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. 2019 Jan;20(2):95-104.
doi: 10.2217/pgs-2018-0162. Epub 2018 Dec 6.

Patients carrying CYP2C8*3 have shorter systemic paclitaxel exposure

Lauren A Marcath  1 , Kelley M Kidwell  2   3 , Adam C Robinson  1 , Kiran Vangipuram  1 , Monika L Burness  2   4 , Jennifer J Griggs  2   4 , Catherine Van Poznak  2   4 , Anne F Schott  2   4 , Daniel F Hayes  2   4 , Norah Lynn Henry  5 , Daniel L Hertz  1   2
Affiliations

Patients carrying CYP2C8*3 have shorter systemic paclitaxel exposure

Lauren A Marcath et al. Pharmacogenomics. 2019 Jan.

Abstract

Aim: First, evaluate if patients carrying putatively diminished activity CYP2C8 genotype have longer paclitaxel exposure (e.g., time above threshold concentration of 0.05 μM [Tc >0.05]). Second, screen additional pharmacogenes for associations with Tc >0.05. Methods: Pharmacogene panel genotypes were translated into genetic phenotypes for associations with Tc >0.05 (n = 58).

Results: Patients with predicted low-activity CYP2C8 had shorter Tc >0.05 after adjustment for age, body surface area and race (9.65 vs 11.03 hrs, β = 5.47, p = 0.02). This association was attributed to CYP2C8*3 (p = 0.006), not CYP2C8*4 (p = 0.58). Patients with predicted low-activity SLCO1B1 had longer Tc >0.05 (12.12 vs 10.15 hrs, β = 0.85, p = 0.012).

Conclusion: Contrary to previous publications, CYP2C8*3 may confer increased paclitaxel metabolic activity. SLCO1B1 and CYP2C8 genotype may explain some paclitaxel pharmacokinetic variability.

Keywords: paclitaxel; pharmacogenomics.

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Conflict of interest statement

Financial & competing interests disclosure

This work was supported by the National Center for Advancing Translational Sciences under award number KL2TR000434 and 2UL1TR000433 (DL Hertz) and the National Cancer Institutes of Health under Award Number P30CA046592 (KM Kidwell).

DL Hertz has an informal, unpaid collaborative relationship with Saladax Biomedical Inc., a company that offers CLIA-approved paclitaxel measurement. Saladax was not involved in the design, conduct, analysis, or sponsorship of this trial, and had no contribution to the writing of this manuscript. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Figures

<b>Figure 1.</b>
Figure 1.. CONSORT Diagram of patient inclusion in the secondary pharmacogenomic analysis.
This diagram shows the reasons for exclusion from the parent clinical registry into the secondary pharmacogenomics analysis.
<b>Figure 2.</b>
Figure 2.. Paclitaxel Tc >0.05 stratified by genotype-predicted metabolic activity phenotype for CYP2C8 and SLCO1B1.
Paclitaxel Tc >0.05 stratified by metabolic activity phenotype (PM/IM and NM) for CYP2C8 (left) and SLCO1B1 (right). Lower activity CYP2C8 genetic phenotype (PM/IM) was associated with shorter Tc >0.05 and lower OATP1B1 (SLCO1B1) activity was associated with longer Tc >0.05 in the univariate analyses. IM: Intermediate metabolizer; NM: Normal metabolizer; PM: Poor metabolizer.
See this image and copyright information in PMC

References

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    2. • In the cohort of patients included in the manuscript, increased paclitaxel exposure was predictive of peripheral neuropathy-induced treatment disruption.

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