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. 2000 Apr 3;82(9):1519–1527. doi: 10.1054/bjoc.2000.1172

Clinical pharmacokinetic and in vitro combination studies of nolatrexed dihydrochloride (AG337, ThymitaqTM) and paclitaxel

A N Hughes 1,2, M J Griffin 1, D R Newell 1, A H Calvert 1,2, A Johnston 3, B Kerr 3, C Lee 3, B Liang 3, A V Boddy 1
PMCID: PMC2363406  PMID: 10789718

Abstract

A clinical study of nolatrexed dihydrochloride (AG337, ThymitaqTM) in combination with paclitaxel was performed. The aims were to optimize the schedule of administration and determine any pharmacokinetic (PK) interactions between the two drugs. In vitro combination studies were performed to assist with schedule optimization. Three patients were entered on each of three different schedules of administration of the two drugs: (1) paclitaxel 0–3 h, nolatrexed 24–144 h; (2) nolatrexed 0–120 h, paclitaxel 48–51 h; (3) nolatrexed 0–120 h, paclitaxel 126–129 h. Paclitaxel was administered at a dose of 80 mg m−2over 3 h and nolatrexed at a dose of 500 mg m−2day−1as a 120-h continuous intravenous infusion. Plasma concentrations of both drugs were determined by high performance liquid chromatography. In vitro growth inhibition studies using corresponding schedules were performed using two head and neck cancer cell lines. In both HNX14C and HNX22B cell lines, synergistic growth inhibition was observed on schedule 2, whereas schedules 1 and 3 demonstrated antagonistic effects. In the clinical study, there was no effect of schedule on the pharmacokinetics of nolatrexed. However, patients on schedules 1 and 3 had a higher clearance of paclitaxel (322–520 ml min−1m−2) than those on schedule 2 (165–238 ml min−1m−2). Peak plasma concentrations (1.66–1.93 vs 0.86–1.32 μM) and areas under the curve (392–565 vs 180–291 μM min−1) of paclitaxel were correspondingly higher on schedule 2. The pharmacokinetic interaction was confirmed by studies with human liver microsomes, nolatrexed being an inhibitor of the major routes of metabolism of paclitaxel. Toxicity was not schedule-dependent. Nolatrexed and paclitaxel may be safely given together when administered sequentially at the doses used in this study. Studies in vitro suggest some synergy, however, due to a pharmacokinetic interaction, paclitaxel doses should be reduced when administered during nolatrexed infusion. © 2000 Cancer Research Campaign

