Cd. Britten et al., A Phase I and pharmacokinetic study of the mitochondrial-specific rhodacyanine dye analog MKT 077, CLIN CANC R, 6(1), 2000, pp. 42-49
This Phase I study was performed to evaluate the tolerability and pharmacok
inetic behavior of MKT-077, a water soluble rhodacyanine dye analogue, whic
h partitions into tumor cell mitochondria where it is thought to act as a m
etabolic poison, leading to G(1) arrest and apoptosis, Thirteen patients wi
th 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/m(2)/week, The principal toxicity was renal magnesium wasting
, which was dose-limiting (grade 3) in one patient at each of the 84- and 1
26-mg/m(2) dose levels, The other three patients at the 126-mg/m(2) dose le
vel developed grade 2 hypomagnesemia, which was cumulative in nature, impro
ved 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 magn
esium levels, dose escalation >126 mg/m(2) was not considered feasible. Thu
s, the recommended dose for disease-oriented studies with this schedule of
MKT-077 is 126 mg/m(2)/week, Pharmacokinetic studies revealed a prolonged t
erminal half-life (37 +/- 17 h) and a large volume of distribution (685 +/-
430 liters/m(2)), Clearance averaged 39 +/- 13 liters/h/m(2). Peak MKT-077
plasma concentrations (1.2 +/- 0.31 to 6.3 +/- 5.3 mu g/ml) exceeded the I
C50 concentrations required for human CX-I colon, MCF-breast, CRL-1420 panc
reas, EJ bladder, and LOX melanoma tumor cell lines in vitro (0.15-0.5 mu g
/ml). These results indicate that at the recommended dose level of 126 mg/m
(2)/week of MKT-077, the toxicity profile was consistent with the preferent
ial accumulation of the agent within tumor cell mitochondria, and biologica
lly relevant plasma concentrations were achieved.