Predictors of vinorelbine pharmacokinetics and pharmacodynamics in patients with cancer.
OBJECTIVE
Marked interindividual variation in drug disposition and toxicity pose an ongoing challenge to chemotherapy dosage individualization. The aim of this study was to evaluate pretreatment clinical features, genotype and functional indicators of drug clearance as predictors of vinorelbine clearance, and myelotoxicity that could inform dosage optimization.


METHODS
Forty-one patients with cancer received a 60 mg intravenous dose of vinorelbine. Pretreatment routine body size measurements and blood tests were performed. Midazolam clearance and hepatic technetium labeled sestamibi (99mTc-MIBI) clearance were used to investigate CYP3A and ABCB1 (MDR1, P-glycoprotein) phenotype respectively and selected single nucleotide polymorphisms in CYP3A and ABCB1 were documented. A limited blood sampling strategy was employed and vinorelbine concentrations were determined by high-performance liquid chromatography. Posterior Bayesian estimates of vinorelbine clearance were obtained for each patient using population pharmacokinetic modeling. Myelotoxicity was estimated from the fractional survival of neutrophils post-treatment.


RESULTS
There was 4.3-fold variation in vinorelbine clearance across the cohort. In a multivariable analysis, pretreatment estimated creatinine clearance (P < .01) and hepatic (99m)Tc-MIBI clearance (P = .01) were independent predictors of vinorelbine clearance. Fractional survival of neutrophils ranged from 1.3% to 100% and was significantly correlated with vinorelbine clearance (P < .01). Body-surface area was the only pretreatment predictor of fractional survival of neutrophils independent of vinorelbine clearance (P = .02).


CONCLUSIONS
Specific indicators of drug clearance provide predictive information about vinorelbine pharmacokinetics, and body-surface area, probably reflecting normal bone marrow reserve, provides an additional pharmacodynamic indicator. Use of a fixed dose of vinorelbine with modifications guided by pretreatment measures is worthy of prospective evaluation.
Wong
Mark
M
Westmead Institute for Cancer Research Westmead Millennium Institute, Department of Translational Oncology, Westmead, Australia.
Balleine
Rosemary L
RL
Blair
Elaine Y L
EY
McLachlan
Andrew J
AJ
Ackland
Stephen P
SP
Garg
Madhu B
MB
Evans
Scott
S
Farlow
David
D
Collins
Michael
M
Rivory
Laurent P
LP
Hoskins
Janelle M
JM
Mann
Graham J
GJ
Clarke
Christine L
CL
Gurney
Howard
H
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000494:pharmacology*; D049628:Body Size; D001830:Body Surface Area; D001853:Bone Marrow / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005240:Feasibility Studies; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008874:Midazolam / Q000493:pharmacokinetics; D008875:Middle Aged; D015999:Multivariate Analysis; D009369:Neoplasms / Q000188:drug therapy; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011237:Predictive Value of Tests; D017256:Technetium Tc 99m Sestamibi / Q000378:metabolism*; D014747:Vinblastine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D000077235:Vinorelbine
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D014747:Vinblastine; D003577:Cytochrome P-450 Enzyme System; D017256:Technetium Tc 99m Sestamibi; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D000077235:Vinorelbine; D008874:Midazolam