Phase I and pharmacokinetic studies with the pentacyclic pyrroloquinone mitoquidone.
Mitoquidone (MTQ) is the first member of a new group of pentacyclic pyrroloquinones developed for clinical evaluation as a potential anticancer agent. MTQ demonstrated good activity in a range of experimental solid tumour models, but was weakly active against standard prescreens such as the P388 murine leukaemia. Bone marrow suppression or other significant toxicity was not observed in preclinical studies. Twenty-seven patients were treated with MTQ given as a 4-h infusion either once every 21 days (150-600 mg/m2), once a week (200 mg/m2 per week), or as 5 daily doses repeated every 28 days (60-180 mg/m2 per day). The major adverse events encountered included nausea and vomiting (in virtually all patients), dyspnoea, tumour-related pain, and thrombocytopenia in several patients with pretreatment bone-marrow impairment. Phase I studies were suspended without a maximum tolerated dose being reached because of formulation difficulties. There were no major responses, although stable disease was observed in a number of patients with gastrointestinal malignancies. Temporary remission of B-symptoms occurred in two patients with lymphoma. The plasma pharmacokinetics of MTQ were investigated using an HPLC assay with fluorescence detection. Linear pharmacokinetics were observed with a terminal plasma half-life of 2.9 +/- 2.1 h (n = 18 doses). The volume of distribution was 3.4 +/- 2.6 l/kg and plasma clearance was 629 +/- 469 ml/min per m2. Several soluble analogues with similar antitumour activity are currently under investigation.
Speth
P A
PA
Department of Hematology, St. Radboud University Hospital, Nijmegen, The Netherlands.
Gore
M E
ME
Pateman
A J
AJ
Newell
D R
DR
Bishop
J A
JA
Ellis
W J
WJ
Green
J A
JA
Gumbrell
L A
LA
Linssen
P C
PC
Miller
A
A
D002277:Carcinoma / Q000188:drug therapy*; D004334:Drug Administration Schedule; D004341:Drug Evaluation; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy*; D006207:Half-Life; D006801:Humans; D054833:Isoindoles; D007546:Isoquinolines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008223:Lymphoma / Q000188:drug therapy*; D008657:Metabolic Clearance Rate; D011809:Quinones / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*
D054833:Isoindoles; D007546:Isoquinolines; D011809:Quinones; C056077:mitoquidone