Pharmacokinetics of NC-6004, a novel micellar formulation of cisplatin, in a Phase I trial

208 NC-6004 is a novel micellar formulation of cisplatin. The micelles (M Wt 660,000) are composed of cisplatin residues conjugated to polyethylene glycol poly(L-glutamate) block co-polymers (M Wt 22,500). Promising preclinical activity has led to a Phase I trial of NC-6004, with doses ranging from 10-120 mg/m2 cisplatin equivalent. In order to characterize the pharmacokinetics of NC-6004 in patients, a combination of separation methods and analytical approaches was used. The total concentration of platinum species in plasma was measured by atomic absorption spectrometry (AAS). The micellar component of the platinum species in plasma was separated by gel-filtration, with a cut-off of 100,000 Da, and the concentration measured by AAS. Plasma ultrafiltrates were prepared and the concentration of free, small molecular weight platinum species, including cisplatin, was measured using inductively-coupled plasma mass spectrometry (ICPMS). For total plasma Pt, the half-life ranged from 20.4 up to 169 hours, with a volume of distribution less than 15 litres in most patients. Clearance was only 44 to186 ml/hr. For the micellar component, half life was shorter (13.1-126 hours) than that for total plasma Pt. AUC for the micellar component was 26 to 73% of the AUC for total Pt. In the ultrafiltrate fraction, there was delayed (tmax = 24 hr) and prolonged (half-life 68 to 580 hours) detection of small molecular weight platinum species. The mean AUC of UF Pt at 90mg/m2 was 12.4 μg/ml.hr, compared to values of 2 to 5 μg/ml.hr for similar doses of cisplatin. The AUC for total Pt at 90mg/m2 was 3000 mg/ml.hr, compared to typical AUC of 40 mg/ml.hr for equivalent cisplatin doses.
 NC-6004 provides a sustained and prolonged release of potentially-active platinum species. Using gel-filtration, we have been able to separate the Pt present in the original formulation from other Pt species in the plasma. The Phase I study is continuing to recruit patients.