title: A phase I and pharmacokinetic study of the mitochondrial-specific rhodacyanine dye analog MKT 077.
abstract: This Phase I study was performed to evaluate the tolerability and pharmacokinetic behavior of MKT-077, a water soluble rhodacyanine dye analogue, which partitions into tumor cell mitochondria where it is thought to act as a metabolic poison, leading to G1 arrest and apoptosis. Thirteen patients with advanced solid malignancies were treated with MKT-077 administered as a 30-min i.v. infusion weekly for 4 weeks every 6 weeks at doses ranging from 42 to 126 mg/m2/week. The principal toxicity was renal magnesium wasting, which was dose-limiting (grade 3) in one patient at each of the 84- and 126-mg/m2 dose levels. The other three patients at the 126-mg/m2 dose level developed grade 2 hypomagnesemia, which was cumulative in nature, improved with i.v. magnesium supplementation, and was controlled in two patients by the administration of prophylactic magnesium before and after treatment with MKT-077. Given the requirement for extensive monitoring of serum magnesium levels, dose escalation >126 mg/m2 was not considered feasible. Thus, the recommended dose for disease-oriented studies with this schedule of MKT-077 is 126 mg/m2/week. Pharmacokinetic studies revealed a prolonged terminal half-life (37 +/- 17 h) and a large volume of distribution (685 +/- 430 liters/m2). Clearance averaged 39 +/- 13 liters/h/m2. Peak MKT-077 plasma concentrations (1.2 +/-0.31 to 6.3 +/- 5.3 microg/ml) exceeded the IC50 concentrations required for human CX-1 colon, MCF-breast, CRL-1420 pancreas, EJ bladder, and LOX melanoma tumor cell lines in vitro (0.15-0.5 microg/ml). These results indicate that at the recommended dose level of 126 mg/m2/week of MKT-077, the toxicity profile was consistent with the preferential accumulation of the agent within tumor cell mitochondria, and biologically relevant plasma concentrations were achieved.
authors.affiliation: Cancer Therapy and Research Center, Institute for Drug Development, and The University of Texas Health Science Center at San Antonio, 78229, USA. cbritten@bccancer.bc.ca
authors.forename: C D
authors.initials: CD
authors.lastname: Britten
authors.forename: E K
authors.initials: EK
authors.lastname: Rowinsky
authors.forename: S D
authors.initials: SD
authors.lastname: Baker
authors.forename: G R
authors.initials: GR
authors.lastname: Weiss
authors.forename: L
authors.initials: L
authors.lastname: Smith
authors.forename: J
authors.initials: J
authors.lastname: Stephenson
authors.forename: M
authors.initials: M
authors.lastname: Rothenberg
authors.forename: L
authors.initials: L
authors.lastname: Smetzer
authors.forename: J
authors.initials: J
authors.lastname: Cramer
authors.forename: W
authors.initials: W
authors.lastname: Collins
authors.forename: D D
authors.initials: DD
authors.lastname: Von Hoff
authors.forename: S G
authors.initials: SG
authors.lastname: Eckhardt
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008274:Magnesium / Q000097:blood / Q000652:urine; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy*; D011507:Proteinuria; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D013844:Thiazoles / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D014018:Tissue Distribution
chemical_list: D000970:Antineoplastic Agents; D011725:Pyridines; D013844:Thiazoles; C097880:MKT 077; D008274:Magnesium