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Disposition of desipramine, a sensitive cytochrome P450 2D6 substrate, when coadministered with intravenous temsirolimus

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Abstract

Purpose

Intravenous (i.v.) temsirolimus, a novel inhibitor of mammalian target of rapamycin (mTOR), is approved for treatment of renal cell carcinoma. In vitro studies with pooled human liver microsomes showed that temsirolimus and its principal metabolite, sirolimus, inhibit the CYP2D6 isozyme (K i  = 1.5 and 5 μM, respectively), indicating potential for pharmacokinetic interaction with agents that are substrates of CYP2D6.

Methods

This 2-period study in healthy subjects investigated the pharmacokinetics of a single oral 50-mg dose of the CYP2D6 substrate desipramine, first without and subsequently with a single coadministered i.v. 25-mg dose of temsirolimus.

Results

The study population consisted of 25 males and 1 female; 10 were black, 12 were white, and 4 were of other races. Plasma and whole blood samples were available from all 26 subjects in period 1 following oral desipramine and from 23 subjects in period 2 following oral desipramine and i.v. temsirolimus coadministration. The 90% confidence intervals for least squares geometric mean ratios of desipramine and 2-hydroxy-desipramine C max, AUCT, and AUC were within 80–125%, indicating that parameter differences did not manifest into clinically relevant exposure changes. A single i.v. 25-mg dose of temsirolimus, alone or with desipramine, was well tolerated in healthy subjects.

Conclusions

A single i.v. 25-mg dose of temsirolimus did not alter disposition of desipramine. Temsirolimus i.v. 25 mg may be safely administered with agents metabolized through the CYP2D6 pathway, but vigilance for drug interaction is warranted in patients with advanced malignancies.

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Abbreviations

CYP:

Cytochrome P450

mTOR:

Mammalian target of rapamycin

References

  1. Torisel [package insert] (2007) Wyeth Pharmaceuticals Inc., Philadelphia, PA

  2. Witzig TE, Geyer SM, Ghobrial I, Inwards DJ, Fonseca R, Kurtin P, Ansell SM, Luyun R, Flynn PJ, Morton RF, Dakhil SR GH, Kaufmann SH (2005) Phase II trial of single-agent temsirolimus (CCI-779) for relapsed mantle cell lymphoma. J Clin Oncol 23:5347–5356

    Article  PubMed  CAS  Google Scholar 

  3. Chan S, Scheulen ME, Johnston S, Mross K, Cardoso F, Dittrich C, Eiermann W, Hess D, Morant R, Semiglazov V, Borner M, Salzberg M, Ostapenko V, Illiger HJ, Behringer D, Bardy-Bouxin N, Boni J, Kong S, Cincotta M, Moore L (2005) Phase II study of temsirolimus (CCI-779), a novel inhibitor of mTOR, in heavily pretreated patients with locally advanced or metastatic breast cancer. J Clin Oncol 23:5314–5322

    Article  PubMed  CAS  Google Scholar 

  4. Galanis E, Buckner JC, Maurer MJ, Kreisberg JI, Ballman K, Boni J, Peralba JM, Jenkins RB, Dakhil SR, Morton RF, Jaeckle KA, Scheithauer BW, Dancey J, Hidalgo M, Walsh DJ (2005) Phase II trial of temsirolimus (CCI-779) in recurrent glioblastoma multiforme: a North Central Cancer Treatment Group Study. J Clin Oncol 23:5294–5304

    Article  PubMed  CAS  Google Scholar 

  5. Bjornsti MA, Houghton PJ (2004) The TOR pathway: a target for cancer therapy. Nat Rev Cancer 4:335–348

    Article  PubMed  CAS  Google Scholar 

  6. DelBufalo D, Ciuffreda L, Trisciuoglio D, Desideri M, Cognetti F, Zupi G, Milella M (2006) Antiangiogenic potential of the mammalian target of rapamycin inhibitor temsirolimus. Cancer Res 66:5549–5554

