Plerixafor ( INN and

USAN 280px, "Samguk Sagi" Book 04. Silla's Records. In 512, Usan-guk（于山國）was Ulleungdo（鬱陵島） Usan-guk, or the State of Usan, occupied Ulleung-do and the adjacent islands during the Korean Three Kingdoms period. According to th ...

, trade name Mozobil) is an immunostimulant used to mobilize

hematopoietic stem cell Hematopoietic stem cells (HSCs) are the stem cells that give rise to other blood cells. This process is called haematopoiesis. In vertebrates, the very first definitive HSCs arise from the ventral endothelial wall of the embryonic aorta within ...

s in cancer patients into the bloodstream. The stem cells are then extracted from the blood and transplanted back to the patient. The drug was developed by AnorMED, which was subsequently bought by

Genzyme Genzyme was an American biotechnology company based in Cambridge, Massachusetts. Since its acquisition in 2011, Genzyme (also known as Genzyme Transgenics Corp or GTC Biotherapeutics) has been a fully owned subsidiary of Sanofi. In 2010, Genzyme ...

Medical uses

Peripheral blood stem cell mobilization, which is important as a source of

hematopoietic stem cells Hematopoietic stem cells (HSCs) are the stem cells that give rise to other blood cells. This process is called haematopoiesis. In vertebrates, the very first definitive HSCs arise from the ventral endothelial wall of the embryonic aorta within ...

for transplantation, is generally performed using

granulocyte colony-stimulating factor Granulocyte colony-stimulating factor (G-CSF or GCSF), also known as colony-stimulating factor 3 (CSF 3), is a glycoprotein that stimulates the bone marrow to produce granulocytes and stem cells and release them into the bloodstream. Functiona ...

(G-CSF), but is ineffective in around 15 to 20% of patients. Combination of G-CSF with plerixafor increases the percentage of persons that respond to the therapy and produce enough stem cells for transplantation. The drug is approved for patients with

lymphoma Lymphoma is a group of blood and lymph tumors that develop from lymphocytes (a type of white blood cell). In current usage the name usually refers to just the cancerous versions rather than all such tumours. Signs and symptoms may include en ...

and

multiple myeloma Multiple myeloma (MM), also known as plasma cell myeloma and simply myeloma, is a cancer of plasma cells, a type of white blood cell that normally produces antibodies. Often, no symptoms are noticed initially. As it progresses, bone pain, ...

. Phase 2 clinical trials started in 2021 exploring the combination of plerixafor and MGTA-145, a CXCL2 ligand.

Contraindications

Pregnancy and lactation

Studies in pregnant animals have shown

teratogenic Teratology is the study of abnormalities of physiological development in organisms during their life span. It is a sub-discipline in medical genetics which focuses on the classification of congenital abnormalities in dysmorphology. The related ...

effects. Plerixafor is therefore contraindicated in pregnant women except in critical cases. Fertile women are required to use

contraception Birth control, also known as contraception, anticonception, and fertility control, is the use of methods or devices to prevent unwanted pregnancy. Birth control has been used since ancient times, but effective and safe methods of birth contr ...

. It is not known whether the drug is secreted into the breast milk. Breast feeding should be discontinued during therapy.

Adverse effects

Nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of th ...

diarrhea Diarrhea, also spelled diarrhoea, is the condition of having at least three loose, liquid, or watery bowel movements each day. It often lasts for a few days and can result in dehydration due to fluid loss. Signs of dehydration often begin w ...

and local reactions were observed in over 10% of patients. Other problems with digestion and general symptoms like dizziness, headache, and muscular pain are also relatively common; they were found in more than 1% of patients. Allergies occur in less than 1% of cases. Most adverse effects in clinical trials were mild and transient. The

European Medicines Agency The European Medicines Agency (EMA) is an agency of the European Union (EU) in charge of the evaluation and supervision of medicinal products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products or Eur ...

has listed a number of safety concerns to be evaluated on a post-marketing basis, most notably the theoretical possibilities of

spleen The spleen is an organ found in almost all vertebrates. Similar in structure to a large lymph node, it acts primarily as a blood filter. The word spleen comes .

rupture and tumor cell mobilisation. The first concern has been raised because

splenomegaly Splenomegaly is an enlargement of the spleen. The spleen usually lies in the left upper quadrant (LUQ) of the human abdomen. Splenomegaly is one of the four cardinal signs of ''hypersplenism'' which include: some reduction in number of circulatin ...

was observed in animal studies, and G-CSF can cause spleen rupture in rare cases. Mobilisation of tumor cells has occurred in patients with leukaemia treated with plerixafor.

