QUININE PHARMACOKINETICS - OTOTOXIC AND CARDIOTOXIC EFFECTS IN HEALTHY CAUCASIAN SUBJECTS AND IN PATIENTS WITH FALCIPARUM-MALARIA

METHOD Quinine-dihydrochloride was administered intravenously as a sin gle dose of 300 mg to 12 healthy subjects and as multiple doses of 600 mg in 4 h every 8 h in 10 patients with falciparum malaria. Plasma qu inine concentrations were measured by high-performance liquid chromato graphy RESULTS Quinine pharmacokinetics are time-dependent: the appare nt elimination halftime is shorter in the accumulation phase than in t he elimination phase; in malaria patients the maximal quinine concentr ation was reached in half the time calculated on the basis of the elim ination phase after the lost quinine infusion. Nevertheless a loading dose seemed advisable to reach adequate therapeutic levels quickly In malaria patients the highest plasma concentrations during or at the en d of the infusions were positively correlated with body weight. There was no correlation between body weight and the volume of distribution of quinine as calculated during the elimination phase. Hearing loss wa s audiometrically documented in 9 healthy subjects at a mean maximal p lasma quinine concentration of only 2 mg/l. All malaria patients suffe red serious cochlear hearing impairment. The ototoxic effects in both healthy subjects and patients appeared to be reversible. No electrogra phic changes were noted in the healthy subjects, whereas a clinically insignificant mean lengthening of the corrected QT interval was seen i n the malaria patients. CONCLUSION Intravenous quinine pharmacokinetic s in healthy Caucasians were similar to those reported for Nigerian or Thai subjects. At effective doses quinine causes considerable but rev ersible cochlear hearing losses in both healthy persons and in patient s. Our findings do support the need for a loading dose. The fact that in malaria patients there was no correlation between body weight and q uinine VD as calculated during the elimination phase renders questiona ble the usefulness of dosing quinine according to body weight.