Top

Published in:

01-02-2013 | Short Communication

Phase I evaluation of the effects of ketoconazole and rifampicin on cediranib pharmacokinetics in patients with solid tumours

Authors: U. Lassen, W. H. Miller, S. Hotte, T. R. J. Evans, C. Kollmansberger, D. Adamson, D. L. Nielsen, J. Spicer, E. Chen, T. Meyer, K. Brown, R. Rafi, M. B. Sawyer

Published in: Cancer Chemotherapy and Pharmacology | Issue 2/2013

Abstract

Purpose

To investigate any effect of a CYP3A4 inhibitor (ketoconazole) or inducer (rifampicin) on cediranib steady-state pharmacokinetics in patients with advanced solid tumours.

Methods

In two Phase I, open-label trials, patients received once-daily oral doses of cediranib alone [20 mg (ketoconazole study); 45 mg (rifampicin study)] for 7 days followed by cediranib at the same dose with ketoconazole 400 mg/day for 3 days or once-daily rifampicin 600 mg/day for 7 days, respectively. Patients then continued to receive once-daily cediranib.

Results

In the ketoconazole study, 46 patients were dosed; 38 were evaluable for C _ss,max, 36 for AUC_ss. gMean AUC_ss and C _ss,max for cediranib 20 mg increased by 21 % (94 % CI 9–35 %) and 26 % (94 % CI 10–43 %), respectively, in the presence of ketoconazole. In the rifampicin study, 64 patients were dosed; 44 were evaluable for C _ss,max and 41 for AUC_ss. gMean AUC_ss and C _ss,max for cediranib 45 mg decreased by 39 % (90 % CI 34–43 %) and 23 % (90 % CI 16–30 %), respectively, in the presence of rifampicin. gMean ratios for AUC_ss and C _ss,max were >1 for ketoconazole and <1 for rifampicin and CIs were outside the pre-specified equivalence boundaries, indicating a statistically significant effect. Significant inter-patient variability in cediranib AUC_ss and C _ss,max was observed. The safety profile of cediranib was similar to that reported previously.

Conclusions

Co-administration of ketoconazole or rifampicin had statistically significant effects on steady-state pharmacokinetics of cediranib in patients with advanced solid tumours. Therefore, caution is advised when administering cediranib with potent enzyme inhibitors or inducers.

Available only for authorised users

Heckman CA, Holopainen T, Wirzenius M, Keskitalo S, Jeltsch M, Yla-Herttuala S, Wedge SR, Jürgensmeier JM, Alitalo K (2008) The tyrosine kinase inhibitor cediranib blocks ligand-induced vascular endothelial growth factor receptor-3 activity and lymphangiogenesis. Cancer Res 68:4754–4762PubMedCrossRef

Wedge SR, Kendrew J, Hennequin LF, Valentine PJ, Barry ST, Brave SR, Smith NR, James NH, Dukes M, Curwen JO, Chester R, Jackson JA, Boffey SJ, Kilburn LL, Barnett S, Richmond GH, Wadsworth PF, Walker M, Bigley AL, Taylor ST, Cooper L, Beck S, Jürgensmeier JM, Ogilvie DJ (2005) AZD2171: a highly potent, orally bioavailable, vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor for the treatment of cancer. Cancer Res 65:4389–4400PubMedCrossRef

Ferrara N (2009) Vascular endothelial growth factor. Arterioscler Thromb Vasc Biol 29:789–791PubMedCrossRef

Soltau J, Drevs J (2009) Mode of action and clinical impact of VEGF signaling inhibitors. Expert Rev Anticancer Ther 9:649–662PubMedCrossRef

Drevs J, Siegert P, Medinger M, Mross K, Strecker R, Zirrgiebel U, Harder J, Blum H, Robertson J, Jürgensmeier JM, Puchalski TA, Young H, Saunders O, Unger C (2007) Phase I clinical study of AZD2171, an oral vascular endothelial growth factor signaling inhibitor, in patients with advanced solid tumors. J Clin Oncol 25:3045–3054PubMedCrossRef

Goss GD, Arnold A, Shepherd FA, Dediu M, Ciuleanu TE, Fenton D, Zukin M, Walde D, Laberge F, Vincent MD, Ellis PM, Laurie SA, Ding K, Frymire E, Gauthier I, Leighl NB, Ho C, Noble J, Lee CW, Seymour L (2010) Randomized, double-blind trial of carboplatin and paclitaxel with either daily oral cediranib or placebo in advanced non-small-cell lung cancer: NCIC clinical trials group BR24 study. J Clin Oncol 28:49–55PubMedCrossRef

Matulonis UA, Berlin S, Ivy P, Tyburski K, Krasner C, Zarwan C, Berkenblit A, Campos S, Horowitz N, Cannistra SA, Lee H, Lee J, Roche M, Hill M, Whalen C, Sullivan L, Tran C, Humphreys BD, Penson RT (2009) Cediranib, an oral inhibitor of vascular endothelial growth factor receptor kinases, is an active drug in recurrent epithelial ovarian, fallopian tube, and peritoneal cancer. J Clin Oncol 27:5601–5606PubMedCrossRef

Batchelor T, Mulholland P, Neyns B, Nabors LB, Campone M, Wick A, Mason W, Xu J, Liu Q, van den Bent M (2010) A Phase III randomized study comparing the efficacy of cediranib as monotherapy, and in combination with lomustine, with lomustine alone in recurrent glioblastoma patients. Ann Oncol 21(Suppl 8):viii4 (abst LBA7)

Hoff PM, Hochhaus A, Pestalozzi BC, Tebbutt NC, Li J, Kim TW, Koynov KD, Kurteva G, Pintér T, Cheng Y, van Eyll B, Pike L, Fielding A, Robertson JD, Saunders MP, on behalf of the HORIZON II study group (2012) Cediranib plus FOLFOX/CAPOX versus placebo plus FOLFOX/CAPOX in patients with previously untreated metastatic colorectal cancer: a randomized, double-blind, Phase III study (HORIZON II). J Clin Oncol 30:3596–3603CrossRef

10.