    Article  CAS  Google Scholar 

  7. Abraham RT, Gibbons JJ (2007) The mammalian target of rapamycin signaling pathway: twists and turns in the road to cancer therapy. Clin Cancer Res 13:3109–3114

    Article  PubMed  CAS  Google Scholar 

  8. Peralba JM, DeGraffenried L, Friedrichs W, Fulcher L, Grunwald V, Weiss G, Hidalgo M (2003) Pharmacodynamic evaluation of CCI-779, an inhibitor of mTOR, in cancer patients. Clin Cancer Res 9:2887–2892

    PubMed  CAS  Google Scholar 

  9. Thomas GV, Tran C, Mellinghoff IK, Welsbie DS, Chan E, Fueger B, Czernin J, Sawyers CL (2006) Hypoxia-inducible factor determines sensitivity to inhibitors of mTOR in kidney cancer. Nat Med 12:122–127

    Article  PubMed  CAS  Google Scholar 

  10. Teachey DT, Obzut DA, Cooperman J, Fang J, Carroll M, Choi JK, Houghton PJ, Brown VI, Grupp SA (2006) The mTOR inhibitor CCI-779 induces apoptosis and inhibits growth in preclinical models of primary adult human ALL. Blood 107:1149–1155

    Article  PubMed  CAS  Google Scholar 

  11. Punt CJ, Boni J, Bruntsch U, Peters M, Thielert C (2003) Phase I and pharmacokinetic study of CCI-779, a novel cytostatic cell-cycle inhibitor, in combination with 5-fluorouracil and leucovorin in patients with advanced solid tumors. Ann Oncol 14:931–937

    Article  PubMed  CAS  Google Scholar 

  12. Raymond E, Alexandre J, Faivre S, Vera K, Materman E, Boni J, Leister C, Korth-Bradley J, Hanauske A, Armand JP (2004) Safety and pharmacokinetics of escalated doses of weekly intravenous infusion of CCI-779, a novel mTOR inhibitor, in patients with cancer. J Clin Oncol 22:2336–2347

    Article  PubMed  CAS  Google Scholar 

  13. Hidalgo M, Buckner JC, Erlichman C, Pollack MS, Boni JP, Dukart G, Marshall B, Speicher L, Moore L, Rowinsky EK (2006) A phase I and pharmacokinetic study of temsirolimus (CCI-779) administered intravenously for 5 days every 2 weeks to patients with advanced cancer. Clin Cancer Res 12:5755–5763

    Article  PubMed  CAS  Google Scholar 

  14. Boni JP, Leister C, Bender G, Fitzpatrick V, Twine N, Stover J, Dorner A, Immermann F, Burczynski ME (2005) Population pharmacokinetics of CCI-779: correlations to safety and pharmacogenomic responses in patients with advanced renal cancer. Clin Pharmacol Ther 77:76–89

    Article  PubMed  CAS  Google Scholar 

  15. Atkins MB, Hidalgo M, Stadler WM, Logan TF, Dutcher JP, Hudes GR, Park Y, Liou SH, Marshall B, Boni JP, Dukart G, Sherman ML (2004) Randomized phase II study of multiple dose levels of CCI-779, a novel mammalian target of rapamycin kinase inhibitor, in patients with advanced refractory renal cell carcinoma. J Clin Oncol 22:909–918

    Article  PubMed  CAS  Google Scholar 

  16. Cai P, Tsao R, Ruppen ME (2007) In vitro metabolic study of temsirolimus: preparation, isolation, and identification of the metabolites. Drug Metab Dispos 35:1554–1563

    Article  PubMed  CAS  Google Scholar 

  17. Boni J, Leister C, Burns J, Cincotta M, Hug B, Moore L (2007) Pharmacokinetic profile of temsirolimus with concomitant administration of cytochrome P450-inducing medications. J Clin Pharmacol 47:1430–1439

