Originally published as JCO Early Release 10.1200/JCO.2005.05.4494 on May 1 2006

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Predicting Vinorelbine Disposition and Toxicity: Does BSA Provide More Than a "Bad Statistical Association"?

The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD
National Cancer Institute, The National Institutes of Health, Bethesda, MD

The concept that chemotherapeutic agents are administered at a dose to the maximum that a patient can tolerate before the onset of unacceptable toxicity, is still in wide clinical use today. However, the therapeutic range for most cytotoxic anticancer agents is extremely narrow, and in most cases no information is available before therapy on the intrinsic sensitivity of a patient's tumor to a particular agent or the patient's tolerability of a given dose. Hence, the dosage of chemotherapeutic agents remains largely empirical and it is typically only normalized to an individual's body-surface area (BSA).¹ From a pharmacologic perspective, interindividual differences in body size and body composition present a challenging role for clinicians, as their effects on the time course of drug response (ie, toxicity and efficacy) are still poorly understood. BSA does seem to be a biologically plausible size descriptor to consider in drug dose calculation as it is derived from height and weight, and because of the intuitive belief that patients with a larger BSA would require more drug to induce the same drug effects. Moreover, there are some data describing general physiologic characteristics being associated with BSA, including glomerular filtration rate, blood volume, and basal metabolic rate.² In contrast, many studies have now convincingly demonstrated that BSA does not account for the marked differences between patients in drug clearance for many widely used agents,³ which may be due, in part, to large interindividual variability in drug-metabolizing enzyme activity that is known to exist irrespective of body size and body composition.⁴ Based on a retrospective analysis involving 33 different drugs, we have previously estimated that BSA-based dosing is statistically significantly associated with a reduction in interindividual pharmacokinetic variability in only approximately 15% of anticancer drugs.⁵ This notion has led several investigators to question the routine use of BSA in dosing strategies for anticancer agents. Overall, however, there is a deficit of knowledge on the influence of body size on interindividual pharmacodynamic variability that does not originate from differences between patients in a drug's pharmacokinetic profile.

In an attempt to overcome this information deficit, Wong et al⁶ describe the feasibility and pharmacokinetic/pharmacodynamic relationships for vinorelbine in a group of 41 cancer patients treated with a flat-fixed dose of 60 mg in this issue of the Journal of Clinical Oncology. Using rank correlation analyses, Wong et al demonstrate that BSA did not correlate with vinorelbine clearance, suggesting that BSA is not significantly contributing to explaining interindividual pharmacokinetic variability. Interestingly, among the variables tested, they found that BSA and vinorelbine clearance were the only statistically significant and independent predictors of the post-treatment fractional survival of neutrophils, used as a measure of vinorelbine-induced myelosuppression. The notion that BSA may predict toxicity based on an association with interindividual pharmacodynamic—as opposed to pharmacokinetic—variability is intriguing and warrants additional exploration for vinorelbine, as well as other myelosuppressive chemotherapeutic agents. Although the underlying mechanism for the possible link between BSA and hematologic toxicity remains to be elucidated, the previous finding that BSA is also a risk factor for severe leukopenia in patients treated with a vindesine/cisplatin-containing regimen suggests that this effect may not be limited to vinorelbine.⁷ Nonetheless, the currently observed association between BSA and vinorelbine-associated neutropenia shows rather wide scatter and hence better tools to individualize chemotherapeutic treatment with this agent are still highly desired.

One of such possible tools evaluated by Wong et al is the application of probe drugs to predict the disposition characteristics of vinorelbine by determining the baseline phenotypic activity of two proteins of putative importance for drug distribution and elimination.⁶ Using midazolam, a widely used phenotypic probe for the cytochrome P450 isoforms CYP3A4 and CYP3A5,⁸ and technetium labeled sestamibi (99mTc-MIBI), which was used to determine the activity of the transporter protein ABCB1 (MDR1; P-glycoprotein),⁹ Wong et al found that only the latter was a significant independent predictor of vinorelbine clearance in the 34 assessable patients.

