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Effect of Food on Pharmacokinetics of an Inhaled Drug: A Case Study with a VLA-4 Antagonist, HMR1031

From Drug Metabolism & Pharmacokinetics, Aventis Pharmaceuticals, Inc., Bridgewater, New Jersey (Dr. Shah, Dr. Jensen, Dr. Zhang, Dr. Rohatagi) and PPD Development, Phase I Clinic, Austin, Texas (Dr. Hunt).

HMR1031 is a potent and specific antagonist of the integrin VLA-4 (₄ß₁) binding to vascular cell adhesion molecule-1 (VCAM-1) and fibronectin. HMR1031 is an inhaled drug being developed for the treatment of asthma using an Ultrahaler® dry-powder inhalation device. A pharmacoscintigraphic study of HMR1031 suggests a lung deposition of 25% and gastrointestinal tract deposition of 75%. Since oral absorption may be contributing to systemic plasma concentrations, the effect of food on HMR1031 was assessed. This was a single-dose (3 mg), open-label, randomized, two-way crossover (fasted vs. fed) study in 8 healthy male subjects. Blood samples were collected at predose and up to 24 hours postdose. Plasma concentrations were determined by the LC/MS/MS method. HMR1031 was rapidly absorbed, with median t_max values of 1.0 and 0.75 hours under fasted and fed conditions, respectively. Under fasted conditions, mean AUC and C_max values were 16.4 ng•h/mL and 4.56 ng/mL, respectively. Under fed conditions, mean AUC and C_max values decreased to 11.7 ng•h/mL and 2.81 ng/mL, respectively. The mean terminal elimination half-life (t_1/2) for both treatment groups was similar (2.7 h). HMR1031 population estimates of the apparent clearance, apparent volume of distribution, and absorption rate were 225 L/h (4.1% coefficient of variation [CV]), 44.5 L (26% CV), and 0.340 h^-1 (7.0% CV), respectively. Food is a significant covariate on clearance. These data suggest that food unexpectedly decreases the systemic exposure of inhaled HMR1031 by 30%, probably due to increased liver blood flow and increased biliary excretion. This decrease in systemic exposure is unlikely to affect the topical effect of the drug but may result in increased variability in plasma pharmacokinetics. The disposition and food effect of HMR1031 can be described using mixed-effect modeling.

Key Words: VLA-4 • food effect • HMR1031 • inhalation

Address for reprints: Shashank Rohatagi, Drug Metabolism & Pharmacokinetics, Aventis Pharmaceuticals, Inc., Route 202-206, P.O. Box 6800, Mail Stop 303B, Room M309, Bridgewater, NJ 08807.

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