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PHARMACOKINETICS AND PHARMACODYNAMICS |
From Clinical Drug Evaluation, Johnson & Johnson Pharmaceutical R&D, Raritan, New Jersey. Dr. Parasrampuria's current affiliation is Clinical Pharmacokinetics/Modeling & Simulation, Clinical Pharmacology & Discovery Medicine, GlaxoSmithKline, King of Prussia, Pennsylvania. Data were presented at the National AAPS meeting, Indianapolis, 2000.
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 ex vivo-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-
, IL-8,
and IL-6 in a concentration-dependent manner with mean IC50 values
of 0.18 µM, 0.04 µM, and 0.43 µM, 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.
Key Words: Pharmacokinetics • pharmacodynamics • RWJ 67657 • biomarker • mitogen-activated protein kinases
Address for reprints: Dolly A. Parasrampuria, PhD, 1636 Tuckerstown Road, Dresher, PA 19025.
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