drug reduced the whole blood mefloquine concentrations. The results do not indicate that there is any advantage in using a single dose of 1250 mg of mefloquine rather than 750 mg. Introduction From the pharmacokinetic point of view, meflo- quine, one of the most successful drugs to have emerged from the U.S. Army's antimalarial drug programme, is an ideal medicament (1-6). A single oral dose has proved to be safe and active against all malaria species in humans, including multidrug- resistant falciparum malaria (7). Despite encouraging data on the activity of mefloquine, evidence of the resistance of falciparum malaria to the drug has been increasing. For example, in a recent clinical trial at Bangkok Hospital for Tropical Diseases, the "S"-type re- sponse with a 750-mg dose of mefloquinea was 85% * From the Department of Clinical Tropical Medicine and Hos- pital for Tropical Diseases, Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Road, Bangkok 10400, Thailand. ' Assistant Professor and Head, Clinical Pharmacology Unit. Requests for reprints should be sent to this author at the above address. 2 Scientist, Clinical Pharmacology Unit. 3 Professor and Head of Department. 4 Professor and Consultant. Reprint No. 5164 (T. Harinasuta, personal communication, 1990), compared with a 95% cure rate in 1983 (7). The risk of mefloquine resistance developing in human mal- aria must be taken seriously. Administration of a higher dose of mefloquine, e.g., 1250 mg, may improve the cure rate of clinical falciparum malaria; however, it could also result in more adverse effects, and the balance between the risks and benefits should be considered. Such adverse effects, i.e., nausea and vomiting, which have been reported to affect up to 51% in patients with falciparum malaria (8-12), are the most important factor limiting the use of mefloquine. These effects are dose-related, being more likely in patients who receive higher doses, i.e., > 15 mg/kg body weight (11), and in conjunction with the nausea and vomiting caused by malaria itself can result in low plasma drug concen- trations and treatment failure. We have carried out a comparative study of the pharmacokinetics and pharmacodynamics of meflo- quine' given as a single oral dose of 750 or 1250 mg to Thai patients with falciparum malaria. 8 Lariam, Hoffman-La Roche. Bulletin of the World Health Organization, 69(2): 207-212 (1991) © World Health Organization 1991 207 J. Karbwang et al. Materials and methods Patients A total of 20 male patients with acute uncomplicated falciparum malaria (asexual form, parasitaemia < 5%), aged 16-42 years and weight 45-60 kg, with no history of liver or kidney diseases, volunteered for the study. Written informed consent was ob- tained from all the patients, and during the study the only drug they took was mefloquine. Each volunteer received a physical examina- tion, routine blood tests, investigations of blood chemistry, chest X-ray, urine analysis, and an electrocardiogram (ECG), and was admitted to the Bangkok Hospital for Tropical Diseases for 42 days. Drug administration The patients were randomly assigned to a regimen of either 1250 mg mefloquine (five tablets) or 750 mg (three tablets). The drug was administered with a glass of water under supervision. Blood collection for pharmacokinetic study A 4-ml sample of whole blood was collected in heparinized tubes 0, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 14, 18, 24, 28, and 36 hours as well as 2, 3, 4, 5, 7, 14, 21, 28, 35 and 42 days after the dose had been taken (28 samples per volunteer). Parasite count The parasite count was performed twice daily until negative, then once daily until day 42 of the study. Blood tests and blood biochemistry Blood tests and investigations of blood biochemistry were carried out weekly until day 42 of the study. Adverse effects All adverse reactions during the study were recorded together with the date and time when they occurred and disappeared. These reactions included gastrointestinal, central nervous system, cardiovas- cular, skin, and blood signs as well as any other changes that could be attributed to mefloquine. The frequency of vomiting and of diarrhoea (number of minutes or hours after dosing) were recorded on days 0, 1, 2, 3, and 4. A history of itching or skin rashes after taking any drugs or after taking mefloquine was noted. The intensity and duration of rashes were recorded. ECGs and blood pressure determinations