Co-administration of vismodegib with rosiglitazone or combined oral contraceptive in patients with locally advanced or metastatic solid tumors: a pharmacokinetic assessment of drug–drug interaction potential
- 606 Downloads
Vismodegib, a first-in-class oral hedgehog pathway inhibitor, is an effective treatment for advanced basal cell carcinoma. Based on in vitro data, a clinical drug–drug interaction (DDI) assessment of cytochrome P450 (CYP) 2C8 was necessary; vismodegib’s teratogenic potential warranted a DDI study with oral contraceptives (OCs).
This single-arm, open-label study included two cohorts of patients with locally advanced or metastatic solid malignancies [Cohort 1: rosiglitazone 4 mg (selective CYP2C8 probe); Cohort 2: OC (norethindrone 1 mg/ethinyl estradiol 35 μg; CYP3A4 substrate)]. On Day 1, patients received rosiglitazone or OC. On Days 2–7, patients received vismodegib 150 mg/day. On Day 8, patients received vismodegib plus rosiglitazone or OC. The effect of vismodegib on rosiglitazone and OC pharmacokinetic parameters (primary objective) was evaluated through pharmacokinetic sampling over a 24-h period (Days 1 and 8).
The mean ± SD vismodegib steady-state plasma concentration (Day 8, N = 51) was 20.6 ± 9.72 μM (range 7.93–62.4 μM). Rosiglitazone AUC0–inf and C max were similar with concomitant vismodegib [≤8 % change in geometric mean ratios (GMRs); N = 24]. Concomitant vismodegib with OC did not affect ethinyl estradiol AUC0–inf and C max (≤5 % change in GMRs; N = 27); norethindrone C max and AUC0–inf GMRs were higher (12 and 23 %, respectively) with concomitant vismodegib.
This DDI study in patients with cancer demonstrated that systemic exposure of rosiglitazone (a CYP2C8 substrate) or OC (ethinyl estradiol/norethindrone) is not altered with concomitant vismodegib. Overall, there appears to be a low potential for DDIs when vismodegib is co-administered with other medications.
KeywordsErivedge™ Vismodegib Drug–drug interaction Oral contraceptive Rosiglitazone
We wish to thank the patients who enrolled in this study and their families for their contributions to medical science; Dr. John Sarantopoulos at the Cancer Therapy & Research Center, San Antonio, TX, USA; our colleagues at Genentech including Dr. Alan Deng (DMPK), Mr. Curt Johnson, and other members of the clinical operations team; and Dr. Ilsung Chang (Biostats) for his contributions to the study design. Their support is gratefully acknowledged. Vismodegib was discovered by Genentech Inc. and was jointly validated through a series of preclinical studies performed under a collaborative agreement between Genentech, Inc. (South San Francisco, CA, USA) and Curis, Inc. (Lexington, MA, USA). This trial was sponsored by Genentech Inc., South San Francisco, CA, USA. Support for third-party writing assistance for this manuscript was provided by F. Hoffman-La Roche Ltd. and Genentech Inc.
Conflict of interest
PML has received funding from GNE and has acted as a consultant for GNE. DC has received honoraria from GNE. V.M., D.C., M.Y., J.A.L., and R.A.G. are employees of Genentech Inc. S.A. P-P and M.M. have no conflicts of interest to declare.
- 11.Sekulic A, Migden MR, Oro AE et al (2012) Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N Engl J Med 366:2171–2179Google Scholar
- 12.Wong H, Chen JZ, Chou B et al (2009) Preclinical assessment of the absorption, distribution, metabolism and excretion of GDC-0449 (2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide), an orally bioavailable systemic Hedgehog signalling pathway inhibitor. Xenobiotica 39:850–861PubMedCrossRefGoogle Scholar
- 18.Doose DR, Wang S-S, Padmanabhan M, Schwabe S, Jacobs P, Bialer M (2003) Effect of topiramate or carbamazepine on the pharmacokinetics of an oral contraceptive containing norethindrone and ethinyl estradiol in healthy obese and nonobese female subjects. Epilepsia 44:540–549PubMedCrossRefGoogle Scholar
- 19.United States Food and Drug Administration (2012) Guidance for Industry. Drug interaction studies—study design, data analysis, implications for dosing, and labeling recommendations. U.S. Department of Health and Human Services, Food and Drug Administration. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm292362.pdf. Accessed 17 Apr 2012
- 20.Ortho-Novum® 1/35 (2010) US prescribing information. Ortho-McNeil-Janssen Pharmaceuticals Inc., USA. http://www.janssenpharmaceuticalsinc.com/assets/orthonov.pdf. Accessed 6 Mar 2012
- 22.Ding X, Chou B, Graham RA et al (2010) Determination of GDC-0449, a small-molecule inhibitor of the Hedgehog signaling pathway, in human plasma by solid phase extraction-liquid chromatographic-tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 878:785–790PubMedCrossRefGoogle Scholar
- 23.Kaye SB, Fehrenbacher L, Holloway R et al (2010) A phase 2, randomized, placebo-controlled study of hedgehog (HH) pathway inhibitor GDC-0449 as maintenance therapy in patients with ovarian cancer in 2nd or 3rd complete remission (CR). Ann Oncol 21(suppl 8):LBA25Google Scholar
- 25.Jinteli™ (2011) Prescribing information. Teva Pharmaceuticals US, Inc., USA. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=d667ca75-1a17-43fc-9077-f25ce0908f8d. Accessed 6 Mar 2012
- 26.Erivedge™ (2012) Prescribing Information. Genentech Inc., USA. http://www.erivedge.com/hcp/prescribing-information.html. Accessed Apr 30, 2012
- 27.United States Food and Drug Administration (2012) Guidance for industry. Drug interaction studies—study design, data analysis, and implications for dosing and labeling. U.S. Department of Health and Human Services, Food and Drug Administration. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm072101.pdf. Accessed 9 Jan 2012
- 28.European Medicines Agency (2010) Guideline on the investigation of drug interactions (draft). http://www.emea.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/05/WC500090112.pdf. Accessed 9 Jan 2012
- 30.Berlin JD, Bendell J, Hart L et al (2010) A phase 2, randomized, double-blind, placebo controlled study of hedgehog pathway inhibitor (HPI) GDC-0449 in patients with previously untreated metastatic colorectal cancer (mCRC). Ann Oncol 21(suppl 8):LBA21Google Scholar