NEW ASPECTS ON THE PHARMACOKINETICS OF MITOXANTRONE AND ITS 2 MAJOR METABOLITES

In spite of its broad clinical application in the treatment of maligna nt disorders, the pharmacokinetics of mitoxantrone are still not fully understood andwarrant further investigation. Information is also limi ted about interindividual differences in the plasma AUC(infinity) (are a-under-the-curve concentration to time infinity) and renal eliminatio n of mitoxantrone and its main metabolites, mono- and dicarboxylic aci d. In the present study, the plasma concentration of mitoxantrone was measured by HPLC during 120 h after the end of a 30-min infusion of 10 mg/m(2) in 18 patients undergoing combination therapy with mitoxantro ne and high-dose cytosine arabinoside for acute myeloid leukemia. Plas ma kinetics and renal elimination of mono- and dicarboxylic acid were analyzed in addition in eight of these patients, and in five cases wit h chronic lymphocytic leukemia receiving a 30-min infusion of 5 mg/m(2 ) mitoxantrone weekly for 3 consecutive weeks. Fitting the results to a three compartment model, a substantial interindividual variation was observed forplasma and urine pharmacokinetics. Plasma AUC(infinity) f or mitoxantrone differed approximately 13-fold between individual pati ents and varied between 80-1030 ngh/ml. The corresponding values for m ono- and dicarboxylic acid ranged from 23-147 ngh/ml and 51-471 ngh/ml , respectively, The median terminalhalf-life for mitoxantrone was simi lar to that of the mono- and dicarboxylic acid and was 75 h. Cumulativ e renal elimination ranged from 670-1950 mu g for mitoxantrone, from 3 66-852 mu g for monocarboxylic acid, and from 792-3420 mu g for dicarb oxylic acid. Penal clearance of mitoxantrone reached a median level of 69 ml/min and for the total plasma clearance a median of 1136 ml/min was found. The corresponding values for the mono- and dicarboxymetabol ites were 57and 67 ml/min. In contrast to the great interindividual di fferences in pharmacokinetic results, a low intraindividual variabilit y was observed upon repeated determinations of renal elimination of mi toxantrone and its metabolites at weekly intervals in five patients. T hese data provide new insights into the pharmacokinetic of mitoxantron e and its main metabolites revealing substantial differences in drug m etabolism and elimination between individual patients. Further studies are needed to explore the potential impact on response and/or toxicit y and the requirement of a pharmacokinetic directed adjustment of drug dosage in clinical trials.