Predictors of Vinorelbine Pharmacokinetics and Pharmacodynamics in Patients With Cancer

Wong, Mark; Balleine, Rosemary L.; Blair, E.; McLachlan, Andrew J.; Ackland, Stephen P.; Garg, Mukesh; Evans, Scott; Farlow, David; Collins, Michael; Rivory, Laurent P.; Hoskins, Janelle M.; Mann, Graham J.

doi:10.1200/jco.2005.02.1295

Cited by 57 publications

(40 citation statements)

References 25 publications

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“…Consistent with the results of our study, clinical data from Wong et al (2006) support a lack of CYP3A5 contribution to clearance of vinorelbine. In contrast, CYP3A5*1 genotype has even been shown to be moderately associated with better overall median survival rates in patients with NSCLC (Pan et al, 2007).…”

Section: Downloaded Fromsupporting

confidence: 82%

“…Wong et al (2006) only found a weak correlation between vinorelbine clearance and both CYP3A5 expression status and a common ABCB1 genotype. In a study with NSCLC patients, the presence of a CYP3A5*1 allele was found to correlate to a slightly higher overall chemotherapy response to vinorelbine (Pan et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

“…Wong et al (2006) reported no association of vinorelbine pharmacokinetic parameters with ABCB1 or CYP3A5 genotypes; however, the study was not adequately powered to truly evaluate for genetics. Furthermore, this study found an association between patient body surface area and myelosuppression; however, they found no association of either of these factors with vinorelbine pharmacokinetics.…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, this study found an association between patient body surface area and myelosuppression; however, they found no association of either of these factors with vinorelbine pharmacokinetics. As such, while there are a number of factors that may be contributing to the significant variability in vinorelbine pharmacokinetics (Baker and Sparreboom, 2006;Wong et al, 2006), one that remains to be systematically investigated is the potential impact of variability of genes encoding important drug metabolizing enzymes on vinorelbine pharmacokinetics.…”

Section: Introductionmentioning

confidence: 99%

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The Relative Contributions of CYP3A4 and CYP3A5 to the Metabolism of Vinorelbine

et al. 2013

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Vinorelbine is a semisynthetic vinca alkaloid used in the treatment of advanced breast and non-small cell lung cancers. Vincristine, a related vinca alkaloid, is 9-fold more efficiently metabolized by CYP3A5 than by CYP3A4 in vitro. This study quantified the relative contribution of CYP3A4 and CYP3A5 to the metabolism of vinorelbine in vitro using cDNA-expressed human cytochrome P450s (P450s) and human liver microsomes (HLMs). CYP3A4 and CYP3A5 were identified as the P450s capable of oxidizing vinorelbine using a panel of human enzymes and selective P450 inhibitors in HLMs. For CYP3A4 coexpressed with cytochrome b 5 (CYP3A4+b 5 ) and CYP3A5 +b 5 , the Michaelis-Menten constants for vinorelbine were 2.6 and 3.6 mM, respectively, but the V max of 1.4 pmol/min/pmol was common to both enzymes. In HLMs, the intrinsic clearance of vinorelbine metabolism was highly correlated with CYP3A4 activity, and there was no significant difference in intrinsic clearance between CYP3A5 high and low expressers. When radiolabeled vinorelbine substrate was used, there were clear qualitative differences in metabolite formation fingerprints between CYP3A4+b 5 and CYP3A5+b 5 as determined by NMR and mass spectrometry analysis. One major metabolite (M2), a didehydro-vinorelbine, was present in both recombinant and microsomal systems but was more abundant in CYP3A4+b 5 incubations. We conclude that despite the equivalent efficiency of recombinant CYP3A4 and CYP3A5 in vinorelbine metabolism the polymorphic expression of CYP3A5, as shown by the kinetics with HLMs, may have a minimal effect on systemic clearance of vinorelbine.