Several factors need to be considered to understand the lack of relationship between the observed phenotypic CYP3A4 activity and vinorelbine clearance. Recent studies have indicated that CYP3A4 probably plays only a modest role in the metabolic breakdown of vinorelbine in vivo, and that this pathway is even relatively insensitive to inhibition (by ritonavir)¹⁰ and induction (by rifampin).¹¹ Furthermore the ability of a probe drug to predict the metabolism of other CYP3A4 substrates will be compromised if differences in transporter affinities are not identified and fully taken into account.¹² It logically follows that only once all factors contributing to the clearance of a particular CYP3A4 substrate drug are known, including nonmetabolic determinants such as reliance on uptake and efflux transporters, should the clinical applicability and usefulness of a probe drug be considered. It is important to note that in the patient cohort studied by Wong et al, vinorelbine clearance ranged less than two-fold, with the exception of two outlier patients, one as a result of low creatinine clearance, a known covariate for vinorelbine clearance,¹³ and one presumably as a result of low baseline activity of ABCB1. This suggests that interindividual pharmacokinetic variability of vinorelbine in this particular cohort of patients was lower than what could be expected for a representative population. Hence, a robustly powered prospective study will still be needed to reveal the true magnitude of the described associations, or the lack thereof.

The observed relationship between 99mTc-MIBI and vinorelbine clearance is theoretically plausible, as vinorelbine undergoes substantial fecal excretion in humans preceded by biliary secretion,¹⁴ which pathway is likely mediated, at least in part, by ABCB1. It should be pointed out, however, that finding a statistically significant correlation does not necessarily guarantee that a clinically meaningful relationship exists. As outlined by Wong et al, the partial correlation between vinorelbine clearance and hepatic 99mTc-MIBI clearance was 0.44 when adjusted for creatinine clearance.⁶ This suggests that ABCB1 activity accounted for only 19% of the total interindividual variability in vinorelbine clearance, and that the use of 99mTc-MIBI does not provide quantitative predictability in the entire population.

Nonetheless, the possible link between ABCB1 activity and the pharmacokinetics of a substrate drug is interesting from several perspectives. One implication explored by Wong et al is that genetic variants in ABCB1 could contribute to interindividual variability in vinorelbine clearance. A recent report showing that the common synonymous single-nucleotide polymorphism in ABCB1 at nucleotide position 3435 in exon 26 is a main factor in allelic variation of mRNA expression in the liver, by changing mRNA stability,¹⁵ supports this possibility. However, in the study reported by Wong et al, vinorelbine clearance was not associated with any of the tested ABCB1 genotypes, as predicted earlier.¹⁶ This finding is also consistent with preclinical data indicating that even the complete lack of ABCB1 in mice with a deletion of the Abcb1a and Abcb1b genes does not affect the plasma pharmacokinetic profile of vinorelbine.¹⁰ It is also likely that the sample size was too small to detect statistically significant differences between the different genotype groups.

The current report on the possible link between BSA and treatment-related hematologic toxicity, as well as the evaluation of phenotyping strategies in patients treated with vinorelbine, is noteworthy. However, additional studies will clearly be needed to define whether BSA is indeed an important consideration in attempts to individualize myelosuppressive chemotherapy, and if so, for which drugs it should be used. Moreover, even if a statistically significant BSA-related change in the ability of a drug to cause neutropenia has been demonstrated, its clinical importance may be completely dwarfed by individual variations in other important, but yet unknown, pharmacokinetic and pharmacodynamic factors. Eventually, independent confirmation of these preliminary data, along with the application of rigorous phenotypic assessment and data analysis, and the use of a sufficiently large and representative patient population are all imperative to the identification of novel approaches to optimize the chemotherapeutic treatment of cancer.

Authors' Disclosures of Potential Conflicts of Interest

The authors indicated no potential conflicts of interest.

Author Contributions

Conception and design: Sharyn D. Baker, Alex Sparreboom Data analysis and interpretation: Sharyn D. Baker, Alex Sparreboom Manuscript writing: Sharyn D. Baker, Alex Sparreboom Final approval of manuscript: Sharyn D. Baker, Alex Sparreboom

 

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