were performed at intervals when samples of blood were being taken and also weekly until day 42. Mefloquine analysis The level of mefloquine in whole blood was deter- mined by high-performance liquid chromatography (HPLC) (13). The lower limit of detection of the method is 50 ng/ml mefloquine. The interassay coefficients of variation for blood samples that contained a known quantity of the drug were 4.2% for 100 ng/ml and 5.7% for 600 ng/ml mefloquine. Pharmacokinetic analysis The area under the whole blood concentration-time curve (AUC) was calculated using the trapezoidal rule. To estimate the area from the last sampling time to t., the first-order elimination rate constant and the half-life (tl12) were calculated by conven- tional methods (14). The mean residence time (MRT) was calculated from the expression: MRT= 2t.Cdt/[ Cdt where t is the time in days and C, the whole blood concentration of mefloquine in ng/ml. The apparent volume of distribution under steady-state conditions (Vd5,/f) was calculated from the expression: Vdss/f = Dose x AUMC/(AUC)2 where AUMC is the area under the plot of drug concentration-time versus time to t., and the systemic clearance (Cl/f) was obtained from the expression: Cl/f = Dose/AUC Statistical analysis Statistical analysis was carried out using the Mann- Whitney U-test for unpaired samples. Results The clinical data on admission and baseline labora- tory findings were comparable for the 10 patients who received 750 mg and the 10 who received 1250 mg of mefloquine (Table 1). There were no significant drug-related differences in the haemato- logical parameters or the results of the biochemical investigations. In the 750-mg group one patient exhibited an RII response, while the other nine patients responded to the treatment with a mean fever clearance time of 50.2 ± 28.2 hours and a mean parasite clearance time of 70.2 ± 17.3 hours. The main adverse effects were dizziness, nausea, vomit- ing, abdominal pain, and diarrhoea. ECG monitor- WHO Bulletin OMS. Vol 69 1991.208 Pharmacokinetics and pharmacodynamics of mefloquine Table 1: Clinical data (mean ±S.D.) on admission, fever clearance times (FCT), and parasite clearance times (PCT) for study patients with falciparum malaria who received mefloquine Dose 750 mg 1250 mg Age (years) 21.2 ± 4.0 28.3 ± 6.6 Weight (kg) 49.4 ± 3.9 52.5 ± 4.8 Haemoglobin level (mg/dl) 13.3 ± 2.9 12.5 ± 1.9 Haematocrit (%) 35.2 ± 9.3 39.5 ± 6.0 White blood cell count (per,l) 4850 ± 980 5090 ± 1774 Parasite count (per,l): range 738-18800 175-163060 FCT (hours) 50.2 ± 28.2 43.4 ± 36.6 PCT (hours) 70.2 ± 17.3 73.4 ± 25.2 ing revealed sinus bradycardia in three patients and sinus arrhythmia in three others (Table 2). In the 1250-mg group one patient exhibited an RII response. The others responded to the treat- ment, with a mean fever clearance time of 43.4 ± 36.6 hours and a parasite clearance time of 73.4 ± 25.2 hours. However, during the follow-up period, one patient recrudesced on day 23 and one on day 31 (RI response). Dizziness, nausea, vomit- ing, abdominal pain, and diarrhoea were the main adverse effects in the 1250-mg group, with dizziness being more frequent than in the lower dose group. The patient described as dizziness confused thought processes and the sensation of movement within the head with unsteadiness. Sinus bradycardia occurred in four patients and sinus arrhythmia in four others (Table 2). The maximum concentration (Cmax) and the whole blood concentration of mefloquine on day 14 in recrudescent patients were significantly different from those who exhibited a sensitive response (mean ± SD, 318 ± 87 ng/ml in the recrudescent group; and 584 ± 183 ng/ml and 384 ± 220 ng/ml, respectively, among patients who responded to Table 2: Comparison of the side-effects in patients who received 1250 mg or 750 mg of mefloquine (10 patients in each group) Dose Side-effect 1250 mg 750 mg Dizziness 6 1 Nausea 1 3 Vomiting 2 3 Abdominal pain 1 2 Diarrhoea 5 3 Sinus bradycardia 4 3 Sinus arrhythmia 4 3 Fig. 1. Whole blood mefloquine concentration-time profiles of patients. 