    Article  PubMed  CAS  Google Scholar 

  18. Hoffman M (2002) Data on file, CCI-779 (WAY-130779): evaluation as an inhibitor of cytochrome P450 enzymes CYP3A4/5, CYP2D6, CYP2C8 and CYP2C9 in human liver microsomes (Protocol 98901). Wyeth Pharmaceuticals, Collegeville, PA

  19. Torisel Clinical Pharmacology (2007) Available at: http://www.rxlist.com/cgi/generic/torisel_cp.htm. Accessed 24 January 2008

  20. Zanger UM, Raimundo S, Eichelbaum M (2004) Cytochrome P450 2D6: overview and update on pharmacology, genetics, biochemistry. Naunyn Schmiedebergs Arch Pharmacol 369:23–37

    Article  PubMed  CAS  Google Scholar 

  21. Desta Z, Ward BA, Soukhova NV, Flockhart DA (2004) Comprehensive evaluation of tamoxifen sequential biotransformation by the human cytochrome P450 system in vitro: prominent roles for CYP3A and CYP2D6. J Pharmacol Exp Ther 310:1062–1075

    Article  PubMed  CAS  Google Scholar 

  22. Fischer V, Vickers AE, Heitz F, Mahadevan S, Baldeck JP, Minery P, Tynes R (1994) The polymorphic cytochrome P-4502D6 is involved in the metabolism of both 5-hydroxytryptamine antagonists, tropisetron and ondansetron. Drug Metab Dispos 22:269–274

    PubMed  CAS  Google Scholar 

  23. Eap CB, Lessard E, Baumann P, Brawand-Amey M, Yessine MA, O’Hara G, Turgeon J (2003) Role of CYP2D6 in the stereoselective disposition of venlafaxine in humans. Pharmacogenetics 13:39–47

    Article  PubMed  CAS  Google Scholar 

  24. Subrahmanyam V, Renwick AB, Walters DG, Young PJ, Price RJ, Tonelli AP, Lake BG (2001) Identification of cytochrome P-450 isoforms responsible for cis-tramadol metabolism in human liver microsomes. Drug Metab Dispos 29:1146–1155

    PubMed  CAS  Google Scholar 

  25. Mizutani T (2003) PM frequencies of major CYPs in Asians and Caucasians. Drug Metab Rev 35:99–106

    Article  PubMed  CAS  Google Scholar 

  26. Brosen K, Gram LF, Kragh-Sorensen P (1991) Extremely slow metabolism of amitriptyline but normal metabolism of imipramine and desipramine in an extensive metabolizer of sparteine, debrisoquine, and mephenytoin. Ther Drug Monit 13:177–182

    Article  PubMed  CAS  Google Scholar 

  27. Steiner E, Dumont E, Spina E, Dahlqvist R (1988) Inhibition of desipramine 2-hydroxylation by quinidine and quinine. Clin Pharmacol Ther 43:577–581

    PubMed  CAS  Google Scholar 

  28. Dahl ML, Iselius L, Alm C, Svensson JO, Lee D, Johansson I, Ingelman-Sundberg M, Sjoqvist F (1993) Polymorphic 2-hydroxylation of desipramine. A population and family study. Eur J Clin Pharmacol 44:445–450

    Article  PubMed  CAS  Google Scholar 

  29. Leucht S, Hackl HJ, Steimer W, Angersbach D, Zimmer R (2000) Effect of adjunctive paroxetine on serum levels and side-effects of tricyclic antidepressants in depressive inpatients. Psychopharmacology (Berl) 147:378–383

    Article  CAS  Google Scholar 

  30. Alderman J, Preskorn SH, Greenblatt DJ, Harrison W, Penenberg D, Allison J, Chung M (1997) Desipramine pharmacokinetics when coadministered with paroxetine or sertraline in extensive metabolizers. J Clin Psychopharmacol 17:284–291