Interactions

No interaction studies have been conducted. The fact that plerixafor does not interact with the cytochrome system indicates a low potential for interactions with other drugs.

Pharmacology

Mechanism of action

In the form of its zinc complex, plerixafor acts as an

antagonist An antagonist is a character in a story who is presented as the chief foe of the protagonist. Etymology The English word antagonist comes from the Greek ἀνταγωνιστής – ''antagonistēs'', "opponent, competitor, villain, enemy, ri ...

(or perhaps more accurately a

partial agonist In pharmacology, partial agonists are drugs that bind to and activate a given receptor, but have only partial efficacy at the receptor relative to a full agonist. They may also be considered ligands which display both agonistic and antagonis ...

) of the alpha

chemokine receptor Chemokine receptors are cytokine receptors found on the surface of certain cells that interact with a type of cytokine called a chemokine. There have been 20 distinct chemokine receptors discovered in humans. Each has a rhodopsin-like 7-trans ...

CXCR4 C-X-C chemokine receptor type 4 (CXCR-4) also known as fusin or CD184 (cluster of differentiation 184) is a protein that in humans is encoded by the ''CXCR4'' gene. The protein is a CXC chemokine receptor. Function CXCR-4 is an alpha-chemokin ...

and an

allosteric In biochemistry, allosteric regulation (or allosteric control) is the regulation of an enzyme by binding an effector molecule at a site other than the enzyme's active site. The site to which the effector binds is termed the ''allosteric sit ...

agonist of

CXCR7 Atypical chemokine receptor 3 also known as C-X-C chemokine receptor type 7 (CXCR-7) and G-protein coupled receptor 159 (GPR159) is a protein that in humans is encoded by the ''ACKR3'' gene. This gene encodes a member of the G protein-coupled re ...

. The CXCR4 alpha-

chemokine Chemokines (), or chemotactic cytokines, are a family of small cytokines or signaling proteins secreted by cells that induce directional movement of leukocytes, as well as other cell types, including endothelial and epithelial cells. In additi ...

receptor and one of its

ligand In coordination chemistry, a ligand is an ion or molecule (functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's elect ...

s, SDF-1, are important in

homing to the

bone marrow Bone marrow is a semi-solid biological tissue, tissue found within the Spongy bone, spongy (also known as cancellous) portions of bones. In birds and mammals, bone marrow is the primary site of new blood cell production (or haematopoiesis). It i ...

and in

quiescence Quiescence (/kwiˈɛsəns/) is a state of quietness or inactivity. It may refer to: * Quiescence search, in game tree searching (adversarial search) in artificial intelligence, a quiescent state is one in which a game is considered stable and unl ...

. The ''

in vivo Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and p ...

'' effect of plerixafor with regard to

ubiquitin Ubiquitin is a small (8.6 kDa) regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ''ubiquitously''. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 1980s. Fo ...

, the alternative endogenous ligand of CXCR4, is unknown. Plerixafor has been found to be a strong inducer of mobilization of

from the bone marrow to the bloodstream as peripheral blood stem cells. Additionally, plerixafor inhibits CD20 expression on B cells by interfering with CXCR4/SDF1 axis that regulates its expression.

Pharmacokinetics

Following

subcutaneous injection Subcutaneous administration is the insertion of medications beneath the skin either by injection or infusion. A subcutaneous injection is administered as a bolus into the subcutis, the layer of skin directly below the dermis and epidermis, c ...