000 800 Time (hours) 1000 12D0 treatment in the 1250-mg and 750-mg groups). Mefloquine concentrations in patients both with or without cardiovascular symptoms (bradycardia or sinus arrhythmia) were similar, i.e., these symptoms were not dependent on the blood concentration of the drug. Although there was considerable inter-indi- vidual variation in the pharmacokinetic parameters, the Cm,,ax and AUC of patients who vomited within 1 hour of receiving the drug were significantly lower than those who did not vomit (Fin. 1). Comparison of the pharmacokinetic parameters for the two dose groups indicates that the AUC was greater with the higher dose (22.87 ± 6.11 ag-day- ml-1 versus 14.80 ± 4.42 ,ug.day.ml-1); however, because of marked inter-individual variability, the Cma values (which would have been expected to be higher with the 1250-mg dose) were not statistically different. The pharmacokinetic parameters obtained are shown in Table 3. Table 3: Comparison of the pharmacokinetic parameters (mean ± SD) for the 1250-mg and 750-mg doses of meflo- quine for patients who did not vomit Dose Pharmacokinetic parameter 1250 mg 750 mg Mean residence time (days) 15.98 ± 2.58 16.15 ± 15.82 C, (ng/ml) 2411 ± 844 1885 ± 388 t,,. (hours) 16.1 ± 7.4 14.1 ± 5.8 AUCO _a (Ag-day-ml ') 22.87 ± 6.11a 14.80 ± 4.42 V..l (I/kg) 18.36 ± 3.42 25.27 ± 9.75 Cl/f (ml-min -'kg-') 0.798 ± 0.230 0.722 ± 0.287 a Statistically significant difference from the value with the 750-mg dose at the P < 0.05 level (Student's t-test). WHO Bulletin OMS. Vol 69 1991. 209 J. Karbwang et al. Discussion No improvement in treatment outcome resulted from using a 1250-mg rather than a 750-mg dose of mefloquine. Although the therapeutic concentration of mefloquine has not yet been determined, usually a single dose of 15 mg/kg body weight is adequate. In situations where resistance is a problem, a higher dose may be required. Although the C,,,, and whole blood concentrations of mefloquine on day 14 for patients with sensitive responses were significantly greater than those who exhibited resistance, the differences should be re-evaluated in a larger-scale study. Adverse effects, including dizziness and diar- rhoea, were more numerous with the higher dose (Table 2). However, the incidence of nausea and vomiting did not increase with the higher dose; this is in contrast to the results of an earlier study (11), where vomiting was found to be more common when the dose of mefloquine exceeded 750 mg. The sample size in the present study was too small to detect any dose-dependent differences and to com- ment on the discrepancy; nevertheless, in one larger study involving 100 patients (T. Harinasuta & D. Bunnag, personal communication, 1990), the inci- dence of vomiting was dose-related. Vomiting is one of the main side-effects of mefloquine, and its incidence has been reported to be as high as 51% (10). The present study showed that vomiting within an hour of receiving mefloquine (four patients) was associated with significantly lower whole blood concentrations of the drug (Cm,,ax and A UC) relative to patients given the same dose but who did not vomit (Fig. 1). This suggests that absorption of the drug was not yet complete 1 hour after its ingestion. However, one patient who vomited 3 hours after receiving mefloquine had a Cma,x and AUC similar to those of patients who did not vomit. This probably indicates that only vomit- ing within an hour requires a repeated dose. Further studies should, however, be carried out to investi- gate this. Sinus bradycardia was observed in 35% of the patients in the study, and has been frequently reported in investigations of the effects of meflo- quine (7-9, 15). As a result, co-administration of mefloquine and beta-blockers may require close observation. Probably the most important adverse effect associated with mefloquine is a propensity to induce two types of dysfunction of the central nervous system. The first-a sensation of light-headedness and dysphoria often accompanied by dizziness, difficulty in concentrating, and nausea, which occurs within 6 hours of taking the drug-usually resolves within a few days (but is on occasion protracted). Dizziness was observed for seven patients in the present study, six being in the 1250-mg group. These symptoms did not correlate with blood concentra- tions of mefloquine, although they were associated with the higher dose. This finding is consistent with the results of other workers (16). The second type of reaction-a more serious abrupt psychosis-often occurs in the second week after taking the drug. In one investigation of over 1000 patients, eight cases of neuropsychiatric disturbances were observed (7 and T. Harinasuta, personal communication, 1990). This adverse effect should be taken seriously since its frequency appears