Population exposure–safety analysis of cediranib for Phase I and II studies in patients with cancer. (31st January 2018)

• Record Type: Journal Article
• Authors: Al‐Huniti, Nidal; Petersson, Klas; Tang, Weifeng; Masson, Eric; Li, Jianguo
• Is Part Of: British journal of clinical pharmacology. Volume 84:Number 4(2018:Oct.)
• Page Start: 726
• Page End: 737
• Publication Date: 2018-01-31
• Subjects: exposure response -- hypertension -- oncology -- population analysis -- safety; Pharmacology -- Periodicals; Drugs -- Periodicals; 615.1
• DOI: 10.1111/bcp.13495
• Languages: English
• ISSNs: 0306-5251

Abstract

Abstract : Aims: A multistudy analysis of cediranib, a potent, selective inhibitor of all three vascular endothelial growth factor receptors (VEGFR‐1, ‐2 and ‐3), was conducted to establish population exposure–safety models for the relationship of cediranib exposure to the safety endpoints, diastolic and systolic blood pressure (DBP and SBP) and diarrhoea in cancer patients. These models were applied to predict safety outcomes for different cediranib dose regimens. Methods: Models for hypertension and diarrhoea were constructed based on data from 10 Phase I and three Phase II studies comprising 631 cancer patients following cediranib once‐daily oral dosing. Daily DBP and SBP were simultaneously characterized using indirect response models for predicted cediranib concentration–time courses, while daily diarrhoea events were modelled as ordered categorical variables with a proportional odds model with a Markov element for predicted average cediranib concentrations. Results: For 20 mg cediranib once‐daily oral administration, the mean increase in DBP and SBP was predicted to be 7 (95% CI 3–13) and 8 mmHg (95% CI 3–16), respectively, while the probability of mild diarrhoea, but not the severity, was predicted to increase over time. Severe diarrhoea was predicted to be resolved rapidly upon discontinuation of cediranib treatment. Conclusions: Maximum blood pressure increase was observed within the first few days of cediranib treatment, consistent with the pharmacokinetic profile of cediranib reaching steady state in about 5 days. The probability of diarrhoea increased with cediranib concentration but was far more dependent on the status of diarrhoea predicted on the previous day.