TY - JOUR
T1 - Population pharmacokinetics of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (Triapine®) in cancer patients
AU - Kolesar, Jill
AU - Brundage, Richard C.
AU - Pomplun, Marcia
AU - Alberti, Dona
AU - Holen, Kyle
AU - Traynor, Anne
AU - Ivy, Percy
AU - Wilding, George
PY - 2011/2/1
Y1 - 2011/2/1
N2 - Purpose: 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/m2 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. Conclusion 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.
AB - Purpose: 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/m2 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. Conclusion 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.
KW - 3-aminopyridine-2-carboxaldehyde thiosemicarbazone
KW - Phase 1
KW - Population pharmacokinetics
KW - Triapine
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UR - http://www.scopus.com/inward/citedby.url?scp=79953793175&partnerID=8YFLogxK
U2 - 10.1007/s00280-010-1331-z
DO - 10.1007/s00280-010-1331-z
M3 - Article
C2 - 20440618
AN - SCOPUS:79953793175
VL - 67
SP - 393
EP - 400
JO - Cancer Chemotherapy and Pharmacology
JF - Cancer Chemotherapy and Pharmacology
SN - 0344-5704
IS - 2
ER -