Cancer Chemotherapy and Pharmacology

, Volume 71, Issue 1, pp 193–202

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
    • Eisenberg Center for Translational TherapeuticsKarmanos Cancer Center
  • Sarina A. Piha-Paul
    • Department of Investigational Cancer TherapeuticsM.D. Anderson Cancer Center
  • Monica Mita
    • Cancer Therapy and Research CenterUniversity of Texas Health Science Center at San Antonio
  • A. Dimitrios Colevas
    • Stanford Cancer Institute
  • Vikram Malhi
    • Genentech Inc.
  • Dawn Colburn
    • Genentech Inc.
  • Ming Yin
    • Genentech Inc.
  • Jennifer A. Low
    • Genentech Inc.
    • Genentech Inc.
Original Article

DOI: 10.1007/s00280-012-1996-6

Cite this article as:
LoRusso, P.M., Piha-Paul, S.A., Mita, M. et al. Cancer Chemother Pharmacol (2013) 71: 193. doi:10.1007/s00280-012-1996-6



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 Cmax 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 Cmax (≤5 % change in GMRs; N = 27); norethindrone Cmax 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™VismodegibDrug–drug interactionOral contraceptiveRosiglitazone

Copyright information

© Springer-Verlag Berlin Heidelberg 2012