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

Brand Name : pixuvri®

Type :Me Too

ATC code: L01DB11

Innovative company : Taizhou Crene

Biotechnology Co., Ltd. ,Country:

Zhejiang, China (Mainland)

Powder for concentrate for solution for

infusion.

Dark blue lyophilised powder. Pixuvri is monotherapy for the treatment of adult patients with multiply relapsed or refractory aggressive Non-Hodgkin B-cell Lymphomas (NHL). Production: small molecule ,chemical synthesis .

Definition

Chemical Synthesis

Pixuvri is indicated as monotherapyfor the treatment of adult patientswith multiply relapsed or refractory aggressive Non-Hodgkin B-cell Lymphomas (NHLtherapy).

Therapeutic indications:

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.

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

Pharmacokinetic

properties

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

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

Elimination

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.

MARKETING AUTHORISATION

HOLDER:

CTI Life Sciences Limited

Highlands House

Basingstoke Road

Spencers Wood, Reading

Berkshire RG7 1NT

United Kingdom

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

Economics

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 submission

60 million upfront payment , 30 million of which was an equity investment in CTI

67 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

Marvin picture (click here)

Drugs related to

pixantrone :

•Mitoxantrone

•Doxorubicin “

Doxil”

ClorambucilAdriamycin 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 cardiotoxictyLow 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 year

This 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