Population pharmacokinetics of troxacitabine, a novel dioxolane nucleoside analogue.
OBJECTIVE
To develop and validate a population pharmacokinetic model for troxacitabine, a novel l-nucleoside analogue, administered by short infusion; to characterize clinical covariates that influence pharmacokinetic variability; and to design a dosage rate for continuous infusion administration to achieve low micromolar concentrations, which may be more efficacious than shorter infusions.


METHODS
Plasma samples from 111 cancer patients receiving troxacitabine (0.12-12.5 mg/m(2)) as a 30-minute infusion in phase I trials were used to develop the model with NONMEM. Clinical covariates evaluated included creatinine clearance, body surface area, age, and sex. From the model, a troxacitabine dosage rate of 2.0 to 3.0 mg/m(2)/d was expected to achieve a target concentration of 0.1 micromol/L; plasma samples were obtained during the infusion from eight patients receiving troxacitabine as a 3-day infusion.


RESULTS
Troxacitabine pharmacokinetics were characterized by a three-compartment linear model. The mean value for systemic clearance [interindividual variability (CV%)] from the covariate-free model was 9.1 L/h (28%). Creatinine clearance and body surface area accounted for 36% of intersubject variation in clearance. Troxacitabine 2.0 mg/m(2)/d (n = 3) and 3.0 mg/m(2)/d (n = 5) for 3 days produced mean +/- SD end of infusion concentrations of 0.12 +/- 0.03 and 0.15 +/- 0.03 micromol/L, respectively.


CONCLUSIONS
Renal function and body surface area were identified as sources of troxacitabine pharmacokinetic variability. The population pharmacokinetic model model-derived dosage rates for continuous infusion administration successfully achieved predetermined target plasma concentrations. The present model may be used to optimize treatment with troxacitabine by developing a dosing strategy based on both renal function and body size.
Lee
Carlton K K
CK
Department of Oncology, Johns Hopkins University and Department of Pharmacy, The Johns Hopkins Hospital, Baltimore, Maryland, USA.
Rowinsky
Eric K
EK
Li
Jing
J
Giles
Francis
F
Moore
Malcolm J
MJ
Hidalgo
Manuel
M
Capparelli
Edmund
E
Jolivet
Jacques
J
Baker
Sharyn D
SD
D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D001825:Body Fluid Compartments; D003596:Cytosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics; D004148:Dioxolanes / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D007677:Kidney Function Tests; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy*; D011237:Predictive Value of Tests; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D004148:Dioxolanes; C074908:troxacitabine; D003596:Cytosine