Delving into the Latest Updates on Dipyridamole/Prednisolone with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Prednisolone/dipyridamole, Synavive, Synavive AR

+ [2]

Target

GR x PDE5A

Action

agonists, inhibitors

Mechanism

GR agonists(Glucocorticoid receptor agonists), PDE5A inhibitors(Phosphodiesterase 5A inhibitors)

Therapeutic Areas

Immune System DiseasesSkin and Musculoskeletal Diseases

Active Indication-

Inactive Indication

Osteoarthritis, KneeRheumatoid Arthritis

Originator Organization

Zalicus, Inc.

Active Organization-

Inactive Organization

Zalicus, Inc.

License Organization-

Drug Highest PhaseDiscontinuedPhase 2

First Approval Date-

Regulation-

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Structure/Sequence

Molecular FormulaC45H68N8O9

InChIKeyKWEDSPWZQTVIPO-WPUDDCNKSA-N

CAS Registry849333-19-3

OBJECTIVETo evaluate the responsiveness of joint counts, patient-reported measures and proposed composite scores in hand osteoarthritis (HOA).METHODSData were used from a previously reported study in which 83 patients with HOA were randomly assigned to CRx-102 or placebo. CRx-102 consists of prednisolone (3 mg/day) and dipyridamole (400 mg/day), and was shown to be superior to placebo. Assessments were performed at baseline and after 7, 14, 28 and 42 days, and included the Australian/Canadian osteoarthritis hand index (AUSCAN), visual analogue pain subscale (VAS) pain and patient global, and counts of distal interphalangeal (DIP), proximal interphalangeal (PIP), metacarpophalangeal and carpometacarpal (CMC) joints (tenderness, soft tissue swelling, bony enlargement, limited motion). Various combinations of patient-reported outcomes and joint counts were computed as composite scores (similar to clinical disease activity index) and tested for responsiveness. For each measure, mean change from baseline to day 42, treatment effect, standardised response mean (SRM) and relative efficiency compared with AUSCAN pain were calculated.RESULTSThe SRM were largest for VAS patient global (0.92), VAS pain (0.77) and AUSCAN pain (0.68), whereas the responsiveness of tender (0.46) and swollen joint counts (0.51) (18 joint assessment of DIP, PIP, CMC) was similar to AUSCAN stiffness (0.53) and physical function (0.37). Composite scores showed similar responsiveness as patient-reported pain and global.CONCLUSIONPatient-reported pain and patient global assessment were the most responsive outcomes, whereas joint counts had similar responsiveness to patient-reported stiffness and physical function. Composite scores were as responsive as VAS pain, and these results encourage further elaboration and validation of composite scores in HOA in larger studies.

01 Sep 2009·Journal of Pharmaceutical and Biomedical AnalysisQ3 · MEDICINE

Biotransformation and in vitro assessment of metabolism-associated drug–drug interaction for CRx-102, a novel combination drug candidate

Q3 · MEDICINE

Article

Author: Chen, Mei ; Kansra, Vikram V. ; Zhang, Zhi-Yi ; Chen, Jennifer ; Padval, Mahesh V.

CRx-102 is an oral synergistic combination drug which contains the cardiovascular agent, dipyridamole (DP) and a very low dose of the glucocorticoid, prednisolone (PRED). CRx-102 works through a novel mechanism of action in which DP selectively amplifies the anti-inflammatory activity of PRED without replicating its side effects. CRx-102 is in clinical trials for the treatment of osteoarthritis. Here we delineate the in vitro metabolism and explore the potential for a drug-drug interaction between the active agents in CRx-102. Our study using human hepatocyte suspensions showed that both DP and PRED were metabolized by CYP3A4 isozymes, resulting in the formation of diverse arrays of both oxidative and oxidative-reduced metabolites. Within phase 1 biotransformation, CYP3A4 was one of the pathways responsible for the metabolism of PRED, while phase 2 biotransformation played a significant role in the metabolism of DP. Glucuronidation of DP was substantial and was catalyzed by many UGT members, specifically those in the UGT1A subfamily. Based on the tandem mass (MS/MS) product ion spectra (PIS) acquired, the major metabolites of both agents, namely, monooxygenated, mono-N-deethanolaminated, dehydrogenated and O-glucuronidated metabolites of DP and the monooxygenated (e.g., 6-hydroxyl), dehydrogenated (prednisone) and reduced (20-hydroxyl) metabolites of PRED, were identified and elucidated. The affinities for DP biotransformation, including CYP3A4-mediated oxidative pathways and UGT-mediated O-glucuronidation, appeared high (K(m)<10 microM), as compared with the modest affinities of PRED biotransformation catalyzed by CYP3A4 (K(m) approximately 40-170 microM). DP, but not PRED, exerted a minimal inhibitory effect on the drug-metabolizing CYP isoforms, including CYP3A4, which was determined using a panel of CYP isoform-preferred substrate activities in pooled human liver microsomal (HLM) preparations and microsomal preparations containing the recombinant enzymes (K(i) approximately 2-12 microM). Using the DP maximal plasma concentration (C(max)) observed in the clinic and a predictive mathematical model for metabolism-associated drug-drug interaction (DDI), we have demonstrated that there is little likelihood of a pharmacokinetic interaction between the two active agents in CRx-102.

