Pharmacokinetics of an antifibrotic agent, pirfenidone, in haemodialysis patients

Taniyama, Masayosih; Ohbayashi, Seiichi; Narita, Masayasu; Nakazawa, Ryoichi; Hasegawa, S.; Azuma, Nakanobu; Teraoka, Shunsuke; K, Ota; Yamauchi, Shitotomo; Margolin, Solomon B.

doi:10.1007/s002280050252

Cited by 25 publications

(18 citation statements)

References 2 publications

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“…This approach is reasonable for estimation of half-lives because distribution volume is less likely to vary among species than clearance. The data for humans involved subjects with renal disease [9] or neurofibromatosis [10] and may not be typical for healthy humans. The half-lives for children, which are quite long, were derived from the last few points of a 24 h oral dosing study [10] and need to be compared with an intravenous study.…”

Section: Pharmacokineticsmentioning

confidence: 99%

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Pharmacokinetics and metabolism of intravenous pirfenidone in sheep

Brüss

Stanley

Margolin³

et al. 2008

Biopharm & Drug Disp

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Pirfenidone, a promising antifibrotic agent, was administered intravenously to six female sheep at 30 mg/kg. Four sheep received 14C-pirfenidone simultaneously. Plasma and urine were obtained for assay of pirfenidone and its metabolites over two days, and tissues were obtained via necropsy. Samples were analysed for pirfenidone and metabolites using HPLC-MS and flow scintillation spectrometry. Plasma pirfenidone disappeared with first order kinetics with a clearance of 1.2 l/kg/h, half-life of 24 min, and distribution volume of 0.71 l/kg. After 48 h, the organs containing the largest quantity of 14C were lungs, liver and intestinal wall. Tissues with the highest concentration of 14C were lung, kidney, brain, liver, lymph node and adipose. Metabolites found in plasma and urine were hydroxypirfenidone (half-life of 44 min) and carboxypirfenidone. Additional metabolites found in urine were hydroxypirfenidone glucuronide and acetoxypirfenidone. Approximately, 80% of the tracer eventually appeared in the urine, and approximately 50% of it was in the form of identifiable metabolites. Less than 1% of the dose appeared in the urine in the form of the parent drug. Quantitatively, most of the metabolites appeared in the urine within 2 h. Thus, the drug is rapidly and completely metabolized.

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Section: Pharmacokineticsmentioning

confidence: 99%

“…Two studies using oral dosing have reported kinetic parameters for humans; however, the subjects were either adults with renal disease [9] or children with neurofibromatosis [10]. Another study utilized 14 Cpirfenidone given i.v.…”

Section: Introductionmentioning

confidence: 98%

Pharmacokinetics and metabolism of intravenous pirfenidone in sheep

Brüss

Stanley

Margolin³

et al. 2008

Biopharm & Drug Disp

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“…A recent comparison with other therapeutic interventions for IPF recommended further clinical trials of this drug entity [11]. However, the pharmacokinetic behavior of PD in any laboratory species is not yet known; only limited data, consisting of 0-4 h AUC values, are available in humans [12]. Therefore, the objective of this study was to determine the pharmacokinetic, metabolic disposition and tissue distribution of PD following intravenous i.v.…”

Section: Introductionmentioning

confidence: 98%

Pharmacokinetics and metabolism of a novel antifibrotic drug pirfenidone, in mice following intravenous administration

Giri

Wang

Xie

et al. 2002

Biopharm & Drug Disp

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The present study describes the pharmacokinetics and metabolism of pirfenidone (PD), a compound which has been shown to have significant antifibrotic effects in rodent models of pulmonary and cardiac fibrosis. Despite the fact that this compound is currently in phase II clinical trials, little data are available on the metabolism and disposition of this agent in rodents or humans. Radioactive PD [benzene ring (14)C(U)] was administered i.v. to mice at 40 mg PD/kg body weight, and animals were killed at varying times for determination of parent compound and metabolites in various tissues. The disappearance of parent compound from the plasma followed apparent 2-compartment elimination kinetics with a terminal elimination half-life of 8.6 min. Cl (0.10 ml/min/g) and V(d(ss)) (0.67 ml/g) indicated that PD was rapidly distributed in body water. This is consistent with the finding that peak tissue radioactivity occurred within 5 min following the i.v. administration of [(14)C]-PD and that well-perfused tissues, kidney>liver>lung have much higher levels of parent compound and metabolites than did fat. Two peaks isolated from plasma samples by HPLC yielded mass spectra that were consistent with initial oxidation to the alcohol followed by further metabolism to the carboxylic acid. The radioactivity recovered in the 24 h urine samples averaged 97% of the administered dose and none of that was associated with the parent compound. The short plasma half-life of parent compound in mice supports the need for additional studies in humans where the compound has been shown to have clinical benefits.

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“…A study of hemodialysis patients with a history of sclerosing peritonitis demonstrated that it may not be necessary to adjust dosages of PFD for renal impairment and that the drug is well tolerated even in ESRD. 18 In an open-label study wherein PFD was administered to patients with advanced refractory focal sclerosis, there was a good safety profile in patients with impaired renal function and heavy proteinuria, and PFD slowed the rate of decline of renal function by 25%. 19 In a Phase III trial for patients with idiopathic pulmonary fibrosis in Japan, PFD was reported to promote stabilization and improvement of lung function.…”

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confidence: 99%

Pirfenidone Is Renoprotective in Diabetic Kidney Disease

RamachandraRao

Zhu

Ravasi

et al. 2009

Journal of the American Society of Nephrology

151

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Although several interventions slow the progression of diabetic nephropathy, current therapies do not halt progression completely. Recent preclinical studies suggested that pirfenidone (PFD) prevents fibrosis in various diseases, but the mechanisms underlying its antifibrotic action are incompletely understood. Here, we evaluated the role of PFD in regulation of the extracellular matrix. In mouse mesangial cells, PFD decreased TGF-␤ promoter activity, reduced TGF-␤ protein secretion, and inhibited TGF-␤-induced Smad2-phosphorylation, 3TP-lux promoter activity, and generation of reactive oxygen species. To explore the therapeutic potential of PFD, we administered PFD to 17-wk-old db/db mice for 4 wk. PFD treatment significantly reduced mesangial matrix expansion and expression of renal matrix genes but did not affect albuminuria. Using liquid chromatography with subsequent electrospray ionization tandem mass spectrometry, we identified 21 proteins unique to PFD-treated diabetic kidneys. Analysis of gene ontology and protein-protein interactions of these proteins suggested that PFD may regulate RNA processing. Immunoblotting demonstrated that PFD promotes dosage-dependent dephosphorylation of eukaryotic initiation factor, potentially inhibiting translation of mRNA. In conclusion, PFD is renoprotective in diabetic kidney disease and may exert its antifibrotic effects, in part, via inhibiting RNA processing.

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Pharmacokinetics of an antifibrotic agent, pirfenidone, in haemodialysis patients

Cited by 25 publications

References 2 publications

Pharmacokinetics and metabolism of intravenous pirfenidone in sheep

Pharmacokinetics and metabolism of intravenous pirfenidone in sheep

Pharmacokinetics and metabolism of a novel antifibrotic drug pirfenidone, in mice following intravenous administration

Pirfenidone Is Renoprotective in Diabetic Kidney Disease

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