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In Reply

University of Pittsburgh Cancer Institute, Pittsburgh, PA

Ramesh K. Ramanathan

Scottsdale Clinical Research Institute/Translational Genomics Institute, Scottsdale, AZ

Joseph Gibbons

Case Comprehensive Cancer Center, Cleveland, OH

William Petros

Mary Babb Randolph Cancer Center, Morgantown, WV

S. Percy Ivy

National Cancer Institute, Bethesda, MD

Scot C. Remick

Mary Babb Randolph Cancer Center, Morgantown, WV

On behalf of the National Cancer Institute–sponsored Organ Dysfunction Working Group imatinib mesylate hepatic and renal dysfunction phase I study teams, we wish to respond to correspondence addressed to Journal of Clinical Oncology by Franke and Sparreboom regarding our recently published studies.^1,2 As stated in our manuscript, reduced imatinib clearance was not anticipated in patients with worsening renal dysfunction, since the major route of clearance is through CYP3A-mediated metabolism to CGP74588, the major metabolite which we measured in our study.² While the precise mechanism is not known, we commented on several plausible explanations in our original report; others were identified in the accompanying editorial for our article.^2,3 Now, there is another intriguing explanation provided by Franke and Sparreboom. Hepatic cytochrome P450 function is diminished in renal dysfunction.^4-7 We speculated that by measuring total drug and not free drug in patients with renal dysfunction, free drug clearance may not be accurately defined. The inverse relationship between renal function and plasma -1 acid glycoprotein, which is known to tightly bind imatinib, may account for reducing imatinib clearance by reducing the free fraction.³ Plasma -1 acid glycoprotein and free imatinib levels in the hepatic study did not correlate, thereby diminishing likelihood that -1 acid glycoprotein is solely responsible.^1,3 Judson³ has provided another explanation for diminished imatinib clearance in patients with renal dysfunction. In a prior study of imatinib pharmacokinetics in patients with gastrointestinal stromal tumors, imatinib clearance directly correlated with hemoglobin level; hence, patients with renal dysfunction are more likely to be anemic.⁸ Finally, Franke and Sparreboom's alternative explanation is that systemic concentrations of uremic toxins, such as 3-carboxy-4-methyl-5-propyl-2-furan propionic acid, can inhibit the hepatic uptake and subsequent metabolism of several anticancer agents leading to diminished clearance. In patients with severe renal dysfunction (Group D, creatinine clearance < 20 mL/min), we observed a decreased metabolite (CGP74599) to drug (imatinib) area under the curve ratio of 0.136 (in two patients) compared with the other cohorts of normal, mild, and moderate renal dysfunction in which this ratio was unaffected (Table 5).² This observation is consistent with the hypothesis proposed by Franke and Sparreboom. In our study, none of the patients enrolled were undergoing renal dialysis and none had clinical signs of uremia, suggesting that altered clearance could be more pronounced.

ACKNOWLEDGMENTS

These authors are writing on behalf of the of the National Cancer Institute (NCI) Organ Dysfunction Working Group Imatinib Mesylate Hepatic (NCI Protocol No. 5331) and Renal (P-5340) Dysfunction Phase I Study teams. Supported in part by Grants No. CA69855, CA47904, RR0056, CA069853, CA62502, RR000080, CA43703, CA62505, CA062487, CA062491, RR03186, CA76642, and CA099168 from the National Institutes of Health.

REFERENCES

1. Ramanathan RK, Egorin MJ, Takimoto CH, et al: Phase I and pharmacokinetic study of imatinib mesylate in patients with advanced malignancies and varying degrees of liver dysfunction: A study by the National Cancer Institute Organ Dysfunction Working Group. J Clin Oncol 26:563-569, 2008[Abstract/Free Full Text]

2. Gibbons J, Egorin MJ, Ramanathan RK, et al: Phase I and pharmacokinetic study of imatinib mesylate in patients with advanced malignancies and varying degrees of renal dysfunction: A study by the National Cancer Institute Organ Dysfunction Working Group. J Clin Oncol 26:570-576, 2008[Abstract/Free Full Text]

3. Judson IR: Imatinib for patients with liver or kidney dysfunction: No need to modify the dose. J Clin Oncol 26:521-522, 2008[Free Full Text]

4. Leblond FA, Giroux L, Villeneuve JP, et al: Decreased in vivo metabolism of drugs in chronic renal failure. Drug Metab Dispos 28:1317-1320, 2000[Abstract/Free Full Text]

5. Leblond F, Guevin C, Demers C, et al: Down-regulation of hepatic cytochrome P450 in chronic renal failure: Role of uremic mediators. J Am Soc Nephrol 12:326-332, 2001[Abstract/Free Full Text]

6. Touchette MA, Slaughter RL: The effect of renal failure on hepatic drug clearance. DICP 25:1214-1224, 1991[Abstract]

7. Dowling TC, Briglia AE, Fink JC, et al: Characterization of hepatic cytochrome P4503A activity in patients with end-stage renal disease. Clin Pharmacol Ther 73:427-434, 2003[CrossRef][Medline]

8. Judson I, Ma P, Peng B, et al: Imatinib pharmacokinetics in patients with gastrointestinal stromal tumor: A retrospective population pharmacokinetic study over time—EORTC Soft Tissue and Bone Sarcoma Group. Cancer Chemother Pharmacol 55:379-386, 2005[CrossRef][Medline]

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Related Correspondence

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