    Article  PubMed  CAS  Google Scholar 

  31. Madani S, Barilla D, Cramer J, Wang Y, Paul C (2002) Effect of terbinafine on the pharmacokinetics and pharmacodynamics of desipramine in healthy volunteers identified as cytochrome P450 2D6 (CYP2D6) extensive metabolizers. J Clin Pharmacol 42:1211–1218

    Article  PubMed  CAS  Google Scholar 

  32. Stamer UM, Bayerer B, Wolf S, Hoeft A, Stuber F (2002) Rapid and reliable method for cytochrome P450 2D6 genotyping. Clin Chem 48:1412–1417

    PubMed  CAS  Google Scholar 

  33. Ingelman-Sundberg M, Daly AK, Nebert DW (eds) (2008) Home page of the human cytochrome P450 (CYP) Allele Nomenclature Committee. Available at: http://www.cypalleles.ki.se/. Accessed 7 October 2008

  34. Jusko WJ (1992) Guidelines for collection and analysis of pharmacokinetic data. In: Evans WE, Schentag JJ, Jusko WJ (eds) Applied pharmacokinetics: principles of therapeutic drug monitoring. Applied Therapeutics Inc, Vancouver, pp 2.1–2.43

  35. Schuirmann DJ (1987) A comparison of the two-one-sided tests procedure and the power approach for assessing the equivalence of average bioavailability. J Pharmacokinet Biopharm 15:657–680

    Article  PubMed  CAS  Google Scholar 

  36. Guidance for industry: in vivo drug metabolism/drug interaction studies—study design, data analysis, and recommendations for dosing and labeling. (1999) Center for Drug Evaluation and Research (CDER), Rockville, MD

  37. Daly AK, Brockmoller J, Broly F et al (1996) Nomenclature for human CYP2D6 alleles. Pharmacogenics 6:193–201

    Article  CAS  Google Scholar 

  38. Shimada T, Yamazaki H, Mimura M, Inui Y, Guengerich FP (1994) Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians. J Pharmacol Exp Ther 270:414–423

    PubMed  CAS  Google Scholar 

  39. Gaedigk A, Simon SD, Pearce RE et al (2008) The CYP2D6 activity score: translating genotype information into a qualitative measure of phenotype. Clin Pharmacol Ther 83:234–242

    Article  PubMed  CAS  Google Scholar 

  40. Baldessarini RJ (1996) Drugs and the treatment of psychiatric disorders. In: Goodman LS, Limbird LE, Milinoff PB, Ruddon RW, Goodman GA (eds) Goodman and Gilman’s The pharmacological basis of therapeutics. McGraw-Hill, New York, pp 431–460

    Google Scholar 

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Acknowledgments

This research was supported by Wyeth Research, Collegeville, PA. The authors thank Peloton Advantage for assistance with manuscript preparation.

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Authors and Affiliations

  1. Department of Early Development and Clinical Pharmacology, Wyeth Research, 500 Arcola Road, Collegeville, PA, 19426, USA

    Joseph Boni, Richat Abbas, Jaime Burns & Bruce Hug

  2. Department of Biostatistics, Wyeth Research, 500 Arcola Road, Collegeville, PA, 19426, USA

    Cathie Leister

  3. Department of Drug Safety and Metabolism, Wyeth Research, 500 Arcola Road, Collegeville, PA, 19426, USA

    Ronald Jordan, Matthew Hoffmann & William DeMaio

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  1. Joseph Boni
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  2. Richat Abbas
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Correspondence to Joseph Boni.

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Boni, J., Abbas, R., Leister, C. et al. Disposition of desipramine, a sensitive cytochrome P450 2D6 substrate, when coadministered with intravenous temsirolimus. Cancer Chemother Pharmacol 64, 263–270 (2009). https://doi.org/10.1007/s00280-008-0865-9

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  • DOI: https://doi.org/10.1007/s00280-008-0865-9

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