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Clinical Pharmacokinetics and Pharmacodynamics of Cediranib

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Abstract

Cediranib potently and selectively inhibits all three vascular endothelial growth factor receptors (VEGFR-1, -2 and -3), and clinical studies have shown that it is effective in patients with ovarian cancer at a dose of 20 mg/day. Cediranib is absorbed moderately slowly; a high-fat meal reduced the cediranib area under the plasma concentration–time curve (AUC) by 24% and maximum plasma concentration (C max) by 33%. Cediranib binds to serum albumin and α1-acid glycoprotein; protein binding in human plasma is approximately 95%. The cediranib AUC and C max increase proportionally with dose from 0.5 to 60 mg, and cediranib has linear pharmacokinetics (PK) over time. Cediranib is metabolized via flavin-containing monooxygenase 1 and 3 (FMO1, FMO3) and uridine 5′-diphospho-glucuronosyltransferase (UGT) 1A4. Cediranib and its metabolites are mainly excreted in faeces (59%), with <1% of unchanged drug being excreted in urine. The apparent oral clearance is moderate and the mean terminal half-life is 22 h. Cediranib is a substrate of multidrug resistance-1 (MDR1) protein (also known as P-glycoprotein [P-gp]). Coadministration with ketoconazole, a potent P-gp inhibitor, increases cediranib AUC at steady-state (AUCss) in patients by 21%, while coadministration with rifampicin, a potent inducer of P-gp, decreases cediranib AUCss by 39%. Administration of cediranib with chemotherapies demonstrated minimal PK impact on each other. No dose adjustment is recommended for patients with mild or moderate hepatic or renal impairment, and no dose adjustment is needed on the basis of age and body weight. A pooled analysis at doses of 0.5–60 mg showed no significant increase in QTc intervals. Increases in blood pressure and the incidence of diarrhoea were associated with increased cediranib dose and systemic exposure.

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Acknowledgements

The authors would like to thank their clinical pharmacology colleague, Dr. K. Brown, and bioanalysis colleague, Dr. C. Bailey, for their support in the preparation of this manuscript. They also thank Clara Tan, PhD, from Mudskipper Business Ltd, who provided editorial assistance funded by AstraZeneca.

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  1. Alex McCormick

    Present address: DMPK Consulting UK Limited, Congleton, UK

Authors and Affiliations

  1. Quantitative Clinical Pharmacology, Early Clinical Development, Innovative Medicines, AstraZeneca, One MedImmune Way, Gaithersburg, MD, 20878, USA

    Weifeng Tang

  2. DMPK Oncology, AstraZeneca, Alderley Park, Cheshire, UK

    Alex McCormick

  3. Quantitative Clinical Pharmacology, Early Clinical Development, Innovative Medicines, AstraZeneca, 35 Gatehouse Drive, Waltham, MA, 02451, USA

    Jianguo Li & Eric Masson

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Correspondence to Weifeng Tang.

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Weifeng Tang, Jianguo Li, and Eric Masson are employees of AstraZeneca. Alex McCormick was an employee of AstraZeneca at the time of manuscript preparation.

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This research was sponsored by AstraZeneca.

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Tang, W., McCormick, A., Li, J. et al. Clinical Pharmacokinetics and Pharmacodynamics of Cediranib. Clin Pharmacokinet 56, 689–702 (2017). https://doi.org/10.1007/s40262-016-0488-y

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