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confidence: 82%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The Relative Contributions of CYP3A4 and CYP3A5 to the Metabolism of Vinorelbine

et al. 2013

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“…Furthermore, in a phase I study in 26 patients with advanced solid tumors, the P-gp inhibitor tariquidar was combined with intravenously applied vinorelbine (20 mg/m 2 ), but alterations in the pharmacokinetics of vinorelbine were not observed (Abraham et al, 2009). On the other hand, Wong et al (2006) found in a cohort of 41 patients receiving intravenous vinorelbine that low hepatic 99m Tc-hexakis-2-methoxybutylisonitrile clearance (used as a measure for P-gp-mediated clearance) significantly correlated with low vinorelbine clearance. In addition, a phase I trial with 19 patients with advanced solid tumors revealed increased exposure and decreased clearance when intravenous vinorelbine (22.5 mg/m 2 ) was combined with the potent P-gp inhibitor zosuquidar (Lê et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

P-Glycoprotein, Multidrug-Resistance Associated Protein 2, Cyp3a, and Carboxylesterase Affect the Oral Availability and Metabolism of Vinorelbine

Lagas

Damen²,

Waterschoot³

et al. 2012

Mol Pharmacol

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We investigated the interactions of the anticancer drug vinorelbine with drug efflux transporters and cytochrome P450 3A drug-metabolizing enzymes. Vinorelbine was transported by human multidrug-resistance associated protein (MRP) 2, and Mrp2 knockout mice displayed increased vinorelbine plasma exposure after oral administration, suggesting that Mrp2 limits the intestinal uptake of vinorelbine. Using P-glycoprotein (Pgp), Cyp3a-, and P-gp/Cyp3a knockout mice, we found that the absence of P-gp or Cyp3a resulted in increased vinorelbine plasma exposure, both after oral and intravenous administration. Surprisingly, P-gp/Cyp3a knockout mice displayed markedly lower vinorelbine plasma concentrations than wild-type mice upon intravenous administration but higher concentrations upon oral administration. This could be explained by highly increased formation of 4Ј-O-deacetylvinorelbine, an active vinorelbine metabolite, especially in P-gp/Cyp3a knockout plasma. Using wild-type and Cyp3a knockout liver microsomes, we found that 4Ј-O-deacetylvinorelbine formation was 4-fold increased in Cyp3a knockout liver and was not mediated by Cyp3a or other cytochrome P450 enzymes. In vitro incubation of vinorelbine with plasma revealed that vinorelbine deacetylation in Cyp3a and especially in P-gp/Cyp3a knockout mice but not in P-gp-deficient mice was strongly up-regulated. Metabolite formation in microsomes and plasma could be completely inhibited with the nonspecific carboxylesterase (CES) inhibitor bis(4-nitrophenyl) phosphate and partly with the CES2-specific inhibitor loperamide, indicating that carboxylesterase Ces2a, which was appropriately up-regulated in Cyp3a and especially in P-gp/Cyp3a knockout liver was responsible for the 4ЈO-deacetylvinorelbine formation. Such compensatory upregulation can complicate the interpretation of knockout mouse data. Nonetheless, P-gp, Mrp2, Cyp3a, and Ces2a clearly restricted vinorelbine availability in mice. Variation in activity of their human homologs may also affect vinorelbine pharmacokinetics in patients.

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A Strategy to Refine the Phenotyping Approach and Its Implementation to Predict Drug Clearance: A Physiologically Based Pharmacokinetic Simulation Study

Adiwidjaja

Boddy

McLachlan

2018

CPT Pharmacom & Syst Pharma

Self Cite

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The phenotyping approach to predict drug metabolism activity is often hampered by a lack of correlation between the probe and the drug of interest. In this article, we present a strategy to refine the phenotyping approach based on a physiologically based pharmacokinetic simulation (implemented in Simcyp Simulator version 17) using previously published models. The apparent clearance (CL/F) of erlotinib was better predicted by the sum of caffeine and i.v. midazolam CL/F (r 2 = 0.60) compared to that of either probe drug alone. The clearance of atorvastatin and repaglinide had a strong correlation (r 2 = 0.70 and 0.63, respectively) with that of pitavastatin (a SLCO1B1 probe). Use of multiple probes for drugs that are predominantly metabolized by more than one cytochrome P450 (CYP) enzyme should be considered. In a case in which hepatic uptake transporters play a significant role in the disposition of a drug, the pharmacokinetic of a transporter probe will provide better predictions of the drug clearance.

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Predictors of Vinorelbine Pharmacokinetics and Pharmacodynamics in Patients With Cancer

Cited by 57 publications

References 25 publications

The Relative Contributions of CYP3A4 and CYP3A5 to the Metabolism of Vinorelbine

The Relative Contributions of CYP3A4 and CYP3A5 to the Metabolism of Vinorelbine

P-Glycoprotein, Multidrug-Resistance Associated Protein 2, Cyp3a, and Carboxylesterase Affect the Oral Availability and Metabolism of Vinorelbine

A Strategy to Refine the Phenotyping Approach and Its Implementation to Predict Drug Clearance: A Physiologically Based Pharmacokinetic Simulation Study

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