Plerixafor
Encyclopedia
Plerixafor is an immunostimulant used in to multiply hematopoietic stem cells in cancer patients. The stem cells are subsequently transplanted back
to the patient. The drug was developed by AnorMED which was subsequently bought by Genzyme
.
Technology Centre for 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 disturbances. Further studies led to the new indication for cancer patients.
(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
and multiple myeloma
.
. It is not known whether the drug is secreted into the breast milk. Breast feeding should be discontinued during therapy.
, diarrhea
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
has listed a number of safety concerns to be evaluated on a post-marketing basis, most notably the theoretical possibilities of spleen
rupture and tumor cell mobilisation. The first concern has been raised because splenomegaly
was observed in animal studies, and G-CSF can cause spleen rupture in rare cases. Mobilisation of tumor cells could occur, not as a direct consequence of plerixafor application, but following the re-infusion of stem cells. Neither of these adverse effects has been observed in humans.
; all eight nitrogen atoms accept proton
s readily. The two macrocyclic rings form chelate complexes with bivalent metal ions, especially zinc
, copper
and nickel
, as well as cobalt
and rhodium
. The biologically active form of plerixafor is its zinc complex.
groups. The product is treated with 1,4-dimethoxybenzene
or 1,4-bis(brommethyl)benzene and potassium carbonate
in acetonitrile
. After cleaving of the tosyl groups with hydrobromic acid
, plerixafor octahydrobromide is obtained.
, 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 compartments. The drug is not metabolized in significant amounts; no interaction with the cytochrome P450 enzymes or P-glycoprotein
s has been found. Plasma half life is 3 to 5 hours. Plerixafor is excreted via the kidney
s, with 70% of the drug being excreted within 24 hours.
(or perhaps more accurately a partial agonist
) of the alpha chemokine receptor
CXCR4
and an allosteric agonist of CXCR7
.
The CXCR4 alpha-chemokine
receptor and one of its ligand
s, SDF-1
, are important in hematopoietic stem cell homing to the bone marrow
and in hematopoietic stem cell quiescence
. The in vivo
effect of plerixafor with regard to ubiquitin
, the alternative endogenous ligand of CXCR4, is unknown. Plerixafor has been found to be a strong inducer of mobilization of hematopoietic stem cells from the bone marrow to the bloodstream as peripheral blood stem cells.
status in the United States and European Union for the mobilization of hematopoietic stem cells. It was approved by the U.S. Food and Drug Administration for this indication on December 15, 2008. In Europe, the drug was approved after a positive Committee for Medicinal Products for Human Use
assessment report on 29 May 2009.
(VEGF) can produce mesenchymal stem cells and endothelial progenitor cell
s in mice.
signalling by plerixafor (AMD3100) has also unexpectedly been found to be effective at counteracting opioid-induced hyperalgesia
produced by chronic treatment with morphine
, though only animal studies have been conducted as yet.
Autologous stem cell transplantation
Autologous stem cell transplantation is a medical procedure in which blood-forming stem cells are removed, stored, and later given back to the same person.- External link :...
to the patient. The drug was developed by AnorMED which was subsequently bought by Genzyme
Genzyme
Genzyme Corporation is a fully owned subsidiary of Sanofi-Aventis. Before its acquisition, Genzyme was an American biotechnology company based in Cambridge, Massachusetts. In 2010, Genzyme was the world’s third-largest biotechnology company, employing more than 11,000 people around the world...
.
History
Plerixafor was initially developed at the Johnson MattheyJohnson Matthey
Johnson Matthey plc is multinational chemicals and precious metals company headquartered in London, United Kingdom.It is listed on the London Stock Exchange and is a constituent of the FTSE 100 Index.-History:...
Technology Centre for potential use in the treatment of HIV
HIV
Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...
because of its role in the blocking of CXCR4
CXCR4
C-X-C chemokine receptor type 4 also known as fusin or CD184 is a protein that in humans is encoded by the CXCR4 gene.- Function :...
, a chemokine receptor
Chemokine receptor
Chemokine receptors are cytokine receptors found on the surface of certain cells, which interact with a type of cytokine called a chemokine. There have been 19 distinct chemokine receptors described in mammals...
which acts as a co-receptor for certain strains of HIV (along with the virus's main cellular receptor, CD4
CD4
CD4 is a glycoprotein expressed on the surface of T helper cells, monocytes, macrophages, and dendritic cells. It was discovered in the late 1970s and was originally known as leu-3 and T4 before being named CD4 in 1984...
