Effects of alpha1-acid glycoprotein on the clinical pharmacokinetics of 7-hydroxystaurosporine.
OBJECTIVE
UCN-01 (7-hydroxystaurosporine) is a small molecule cyclin-dependent kinase modulator currently under clinical development as an anticancer agent. In vitro studies have demonstrated that UCN-01 is strongly bound to the acute-phase reactant alpha (1)-acid glycoprotein (AAG). Here, we examined the role of protein binding as a determinant of the pharmacokinetic behavior of UCN-01 in patients.


METHODS
Pharmacokinetic data were obtained from a group of 41 patients with cancer receiving UCN-01 as a 72-hour i.v. infusion (dose, 3.6 to 53 mg/m(2)/day).


RESULTS
Over the tested dose range, total drug clearance was distinctly nonlinear (P = 0.0076) and increased exponentially from 4.33 mL/hour (at 3.6 mg/m(2)/day) to 24.1 mL/hour (at 54 mg/m(2)/day). As individual values for AAG increased, values for clearance decreased in a linear fashion (R(2) = 0.264; P = 0.0008), although the relationship was shallow, and the data showed considerable scatter. Interestingly, no nonlinearity in the unbound concentration (P = 0.083) or fraction at the peak plasma concentration of UCN-01 was apparent (P = 0.744).


CONCLUSIONS
The results suggest the following: (1) that extensive binding to AAG may explain, in part, the unique pharmacokinetic profile of UCN-01 described previously with a small volume of distribution and slow systemic clearance, and (2) that measurement of total UCN-01 concentrations in plasma is a poor surrogate for that of the pharmacologically active fraction unbound drug.
Sparreboom
Alex
A
Clinical Pharmacology Research Core, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, Maryland 20892, USA.
Chen
Huachen
H
Acharya
Milin R
MR
Senderowicz
Adrian M
AM
Messmann
Richard A
RA
Kuwabara
Takashi
T
Venzon
David J
DJ
Murgo
Anthony J
AJ
Headlee
Donna
D
Sausville
Edward A
EA
Figg
William D
WD
D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D005260:Female; D006207:Half-Life; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D009369:Neoplasms / Q000188:drug therapy; D009961:Orosomucoid / Q000494:pharmacology*; D019311:Staurosporine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics*
D000970:Antineoplastic Agents; D009961:Orosomucoid; C054852:7-hydroxystaurosporine; D019311:Staurosporine