From AAAAI 58th Annual Meeting
157 Safety and Pharmacokinetics of an Oral p38 MAP Kinase Inhibitor (BIRB 796 BS), Administered Twice Daily for 14 Days to Healthy Volunteers
S H Polmar*
Chan-Loi Yong*
Chester C Wood*
Hildegard Staehle§
A Gupta§
*Boehringer-Ingelheim Pharmaceuticals,
Ridgefield, CT
§Boehringer-Ingelheim Pharmaceuticals,
Biberach an der, Riss, Germany
BIRB 796 BS is a potent inhibitor of the synthesis of TNF-alpha and other pro-inflammatory cytokines in mice, monkeys and man in vivo. This study was a Phase I, randomized, double-blind, placebo-controlled, multiple-dose trial to investigate the safety and pharmacokinetics of 15 or 30 mg of an orally available p38MAPK inhibitor administered twice daily compared to placebo for 14 days. Subjects were 49 healthy males, 16 per treatment group (one subject on placebo was discontinued). A previous study with this drug at doses of 20, 50 and 150 mg once daily for one week showed a reversible, asymptomatic, dose-related rise in ALT and AST primarily with the 150 mg dose. Doses up to 50 mg QD for one week were well tolerated. Based on preliminary analysis of this study, 9 of 48 subjects had transaminase values above the upper limit of normal (UNL), 2 in the placebo, 3 in the 15 mg dose group and 4 in 30 mg dose group. Three subjects experienced ALT rises 2-3 fold greater than UNL, one in each dose group. One subject in the 15-mg dose group had a transient elevation of AST of one-day duration. None of the other subjects who had ALT rises had concurrent elevations of AST or bilirubin (except one subject on the 30-mg dose that had a transient increase in total bilirubin at same time as ALT), and all subjects remained asymptomatic. There were no relevant changes in other laboratory studies, EKGs or physical examinations. Eight subjects (three each in placebo and 30 mg bid groups and two in 15 mg bid group) had a total of 16 adverse events in 10 overall episodes, none of which were serious or considered drug related. The pharmacokinetic assessment showed good systemic exposure to drug with a Cmax and AUC0-12 (mean ±SD) on day 14 of 109±51 ng/ml and 334±145 ng* hr/ml (15 mg); and 208±109 ng/ml and 659±449 ng* hr/ml (30 mg), respectively. Dose proportionality was observed for both Cmax and AUC0-12. Mean elimination half-life was 7.3 hr. Based on these results, this oral p38MAPK inhibitor exhibits good pharmacokinetic profiles when administered twice daily at 15 and 30 mg, and is well tolerated at doses up to 30 mg twice daily for two weeks.
158 Safety, Pharmacokinetics, and Pharmacodynamics of Single Doses of an Oral p38 MAP Kinase Inhibitor (BIRB 796 BS) in Healthy Human Males a Placebo-Controlled, Randomised Study, Double Blinded at Each Dose Level
Abhya Gupta*
Chan-Loi Yong§
Jeffrey B Madwed§
Hildegard Staehle*
Chester C Wood§
*Boehringer-Ingelheim Pharmaceuticals,
Biberach an der, Riss, Germany
§Boehringer-Ingelheim Pharmaceuticals,
Ridgefield, CT
This was a Phase 1, randomised, placebo-controlled (2:6 ratio per dose group), double-blind, single escalating dose (1, 4, 15, 50, 100, 200, 400, 600 mg) study to assess safety, tolerability, pharmacokinetics and pharmacodynamics of an orally available p38 MAPK inhibitor in a polyethylene glycol 400 (PEG) solution. Safety was determined by laboratory measurements and clinical examination. Kinetics was assessed by determining plasma concentrations of drug. Dynamics (including kinetic modeling) was assessed by measuring LPS-induced production of TNF- ex vivo and expression of Mac-1 and L-selectin cell surface markers. Sixty-four healthy males (mean age 30 yrs, mean weight 79 kg, mean BMI 23.9) participated. There were no significant changes in ECGs, vital signs or physical examination. There was a mild, reversible, clinically non-significant rise in GGT at the 400 and 600 mg doses. There was also a minor, reversible, increase in total bilirubin associated with the vehicle (15 ml PEG 400). The pharmacokinetic assessment showed good systemic exposure to the drug with a mean Tmax occurring 0.75 to 1.75 hours. Mean Cmax was 2,196 ng/ml at the 600 mg dose and elimination half-life was 6.7 to 9.9 hours throughout the dose range. Dose proportionality was observed for AUC up to 600 mg dose. An Emax model best described the effects of the drug on LPS-induced production of TNF- and on the activation state of human whole blood PMN demonstrating a good relationship between the effects and plasma concentrations. The ex vivo EC50 for inhibiting 1) LPS-induced TNF-max production was 1,228 ng/ml and 2) Mac-1/L-selectin ratio was 91.5 ng/ml with TNF- stimulation and 238 ng/ml with fMLP stimulation. The results indicate that this orally available p38 MAPK inhibitor is well tolerated at single doses up to 600 mg with a good pharmacokinetic profile and a favorable pharmacodynamic effect. |