Keywords: metabolism, interaction, schedule, inhibition

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Selected References

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  1. Aisner J., Cortés-Funes H. Paclitaxel in head and neck and other cancers: future prospects. Semin Oncol. 1997 Feb;24(1 Suppl 2):S2–113-S2-115. [PubMed] [Google Scholar]
  2. Berg S. L., Tolcher A., O'Shaughnessy J. A., Denicoff A. M., Noone M., Ognibene F. P., Cowan K. H., Balis F. M. Effect of R-verapamil on the pharmacokinetics of paclitaxel in women with breast cancer. J Clin Oncol. 1995 Aug;13(8):2039–2042. doi: 10.1200/JCO.1995.13.8.2039. [DOI] [PubMed] [Google Scholar]
  3. Chao Y., Chan W. K., Birkhofer M. J., Hu O. Y., Wang S. S., Huang Y. S., Liu M., Whang-Peng J., Chi K. H., Lui W. Y. Phase II and pharmacokinetic study of paclitaxel therapy for unresectable hepatocellular carcinoma patients. Br J Cancer. 1998 Jul;78(1):34–39. doi: 10.1038/bjc.1998.438. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Chou T. C., Talalay P. Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul. 1984;22:27–55. doi: 10.1016/0065-2571(84)90007-4. [DOI] [PubMed] [Google Scholar]
  5. Cresteil T., Monsarrat B., Alvinerie P., Tréluyer J. M., Vieira I., Wright M. Taxol metabolism by human liver microsomes: identification of cytochrome P450 isozymes involved in its biotransformation. Cancer Res. 1994 Jan 15;54(2):386–392. [PubMed] [Google Scholar]
  6. Gianni L., Kearns C. M., Giani A., Capri G., Viganó L., Lacatelli A., Bonadonna G., Egorin M. J. Nonlinear pharmacokinetics and metabolism of paclitaxel and its pharmacokinetic/pharmacodynamic relationships in humans. J Clin Oncol. 1995 Jan;13(1):180–190. doi: 10.1200/JCO.1995.13.1.180. [DOI] [PubMed] [Google Scholar]
  7. Gianni L., Kearns C. M., Giani A., Capri G., Viganó L., Lacatelli A., Bonadonna G., Egorin M. J. Nonlinear pharmacokinetics and metabolism of paclitaxel and its pharmacokinetic/pharmacodynamic relationships in humans. J Clin Oncol. 1995 Jan;13(1):180–190. doi: 10.1200/JCO.1995.13.1.180. [DOI] [PubMed] [Google Scholar]
  8. Gianni L., Viganò L., Locatelli A., Capri G., Giani A., Tarenzi E., Bonadonna G. Human pharmacokinetic characterization and in vitro study of the interaction between doxorubicin and paclitaxel in patients with breast cancer. J Clin Oncol. 1997 May;15(5):1906–1915. doi: 10.1200/JCO.1997.15.5.1906. [DOI] [PubMed] [Google Scholar]
  9. Harris J. W., Rahman A., Kim B. R., Guengerich F. P., Collins J. M. Metabolism of taxol by human hepatic microsomes and liver slices: participation of cytochrome P450 3A4 and an unknown P450 enzyme. Cancer Res. 1994 Aug 1;54(15):4026–4035. [PubMed] [Google Scholar]
  10. Huizing M. T., Keung A. C., Rosing H., van der Kuij V., ten Bokkel Huinink W. W., Mandjes I. M., Dubbelman A. C., Pinedo H. M., Beijnen J. H. Pharmacokinetics of paclitaxel and metabolites in a randomized comparative study in platinum-pretreated ovarian cancer patients. J Clin Oncol. 1993 Nov;11(11):2127–2135. doi: 10.1200/JCO.1993.11.11.2127. [DOI] [PubMed] [Google Scholar]
  11. Jamis-Dow C. A., Klecker R. W., Katki A. G., Collins J. M. Metabolism of taxol by human and rat liver in vitro: a screen for drug interactions and interspecies differences. Cancer Chemother Pharmacol. 1995;36(2):107–114. doi: 10.1007/BF00689193. [DOI] [PubMed] [Google Scholar]
  12. Jamis-Dow C. A., Pearl M. L., Watkins P. B., Blake D. S., Klecker R. W., Collins J. M. Predicting drug interactions in vivo from experiments in vitro. Human studies with paclitaxel and ketoconazole. Am J Clin Oncol. 1997 Dec;20(6):592–599. doi: 10.1097/00000421-199712000-00013. [DOI] [PubMed] [Google Scholar]
  13. Kano Y., Akutsu M., Tsunoda S., Mori K., Suzuki K., Adachi K. I. In vitro schedule-dependent interaction between paclitaxel and SN-38 (the active metabolite of irinotecan) in human carcinoma cell lines. Cancer Chemother Pharmacol. 1998;42(2):91–98. doi: 10.1007/s002800050790. [DOI] [PubMed] [Google Scholar]
  14. Kearns C. M. Pharmacokinetics of the taxanes. Pharmacotherapy. 1997 Sep-Oct;17(5 Pt 2):105S–109S. [PubMed] [Google Scholar]
  15. Kennedy M. J., Zahurak M. L., Donehower R. C., Noe D., Grochow L. B., Sartorius S., Chen T. L., Bowling K., Duerr M., Rowinsky E. K. Sequence-dependent hematological toxicity associated with the 3-hour paclitaxel/cyclophosphamide doublet. Clin Cancer Res. 1998 Feb;4(2):349–356. [PubMed] [Google Scholar]
  16. Lillibridge J. H., Liang B. H., Kerr B. M., Webber S., Quart B., Shetty B. V., Lee C. A. Characterization of the selectivity and mechanism of human cytochrome P450 inhibition by the human immunodeficiency virus-protease inhibitor nelfinavir mesylate. Drug Metab Dispos. 1998 Jul;26(7):609–616. [PubMed] [Google Scholar]
