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



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.


Erivedge™ 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.


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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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