Abstract B188: Pharmacokinetic assessment of drug-drug interaction potential when rosiglitazone or combined oral contraceptive is coadministered with vismodegib in patients with locally advanced or metastatic solid tumors.
Authors: LoRusso Patricia M. , Piha-Paul Sarina A. , Colevas Alexander D. , Malhi Vikram , Colburn Dawn , Yin Ming , Low Jennifer A. , Graham Richard A. 
Published: June 2012

Abstract
Vismodegib is a first-in-class small molecule Hedgehog pathway inhibitor that is being developed for the treatment of advanced basal cell carcinoma. In a previous phase I study for patients with advanced malignancies, vismodegib was well tolerated and tumor regressions were seen in patients with advanced basal cell carcinoma and medulloblastoma. In vitro, vismodegib inhibits CYP2C8 with a Ki of 6.0 μM, which was the most potent relative to other CYP isoforms. With the average steady-state plasma concentration of total vismodegib being approximately 20 μM, inhibition of CYP2C8 by vismodegib may be important when patients are taking drugs known to be metabolized by CYP2C8. Furthermore, while vismodegib was not shown to induce CYP enzymes in vitro, it is a known teratogen. A DDI assessment with combined oral contraceptive (OC) was therefore conducted to ensure efficacious levels of OC would be maintained in patients taking vismodegib and OC in combination.
This single-arm study consisted of two cohorts; 24 patients took 4 mg rosiglitazone (a known CYP2C8 substrate) and 27 patients took OC (norethindrone 1 mg/ethinyl estradiol 35 mcg, Ortho-Novum 1/35®). On Day 1 patients took rosiglitazone or OC followed by extensive PK sampling for 24 hrs. From Day 2 to Day 7 patients took 150 mg vismodegib once per day. On Day 8 patients took either vismodegib and rosiglitazone or vismodegib and OC followed by extensive PK sampling for 24 hrs. From Day 9 onward patients took vismodegib until disease progression or lack of benefit. The primary objective of this study was to evaluate the relative effect of vismodegib on AUC and Cmax for rosiglitazone and OC (ethinyl estradiol and norethindrone).
The average steady state plasma concentration of total vismodegib (N=51) was 20.6 μM (range, 7.93 − 62.4 μM). There was no clinically meaningful difference in rosiglitazone PK parameters between Day 1 (without vismodegib) and Day 8 (with vismodegib) with a less than 10% difference in AUCinf and Cmax, on average. The geometric mean ratios (GMRs) for rosiglitazone AUC0−inf and Cmax were 93.1 and 93.4 with corresponding 90% confidence intervals (CIs) of (85.0, 102) and (89.4, 97.6), respectively. Concomitant administration of vismodegib with OC did not strongly impact the plasma concentrations of ethinyl estradiol or norethindrone, as evidenced by a less than 20% change in AUCinf and Cmax, on average, for both components. The GMRs for ethinyl estradiol AUC0−inf and Cmax were 99.3 and 106 with corresponding 90% CIs of (91.9, 107) and (94.8, 117), respectively while the GMRs for norethindrone AUC0−inf and Cmax were 124 and 112 with corresponding 90% CIs of (116, 132) and (101, 124), respectively.
In the current study, the steady state plasma concentration of total vismodegib was above the in vitro Ki for CYP2C8. In addition, daily dosing of 150 mg vismodegib for 7 days should have been adequate to result in enzyme induction, if applicable. Overall, results from this study indicate that there was no clinically meaningful difference in AUC0−inf and Cmax for rosiglitazone, ethinyl estradiol, or norethindrone when co-administered with vismodegib. Taken together these results suggest that vismodegib can be co-administered with CYP substrates and combined oral contraceptive without the risk of a pharmacokinetic DDI.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B188.