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

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 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.

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™VismodegibDrug–drug interactionOral contraceptiveRosiglitazone

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