title: Population pharmacokinetics of afatinib, an irreversible ErbB family blocker, in patients with various solid tumors.
abstract: OBJECTIVE
  This population pharmacokinetic model was developed to characterize the pharmacokinetics of the oral irreversible ErbB family blocker afatinib in patients with solid tumors and to investigate the impact of selected intrinsic and extrinsic factors.
  
  
  METHODS
  Data from 927 patients (4,460 plasma concentrations) with advanced solid tumors in 7 Phase II or III studies were analyzed. Afatinib was administered orally in continuous 3 or 4 week cycles (starting dose 20, 40 or 50 mg once-daily). Plasma concentration-time data for up to 7 months dosing were analyzed using nonlinear mixed-effects modeling.
  
  
  RESULTS
  The pharmacokinetic profile of afatinib was best described by a two-compartment disposition model with first-order absorption and linear elimination. There was a slightly more than proportional increase in exposure with increasing dose, accounted for by a dose-dependent relative bioavailability. For the therapeutic dose of 40 mg, the estimated apparent total clearance and distribution volume at steady state were 734 mL/min and 2,370 L, respectively. While food intake, body weight, gender, Eastern Cooperative Oncology Group performance score, renal function, and the level of alkaline phosphatase, lactate dehydrogenase or total protein were statistically significant covariates influencing afatinib exposure, none resulted in a proportional change in exposure of more than 27.8 % in a typical patient at model extremes (2.5th and 97.5th percentiles of baseline values for continuous covariates). In simulations of the individual covariate effects, none caused a change in the typical profile exceeding the observed variability range (90 % prediction interval) of afatinib.
  
  
  CONCLUSIONS
  This population pharmacokinetic model adequately described the pharmacokinetics of afatinib in different cancer patient populations and therefore can be used for simulations exploring covariate effects and possible dose adaptations. The effect size for each of the individual covariates is not considered clinically relevant.
authors: Department of Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co KG, Birkendorfer Strasse 65, 88397, Biberach an der Riss, Germany, matthias.freiwald@boehringer-ingelheim.com.
authors: Matthias
authors: M
authors: Freiwald
authors: Ulrike
authors: U
authors: Schmid
authors: Angele
authors: A
authors: Fleury
authors: Sven
authors: S
authors: Wind
authors: Peter
authors: P
authors: Stopfer
authors: Alexander
authors: A
authors: Staab
mesh_terms: D000042:Absorption; D000328:Adult; D000077716:Afatinib; D000368:Aged; D000369:Aged, 80 and over; D017322:Clinical Trials, Phase II as Topic; D017326:Clinical Trials, Phase III as Topic; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D011799:Quinazolines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D000077716:Afatinib; D066246:ErbB Receptors; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases