title: Population pharmacokinetics of losmapimod in healthy subjects and patients with rheumatoid arthritis and chronic obstructive pulmonary diseases.
abstract: OBJECTIVE
  Losmapimod is an orally available, potent p38 mitogen-activated protein kinase inhibitor. It is in development as an anti-inflammatory drug in different therapeutic areas. Clinical studies have shown that losmapimod is well tolerated and safe in humans and several studies have shown its pharmacological effect in the target diseases. The aim of this work was to develop a population pharmacokinetic model and to explore the covariates affecting the pharmacokinetics of losmapimod using data collected from healthy volunteers and patients with rheumatoid arthritis (RA) and chronic obstructive pulmonary diseases (COPD).
  
  
  METHODS
  The plasma concentration data were pooled from four of the losmapimod clinical studies, with 30 healthy subjects, 23 subjects with RA and 24 subjects with COPD. Non-linear mixed-effects modelling was used to build a base model to characterize the structure and describe the variability of the pharmacokinetics of losmapimod. The available demographic covariates were explored to further explain the inter-subject variability. New data generated from another RA study with 34 subjects were used to validate the final model. All modelling was conducted using NONMEM(®) VI.
  
  
  RESULTS
  A two-compartment model with first-order elimination and time-dependent first-order absorption was found to best fit the concentration-time profiles of losmapimod following oral administration. The first phase of the absorption was more variable than the second phase for most of the subjects in the dataset. There was no apparent difference in the structure of the pharmacokinetic model among healthy subjects and patients with RA and COPD. A slightly higher residual error was associated with COPD patients compared with the healthy and RA subjects. Three demographic covariates, namely sex, age and bodyweight, were retained in the final model to explain the inter-individual variability on pharmacokinetic parameters apparent total oral clearance (CL/F), apparent volume of distribution of the central compartment (V(1)) and the first-order absorption rate constant (k(a)). Most of the fixed effect parameters (θ(pop,j) and θ for covariate) of the final model were estimated with good precision (% relative standard error [RSE] ≤30 %). The inter-individual variability was precisely estimated (%RSE ≤30 %) for clearance and k(a), but less precise for inter-compartmental clearance and volumes of distribution. The mean clearance following oral administration of losmapimod was approximately 31.2 L/h (95 % CI 27.7-35.2) for males and 24.6 L/h (95 % CI 22.1-27.3) in females.
  
  
  CONCLUSIONS
  The population pharmacokinetic model described in this work well characterized the pharmacokinetic profile of losmapimod following administration of a single oral dose and repeated oral doses in healthy subjects and patients with RA and COPD. Although sex, bodyweight and age were significant factors influencing some pharmacokinetic parameters of losmapimod, the relatively small magnitude of the effect did not result in concerns for dose adjustment.
authors.affiliation: Clinical Pharmacology Modelling and Simulation, Quantitative Sciences, GlaxoSmithKline, Building 11, 1-2 Iron Bridge Road, Stockley Park West, Middlesex, UK. shuying.y.yang@gsk.com
authors.forename: Shuying
authors.initials: S
authors.lastname: Yang
authors.forename: Pauline
authors.initials: P
authors.lastname: Lukey
authors.forename: Misba
authors.initials: M
authors.lastname: Beerahee
authors.forename: Frank
authors.initials: F
authors.lastname: Hoke
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000378:metabolism*; D018592:Cross-Over Studies; D003521:Cyclopropanes / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D029424:Pulmonary Disease, Chronic Obstructive / Q000378:metabolism*; D011725:Pyridines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D055815:Young Adult; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors
chemical_list: C543534:6-(5-((cyclopropylamino)carbonyl)-3-fluoro-2-methylphenyl)-N-(2,2-dimethylprpyl)-3-pyridinecarboxamide; D003521:Cyclopropanes; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D048051:p38 Mitogen-Activated Protein Kinases