to be increasing (16, 17), and the reporting of its occurrence should be encour- aged. The pharmacokinetic parameters for the two doses studied were similar, except for the AUC values, which were greater for the higher dose. These values increased in proportion to the dose, which suggests that absorption of mefloquine in- creases linearly with the dose (Table 3, Fig. 1). The pharmacokinetic parameters obtained are in accord with those found in previous studies of patients with uncomplicated falciparum malaria (2-6, 18), for whom the value of t1/2 was less than that of normal healthy subjects (1, 18-23). The lower value of t1/2 may be caused by a decrease in the enterohepatic recirculation of mefloquine in patients with malaria, and consequently greater faecal clearance (4-6, 16, 24, 25). However, com- pletely the opposite findings were found in a recent study (26), where the patients recruited were severely ill. This difference perhaps arose partly because the disease was milder in the present study. Acknowledgements J. Karbwang is in receipt of a Mahidol Univer- sity-Wellcome Trust Research Fellowship, and K.Na Bangchang of a UNDP/World Bank/WHO Special Pro- gramme for Research and Training Fellowship. We are grateful to Professor Gilles for his comments on the manuscript, and thank Dr G. Edwards for his advice on interpreting the pharmacokinetic parameters. The study was supported by WHO (project THA DPC 001). Resume Pharmacocinetique et pharmacodynamique de la m6floquine chez des malades thaflan- dais atteints de paludisme aigu a falciparum La m6floquine s'est montree efficace contre le palu- WHO Bulletin OMS. Vol 69 1991.210 Pharmacokinetics and pharmacodynamics of mefloquine disme a falciparum polypharmacoresistant. Cepen- dant, les taux de guerison diminuent. En conse- quence, nous avons effectue une 6tude randomisee, en double aveugle, chez 20 malades thallandais de sexe masculin, atteints de paludisme aigu a falcipa- rum non complique (parasitemie <5%) pour compa- rer la pharmacocin6tique et la pharmacodynamique de doses orales uniques de 750 mg (10 malades) et de 1250 mg (10 malades) de m6floquine. Au total, 28 6chantillons de sang total pour mesure des concentrations de m6floquine ont ete pr6lev6s chez chaque malade pendant la periode d'6tude, soit 42 jours, a des intervalles vari6s apres administration du m6dicament. Des numerations pa- rasitaires ont ete effectu6es deux fois par jour jus- qu'a ce qu'elles soient negatives, puis une fois par jour jusqu'au quarante-deuxieme jour. Les effets se- condaires ont e surveilles en questionnant les ma- lades et en les soumettant a un examen physique, a un 6lectrocardiogramme (ECG) et a des examens de laboratoire (hematologie et biochimie sanguine), au moment de leur admission et a diverses reprises pendant la duree de l'etude. Dans le groupe a 750 mg, un malade a presente une r6ponse de type RII. Les neuf autres malades ont repondu au traitement avec un temps moyen de disparition de la fievre de 50,2 ± 28,2 heures et un temps moyen de disparition des parasites de 70,2 ± 17,3 heures. Les principaux effets secon- daires ont 6t6 des vertiges, des naus6es, des vomis- sements, des douleurs abdominales et de la diar- rhee. Les ECG de contr6le ont montre des bradycar- dies sinusales chez trois malades et une arythmie sinusale chez trois autres. Dans le groupe a 1250 mg, un malade a presen- t6 une r6ponse de type RIl. Les autres malades ont repondu au traitement, avec un temps moyen de disparition de la fievre de 43,4 ± 36,6 heures et un temps moyen de disparition des parasites de 73,4 ± 25,2 heures. Cependant, pendant la p6riode de suivi, deux malades ont eu une recrudescence au vingt-troisibme et au trente et unieme jour (r6ponse de type RI). Des vertiges, des nausees, des vomis- sements, des douleurs abdominales et de la diarrh6e etaient les principaux effets secondaires du traite- ment. Une bradycardie sinusale a e observ6e chez quatre malades et une arythmie sinusale chez quatre autres. La pharmacocin6tique de ces deux posologies 6tait semblable, un seul parametre, I'aire sous la courbe de concentration en m6floquine dans le sang total en fonction du temps, etant significativement plus grand dans le groupe a 1250 mg. L'absorption de la m6floquine augmentait de fa9on lineaire avec la dose; cependant, des vomissements precoces ont diminue la concentration du medicament dans le sang total. 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