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| Clinical data | |
|---|---|
| Trade names | Mytesi |
| Other names | SP-303 |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a613016 |
| License data | |
| Routes of administration | By mouth (oral tablets) |
| ATC code | |
| Legal status | |
| Legal status | |
| Pharmacokinetic data | |
| Bioavailability | Little or no absorption from the gut |
| Identifiers | |
| CAS Number | |
| PubChem SID | |
| DrugBank | |
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| UNII | |
| KEGG | |
| CompTox Dashboard(EPA) | |
| Chemical and physical data | |
| Formula | (C15O6,7H12)n |
| Molar mass | 860–9100 g·mol−1 |
Crofelemer (USAN, trade nameMytesi) is an antidiarrheal indicated for the symptomatic relief of non-infectious diarrhea in adult patients with HIV/AIDS on antiretroviral therapy.[1] Other possible uses include diarrhea in children, acuteinfectious diarrhea, and diarrhea in patients withirritable bowel syndrome.[2] It is a purifiedoligomericproanthocyanidin from "dragon's blood", thesap of the South American treeCroton lechleri.[3]
Crofelemer treats the symptoms of disease, but it is not used to treat infectious diarrhea (diarrhea caused by infection of the digestive system by a bacterium, virus or parasite).It was initially developed byNapo Pharmaceuticals, which is a wholly owned subsidiary ofJaguar Health, Inc. A Phase IIIclinical trial for diarrhea in HIV patients was completed in 2012, and the drug was approved by the USFood and Drug Administration (FDA) on 31 December 2012.[4][5][6]
The drug is taken orally and works by modulatingcystic fibrosis transmembrane conductance regulator (CFTR) and thecalcium-activated chloride channel (CaCC), two chloride ion channels from the luminal side of the gastrointestinal tract.[3] This is a first-in-class antisecretory antidiarrheal mechanism of action and it does not affect gastrointestinal motility, unlike the traditional antimotility drugs. As a result of the channel regulation, fewerchloride ions are secreted into the gut, which decreases the associated secretion ofsodium ions and accompanying water, thus improving stool consistency and reducing the frequency of watery stools and duration of the diarrhea.[4][7] The mechanism is selective for the CFTR and CaCC, as other channels involved in intestinal fluid secretion, namelysodium andpotassium channels, are not affected by crofelemer, nor iscAMP orcalcium signaling.[3]
Crofelemer is minimally, if at all, absorbed from the gut into the bloodstream, and is mostly excreted in the stools.[7]
Crofelemer is well tolerated; and the only adverse effects found in clinical studies were mild gastrointestinal effects at the same level as underplacebo.[7] The most common adverse reactions (≥ 3%) are: upper respiratory tract infection, bronchitis, cough, flatulence and increased bilirubin.[1]
Crofelemer is an oligomeric proanthocyanidin mixture primarily composed of (+)–catechin, (–)–epicatechin, (+)–gallocatechin, and (–)–epigallocatechin monomer units linked in random sequence, as represented below. The average degree of polymerization for the oligomers ranges between 5 and 7.5, as determined by phloroglucinol degradation. The substance is a purifiedoligomericproanthocyanidin from the sap, or more correctly thelatex, of the South American treeCroton lechleri (locally calledsangre de grado orsangre de drago). This is one of several plants producing bright red latex or resin called "dragon's blood".[3] Crofelemer is a complex mixture ofprocyanidins andprodelphinidins with up to 30(epi)catechin or(epi)gallocatechin units per molecule, resulting in a molecular mass of up to 9 kDa.[3]
The crude plant latex ofC. lechleri is traditionally used in South American medicine for the treatment of diarrhea, wounds, inflammations,tumors, insect bites, and other conditions.[3][8] A number of chemicals were isolated in the late 1980s and 1990s and tested in cellular and animal models, for example identifyingtaspine as acicatrizant (wound healing promoter).[9]Immunomodulatory,antioxidative,antiproliferative andmutagenic effects of dragon's blood and its components also received some attention from the scientific community. The purified oligomeric proanthocyanidin fraction was first described in 1994 under the name SP-303 as anantiviral drug,[10] but a study testing it for the treatment ofherpes simplex did not show any benefit.[11] In 1999, crofelemer was reported to improve the symptoms ofcholera toxin induced diarrhea in mice.[12] Crofelemer demonstrated reduction of duration of diarrhea and frequency of watery stools in patients with traveler's diarrhea[13] and patients with HIV/AIDS.[14] Crofelemer has also shown benefit in adult patients with acute infectious diarrhea fromE. coli andsalmonella,[15] and in patients with moderate to severe watery diarrhea fromvibrio cholerae. Crofelemer has also been shown to improve abdominal pain and discomfort in patients with diarrhea-predominate irritable bowel syndrome.[16][17]
SP-303 was eventually named crofelemer and patented by Napo Pharmaceuticals, which licensed it to Glenmark Pharmaceuticals in 2005, for exclusive development and marketing rights in 140 emerging markets including India,[18] and to Salix Pharmaceuticals for exclusive development and marketing rights in North America, the European Union and Japan, in 2008.[19] Subsequently, Napo sued Salix and terminated the agreements with Salix and Glenmark in 2011, alleging that they were stalling the drug's development.[20] In 2012, crofelemer completed a Phase III trial, and it was approved in December 2012 by the FDA for the indication "symptomatic relief of non-infectious diarrhea in patients with HIV/AIDS onanti-retroviral therapy".[2][6]
The drug substance is manufactured by Glenmark Pharmaceuticals, and is manufactured as 125 mg delayed-release tablets byPatheon Pharmaceuticals Inc. for Napo Pharmaceuticals.[citation needed]