01 Jul 2009·Journal of Pharmaceutical and Biomedical AnalysisQ3 · MEDICINE

Development and validation of a liquid chromatography–tandem mass spectrometry assay for the simultaneous quantitation of prednisolone and dipyridamole in human plasma and its application in a pharmacokinetic study

Q3 · MEDICINE

Article

Author: Zhi-Yi Zhang ; Vikram V. Kansra ; Qin C. Ji ; Camille Granvil ; Mei Chen ; Mahesh V. Padval

We have developed and validated an accurate, sensitive, and robust LC-MS/MS method that determines the concentration of CRx-102 (the combination of prednisolone and dipyridamole) in human plasma. In this method, prednisolone, dipyridamole, and the combined internal standards (IS) prednisolone-d(6) (IS for prednisolone) and dipyridamole-d(20) (IS for dipyridamole) were extracted from 100 microL human EDTA plasma using methylbutyl ether. Calibration curves were linear over a concentration range of 0.4-200 ng/mL for prednisolone and 5-3000 ng/mL for dipyridamole. The analytes were quantitatively determined using tandem mass spectrometry operated in positive electrospray ionization in a multiple reaction monitoring (MRM) mode. This validated method has been used successfully in clinical pharmacokinetic studies of CRx-102 in healthy volunteers.

100 Deals associated with Dipyridamole/Prednisolone

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Osteoarthritis, Knee	Phase 2	United States	Zalicus, Inc.	01 Aug 2007
Osteoarthritis, Knee	Phase 2	Canada	Zalicus, Inc.	01 Aug 2007
Rheumatoid Arthritis	Phase 2	-	Zalicus, Inc.	01 Nov 2004
Rheumatoid Arthritis	Phase 2	-	Zalicus, Inc.	01 Nov 2004

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT00747214 (CTgov)	Phase 2	Rheumatoid Arthritis	59	DMARD Therapy+CRx-102 (CRx-102 Plus DMARD Therapy)	futplcybac(yjlkovkzsy) = ztacqrxlof klbiobujls (fvpcwjzzcy, jrfoewbleq - nxhyiqzbsl) View more	-	20 May 2014
				DMARD Therapy (Placebo Plus DMARD Therapy)	futplcybac(yjlkovkzsy) = uqhrhcbyav klbiobujls (fvpcwjzzcy, zkumzabplx - pouzqfosmg) View more
NCT00551707 (MARS-1, CTgov)	Phase 2	Rheumatoid Arthritis	51	CRx-102 (2.7/180) (CRx-102 (2.7/180))	uoykhlrgeq(ajreygcwpn) = uatpmecdlb xyypbbencq (ubcbwhouoe, qcpjouuwuq - pmsejlzffd) View more	-	29 Apr 2014
				CRx-102 (2.7/180) (CRx-102 (2.7/360))	uoykhlrgeq(ajreygcwpn) = budekvzmds xyypbbencq (ubcbwhouoe, rycknluecn - pcbizlwury) View more
EULAR2007	Phase 2	Rheumatoid Arthritis	59	CRx-102	(lrgplcjjtx) = agzlrtcoxc emvzuikqis (ouwudvixnc ) View more	Positive	13 Jun 2007
				Placebo	(lrgplcjjtx) = babnrslhkn emvzuikqis (ouwudvixnc ) View more
EULAR2007	Phase 2	-	-	CRx-102	cdxgogorxt(jdxvkvoebg) = mwxvunwdcu knijsenjho (nzghsklfez ) View more	-	13 Jun 2007