Single-dose pharmacokinetics and pharmacodynamics of RWJ 67657, a specific p38 mitogen-activated protein kinase inhibitor: a first-in-human study.
The objective of this study was to investigate the pharmacokinetics and ex vivo pharmacodynamics of increasing doses of RWJ 67657, along with the effect of food at one dose level in a first-in-human (FIH) study. This was a placebo-controlled, double-blind, randomized trial in healthy male subjects. Subjects received increasing doses of RWJ 67657 or placebo as a single oral dose (0.25-30 mg/kg) under fasting conditions. The effect of food was investigated for the 10-mg/kg dose. Plasma concentrations of RWJ 67657 were measured over a period of 48 hours using a validated LC-MS/MS method. To evaluate the pharmacodynamics of RWJ 67657, inhibition of cytokine production was monitored from exvivo-stimulated polymorphonuclear blood cells (PBMCs). Pharmacokinetic/pharmacodynamic modeling was used to characterize the inhibitory activity of RWJ 67657. RWJ 67657 was rapidly absorbed (mean tmax = 0.6-2.5 h). The pharmacokinetics of RWJ 67657 appear to be nonlinear with respect to single-dose administration of the investigative formulation. Coadministration of food did not have a significant effect on half-life or time to peak concentration (tmax) but decreased the exposure. Mean Cmax values in the presence of food were almost 50% lower than during fasting (542 vs. 1283 ng/mL), and the AUC decreased from 2832 to 1904 ng.h/mL with food. RWJ 67657 inhibited TNF-alpha, IL-8, and IL-6 in a concentration-dependent manner with mean IC50 values of 0.18 microM, 0.04 microM, and 0.43 microM, respectively. At 20 mg/kg, the median inhibition was greater than 85%. There were no significant adverse effects associated with single doses of this drug. This study demonstrates that RWJ 67657 has acceptable safety and pharmacokinetics to warrant further investigation in a repeat-dose setting. In addition, the early determination of effect on biomarkers suggests potential efficacy in diseases mediated by proinflammatory and inflammatory cytokines.
Parasrampuria
Dolly A
DA
Johnson & Johnson Pharmaceutical R&D, Raritan, New Jersey, USA.
de Boer
Peter
P
Desai-Krieger
Daksha
D
Chow
Andrew T
AT
Jones
C Richard
CR
D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D015415:Biomarkers; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D018565:Food-Drug Interactions; D008401:Gas Chromatography-Mass Spectrometry; D006207:Half-Life; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007093:Imidazoles / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases
D015415:Biomarkers; D007093:Imidazoles; D011725:Pyridines; C400277:RWJ 67657; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases