Valganciclovir, sold under the brand name Valcyte among others, is an

antiviral medication Antiviral drugs are a class of medication used for treating viral infections. Most antivirals target specific viruses, while a broad-spectrum antiviral is effective against a wide range of viruses. Unlike most antibiotics, antiviral drugs do ...

used to treat cytomegalovirus (CMV) infection in those with

HIV/AIDS Human immunodeficiency virus infection and acquired immunodeficiency syndrome (HIV/AIDS) is a spectrum of conditions caused by infection with the human immunodeficiency virus (HIV), a retrovirus. Following initial infection an individual ...

or following

organ transplant Organ transplantation is a medical procedure in which an organ (anatomy), organ is removed from one body and placed in the body of a recipient, to replace a damaged or missing organ. The donor and recipient may be at the same location, or organ ...

. It is often used long term as it only suppresses rather than cures the infection. Valganciclovir is taken by mouth. Common side effects include

abdominal pain Abdominal pain, also known as a stomach ache, is a symptom associated with both non-serious and serious medical issues. Common causes of pain in the abdomen include gastroenteritis and irritable bowel syndrome. About 15% of people have a m ...

, headaches, trouble sleeping, nausea, fever, and low blood cell counts. Other side effects may include infertility and

kidney problems Kidney failure, also known as end-stage kidney disease, is a medical condition in which the kidneys can no longer adequately filter waste products from the blood, functioning at less than 15% of normal levels. Kidney failure is classified as eit ...

. When used during

pregnancy Pregnancy is the time during which one or more offspring develops (gestation, gestates) inside a woman, woman's uterus (womb). A multiple birth, multiple pregnancy involves more than one offspring, such as with twins. Pregnancy usually occur ...

, it causes birth defects in some animals. Valganciclovir is the L- valyl

ester In chemistry, an ester is a compound derived from an oxoacid (organic or inorganic) in which at least one hydroxyl group () is replaced by an alkoxy group (), as in the substitution reaction of a carboxylic acid and an alcohol. Glycerides a ...

ganciclovir Ganciclovir, sold under the brand name Cytovene among others, is an antiviral medication used to treat cytomegalovirus (CMV) infections. Ganciclovir was patented in 1980 and approved for medical use in 1988. Medical use Ganciclovir is indicated ...

and works when broken down into ganciclovir by the intestine and

liver The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it ...

. Valganciclovir was approved for medical use in 2001. It is on the

World Health Organization's List of Essential Medicines The WHO Model List of Essential Medicines (aka Essential Medicines List or EML), published by the World Health Organization (WHO), contains the medications considered to be most effective and safe to meet the most important needs in a health s ...

. In 2017, a generic version was approved.

Medical uses

Adults

Valganciclovir is commonly used for treatment of cytomegalovirus (CMV)

retinitis Retinitis is inflammation of the retina in the eye, which can permanently damage the retina and lead to blindness. The retina is the eye's "sensing" tissue. Retinitis may be caused by a number of different infectious agents. Its most common form, ...

(eye infection may cause blindness) in people who have acquired immunodeficiency syndrome (AIDS). Valganciclovir is also used to prevent cytomegalovirus disease in people who have received a heart, kidney, or kidney-pancreas transplant and who have a chance of getting CMV disease. Overall, valganciclovir works by preventing the spread of CMV disease or slowing the growth of CMV.

Children

Valganciclovir is used for the prevention of CMV disease in people following kidney transplant (4 months to 16 years of age) and heart transplant (1 month to 16 years of age) at high risk.

Side effects

Valganciclovir is commonly associated with vomiting, abdominal pain, diarrhea, and headache. Other side effects include fever,

trouble sleeping Insomnia, also known as sleeplessness, is a sleep disorder in which people have trouble sleeping. They may have difficulty falling asleep, or staying asleep as long as desired. Insomnia is typically followed by daytime sleepiness, low energy, ...

peripheral neuropathy Peripheral neuropathy, often shortened to neuropathy, is a general term describing disease affecting the peripheral nerves, meaning nerves beyond the brain and spinal cord. Damage to peripheral nerves may impair sensation, movement, gland, or or ...

, and retinal detachment. Of note, the FDA issued several black box warnings concerning potential severe toxicities. These include: * Blood toxicities: neutropenia,

anemia Anemia or anaemia (British English) is a blood disorder in which the blood has a reduced ability to carry oxygen due to a lower than normal number of red blood cells, or a reduction in the amount of hemoglobin. When anemia comes on slowly, t ...

thrombocytopenia Thrombocytopenia is a condition characterized by abnormally low levels of platelets, also known as thrombocytes, in the blood. It is the most common coagulation disorder among intensive care patients and is seen in a fifth of medical patients a ...

* Impairment of fertility (based on animal studies only) * Fetal toxicities (based on animal studies only) *

Mutagenesis Mutagenesis () is a process by which the genetic information of an organism is changed by the production of a mutation. It may occur spontaneously in nature, or as a result of exposure to mutagens. It can also be achieved experimentally using lab ...

and

carcinogenesis Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abno ...

(based on animal studies only)

Drug interactions

While not studied in people, it can be assumed that interactions will be similar as those with

, since valganciclovir is converted into ganciclovir in the body.

Zidovudine Zidovudine (ZDV), also known as azidothymidine (AZT), is an antiretroviral medication used to prevent and treat HIV/AIDS. It is generally recommended for use in combination with other antiretrovirals. It may be used to prevent mother-to-child ...

may decrease the concentration of ganciclovir, and together the drugs can cause

and neutropenia.