Schmoll H-J, Cunningham D, Sobrero A, Karapetis CS, Rougier P, Koski SL, Kocakova I, Bondarenko I, Bodoky G, Mainwaring P, Salazar R, Barker P, Mookerjee B, Robertson J, Van Cutsem E, on behalf of the HORIZON III study group (2012) Cediranib with mFOLFOX6 versus bevacizumab with mFOLFOX6 as first-line treatment for patients with advanced colorectal cancer: a double-blind, randomized Phase III study (HORIZON III). J Clin Oncol 30:3588–3595CrossRef

11.

AstraZeneca (2011) Global policy: bioethics. Available at: http://www.astrazeneca.com/Responsibility/Code-policies-standards/Policiesstandards

12.

Pocock SJ (2011) Group sequential methods in the design and analysis of clinical trials. Biometrika 64:191–199CrossRef

13.

van Cruijsen H, Voest EE, Punt CJ, Hoekman K, Witteveen PO, Meijerink MR, Puchalski TA, Robertson J, Saunders O, Jürgensmeier JM, van Herpen CM, Giaccone G (2010) Phase I evaluation of cediranib, a selective VEGFR signalling inhibitor, in combination with gefitinib in patients with advanced tumours. Eur J Cancer 46:901–911PubMedCrossRef

14.

Lenz EM, Spear M, Drake C, Pollard CR, Ward M, Schulz-Utermoehl T, Harrison M (2010) Characterisation and identification of the human N+ -glucuronide metabolite of cediranib. J Pharm Biomed Anal 53:526–536PubMedCrossRef

15.

Schulz-Utermoehl T, Spear M, Pollard CR, Pattison C, Rollison H, Sarda S, Ward M, Bushby N, Jordan A, Harrison M (2010) In vitro hepatic metabolism of cediranib, a potent vascular endothelial growth factor tyrosine kinase inhibitor: interspecies comparison and human enzymology. Drug Metab Dispos 38:1688–1697PubMedCrossRef

16.

Smith DA, Koch KM, Arya N, Bowen CJ, Herendeen JM, Beelen A (2009) Effects of ketoconazole and carbamazepine on lapatinib pharmacokinetics in healthy subjects. Br J Clin Pharmacol 67:421–426PubMedCrossRef

17.

Pithavala YK, Tong W, Mount J, Rahavendran SV, Garrett M, Hee B, Selaru P, Sarapa N, Klamerus KJ (2012) Effect of ketoconazole on the pharmacokinetics of axitinib in healthy volunteers. Invest New Drugs 30:273–281PubMedCrossRef

18.

Swaisland HC, Ranson M, Smith RP, Leadbetter J, Laight A, McKillop D, Wild MJ (2005) Pharmacokinetic drug interactions of gefitinib with rifampicin, itraconazole and metoprolol. Clin Pharmacokinet 44:1067–1081PubMedCrossRef

19.

Yamamoto N, Tamura T, Yamamoto N, Yamada K, Yamada Y, Nokihara H, Fujiwara Y, Takahashi T, Murakami H, Boku N, Yamazaki K, Puchalski TA, Shin E (2009) Phase I, dose escalation and pharmacokinetic study of cediranib (RECENTIN), a highly potent and selective VEGFR signaling inhibitor, in Japanese patients with advanced solid tumors. Cancer Chemother Pharmacol 64:1165–1172PubMedCrossRef

20.

Laurie SA, Gauthier I, Arnold A, Shepherd FA, Ellis PM, Chen E, Goss G, Powers J, Walsh W, Tu D, Robertson J, Puchalski TA, Seymour L (2008) Phase I and pharmacokinetic study of daily oral AZD2171, an inhibitor of vascular endothelial growth factor tyrosine kinases, in combination with carboplatin and paclitaxel in patients with advanced non-small-cell lung cancer: the National Cancer Institute of Canada clinical trials group. J Clin Oncol 26:1871–1878PubMedCrossRef

Title: Phase I evaluation of the effects of ketoconazole and rifampicin on cediranib pharmacokinetics in patients with solid tumours
Authors: U. Lassen
W. H. Miller
S. Hotte
T. R. J. Evans
C. Kollmansberger
D. Adamson
D. L. Nielsen
J. Spicer
E. Chen
T. Meyer
K. Brown
R. Rafi
M. B. Sawyer
Publication date: 01-02-2013
Publisher: Springer-Verlag
Published in: Cancer Chemotherapy and Pharmacology / Issue 2/2013
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-012-2038-0

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 2/2013

Absorption, metabolism and excretion of [14C]pomalidomide in humans following oral administration

Erratum to: Phase I study of lonafarnib (SCH66336) in combination with trastuzumab plus paclitaxel in Her2/neu overexpressing breast cancer: EORTC study 16023

In vitro and in vivo studies of pharmacokinetics and antitumor efficacy of D07001-F4, an oral gemcitabine formulation

Combination of three cytotoxic agents in small-cell lung cancer

Modulation of multidrug resistance gene expression in peripheral blood mononuclear cells of lung cancer patients and evaluation of their clinical significance

Response to trastuzumab by HER2 expressing breast tumour xenografts is accompanied by decreased Hexokinase II, glut1 and [18F]-FDG incorporation and changes in 31P-NMR-detectable phosphomonoesters

Keynote webinar | Spotlight on antibody–drug conjugates in cancer