Effect of food and antacids on the pharmacokinetics of pirfenidone in older healthy adults
Introduction
Idiopathic pulmonary fibrosis (IPF) is a relatively rare and fatal lung disease of unknown etiology characterized by unremitting fibrosis of the lung interstitium, decreased lung volume, and progressive pulmonary insufficiency [1]. IPF is the most common form of interstitial pneumonia, with an approximate prevalence of 42.7 per 100,000 adults in the United States [2]. The disease is more common in men than in women, and patients most commonly present with disease between 50 and 70 years of age [3]. There are currently no proven treatments, although current therapeutic guidelines suggest combination therapy with corticosteroids and immunosuppressive agents until adequate studies are completed that define the best treatment options [4].
Pirfenidone is a small, synthetic, non-peptide molecule of low molecular weight that exhibits antifibrotic properties in a variety of in vitro and animal models [5], [6], [7]. Several recent observational and randomized controlled trials in patients with IPF provided preliminary evidence of a treatment effect that is currently being evaluated in two large Phase III randomized, placebo-controlled trials [8], [9], [10]. These studies have been designed to assess the clinical efficacy and safety of pirfenidone administered at a dose of 801 mg three-times daily. The current study was undertaken to determine the single-dose pharmacokinetics of pirfenidone in healthy volunteers of an age range similar to that of patients with IPF and to evaluate the effect of concomitant food and/or antacid on pirfenidone pharmacokinetics.
Section snippets
Study design
This was a randomized, open-label, single-dose, four-way crossover study in which healthy subjects of either sex, aged between 50 and 79 years, were randomized to one of four treatment sequences. The four treatments were as follows:
Treatment A = pirfenidone administered in the fasted state
Treatment B = pirfenidone administered in the fasted state within 1 min following a dose of antacid (Mylanta® Maximum Strength Liquid)
Treatment C = pirfenidone administered in the fed state
Treatment D = pirfenidone
Data description
Sixteen subjects were included in the PK analyses. The demographics for this cohort are provided in Table 1. All subjects had the full complement of plasma and urine PK samples available for analysis, with the exception of one subject who was discontinued early for reasons not related to the study drug. This subject had five missing plasma samples and no urine data for the final three collection intervals after the final dose of study drug. Plasma parameter estimates were available for this
Discussion
The results of this analysis of plasma concentration data obtained after single-dose administration of pirfenidone to healthy adults indicate that the pharmacokinetics of pirfenidone are best described by a five-compartment linear model with first-pass effect and first-order absorption following a lag time. In addition to the absorption compartment, both the parent drug and the 5-carboxy metabolite required two compartments (one central and one peripheral) to adequately fit the measured
Acknowledgments
The authors wish to thank Ken Glasscock and Charlemagne Lacza for editorial support in the preparation of this manuscript. In addition, the authors acknowledge Sandra Gilbert for editorial assistance in preparation of the manuscript, with funding from InterMune, Inc. This study was supported by a grant from InterMune, Inc.
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