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Population exposure–safety analysis of cediranib for Phase I and II studies in patients with cancer
Author(s) -
AlHuniti Nidal,
Petersson Klas,
Tang Weifeng,
Masson Eric,
Li Jianguo
Publication year - 2018
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/bcp.13495
Subject(s) - medicine , dosing , discontinuation , population , pharmacokinetics , pharmacology , oncology , environmental health
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.