  17. Panday V. R., Huizing M. T., Willemse P. H., De Graeff A., ten Bokkel Huinink W. W., Vermorken J. B., Beijnen J. H. Hepatic metabolism of paclitaxel and its impact in patients with altered hepatic function. Semin Oncol. 1997 Aug;24(4 Suppl 11):S11–34-S11-38. [PubMed] [Google Scholar]
  18. Rafi I., Boddy A. V., Calvete J. A., Taylor G. A., Newell D. R., Bailey N. P., Lind M. J., Green M., Hines J., Johnstone A. Preclinical and phase I clinical studies with the nonclassical antifolate thymidylate synthase inhibitor nolatrexed dihydrochloride given by prolonged administration in patients with solid tumors. J Clin Oncol. 1998 Mar;16(3):1131–1141. doi: 10.1200/JCO.1998.16.3.1131. [DOI] [PubMed] [Google Scholar]
  19. Rafi I., Taylor G. A., Calvete J. A., Boddy A. V., Balmanno K., Bailey N., Lind M., Calvert A. H., Webber S., Jackson R. C. Clinical pharmacokinetic and pharmacodynamic studies with the nonclassical antifolate thymidylate synthase inhibitor 3, 4-dihydro-2-amino-6-methyl-4-oxo-5-(4-pyridylthio)-quinazolone dihydrochloride (AG337) given by 24-hour continuous intravenous infusion. Clin Cancer Res. 1995 Nov;1(11):1275–1284. [PubMed] [Google Scholar]
  20. Rowinsky E. K., Gilbert M. R., McGuire W. P., Noe D. A., Grochow L. B., Forastiere A. A., Ettinger D. S., Lubejko B. G., Clark B., Sartorius S. E. Sequences of taxol and cisplatin: a phase I and pharmacologic study. J Clin Oncol. 1991 Sep;9(9):1692–1703. doi: 10.1200/JCO.1991.9.9.1692. [DOI] [PubMed] [Google Scholar]
  21. Rowinsky E. K. The taxanes: dosing and scheduling considerations. Oncology (Williston Park) 1997 Mar;11(3 Suppl 2):7–19. [PubMed] [Google Scholar]
  22. Siddiqui N., Boddy A. V., Thomas H. D., Bailey N. P., Robson L., Lind M. J., Calvert A. H. A clinical and pharmacokinetic study of the combination of carboplatin and paclitaxel for epithelial ovarian cancer. Br J Cancer. 1997;75(2):287–294. doi: 10.1038/bjc.1997.47. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Skehan P., Storeng R., Scudiero D., Monks A., McMahon J., Vistica D., Warren J. T., Bokesch H., Kenney S., Boyd M. R. New colorimetric cytotoxicity assay for anticancer-drug screening. J Natl Cancer Inst. 1990 Jul 4;82(13):1107–1112. doi: 10.1093/jnci/82.13.1107. [DOI] [PubMed] [Google Scholar]
  24. Slichenmyer W. J., Donehower R. C., Chen T. L., Bowling M. K., McGuire W. P., Rowinsky E. K. Pretreatment H2 receptor antagonists that differ in P450 modulation activity: comparative effects on paclitaxel clearance rates and neutropenia. Cancer Chemother Pharmacol. 1995;36(3):227–232. [PubMed] [Google Scholar]
  25. Sonnichsen D. S., Liu Q., Schuetz E. G., Schuetz J. D., Pappo A., Relling M. V. Variability in human cytochrome P450 paclitaxel metabolism. J Pharmacol Exp Ther. 1995 Nov;275(2):566–575. [PubMed] [Google Scholar]
  26. Sonnichsen D. S., Relling M. V. Clinical pharmacokinetics of paclitaxel. Clin Pharmacokinet. 1994 Oct;27(4):256–269. doi: 10.2165/00003088-199427040-00002. [DOI] [PubMed] [Google Scholar]
  27. Vanhoefer U., Harstrick A., Wilke H., Schleucher N., Walles H., Schröder J., Seeber S. Schedule-dependent antagonism of paclitaxel and cisplatin in human gastric and ovarian carcinoma cell lines in vitro. Eur J Cancer. 1995;31A(1):92–97. doi: 10.1016/0959-8049(94)00440-g. [DOI] [PubMed] [Google Scholar]
  28. Venook A. P., Egorin M. J., Rosner G. L., Brown T. D., Jahan T. M., Batist G., Hohl R., Budman D., Ratain M. J., Kearns C. M. Phase I and pharmacokinetic trial of paclitaxel in patients with hepatic dysfunction: Cancer and Leukemia Group B 9264. J Clin Oncol. 1998 May;16(5):1811–1819. doi: 10.1200/JCO.1998.16.5.1811. [DOI] [PubMed] [Google Scholar]
  29. Vokes E. E., Haraf D. J., Stenson K., Stupp R., Malone D., Levin J., Weichselbaum R. R. The role of paclitaxel in the treatment of head and neck cancer. Semin Oncol. 1995 Oct;22(5 Suppl 12):8–12. [PubMed] [Google Scholar]
  30. Webber S. E., Bleckman T. M., Attard J., Deal J. G., Kathardekar V., Welsh K. M., Webber S., Janson C. A., Matthews D. A., Smith W. W. Design of thymidylate synthase inhibitors using protein crystal structures: the synthesis and biological evaluation of a novel class of 5-substituted quinazolinones. J Med Chem. 1993 Mar 19;36(6):733–746. doi: 10.1021/jm00058a010. [DOI] [PubMed] [Google Scholar]
  31. Wilson W. H., Berg S. L., Bryant G., Wittes R. E., Bates S., Fojo A., Steinberg S. M., Goldspiel B. R., Herdt J., O'Shaughnessy J. Paclitaxel in doxorubicin-refractory or mitoxantrone-refractory breast cancer: a phase I/II trial of 96-hour infusion. J Clin Oncol. 1994 Aug;12(8):1621–1629. doi: 10.1200/JCO.1994.12.8.1621. [DOI] [PubMed] [Google Scholar]

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