, plerixafor is absorbed quickly and peak concentrations are reached after 30 to 60 minutes. Up to 58% are bound to plasma proteins, the rest mostly resides in

extravascular compartment The human body and even its individual body fluids may be conceptually divided into various fluid compartments, which, although not literally anatomic compartments, do represent a real division in terms of how portions of the body's water, solute ...

s. The drug is not

metabolized Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cell ...

in significant amounts; no interaction with the

cytochrome P450 Cytochromes P450 (CYPs) are a superfamily of enzymes containing heme as a cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are important for the clearance of various co ...

enzymes or

P-glycoprotein P-glycoprotein 1 (permeability glycoprotein, abbreviated as P-gp or Pgp) also known as multidrug resistance protein 1 (MDR1) or ATP-binding cassette sub-family B member 1 (ABCB1) or cluster of differentiation 243 (CD243) is an important protein ...

s has been found. Plasma half life is 3 to 5 hours. Plerixafor is excreted via the

kidney The kidneys are two reddish-brown bean-shaped organs found in vertebrates. They are located on the left and right in the retroperitoneal space, and in adult humans are about in length. They receive blood from the paired renal arteries; blo ...

s, with 70% of the drug being excreted within 24 hours.

Chemistry

Plerixafor is a macrocyclic compound and a bi

cyclam Cyclam (1,4,8,11-tetraazacyclotetradecane) is an organic compound with the formula (NHCH2CH2NHCH2CH2CH2)2. Classified as an aza-crown ether, it is a white solid that is soluble in water. As a macrocyclic ligand, it binds strongly to many transit ...

derivative, the cyclam rings being linked at the amine nitrogen atoms by a 1,4-

xylyl In organic chemistry, xylene or xylol (; IUPAC name: dimethylbenzene) are any of three organic compounds with the formula . They are derived from the substitution of two hydrogen atoms with methyl groups in a benzene ring; which hydrogens are su ...

spacer. It is a base; all eight nitrogen atoms accept

proton A proton is a stable subatomic particle, symbol , H+, or 1H+ with a positive electric charge of +1 ''e'' elementary charge. Its mass is slightly less than that of a neutron and 1,836 times the mass of an electron (the proton–electron mass ...

s readily. The two macrocyclic rings form chelate complexes with bivalent metal ions, especially

zinc Zinc is a chemical element with the symbol Zn and atomic number 30. Zinc is a slightly brittle metal at room temperature and has a shiny-greyish appearance when oxidation is removed. It is the first element in group 12 (IIB) of the periodi ...

copper Copper is a chemical element with the symbol Cu (from la, cuprum) and atomic number 29. It is a soft, malleable, and ductile metal with very high thermal and electrical conductivity. A freshly exposed surface of pure copper has a pink ...

and

nickel Nickel is a chemical element with symbol Ni and atomic number 28. It is a silvery-white lustrous metal with a slight golden tinge. Nickel is a hard and ductile transition metal. Pure nickel is chemically reactive but large pieces are slow t ...

, as well as

cobalt Cobalt is a chemical element with the symbol Co and atomic number 27. As with nickel, cobalt is found in the Earth's crust only in a chemically combined form, save for small deposits found in alloys of natural meteoric iron. The free element, p ...

and

rhodium Rhodium is a chemical element with the symbol Rh and atomic number 45. It is a very rare, silvery-white, hard, corrosion-resistant transition metal. It is a noble metal and a member of the platinum group. It has only one naturally occurring i ...

. The biologically active form of plerixafor is its zinc complex.

Synthesis

Three of the four nitrogen atoms of the macrocycle cyclam... (1,4,8,11-tetraazacyclotetradecane) are protected with

tosyl In organic chemistry, a toluenesulfonyl group (tosyl group, abbreviated Ts or Tos) is a univalent functional group with the chemical formula –. It consists of a tolyl group, –, joined to a sulfonyl group, ––, with the open valence o ...

groups. The product is treated with 1,4-bis(brommethyl)benzene and

potassium carbonate Potassium carbonate is the inorganic compound with the formula K2 CO3. It is a white salt, which is soluble in water. It is deliquescent, often appearing as a damp or wet solid. Potassium carbonate is mainly used in the production of soap and gl ...

acetonitrile Acetonitrile, often abbreviated MeCN (methyl cyanide), is the chemical compound with the formula and structure . This colourless liquid is the simplest organic nitrile ( hydrogen cyanide is a simpler nitrile, but the cyanide anion is not clas ...