). Development of this indication was terminated because of lacking oral availability and cardiac disturbances. Further studies led to the new indication for cancer patients.
Indications
Peripheral blood stem cell mobilization, which is important as a source of hematopoietic stem cells for transplantation, is generally performed using granulocyte colony-stimulating factorGranulocyte colony-stimulating factor
Granulocyte colony-stimulating factor is a colony-stimulating factor hormone. G-CSF is also known as colony-stimulating factor 3 ....
(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
Lymphoma is a cancer in the lymphatic cells of the immune system. Typically, lymphomas present as a solid tumor of lymphoid cells. Treatment might involve chemotherapy and in some cases radiotherapy and/or bone marrow transplantation, and can be curable depending on the histology, type, and stage...
and multiple myeloma
Multiple myeloma
Multiple myeloma , also known as plasma cell myeloma or Kahler's disease , is a cancer of plasma cells, a type of white blood cell normally responsible for the production of antibodies...
.
Pregnancy and lactation
Studies in pregnant animals have shown teratogenic effects. Plerixafor is therefore contraindicated in pregnant women except in critical cases. Fertile women are required to use contraceptionContraception
Contraception is the prevention of the fusion of gametes during or after sexual activity. The term contraception is a contraction of contra, which means against, and the word conception, meaning fertilization...
. It is not known whether the drug is secreted into the breast milk. Breast feeding should be discontinued during therapy.
Adverse effects
NauseaNausea
Nausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...
, diarrhea
Diarrhea
Diarrhea , also spelled diarrhoea, is the condition of having three or more loose or liquid bowel movements per day. It is a common cause of death in developing countries and the second most common cause of infant deaths worldwide. The loss of fluids through diarrhea can cause dehydration and...
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
European Medicines Agency
The European Medicines Agency is a European agency for the evaluation of medicinal products. From 1995 to 2004, the European Medicines Agency was known as European Agency for the Evaluation of Medicinal Products.Roughly parallel to the U.S...
has listed a number of safety concerns to be evaluated on a post-marketing basis, most notably the theoretical possibilities of spleen
Spleen
The spleen is an organ found in virtually all vertebrate animals with important roles in regard to red blood cells and the immune system. In humans, it is located in the left upper quadrant of the abdomen. It removes old red blood cells and holds a reserve of blood in case of hemorrhagic shock...
rupture and tumor cell mobilisation. The first concern has been raised because splenomegaly
Splenomegaly
Splenomegaly is an enlargement of the spleen. The spleen usually lies in the left upper quadrant of the human abdomen. It is one of the four cardinal signs of hypersplenism, some reduction in the number of circulating blood cells affecting granulocytes, erythrocytes or platelets in any...
was observed in animal studies, and G-CSF can cause spleen rupture in rare cases. Mobilisation of tumor cells could occur, not as a direct consequence of plerixafor application, but following the re-infusion of stem cells. Neither of these adverse effects has been observed in humans.
Chemical properties
Plerixafor is a macrocyclic compound and a bicyclam derivative. It is a strong baseBase (chemistry)
For the term in genetics, see base A base in chemistry is a substance that can accept hydrogen ions or more generally, donate electron pairs. A soluble base is referred to as an alkali if it contains and releases hydroxide ions quantitatively...
; all eight nitrogen atoms accept proton
Proton
The proton is a subatomic particle with the symbol or and a positive electric charge of 1 elementary charge. One or more protons are present in the nucleus of each atom, along with neutrons. The number of protons in each atom is its atomic number....
s readily. The two macrocyclic rings form chelate complexes with bivalent metal ions, especially zinc
Zinc
Zinc , or spelter , is a metallic chemical element; it has the symbol Zn and atomic number 30. It is the first element in group 12 of the periodic table. Zinc is, in some respects, chemically similar to magnesium, because its ion is of similar size and its only common oxidation state is +2...
, copper
Copper
Copper is a chemical element with the symbol Cu and atomic number 29. It is a ductile metal with very high thermal and electrical conductivity. Pure copper is soft and malleable; an exposed surface has a reddish-orange tarnish...
and nickel
Nickel
Nickel is a chemical element with the chemical symbol Ni and atomic number 28. It is a silvery-white lustrous metal with a slight golden tinge. Nickel belongs to the transition metals and is hard and ductile...