Probenecid Probenecid, also sold under the brand name Probalan, is a medication that increases uric acid excretion in the urine. It is primarily used in treating gout and hyperuricemia. Probenecid was developed as an alternative to caronamide to competitive ...

can increase the concentration of ganciclovir, which could increase the chances of ganciclovir toxicity. People with kidney problems could have an increase in both

mycophenolate mofetil Mycophenolic acid (MPA) is an immunosuppressant medication used to prevent rejection following organ transplantation and to treat autoimmune conditions such as Crohn's disease and lupus. Specifically it is used following kidney, heart, and liv ...

and ganciclovir concentrations when both drugs are taken together. Ganciclovir can also increase the concentration of

didanosine Didanosine (ddI, DDI), sold under the brand name Videx, is a medication used to treat HIV/AIDS. It is used in combination with other medications as part of highly active antiretroviral therapy (HAART). It is of the reverse-transcriptase inhibitor ...

Mechanism of action

Valganciclovir is a prodrug for

, which is a synthetic analog of 2′-deoxy-

guanosine Guanosine (symbol G or Guo) is a purine nucleoside comprising guanine attached to a ribose ( ribofuranose) ring via a β-N9- glycosidic bond. Guanosine can be phosphorylated to become guanosine monophosphate (GMP), cyclic guanosine monophosphate ...

. Its structure is the same as ganciclovir, except for the addition of a L-valyl ester at the 5' end of the incomplete

deoxyribose Deoxyribose, or more precisely 2-deoxyribose, is a monosaccharide with idealized formula H−(C=O)−(CH2)−(CHOH)3−H. Its name indicates that it is a deoxy sugar, meaning that it is derived from the sugar ribose by loss of a hydroxy group. D ...

ring. The valine increases both the absorption of the drug in the intestines, as well as the bioavailability of the drug once it is absorbed. The L-valyl ester is cleaved by

esterase An esterase is a hydrolase enzyme that splits esters into an acid and an alcohol in a chemical reaction with water called hydrolysis. A wide range of different esterases exist that differ in their substrate specificity, their protein structure ...

s in the intestines and the liver, leaving ganciclovir to be absorbed by the virus-infected cells. Ganciclovir is first

phosphorylated In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...

to ganciclovir monophosphate by a viral thymidine kinase encoded by the cytomegalovirus (CMV) upon infection. Human cellular kinases further phosphorylate the molecule to create ganciclovir diphosphate, then ganciclovir triphosphate. These kinases are present in 10-fold greater concentrations in CMV or herpes simplex virus (HSV)-infected cells compared to uninfected human cells, allowing ganciclovir triphosphate to concentrate in infected cells. Ganciclovir triphosphate is a competitive inhibitor of deoxyguanosine triphosphate (dGTP). It is incorporated into viral DNA and preferentially inhibits viral DNA polymerases more than cellular DNA polymerases. Ganciclovir triphosphate serves as a poor substrate for chain elongation. Once incorporated into viral DNA due to its structure similarity to dGTP, chain termination occurs once a single nucleotide is added to the distal hydroxyl group of the incomplete deoxyribose ring of ganciclovir.

Pharmacokinetics

# Oral

bioavailability In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation. By definition, when a medication is administered intravenously, its bioavailability is 100%. Ho ...

is approximately 60%. Fatty foods significantly increase the bioavailability and the peak level in the serum. # It takes about 2 hours to reach maximum

concentration In chemistry, concentration is the abundance of a constituent divided by the total volume of a mixture. Several types of mathematical description can be distinguished: '' mass concentration'', ''molar concentration'', '' number concentration'', ...

s in the serum. # Valganciclovir is eliminated as ganciclovir in the urine, with a

half-life Half-life (symbol ) is the time required for a quantity (of substance) to reduce to half of its initial value. The term is commonly used in nuclear physics to describe how quickly unstable atoms undergo radioactive decay or how long stable at ...

of about 4 hours in people with normal

kidney function Assessment of kidney function occurs in different ways, using the presence of symptoms and signs, as well as measurements using urine tests, blood tests, and medical imaging. Functions of a healthy kidney include maintaining a person's fluid ...

. # The mechanism of this drug is activation via a viral protein kinase HCMV UL97 and subsequent phosphorylation by cellular kinases. The phosphotransferase enzyme can likewise activate valganciclovir.

Chemistry

The synthesis of valganciclovir has been reviewed. Many routes use ganciclovir as a starting material.

Society and culture

Price and patent status

Roche's Valcyte is protected by

patent A patent is a type of intellectual property that gives its owner the legal right to exclude others from making, using, or selling an invention for a limited period of time in exchange for publishing an enabling disclosure of the invention."A ...

. However a generic version manufactured by Japanese-owned Indian company Daiichi-Ranbaxy was found by the District Court of New Jersey, USA not to infringe Roche's patent. In November 2014, FDA approved generics by two manufacturers. The price of a four-month course of valganciclovir from Roche is about US$8,500 in high-income countries, $6,000 in India. However, the valganciclovir patent was rejected by the

Indian Patent Office The Office of the Controller General of Patents, Designs and Trade Marks (CGPDTM) generally known as the Indian Patent Office, is an agency under the Department for Promotion of Industry and Internal Trade which administers the Indian law of ...

Valganciclovir rejected by the Indian Patent Office
/ref> in 2010, although Roche may appeal the rejection.

Names

Also known as Cymeval, Valcyt, Valixa, Darilin, Rovalcyte, Patheon, and Syntex.

References

External links

* {{Portal bar , Medicine , Viruses Amino acid derivatives Anti-herpes virus drugs Carboxylate esters Ethers Genentech brands Hoffmann-La Roche brands Primary alcohols Prodrugs Purines Wikipedia medicine articles ready to translate World Health Organization essential medicines