Abstract:
BACKGROUND AND 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). SUBJECTS AND 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. CONCLUSION: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.
journal_name
Clin Pharmacokinetjournal_title
Clinical pharmacokineticsauthors
Yang S,Lukey P,Beerahee M,Hoke Fdoi
10.1007/s40262-012-0025-6subject
Has Abstractpub_date
2013-03-01 00:00:00pages
187-98issue
3eissn
0312-5963issn
1179-1926journal_volume
52pub_type
杂志文章,随机对照试验abstract::Since its discovery in 1970, and introduction into clinical practice in 1978, cyclosporin has become the most important immunosuppressive drug used to prevent organ transplant rejection. This has been achieved by virtue of the improved graft survival rates and adverse effect profiles in patients when compared with tha...
journal_title:Clinical pharmacokinetics
pub_type: 杂志文章,评审
doi:10.2165/00003088-199732050-00002
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abstract::Amiodarone is an iodinated benzofuran derivative with recognised antiarrhythmic activity in man. As yet, its pharmacokinetic behaviour has not been satisfactorily characterised. Specific and sensitive high-pressure liquid chromatographic methods have become available only recently and this partly explains the scarcity...
journal_title:Clinical pharmacokinetics
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journal_title:Clinical pharmacokinetics
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pub_type: 临床试验,杂志文章,随机对照试验
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journal_title:Clinical pharmacokinetics
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pub_type: 临床试验,杂志文章,随机对照试验
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journal_title:Clinical pharmacokinetics
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journal_title:Clinical pharmacokinetics
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journal_title:Clinical pharmacokinetics
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