title: Population pharmacokinetic and exposure simulation analysis for cediranib (AZD2171) in pooled Phase I/II studies in patients with cancer.
abstract: A population pharmacokinetic (PK) model was developed for cediranib to simulate cediranib exposure for different doses, including comedication with strong uridine glucuronosyl transferase/P-glycoprotein inducers such as rifampicin, in cancer patients.
  
  
  
  Plasma concentrations and covariates from 625 cancer patients after single or multiple oral cediranib administrations ranging from 0.5 to 90 mg in 19 Phase I and II studies were included in the analysis. Stepwise covariate modelling was used to develop the population PK model. The final model was used to simulate cediranib exposure in cancer patients to evaluate cediranib target coverage and the need for dose adjustment for covariates or coadministration with rifampicin.
  
  
  
  A two-compartment model with sequential zero- and first-order absorption and first-order elimination adequately described the cediranib concentration-time courses. Body weight and age were identified as having statistically significant impact on cediranib PK, but only <21% impact on AUC and maximum concentrations. Simulated lower bounds of 90% prediction interval or median of unbound cediranib concentrations after cediranib 15 or 20 mg exceeded the IC50for vascular endothelial growth factor receptors-1, -2 and -3. Exposures of cediranib 20 or 30 mg with coadministration of rifampicin were comparable to those of 15 or 20 mg, respectively, without coadministration.
  
  
  
  No covariate was identified to require dose adjustment for cediranib. Cediranib exposure following 15 or 20 mg daily dose administration is adequate overall for inhibition of in vitro estimated vascular endothelial growth factor receptor-1, -2 and -3 activities. An increase in cediranib dose may be needed for cediranib coadministered with strong uridine glucuronosyl transferase/P-glycoprotein inducers such as rifampicin.
authors.affiliation: Quantitative Clinical Pharmacology, Early Clinical Development, Innovative Medicine and Early Development, AstraZeneca, Waltham, Massachusetts, USA.
authors.forename: Jianguo
authors.initials: J
authors.lastname: Li
authors.affiliation: Quantitative Clinical Pharmacology, Early Clinical Development, Innovative Medicine and Early Development, AstraZeneca, Waltham, Massachusetts, USA.
authors.forename: Nidal
authors.initials: N
authors.lastname: Al-Huniti
authors.affiliation: qPharmetra, LLC, Stockholm, Sweden.
authors.forename: Anja
authors.initials: A
authors.lastname: Henningsson
authors.affiliation: Quantitative Clinical Pharmacology, Early Clinical Development, Innovative Medicine and Early Development, AstraZeneca, Waltham, Massachusetts, USA.
authors.forename: Weifeng
authors.initials: W
authors.lastname: Tang
authors.affiliation: Quantitative Clinical Pharmacology, Early Clinical Development, Innovative Medicine and Early Development, AstraZeneca, Waltham, Massachusetts, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Masson
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000096:biosynthesis / Q000187:drug effects; D000284:Administration, Oral; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001835:Body Weight; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D004334:Drug Administration Schedule; D005260:Female; D014453:Glucuronosyltransferase / Q000096:biosynthesis / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy*; D019338:Polypharmacy; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011799:Quinazolines / Q000493:pharmacokinetics* / Q000627:therapeutic use; D012293:Rifampin / Q000494:pharmacology; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000037:antagonists & inhibitors; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000037:antagonists & inhibitors; D055815:Young Adult; D007211:Indoles
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents; D014453:Glucuronosyltransferase; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D012293:Rifampin; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2; D040321:Vascular Endothelial Growth Factor Receptor-3; C501162:FLT1 protein, human; C581309:FLT4 protein, human; C000588866:KDR protein, human; C500926:cediranib; D007211:Indoles
keywords: AZD2171; cediranib; exposure prediction; pharmacometrics; population pharmacokinetics; vascular endothelial growth factor receptor inhibitors