Cancer Chemotherapy and Pharmacology

, Volume 71, Issue 1, pp 193–202 | Cite as

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

  • Patricia M. LoRusso
  • Sarina A. Piha-Paul
  • Monica Mita
  • A. Dimitrios Colevas
  • Vikram Malhi
  • Dawn Colburn
  • Ming Yin
  • Jennifer A. Low
  • Richard A. Graham
Original Article

Abstract

Purpose

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).

Methods

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).

Results

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.

Conclusions

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.

Keywords

Erivedge™ Vismodegib Drug–drug interaction Oral contraceptive Rosiglitazone 

Notes

Acknowledgments

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.

References

  1. 1.
    Dierks C, Grbic J, Zirlik K et al (2007) Essential role of stromally induced hedgehog signaling in B-cell malignancies. Nat Med 13:944–951PubMedCrossRefGoogle Scholar
  2. 2.
    Fan L, Pepicelli CV, Dibble CC et al (2004) Hedgehog signaling promotes prostate xenograft tumor growth. Endocrinology 145:3961–3970PubMedCrossRefGoogle Scholar
  3. 3.
    Hahn H, Christiansen J, Wicking C et al (1996) A mammalian patched homolog is expressed in target tissues of sonic hedgehog and maps to a region associated with developmental abnormalities. J Biol Chem 271:12125–12128PubMedCrossRefGoogle Scholar
  4. 4.
    Johnson RL, Rothman AL, Xie J et al (1996) Human homolog of patched, a candidate gene for the basal cell nevus syndrome. Science 272:1668–1671PubMedCrossRefGoogle Scholar
  5. 5.
    Pietsch T, Waha A, Koch A et al (1997) Medulloblastomas of the desmoplastic variant carry mutations of the human homologue of Drosophila patched. Cancer Res 57:2085–2088PubMedGoogle Scholar
  6. 6.
    Raffel C, Jenkins RB, Frederick L et al (1997) Sporadic medulloblastomas contain PTCH mutations. Cancer Res 57:842–845PubMedGoogle Scholar
  7. 7.
    Scales SJ, de Sauvage FJ (2009) Mechanisms of hedgehog pathway activation in cancer and implications for therapy. Trends Pharmacol Sci 30:303–312PubMedCrossRefGoogle Scholar
  8. 8.
    Vorechovský I, Tingby O, Hartman M et al (1997) Somatic mutations in the human homologue of Drosophila patched in primitive neuroectodermal tumours. Oncogene 15:361–366PubMedCrossRefGoogle Scholar
  9. 9.
    Yauch RL, Gould SE, Scales SJ et al (2008) A paracrine requirement for hedgehog signalling in cancer. Nature 455:406–410PubMedCrossRefGoogle Scholar
  10. 10.
    LoRusso PM, Rudin CM, Reddy JC et al (2011) Phase 1 trial of hedgehog pathway inhibitor vismodegib (GDC-0449) in patients with refractory, locally advanced or metastatic solid tumors. Clin Cancer Res 17:2502–2511PubMedCrossRefGoogle Scholar
  11. 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. 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
  13. 13.
    Kimura H, Ng JM, Curran T (2008) Transient inhibition of the Hedgehog pathway in young mice causes permanent defects in bone structure. Cancer Cell 13:249–260PubMedCrossRefGoogle Scholar
  14. 14.
    Lipinski RJ, Hutson PR, Hannam PW et al (2008) Dose- and route-dependent teratogenicity, toxicity, and pharmacokinetic profiles of the hedgehog signaling antagonist cyclopamine in the mouse. Toxicol Sci 104:189–197PubMedCrossRefGoogle Scholar
  15. 15.
    Lipinski RJ, Song C, Sulik KK et al (2010) Cleft lip and palate results from Hedgehog signaling antagonism in the mouse: phenotypic characterization and clinical implications. Birth Defects Res A Clin Mol Teratol 88:232–240PubMedGoogle Scholar
  16. 16.
    Baldwin SJ, Clarke SE, Chenery RJ (1999) Characterization of the cytochrome P450 enzymes involved in the in vitro metabolism of rosiglitazone. Br J Clin Pharmacol 48:424–432PubMedCrossRefGoogle Scholar
  17. 17.
    Yee LD, Williams N, Wen P et al (2007) Pilot study of rosiglitazone therapy in women with breast cancer: effects of short-term therapy on tumor tissue and serum markers. Clin Cancer Res 13:246–252PubMedCrossRefGoogle Scholar
  18. 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. 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. 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
  21. 21.
    Graham RA, Lum BL, Cheeti S et al (2011) Pharmacokinetics of hedgehog pathway inhibitor vismodegib (GDC-0449) in patients with locally advanced or metastatic solid tumors: the role of alpha-1-acid glycoprotein binding. Clin Cancer Res 17:2512–2520PubMedCrossRefGoogle Scholar
  22. 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. 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
  24. 24.
    Andrews E, Damle BD, Fang A et al (2008) Pharmacokinetics and tolerability of voriconazole and a combination oral contraceptive co-administered in healthy female subjects. Br J Clin Pharmacol 65:531–539PubMedCrossRefGoogle Scholar
  25. 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. 26.
    Erivedge™ (2012) Prescribing Information. Genentech Inc., USA. http://www.erivedge.com/hcp/prescribing-information.html. Accessed Apr 30, 2012
  27. 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. 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
  29. 29.
    LoRusso PM, Jimeno A, Dy G et al (2011) Pharmacokinetic dose-scheduling study of hedgehog pathway inhibitor vismodegib (GDC-0449) in patients with locally advanced or metastatic solid tumors. Clin Cancer Res 17:5774–5782PubMedCrossRefGoogle Scholar
  30. 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
  31. 31.
    Hall JM, Bell ML, Finger TE (2003) Disruption of sonic Hedgehog signaling alters growth and patterning of lingual taste papillae. Dev Biol 255:263–277PubMedCrossRefGoogle Scholar
  32. 32.
    Liu H-X, MacCallum DK, Edwards C, Gaffield W, Mistretta CM (2004) Sonic Hedgehog exerts distinct, stage-specific effects on tongue and taste papilla development. Dev Biol 276:280–300PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  • Patricia M. LoRusso
    • 1
  • Sarina A. Piha-Paul
    • 2
  • Monica Mita
    • 3
  • A. Dimitrios Colevas
    • 4
  • Vikram Malhi
    • 5
  • Dawn Colburn
    • 5
  • Ming Yin
    • 5
  • Jennifer A. Low
    • 5
  • Richard A. Graham
    • 5
  1. 1.Eisenberg Center for Translational TherapeuticsKarmanos Cancer CenterDetroitUSA
  2. 2.Department of Investigational Cancer TherapeuticsM.D. Anderson Cancer CenterHoustonUSA
  3. 3.Cancer Therapy and Research CenterUniversity of Texas Health Science Center at San AntonioSan AntonioUSA
  4. 4.Stanford Cancer InstituteStanfordUSA
  5. 5.Genentech Inc.South San FranciscoUSA

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