Pixantrone maleate professional chemist information

NDA 22481

By Ail Ibrahim Al Shafay (sec 5)(684)faculty of Tanta pharmacy ,Egypt

aly10aly@yahoo.com

Generic name: Pixantrone maleateChemical name: 6,9-bis[(2-aminoethyl)amino]benzo[g]isoquinoline-5,10-dione

ATC code: L01DB11

Brand Name : pixuvri®

Type : Me Too

SMILES : O=C2c3c(C(=O)c1c(ccc(NCCN)c12)NCCN)cncc3

Innovative company : Taizhou Crene Biotechnology Co., Ltd. ,Country: Zhejiang, China (Mainland)

Definition :Powder for concentrate for solution for infusion .

Dark blue lyophilised powder. Pixuvri is indicated as monotherapy for the treatment of adult patients with multiply relapsed or refractory aggressive Non-Hodgkin B-cell Lymphomas (NHL).

Production: small molecule ,chemical synthesis .

Pixuvri is indicated as monotherapy for the treatment of adult patients

with multiply relapsed or refractory aggressive Non-Hodgkin B-cell Lymphomas (NHLtherapy) .

a cytotoxic aza-anthracenedione .Unlike approved anthracyclines (doxorubicin and others) and anthracenediones (mitoxantrone), pixantrone is only a weak inhibitor of topoisomerase II. Moreover, unlike anthracyclines or anthracenediones, pixantrone directly alkylates DNA forming stable DNA adducts and cross-strand breaks. Furthermore, because it incorporates a nitrogen heteroatom into the ring structure and does not have ketone groups, pixantrone has less potential for generating reactive oxygen species, binding iron, and forming alcohol metabolites that are felt to cause the cardiac toxicity of anthracyclines. Due to this unique structure, pixantrone produced minimal cardiotoxicity in animal models compared with doxorubicin or mitoxantrone.

Therapeutic indications :

Mechanism of action

:The presence of the amino group at C-3′ has been implicated as a determinant of DNA binding affinity (3). The results from some studies (5–7), however, indicated that the presence of the amino group is not a strict requirement for the pharmacologic activity of anthracyclines. Although substitution of the amino group for a hydroxyl group appreciably reduces drug affinity for DNA, lack of the amino group increases the drug's ability to stimulate DNA cleavage mediated by topoisomerase II (7). Indeed, the non-intercalating moieties of doxorubicin are expected to critically influence the formation of the ternary complex, since in the latter the drug has been proposed to be positioned at the interface of the active site of the enzyme and the DNA cleavage site (3).Bioactivity as a consequence of this type of structural modification in the idarubicin-related series was highly dependent on the orientation of the second, aminated, sugar moiety, whether axial or equatorial (Arcamone F, Animati F, Bigioni M, Capranico G, Caserini C, De Cesare M, et al.: manuscript in preparation). Since the presence of an additional sugar in the disaccharide analogue is expected to reduce cellular uptake, the demethoxy derivatives of this series appeared to have a more favorable behavior than the derivatives with natural aglycone. The selected compound 4-demethoxy-7-O-[2,6-dideoxy-4-O-(2,3,6-trideoxy-3-amino-α-L-lyxo-hexopyranosyl)-α-L-lyxo-hexopyranosyl]-adriamycinone, i.e., MEN 10755, the first example of a doxorubicin disaccharide analogue, was characterized by its marked ability to induce DNA breaks in tumor cells (apparently as a consequence of topoisomerase II poisoning) and in our experience exhibited unprecedented superior activity compared with doxorubicin in a number of human tumor xenografts growing subcutaneously in athymic mice.

SAR

Following intravenous administration, plasma concentrations of pixantrone reached the maximal concentration at the end of infusion and then declined poly-exponentially. The pharmacokinetics of Pixuvri was dose-independent

Pixuvri Dose (mg/m2)

Number of patients

AUC (0-24h) (ng.hr/ml )

33 3 982 ±115 49 6 1727 ±474 88 2 3811

Absorption

Pharmacokinetic properties

Pixuvri has a large volume of distribution of 25.8 l and is approximately 50% bound to plasma proteins.

Distribution

Acetylated metabolites are the major biotransformation products of pixantrone. However, in vitro, conversion of pixantrone into the acetylated metabolites by either NAT1 or NAT2 was very limited. In human urine, the compound was mainly excreted unchanged, and very small amounts of phase I and phase II acetylated metabolites were found. Therefore, metabolism does not appear to be an important elimination pathway for pixantrone. Acetylated metabolites were pharmacologically inactive and metabolically stable.

Biotransformation

low renal excretion . plasma clearance is mainly non-renal. Pixuvri may be metabolised in the liver and/or excreted in the bile. As metabolism appears to be limited, biliary excretion of unchanged pixantrone may be the major elimination pathway. Hepatic clearance approximates the hepatic plasma flow, suggesting a high hepatic extraction ratio and, therefore, efficient parent active substance elimination. Hepatic uptake of pixantrone is possibly mediated by OCT1 active transporters and biliary excretion by P-gp and BCRP. Pixantrone had only a weak or no capability to inhibit P-gp, BCRP, and BSEP transport mechanism in vitro. Pixantrone did inhibit OCT1-mediated metformin transport in vitro, but is not expected to inhibit OTC1 in vivo at clinically relevant concentrations. Pixantrone was a poor inhibitor of OATP1B1 and OATP1B3 uptake transporters in vitro. Linearity/non-linearity Pharmacokinetics of pixantrone proved to be linear in a broad range of doses, from 3 mg/m2 to 105 mg/m2. Pharmacokinetic/pharmacodynamic relationship(s) A relationship between plasma exposure to pixantrone and neutrophil count has been observed.

Elimination

MARKETING AUTHORISATION HOLDER:

CTI Life Sciences LimitedHighlands HouseBasingstoke RoadSpencers Wood, Reading Berkshire RG7 1NTUnited Kingdom

.Marketing-authorisation holderCTI Life Sciences LimitedRevision7Date of issue of marketing authorisation valid throughout the European Union10/05/2012

PIXUVRI : Marketed in 10 EU Countries Potential Addressable market in E.U.13.500 patients/year PIXUVRI European sales, expected to provide adequate capital into 3Q 2015

Summer of Financial Terms:Total deal value: 362 million dollars; 127 million through regulatory submission60 million upfront payment , 30 million of which was an equity investment in CTI67 million potential milestone progress payments expected through 2015

Feb 2014 : Nice published final guidance recommending prescription of PIXUVRI in England and Wales as cost effective therapy

Dec. 2013 Reached agreement with the German National Association of Statutory Health Insurance funds ( GKV-SV)

Weighted average pricing : 16.500 euro or 20.000 dollars / patient/year( 10 vials/cycle)Expanding Global Reach and Revenue Potential

Economics

Marvin (picture clic

) k here

Drugs related to pixantrone:

•Mitoxantrone•Doxorubicin “ Doxil”Clorambucil

Adriamycin Clorambucil

disadvantage over related drugs:

Advantage over related drugs

not like anthracycline "not inhibit topomerase ІІ "…….many side effect but in general less than other alkylating agent

Less side effects , less cardiotoxicty

Low dose and low resistant

Vision of student :It will be drug of choice in NHL B. high cost is the main problem which is 140000 EP per yearThis type of disease not common in Egypt as EU.so I think the company will not decrease price or get target in Egypt unless ministry of health go ahead into get great deal of this drug

References:•www.pixuvri.com •www.FDA.com•www.EMEA.com •www. oxfordjournals.org•www.wikipidea.com•Prscribing information from FDA

Thank you for attention