Effect of food and antacids on the pharmacokinetics of pirfenidone in older healthy adults

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Abstract

Pirfenidone is a small, synthetic molecule under investigation for treatment of idiopathic pulmonary fibrosis. In an open-label, single-dose crossover study, the pharmacokinetics (PK) of pirfenidone were investigated with or without food and antacids in healthy adult volunteers. Concentrations of pirfenidone and its metabolites in plasma and urine were determined by liquid chromatography with tandem mass spectrometry, and candidate pharmacokinetic models were fit to plasma data using weighted, non-linear regression. The effect of food and antacids on pirfenidone exposure was evaluated by determining ‘equivalence’ using FDA guidelines. Adverse events were recorded by site personnel and classified by investigators on the basis of severity and relationship to study drug.

Sixteen subjects yielded 64 pharmacokinetic profiles. The best fit was achieved using a five-compartment, linear model with an allowance for direct conversion to the primary metabolite (5-carboxy-pirfenidone). Coadministration with food decreased the rate and, to a lesser degree, the extent of pirfenidone absorption of absorption. Analysis of adverse events revealed a correlation between pirfenidone Cmax and the risk of gastrointestinal (GI) adverse events, suggesting that food may reduce the risk of certain adverse events associated with pirfenidone. Administration of pirfenidone with food has a modest effect on overall exposure but results in lower peak concentrations, which may improve tolerability.

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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