Exploring pharmacogenetics of paclitaxel- and docetaxel-induced peripheral neuropathy by evaluating the direct pharmacogenetic-pharmacokinetic and pharmacokinetic-neuropathy relationships

ABSTRACT

Introduction: Peripheral neuropathy (PN) is an adverse effect of several classes of chemotherapy including the taxanes. Predictive PN biomarkers could inform individualized taxane treatment to reduce PN and enhance therapeutic outcomes. Pharmacogenetics studies of taxane-induced PN have focused on genes involved in pharmacokinetics, including enzymes and transporters. Contradictory findings from these studies prevent translation of genetic biomarkers into clinical practice.

Areas covered: This review discusses the progress toward identifying pharmacogenetic predictors of PN by assessing the evidence for two independent associations; the effect of pharmacogenetics on taxane pharmacokinetics and the evidence that taxane pharmacokinetics affects PN. Assessing these direct relationships allows the reader to understand the progress toward individualized taxane treatment and future research opportunities.

Expert opinion: Paclitaxel pharmacokinetics is a major determinant of PN. Additional clinical trials are needed to confirm the clinical benefit of individualized dosing to achieve target paclitaxel exposure. Genetics does not meaningfully contribute to paclitaxel pharmacokinetics and may not be useful to inform dosing. However, genetics may contribute to PN sensitivity and could be useful for estimating patients’ optimal paclitaxel exposure. For docetaxel, genetics has not been demonstrated to have a meaningful effect on pharmacokinetics and there is no evidence that pharmacokinetics determines PN.

KEYWORDS:

• Chemotherapy-induced peripheral neuropathy
• genome-wide association study (GWAS)
• individualized therapy
• pharmacogenetics
• pharmacokinetics
• taxane
• therapeutic drug monitoring

Declaration of interest

Dl Hertz has an unpaid, informal, collaborative relationship with Saladax Inc., a company that markets CLIA-approved taxane measurement for therapeutic drug monitoring. He has no formal role in this company and has never received any financial support, stock options, or anything else of value from this company.

Article highlights

Introduction:

• Peripheral neuropathy (PN) is a debilitating taxane adverse effect that cannot be prevented or treated

• Predictive PN biomarkers could inform individualized treatment to reduce PN and enhance treatment outcomes

• Pharmacogenetics (PGx) studies of taxane-induced PN have focused on enzymes and transporters that affect pharmacokinetics (PK)

• Results of PGx studies are highly contradictory

• The PGx-PN association is an indirect association comprised of two direct associations: PGx-PK and PK-PN

• Assessing the evidence for these direct associations could help explain inconsistent PGx study findings and highlight opportunities for future researchPaclitaxel:

• Paclitaxel PK, described by area under the curve (AUC), maximum concentration (C_max) or time above threshold (T_c>0.05), is a major determinant of PN

• Prospective clinical trials demonstrate that individualized dosing to achieve a target exposure, referred to as therapeutic drug monitoring (TDM), reduces PN

• Additional clinical trials are needed to confirm the clinical benefit of paclitaxel TDM across tumor types and dosing schedules

• Genetics does not have a robust contribution to paclitaxel PK

• Genetics related to inherited neuropathy conditions may cause some patients to be inherently sensitive to PN

• These patients may benefit from individualized treatment that achieves an individualized paclitaxel exposure target

• OATP transporters are necessary for paclitaxel uptake into neurons and neurotoxicity in miceDocetaxel

• There is no evidence that docetaxel PK is a determinant of PN

• There is weak evidence that genetics affects docetaxel PK, though some candidate variants such as CYP3A4*22 have not been investigated to our knowledge

• It is unlikely that genetic variants meaningfully affect PN via an effect on docetaxel PKConclusion

• Additional work is needed to confirm the clinical benefit of paclitaxel TDM and translate this strategy into clinical practice

• There is less evidence supporting the potential of individualized docetaxel dosing to prevent PN

• Future work is needed to confirm the importance of OATP uptake transporters in determining taxane distribution into neurons and PNThis box summarizes key points contained in the article.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This research was supported by the National Center for Advancing Translational Sciences under award numbers KL2TR000434 and 2UL1TR000433.