Ocular pharmacokinetics and hypotensive activity of PF-04475270, an EP4 prostaglandin agonist in preclinical models

Prasanna, Ganesh; Fortner, Jay H.; Xiang, Cathie; Zhang, Eric; Carreiro, Samantha; Anderson, Scott; Sartnurak, Soisurin; Wu, Grace; Gukasyan, Hovhannes J.; Niesman, Michael R.; Nair, Sajiv K.; Rui, Eugene; Lafontaine, Jennifer; Almaden, Chau; Wells, Peter A.; Krauss, Achim H.-P.

doi:10.1016/j.exer.2009.05.002

Cited by 27 publications

(19 citation statements)

References 18 publications

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“…CP-734432 (Fig. 4), the active metabolite of 5- (3-(2-(3-hydroxy-4-(3-(trifluoromethyl)phenyl)butyl)-5-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate (PF-04475270), has an EC 50 value of 1 nM in a human rc-EP 4 assay (Prasanna et al, 2009). However, 8-aza-9-oxo prostanoids, with a 15,16-didehydro-15-methyl structure, switch from EP 4 to EP 2 agonist selectivity (Brugger et al, 2008).…”

Section: Distribution and Biological Functionsmentioning

confidence: 99%

“…Set against this, EP 4 receptors are implicated in colon carcinogenesis (Mutoh et al, 2002;Chell et al, 2006;Doherty et al, 2009), a highly undesirable side effect. In glaucoma therapy, where local topical drug administration is routinely employed, the highly efficacious ocular hypotensive effects produced by EP 4 agonists are accompanied by ocular surface hyperemia and corneal neovascularization (Aguirre et al, 2009;Prasanna et al, 2009;Woodward et al, 2009). Although some redness of the eyes is not harmful, the patients do not necessarily want it.…”

Section: Distribution and Biological Functionsmentioning

confidence: 99%

See 1 more Smart Citation

International Union of Basic and Clinical Pharmacology. LXXXIII: Classification of Prostanoid Receptors, Updating 15 Years of Progress

Woodward

Jones

Narumiya³

2011

Pharmacol Rev

391

414

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Section: Distribution and Biological Functionsmentioning

confidence: 99%

Section: Distribution and Biological Functionsmentioning

confidence: 99%

International Union of Basic and Clinical Pharmacology. LXXXIII: Classification of Prostanoid Receptors, Updating 15 Years of Progress

Woodward

Jones

Narumiya³

2011

Pharmacol Rev

391

414

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“…Topical application of the EP4 agonist prodrug PF-04475270 lowered ocular pressure through its active metabolite CP-734432 in normotensive dogs (Prasanna et al, 2009). However, conjunctival hyperemia and corneal neovascularization were also observed (Aguirre et al, 2009).…”

Section: Miscellaneousmentioning

confidence: 99%

E-type prostanoid receptor 4 (EP4) in disease and therapy

Kónya

Marsche

Schuligoi

et al. 2013

Pharmacology & Therapeutics

128

151

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The large variety of biological functions governed by prostaglandin (PG) E2 is mediated by signaling through four distinct E-type prostanoid (EP) receptors. The availability of mouse strains with genetic ablation of each EP receptor subtype and the development of selective EP agonists and antagonists have tremendously advanced our understanding of PGE2 as a physiologically and clinically relevant mediator. Moreover, studies using disease models revealed numerous conditions in which distinct EP receptors might be exploited therapeutically. In this context, the EP4 receptor is currently emerging as most versatile and promising among PGE2 receptors. Anti-inflammatory, anti-thrombotic and vasoprotective effects have been proposed for the EP4 receptor, along with its recently described unfavorable tumor-promoting and pro-angiogenic roles. A possible explanation for the diverse biological functions of EP4 might be the multiple signaling pathways switched on upon EP4 activation. The present review attempts to summarize the EP4 receptor-triggered signaling modules and the possible therapeutic applications of EP4-selective agonists and antagonists.

