PMID- 29944949 OWN - NLM STAT- MEDLINE DCOM- 20190207 LR - 20220409 IS - 1522-9629 (Electronic) IS - 1094-5539 (Linking) VI - 51 DP - 2018 Aug TI - Effect of pirfenidone on gastric emptying in a rat model. PG - 41-47 LID - S1094-5539(18)30019-1 [pii] LID - 10.1016/j.pupt.2018.06.001 [doi] AB - INTRODUCTION: Gastrointestinal (GI) adverse events (AEs) are commonly reported in patients with idiopathic pulmonary fibrosis who are treated with pirfenidone. Taking pirfenidone with a substantial amount of food or dividing the dose over the course of a meal has been reported to reduce the frequency of GI AEs in clinical practice. In humans, the maximum plasma concentration (C(max)) of pirfenidone was reduced when the drug was taken with food compared with the fasting state, and the lower C(max) was associated with a reduction in GI AE rates. In this study, the effects of the divided-dose approach and timing of pirfenidone administration relative to meal intake on gastric emptying were assessed using a rat model. The aim of this study was to investigate whether modification of dosing regimens could minimize pirfenidone's effect on inhibition of gastric emptying. METHODS: Gastric emptying was assessed in male Sprague-Dawley rats after administration of a test meal by weighing stomach contents at various time points up to 120 min after the meal. Pirfenidone was administered via oral gavage either as a single-bolus dose of 30 mg/kg or as divided doses of 3 x 10 mg/kg at intervals ranging from 10 to 30 min for a total duration of 30 to 90 min. In addition, the test meal was given either at 30 min before, coincident with, or 30 min following pirfenidone oral administration. RESULTS: Administration of an oral 30-mg/kg single-bolus dose of pirfenidone with a meal resulted in a statistically significant decrease in gastric emptying in a rat model. The effect of pirfenidone on decreasing gastric emptying was lessened when the same total dose (i.e., 30 mg/kg) was administered as 3 divided doses (i.e., 3 x 10 mg/kg) over intervals up to 30 min in between each divided dose. Pharmacokinetic simulation suggested that a divided-dosing regimen would decrease pirfenidone C(max) relative to single-bolus administration. When the same single-bolus dose of 30 mg/kg was administered 30 min following a meal rather than coincident with a meal, pirfenidone's effect on decreasing gastric emptying was reduced to the same extent as when the dose was divided as 3 x 10 mg/kg over a 90-min period. CONCLUSIONS: Administration of pirfenidone 30 min after a meal as a single-bolus dose or a divided dose over a 90-min period blunted pirfenidone's effect on inhibition of gastric emptying in rats compared with pirfenidone administration as a single-bolus dose coincident with a meal. Decreased gastric emptying, which is associated with pirfenidone administration, may be one of the contributing factors leading to GI tolerability issues associated with pirfenidone use in humans. Modification of the dosing regimen diminished this impact and may provide insight into possible mitigation strategies to minimize GI-related toxicities in the clinic. CI - Copyright (c) 2018. Published by Elsevier Ltd. FAU - Pan, Lin AU - Pan L AD - Genentech, Inc., South San Francisco, CA, USA. Electronic address: pan.lin@gene.com. FAU - Gelzleichter, Thomas AU - Gelzleichter T AD - Genentech, Inc., South San Francisco, CA, USA. FAU - Chen, Yuan AU - Chen Y AD - Genentech, Inc., South San Francisco, CA, USA. FAU - Burg, Cindy AU - Burg C AD - Genentech, Inc., South San Francisco, CA, USA. FAU - Limb, Susan L AU - Limb SL AD - Genentech, Inc., South San Francisco, CA, USA. FAU - Nguyen, Linda AU - Nguyen L AD - Department of Medicine, Stanford University, Palo Alto, CA, USA. LA - eng PT - Comparative Study PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20180623 PL - England TA - Pulm Pharmacol Ther JT - Pulmonary pharmacology & therapeutics JID - 9715279 RN - 0 (Anti-Inflammatory Agents, Non-Steroidal) RN - 0 (Pyridones) RN - D7NLD2JX7U (pirfenidone) SB - IM MH - Administration, Oral MH - Animals MH - Anti-Inflammatory Agents, Non-Steroidal/*administration & dosage/pharmacokinetics/toxicity MH - Drug Administration Schedule MH - Gastric Emptying/*drug effects MH - Male MH - Pyridones/*administration & dosage/pharmacokinetics/toxicity MH - Rats MH - Rats, Sprague-Dawley MH - Time Factors OTO - NOTNLM OT - Gastric emptying OT - Idiopathic pulmonary fibrosis OT - Pharmacokinetics OT - Pirfenidone EDAT- 2018/06/27 06:00 MHDA- 2019/02/08 06:00 CRDT- 2018/06/27 06:00 PHST- 2018/01/23 00:00 [received] PHST- 2018/04/18 00:00 [revised] PHST- 2018/06/22 00:00 [accepted] PHST- 2018/06/27 06:00 [pubmed] PHST- 2019/02/08 06:00 [medline] PHST- 2018/06/27 06:00 [entrez] AID - S1094-5539(18)30019-1 [pii] AID - 10.1016/j.pupt.2018.06.001 [doi] PST - ppublish SO - Pulm Pharmacol Ther. 2018 Aug;51:41-47. doi: 10.1016/j.pupt.2018.06.001. Epub 2018 Jun 23.