Population Pharmacokinetics and Pharmacodynamics of GSK961081 (Batefenterol), a Muscarinic Antagonist and β2-Agonist, in Moderate-to-Severe COPD Patients: Substudy of a Randomized Trial.
GSK961081 (batefenterol) is a novel bifunctional molecule composed of a muscarinic antagonist and a β2-agonist. The aims of this substudy were (1) to characterize the population pharmacokinetics (PK) and pharmacodynamics (PD) of GSK961081 in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD); and (2) to investigate the relationship between systemic exposure to GSK961081 and key cardiac-related safety parameters. Three once-daily doses (100, 400, and 800 μg) and three twice-daily doses (100, 200, and 400 μg) of GSK961081 DISKUS were investigated. A two-compartment disposition PK model with first-order absorption adequately described the plasma GSK961081 concentration-time data. An empirical maximum-effects PD model adequately described the forced expiratory volume in 1 s (FEV1) response relationship with the covariate baseline FEV1 on day 1. No clear relationships between GSK961081 plasma drug levels and cardiac-related safety parameters were apparent. The PK and PD models will be used to guide the dose selection and development of GSK961081 in patients with COPD.
GlaxoSmithKline, Stockley Park West, 1-3 Ironbridge Road, Uxbridge, Middlesex, UB11 1BT, UK, claire.l.ambery@gsk.com.
Claire L
CL
Ambery
Pascal
P
Wielders
Andrea
A
Ludwig-Sengpiel
Robert
R
Chan
John H
JH
Riley
D058666:Adrenergic beta-2 Receptor Agonists / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D000328:Adult; D000368:Aged; D002219:Carbamates / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D005541:Forced Expiratory Volume / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D018727:Muscarinic Antagonists / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy / Q000378:metabolism*; D015363:Quinolones / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*
D058666:Adrenergic beta-2 Receptor Agonists; D002219:Carbamates; D018727:Muscarinic Antagonists; D015363:Quinolones; C588122:batefenterol