Population pharmacokinetics of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (Triapine®) in cancer patients.
OBJECTIVE
The purpose of this study was to develop a population pharmacokinetic (PK) model for 3-AP, to evaluate the effect of ABCB1 polymorphisms on the pharmacokinetic profile of 3-AP, and to assess the relationship between 3AP disposition and patient covariates.


METHODS
A total of 40 patients with advanced cancer from two phase 1 studies were included in the population PK model building. Patients received 3-AP 25-105 mg/m(2) IV on day 1. 3-AP plasma and erythrocyte levels were sampled at 10 timepoints over a 24-h period and measured by a validated HPLC method. Data were analyzed by a nonlinear mixed-effects modeling approach using the NONMEM system.


RESULTS
3-AP pharmacokinetics were described as a 3-compartment model with first-order elimination, with one compartment representing the plasma and another representing erythrocyte concentrations. Gender was associated with volume of distribution, in which women had a lower V2. The number of cycles administered was associated with clearance; those with decreased clearance were more likely to receive less than 2 cycles before going off study.


CONCLUSIONS
This study suggests that monitoring 3-AP plasma concentrations in the first cycle and dose adjustment in those with decreased clearance may be helpful in decreasing toxicity associated with the 3-AP.
Kolesar
Jill
J
Paul P. Carbone Comprehensive Cancer Center, University of Wisconsin, 600 Highland Avenue, K4/554, Madison, WI 53792, USA. jmkolesar@pharmacy.wisc.edu
Brundage
Richard C
RC
Pomplun
Marcia
M
Alberti
Dona
D
Holen
Kyle
K
Traynor
Anne
A
Ivy
Percy
P
Wilding
George
G
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001769:Blood / Q000378:metabolism; D001830:Body Surface Area; D017321:Clinical Trials, Phase I as Topic; D003198:Computer Simulation; D004912:Erythrocytes / Q000378:metabolism; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008954:Models, Biological; D015233:Models, Statistical; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D011725:Pyridines / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D012727:Sex Characteristics; D013882:Thiosemicarbazones / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D011725:Pyridines; D013882:Thiosemicarbazones; C078157:3-aminopyridine-2-carboxaldehyde thiosemicarbazone