, as well as cobalt
Cobalt
Cobalt is a chemical element with symbol Co and atomic number 27. It is found naturally only in chemically combined form. The free element, produced by reductive smelting, is a hard, lustrous, silver-gray metal....
and rhodium
Rhodium
Rhodium is a chemical element that is a rare, silvery-white, hard and chemically inert transition metal and a member of the platinum group. It has the chemical symbol Rh and atomic number 45. It is composed of only one isotope, 103Rh. Naturally occurring rhodium is found as the free metal, alloyed...
. The biologically active form of plerixafor is its zinc complex.
Synthesis
Three of the four nitrogen atoms of the macrocycle 1,4,8,11-tetraazacyclotetradecan are protected with tosylTosyl
A tosyl group is CH3C6H4SO2. This group is usually derived from the compound 4-toluenesulfonyl chloride, CH3C6H4SO2Cl, which forms esters and amides of toluenesulfonic or tosylic acid...
groups. The product is treated with 1,4-dimethoxybenzene
1,4-Dimethoxybenzene
1,4-Dimethoxybenzene is the para form of dimethoxybenzene, a volatile aromatic ether with a sweet floral odor. It occurs naturally in willow and zucchini . It appears to attract bees as it has a powerful response in their antenna.-Uses:Dimethoxybenzene is useful as an intermediate in synthesis...
or 1,4-bis(brommethyl)benzene and potassium carbonate
Potassium carbonate
Potassium carbonate is a white salt, soluble in water , which forms a strongly alkaline solution. It can be made as the product of potassium hydroxide's absorbent reaction with carbon dioxide. It is deliquescent, often appearing a damp or wet solid...
in acetonitrile
Acetonitrile
Acetonitrile is the chemical compound with formula . This colourless liquid is the simplest organic nitrile. It is produced mainly as a byproduct of acrylonitrile manufacture...
. After cleaving of the tosyl groups with hydrobromic acid
Hydrobromic acid
Hydrobromic acid is a strong acid formed by dissolving the diatomic molecule hydrogen bromide in water. "Constant boiling" hydrobromic acid is an aqueous solution that distills at 124.3 °C and contains 47.6% HBr by weight, which is 8.89 mol/L. Hydrobromic acid has a pKa of −9, making it a...
, plerixafor octahydrobromide is obtained.
Pharmacokinetics
Following subcutaneous injectionSubcutaneous injection
A subcutaneous injection is administered as a bolus into the subcutis, the layer of skin directly below the dermis and epidermis, collectively referred to as the...
, 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 compartments. The drug is not metabolized in significant amounts; no interaction with the cytochrome P450 enzymes or P-glycoprotein
P-glycoprotein
P-glycoprotein 1 also known as multidrug resistance protein 1 or ATP-binding cassette sub-family B member 1 or cluster of differentiation 243 is a glycoprotein that in humans is encoded by the ABCB1 gene...
s has been found. Plasma half life is 3 to 5 hours. Plerixafor is excreted via the kidney
Kidney
The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...
s, with 70% of the drug being excreted within 24 hours.
Pharmacodynamics
In the form of its zinc complex, plerixafor acts as an antagonistReceptor antagonist
A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...
(or perhaps more accurately a partial agonist
Partial agonist
Partial agonists bind and activate a given receptor, but have only partial efficacy at the receptor relative to a full agonist...
) of the alpha chemokine receptor
Chemokine receptor
Chemokine receptors are cytokine receptors found on the surface of certain cells, which interact with a type of cytokine called a chemokine. There have been 19 distinct chemokine receptors described in mammals...
CXCR4
CXCR4
C-X-C chemokine receptor type 4 also known as fusin or CD184 is a protein that in humans is encoded by the CXCR4 gene.- Function :...
and an allosteric agonist of CXCR7
CXCR7
C-X-C chemokine receptor type 7 is a protein that in humans is encoded by the CXCR7 gene.This gene encodes a member of the G-protein coupled receptor family. This protein was earlier thought to be a receptor for vasoactive intestinal peptide and was considered to be an orphan receptor...
.
