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Evaluation of the effect of food and ketoconazole on the pharmacokinetics of the smoothened inhibitor PF-04449913 in healthy volunteers

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Abstract

Purpose

To evaluate the effect of a potent cytochrome P450 3A4 (CYP3A4) inhibitor, ketoconazole, and separately the effect of food on PF-04449913 pharmacokinetics in healthy volunteers.

Methods

This was an open-label, two-sequence, three-period, three-treatment, single-dose, crossover study. Subjects were randomized to receive single doses of 200 mg PF-04449913 after an overnight fast or after consuming a high-fat meal during Period 1 or 2, with a washout period of at least 8 days. In Period 3, all subjects received ketoconazole (400 mg/day) (days 1–7) and a co-administered single 200-mg PF-04449913 dose (day 4).

Results

Geometric mean ratio of PF-04449913 in the presence of ketoconazole versus PF-04449913 alone was 2.40 [90 % confidence interval (CI) 2.15, 2.68] for area under the plasma concentration–time curve from time zero to infinity (AUC0–inf) and 1.40 (90 % CI 1.24, 1.58) for peak plasma concentration (C max). The geometric mean ratio for fed state compared with fasted state for AUC0–inf was 0.87 (90 % CI 0.78, 0.97) and for C max was 0.66 (90 % CI 0.56, 0.78). PF-04449913 was well tolerated, and all adverse events were mild to moderate.

Conclusions

PF-04449913 plasma exposures and peak concentrations were increased following concurrent administration of ketoconazole in healthy volunteers. These findings provide the upper limit for expected PF-04449913 exposures after co-administration of a strong CYP3A4 inhibitor in patients with cancer who routinely receive antifungal azoles. While a high-fat meal decreased PF-04449913 exposure, the differences in plasma exposure under the two conditions were not considered clinically meaningful.

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Acknowledgments

This study was sponsored by Pfizer Inc. The authors thank Yazdi K. Pithavala, for his in depth review of the manuscript. Editorial support was provided by Sara Mariani, M.D., Ph.D., of Engage Scientific Solutions and was funded by Pfizer Inc.

Conflict of interest

M.N.S., R.R.L., D.R., and W.J.L. were full-time employees of Pfizer Inc during the conduct of this study.

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Authors and Affiliations

  1. Pfizer Inc, 10555 Science Center Dr, San Diego, CA, 92121, USA

    M. Naveed Shaik & Wendy J. Levin

  2. Pfizer Inc, MS 8260-2147 Eastern Point Rd, Groton, CT, 06340, USA

    Robert R. LaBadie

  3. Pfizer Clinical Research Unit, One Howe St, New Haven, CT, 06511, USA

    Dan Rudin

Authors
  1. M. Naveed Shaik
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  2. Robert R. LaBadie
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  3. Dan Rudin
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  4. Wendy J. Levin
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Correspondence to M. Naveed Shaik.

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Shaik, M.N., LaBadie, R.R., Rudin, D. et al. Evaluation of the effect of food and ketoconazole on the pharmacokinetics of the smoothened inhibitor PF-04449913 in healthy volunteers. Cancer Chemother Pharmacol 74, 411–418 (2014). https://doi.org/10.1007/s00280-014-2502-0

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  • DOI: https://doi.org/10.1007/s00280-014-2502-0

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