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“…From the results of model B fitting, the high estimates of parameters values for k 34 and k 43 indicate, that the AH and ICB are well equilibrated. Based on the high ex vivo corneal permeability assessment of PF-04475270 (Prasanna et al, 2009), the k a value, 0.188 h Ϫ1 , estimated from our model would seem lower than expected. However, because bioavailability fraction was not accounted for, the k a as represented in this model is a lumped parameter consisting of both k a and the fraction of the dose absorbed (F), which can be extremely low due to , and 96 h after dose.…”

Section: Resultsmentioning

confidence: 59%

“…CP-734432 is a full agonist to the EP4 receptor and has significantly greater affinity for the human EP4 receptor (K i Ͻ 2 nM) compared with other studied prostaglandin receptors (Ͼ30-fold selectivity over human EP2 and Ͼ500-fold selectivity over human EP1 and EP3) (Ke et al, 2006;Prasanna et al, 2009). In vitro corneal permeability studies showed that PF-04475270 more robustly crossed the cornea compared with the CP-734432 isoform (Prasanna et al, 2009). After topical administration to the eye, PF-04475270 was seen to rapidly hydrolyze to CP-734432 by esterases.…”

mentioning

confidence: 99%

Pharmacokinetic-Pharmacodynamic and Response Sensitization Modeling of the Intraocular Pressure-Lowering Effect of the EP4 Agonist 5-{3-[(2S)-2-{(3R)-3-hydroxy-4-[3-(trifluoromethyl)phenyl]butyl}-5-oxopyrrolidin-1-yl]propyl}thiophene-2-carboxylate (PF-04475270)

Luu

Zhang

Prasanna

et al. 2009

J Pharmacol Exp Ther

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Developing a population-based pharmacokinetic-pharmacodynamic (PKPD) model is a challenge in ophthalmology due to the difficulty of obtaining adequate pharmacokinetic (PK) samples from ocular tissues to inform the pharmacodynamic (PD) model. Using limited PK data, we developed a preclinical population-based PD model suitable for capturing the time course of dog intraocular pressure (IOP) that exhibited time-dependent sensitization after topical administration of PF-04475270A physiologically relevant PK model was chosen to simultaneously capture the concentration profiles of CP-734432, a potent EP4 agonist and the active metabolite of PF-04475270, sampled from three ocular tissues of the anterior chamber: cornea, aqueous humor, and iris-ciliary body. Two population-based PD models were developed to characterize the IOP lowering profiles: model I, a standard indirect-response model (IRM); and model II, an extension of a standard IRM that empirically incorporated a response-driven positive feedback loop to account for the observed PD sensitization. The PK model reasonably described the PK profiles in all three ocular tissues. As for the PD, model I failed to capture the overall trend in the population IOP data, and model II more adequately characterized the overall data set. This integrated PKPD model may have general utility when PD sensitization is observed and is not a result of time-dependent PK. In addition, the model is applicable in the ophthalmology drug development setting in which PK information is limited but a population-based PD model could reasonably be established.

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Ocular pharmacokinetics and hypotensive activity of PF-04475270, an EP4 prostaglandin agonist in preclinical models

Cited by 27 publications

References 18 publications

International Union of Basic and Clinical Pharmacology. LXXXIII: Classification of Prostanoid Receptors, Updating 15 Years of Progress

International Union of Basic and Clinical Pharmacology. LXXXIII: Classification of Prostanoid Receptors, Updating 15 Years of Progress

E-type prostanoid receptor 4 (EP4) in disease and therapy

Pharmacokinetic-Pharmacodynamic and Response Sensitization Modeling of the Intraocular Pressure-Lowering Effect of the EP4 Agonist 5-{3-[(2S)-2-{(3R)-3-hydroxy-4-[3-(trifluoromethyl)phenyl]butyl}-5-oxopyrrolidin-1-yl]propyl}thiophene-2-carboxylate (PF-04475270)

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