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Pharmacokinetic Evaluations of the Co-Administrations of Vandetanib and Metformin, Digoxin, Midazolam, Omeprazole or Ranitidine

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An Erratum to this article was published on 26 September 2014

Abstract

Background and Objective

Vandetanib is a selective inhibitor of vascular endothelial growth factor receptor (VEGFR), epidermal growth factor receptor (EGFR) and rearranged during transfection (RET) signalling, indicated for the treatment of medullary thyroid cancer. We investigated potential drug–drug interactions between vandetanib and metformin [organic cation transporter 2 (OCT2) substrate; NCT01551615]; digoxin [P-glycoprotein (P-gp) substrate; NCT01561781]; midazolam [cytochrome P450 (CYP) 3A4 substrate; NCT01544140]; omeprazole (proton pump inhibitor) or ranitidine (histamine H2-receptor antagonist; both NCT01539655).

Methods

Four open-label, phase I studies were conducted in healthy volunteers: n = 14 (metformin), n = 14 (digoxin), n = 17 (midazolam), n = 16 (omeprazole), n = 18 (ranitidine). Three of these comprised the following regimens: metformin 1000 mg ± vandetanib 800 mg, midazolam 7.5 mg ± vandetanib 800 mg, or digoxin 0.25 mg ± vandetanib 300 mg. The randomized study comprised vandetanib 300 mg alone and then either (i) omeprazole 40 mg (days 1–4), and omeprazole + vandetanib (day 5); or (ii) ranitidine 150 mg (day 1), and ranitidine + vandetanib (day 2). The primary objective assessed metformin, digoxin, midazolam and vandetanib pharmacokinetics.

Results

Vandetanib + metformin increased metformin area under the plasma concentration–time curve from zero to infinity (AUC0–∞) and maximum observed plasma concentration (Cmax) by 74 and 50 %, respectively, and decreased the geometric mean metformin renal clearance (CLR) by 52 % versus metformin alone. Vandetanib + digoxin increased digoxin area under the concentration-time curve from zero to the last quantifiable concentration (AUC0–last) and Cmax by 23 and 29 %, respectively, versus digoxin alone, with only a 9 % decrease in CLR. Vandetanib had no effect on midazolam exposure. Vandetanib exposure was unchanged during co-administration with omeprazole/ranitidine. Treatment combinations were generally well tolerated.

Conclusion

Patients receiving vandetanib with metformin/digoxin may require additional monitoring of metformin/digoxin, with dose adjustments where necessary. Vandetanib with CYP3A4 substrates or omeprazole/ranitidine is unlikely to result in clinically relevant drug–drug interactions.

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Acknowledgments

These studies were sponsored by AstraZeneca. Claire Routley, PhD, from Mudskipper Business Ltd, provided medical writing support, funded by AstraZeneca.

Susanne Johansson, Jessica Read, Stuart Oliver, Mark Steinberg, Yan Li, and Paul Martin are employees of AstraZeneca; Eleanor Lisbon, David Mathews and Philip T. Leese declare no conflicts of interest.

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Authors and Affiliations

  1. AstraZeneca R&D Mölndal, Quantitative Clinical Pharmacology, SE-431 83, Mölndal, Sweden

    Susanne Johansson

  2. PRA International, Reading, UK

    Jessica Read

  3. AstraZeneca, Alderley Park, Macclesfield, UK

    Stuart Oliver & Paul Martin

  4. AstraZeneca, Wilmington, DE, USA

    Mark Steinberg & Yan Li

  5. Quintiles Phase I Services, Overland Park, KS, USA

    Eleanor Lisbon, David Mathews & Philip T. Leese

Authors
  1. Susanne Johansson
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  2. Jessica Read
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  3. Stuart Oliver
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  6. Eleanor Lisbon
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  8. Philip T. Leese
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  9. Paul Martin
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Correspondence to Susanne Johansson.

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Johansson, S., Read, J., Oliver, S. et al. Pharmacokinetic Evaluations of the Co-Administrations of Vandetanib and Metformin, Digoxin, Midazolam, Omeprazole or Ranitidine. Clin Pharmacokinet 53, 837–847 (2014). https://doi.org/10.1007/s40262-014-0161-2

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