. After cleaving of the tosyl groups with

hydrobromic acid Hydrobromic acid is a strong acid formed by dissolving the diatomic molecule hydrogen bromide (HBr) in water. "Constant boiling" hydrobromic acid is an aqueous solution that distills at and contains 47.6% HBr by mass, which is 8.77 mol/L. ...

, plerixafor octahydrobromide is obtained.

History

The molecule was first synthesised in 1987 to carry out basic studies on the

redox Redox (reduction–oxidation, , ) is a type of chemical reaction in which the oxidation states of substrate change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is the gain of electrons or ...

chemistry of dimetallic coordination compounds. Then, it was serendipitously discovered by another chemist that such a molecule could have a potential use in the treatment of HIV because of its role in the blocking of CXCR4, a chemokine receptor which acts as a co-receptor for certain strains of HIV (along with the virus's main cellular receptor, CD4). Development of this indication was terminated because of lacking oral availability and

cardiac The heart is a muscular organ in most animals. This organ pumps blood through the blood vessels of the circulatory system. The pumped blood carries oxygen and nutrients to the body, while carrying metabolic waste such as carbon dioxide to t ...

disturbances. Further studies led to the new indication for cancer patients.

Society and culture

Plerixafor has

orphan drug An orphan drug is a pharmaceutical agent developed to treat medical conditions which, because they are so rare, would not be profitable to produce without government assistance. The conditions are referred to as orphan diseases. The assignment of ...

status in the United States and European Union for the mobilization of

. It was approved by the U.S.

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...

(FDA) for this indication on 15 December 2008. In the European Union, the drug was approved after a positive

Committee for Medicinal Products for Human Use The Committee for Medicinal Products for Human Use (CHMP), formerly known as Committee for Proprietary Medicinal Products (CPMP), is the European Medicines Agency's committee responsible for elaborating the agency's opinions on all issues regardin ...

assessment report on 29 May 2009. The drug was approved for use in Canada by

Health Canada Health Canada (HC; french: Santé Canada, SC)Health Canada is the applied title under the Federal Identity Program; the legal title is Department of Health (). is the department of the Government of Canada responsible for national health poli ...

on 8 December 2011.

Research

Anti-cancer properties

Plerixafor was seen to reduce metastasis in mice in several studies. It has also been shown to reduce recurrence of

glioblastoma Glioblastoma, previously known as glioblastoma multiforme (GBM), is one of the most aggressive types of cancer that begin within the brain. Initially, signs and symptoms of glioblastoma are nonspecific. They may include headaches, personality ...

in a mouse model after radiotherapy. In this model, the cancer cells that survived radiation critically depended on bone marrow derived cells for vasculogenesis, and the recruitment of the latter was mediated by SDF-1 CXCR4 interactions, which are blocked by plerixafor.

Use in stem cell research

Researchers at Imperial College have demonstrated that plerixafor in combination with vascular endothelial growth factor (VEGF) can mobilise

mesenchymal stem cells Mesenchymal stem cells (MSCs) also known as mesenchymal stromal cells or medicinal signaling cells are multipotent stromal cells that can differentiate into a variety of cell types, including osteoblasts (bone cells), chondrocytes (cartilage c ...

and endothelial progenitor cells into the peripheral blood of mice. In double‐blind, randomized, placebo‐controlled trial, stem cell mobilization with plerixafor did not improve healing of ischemic diabetic wounds.

Neurologic

Blockade of

signalling by plerixafor has also unexpectedly been found to be effective at counteracting opioid-induced hyperalgesia produced by chronic treatment with

morphine Morphine is a strong opiate that is found naturally in opium, a dark brown resin in poppies ('' Papaver somniferum''). It is mainly used as a pain medication, and is also commonly used recreationally, or to make other illicit opioids. T ...

, though only animal studies have been conducted as yet.

References

External links

* * {{Portal bar , Medicine Orphan drugs Immunostimulants Nitrogen heterocycles Sanofi