The CXCR4 alpha-chemokine
Chemokine
Chemokines are a family of small cytokines, or proteins secreted by cells. Their name is derived from their ability to induce directed chemotaxis in nearby responsive cells; they are chemotactic cytokines...
receptor and one of its ligand
Ligand (biochemistry)
In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. In a narrower sense, it is a signal triggering molecule, binding to a site on a target protein.The binding occurs by intermolecular forces, such as ionic bonds, hydrogen...
s, SDF-1
SDF-1 (biology)
SDF-1 is small cytokine belonging to the chemokine family that is officially designated Chemokine ligand 12 ....
, are important in hematopoietic stem cell homing to the bone marrow
Bone marrow
Bone marrow is the flexible tissue found in the interior of bones. In humans, bone marrow in large bones produces new blood cells. On average, bone marrow constitutes 4% of the total body mass of humans; in adults weighing 65 kg , bone marrow accounts for approximately 2.6 kg...
and in hematopoietic stem cell quiescence
Quiescence
Quiescence may refer to:*Quiescence search, in Game searching in artificial intelligence, a quiescent state is one in which a game is considered stable and unlikely to change drastically the next few plays...
. The in vivo
In vivo
In vivo is experimentation using a whole, living organism as opposed to a partial or dead organism, or an in vitro controlled environment. Animal testing and clinical trials are two forms of in vivo research...
effect of plerixafor with regard to ubiquitin
Ubiquitin
Ubiquitin is a small regulatory protein that has been found in almost all tissues of eukaryotic organisms. Among other functions, it directs protein recycling.Ubiquitin can be attached to proteins and label them for destruction...
, the alternative endogenous ligand of CXCR4, is unknown. Plerixafor has been found to be a strong inducer of mobilization of hematopoietic stem cells from the bone marrow to the bloodstream as peripheral blood stem cells.
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.Legal status
Plerixafor has orphan drugOrphan drug
An orphan drug is a pharmaceutical agent that has been developed specifically to treat a rare medical condition, the condition itself being referred to as an orphan disease...
status in the United States and European Union for the mobilization of hematopoietic stem cells. It was approved by the U.S. Food and Drug Administration for this indication on December 15, 2008. In Europe, the drug was approved after a positive Committee for Medicinal Products for Human Use
Committee for Medicinal Products for Human Use
The Committee for Medicinal Products for Human Use , formerly known as Committee for Proprietary Medicinal Products , is the European Medicines Agency's committee responsible for elaborating the agency's opinions on all issues regarding medicinal products for human use.E.g.: In June 2007 the CHMP...
assessment report on 29 May 2009.
Small molecule cancer therapy
Plerixafor was seen to reduce metastasis in mice in several studies. It has also been shown to reduce recurrence of glioblastoma in a mouse model after radiotherapy. In this model, the cancer surviving radiation are critically depended on bone marrow derived cells for vasculogenesis whose recruitment mediated by SDF-1 CXCR4 interaction is blocked by plerixafor.Use in generation of other stem cells
Researchers at Imperial College have demonstrated that plerixafor in combination with vascular endothelial growth factorVascular endothelial growth factor
Vascular endothelial growth factor is a signal protein produced by cells that stimulates vasculogenesis and angiogenesis. It is part of the system that restores the oxygen supply to tissues when blood circulation is inadequate....
(VEGF) can produce mesenchymal stem cells and endothelial progenitor cell
Endothelial progenitor cell
Endothelial progenitor cells are a population of rare cells that circulate in the blood with the ability to differentiate into endothelial cells, the cells that make up the lining of blood vessels. The process by which blood vessels are born de novo from endothelial progenitor cells is known as...
s in mice.
Other uses
Blockade of CXCR4CXCR4
C-X-C chemokine receptor type 4 also known as fusin or CD184 is a protein that in humans is encoded by the CXCR4 gene.- Function :...
signalling by plerixafor (AMD3100) has also unexpectedly been found to be effective at counteracting opioid-induced hyperalgesia
Opioid-induced hyperalgesia
Opioid-induced hyperalgesia or opioid-induced abnormal pain sensitivity is a phenomenon associated with the long term use of opioids such as morphine, hydrocodone, oxycodone, and methadone. Over time, individuals taking opioids can develop an increasing sensitivity to noxious stimuli, even...
produced by chronic treatment with morphine
Morphine
Morphine is a potent opiate analgesic medication and is considered to be the prototypical opioid. It was first isolated in 1804 by Friedrich Sertürner, first distributed by same in 1817, and first commercially sold by Merck in 1827, which at the time was a single small chemists' shop. It was more...
, though only animal studies have been conducted as yet.