Contribution of protein binding to the pharmacokinetics of the ghrelin receptor agonist TZP-101 in healthy volunteers and adults with symptomatic gastroparesis: two randomized, double-blind studies and a binding profile study.
OBJECTIVE
TZP-101 is a selective, small molecule ghrelin receptor agonist in clinical development for the treatment of gastric motility disorders. The objectives of this study was to assess pharmacokinetic parameters of TZP-101 after multiple- and single-dose administration to healthy subjects and patients with gastroparesis, respectively, and to determine the contribution of protein binding to its pharmacokinetic behaviour.


METHODS
Pharmacokinetics following 30-minute intravenous infusions of single (160-600 microg/kg) doses of TZP-101 in patients with gastroparesis and multiple (80-600 mug/kg/day) doses of TZP-101 in healthy subjects were characterized. TZP-101 protein binding was measured in human, dog, rat, rabbit and monkey plasma using equilibrium dialysis.


RESULTS
TZP-101 pharmacokinetic profiles were less than dose proportional in both healthy subjects and patients, most likely because of concentration-dependent protein binding. A small volume of distribution (99-180 mL/kg following single doses) and long half-life (10-20 hours) were concentration independent in both healthy subjects and patients. Systemic clearance increased with increasing dose. Incidence of adverse events was not related to dose or treatment (active vs placebo). TZP-101 binding to human plasma proteins (primarily alpha(1)-acid glycoprotein) was >/=99% between 5 and 15 mumol/L (2.7 and 8.1 microg/mL) and was significantly higher than in other species.


CONCLUSIONS
The pharmacokinetic parameters of TZP-101 in patients with gastroparesis and healthy subjects are comparable and display a similar trend toward increased clearance at higher dose levels resulting in little accumulation of TZP-101 at high dose levels and after multiple dosing. Significant protein binding indicates that the fraction of free drug rather than the total plasma concentration should be taken into consideration for human risk assessment based on animal safety data. Furthermore, the concentration of unbound drug should be considered when optimizing the clinical dose.
Wargin
William
W
PK-PM Associates, LLC, Research Triangle Park, North Carolina, USA.
Thomas
Helmut
H
Clohs
Lilian
L
St-Louis
Carl
C
Ejskjaer
Niels
N
Gutierrez
Maria
M
Shaughnessy
Laura
L
Kosutic
Gordana
G
D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D018592:Cross-Over Studies; D004285:Dogs; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D018589:Gastroparesis / Q000188:drug therapy*; D006801:Humans; D007262:Infusions, Intravenous; D008252:Macaca fascicularis; D047028:Macrocyclic Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009961:Orosomucoid / Q000378:metabolism; D011485:Protein Binding; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D054440:Receptors, Ghrelin / Q000819:agonists*; D012709:Serum Albumin / Q000378:metabolism
D047028:Macrocyclic Compounds; D009961:Orosomucoid; D054440:Receptors, Ghrelin; D012709:Serum Albumin; C528884:ulimorelin