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Maraviroc (brand-named Selzentry, or Celsentri outside the U.S.) is an antiretroviral drug in the CCR5 receptor antagonist class used in the treatment of HIV infection. It is also classed as an entry inhibitor. It also appeared to reduce graft-versus-host disease in patients treated with allogeneic bone marrow transplantation for leukemia, in a phase 1/2 study.^[3]^[4]

Mechanism of action

Maraviroc is an entry inhibitor. Specifically, maraviroc is a negative allosteric modulator of the CCR5 receptor, which is found on the surface of certain human cells. The chemokine receptor CCR5 is an essential co-receptor for most HIV strains and necessary for the entry process of the virus into the host cell. The drug binds to CCR5, thereby blocking the HIV protein gp120 from associating with the receptor. HIV is then unable to enter human macrophages and T-cells.^[5] Because HIV can also use other coreceptors, such as CXCR4, an HIV tropism test such as a trofile assay must be performed to determine if the drug will be effective.^[6]

Development and approval

Maraviroc, originally designated UK-427857, was developed by the drug company Pfizer in its UK labs located in Sandwich. On April 24, 2007 the U.S. Food and Drug Administration advisory panel reviewing maraviroc's New Drug Application unanimously recommended approval for the new drug,^[7] and the drug received full FDA approval on August 6, 2007 for use in treatment experienced patients.^[8]

On September 24, 2007, Pfizer announced that the European Commission approved maraviroc. Industry experts forecast annual maraviroc sales of $500 million by 2011.^[9]

Efficacy

Two randomized, placebo-controlled clinical trials, known as MOTIVATE 1 & 2, compared 209 patients receiving optimized therapy plus a placebo to 426 patients receiving optimized therapy plus 150 mg maraviroc once daily and 414 patients receiving optimized therapy plus 150 mg maraviroc twice daily. At 48 weeks, 55% of participants receiving maraviroc once daily and 60% of participants receiving the drug twice daily achieved a viral load of less than 400 copies/mL compared with 26% of those taking placebo; about 44% of the once-daily and 45% of the twice-daily maraviroc group had a viral load of less than 50 copies/mL compared with about 23% of those who received placebo. In addition, those who received the entry inhibitor had a mean increase in CD4 cells of 110 cells/µL in the once-daily group, 106 cells/µL in the twice-daily group, and 56 cells/µL in the placebo group.^[10]^[11]^[12]

Safety

The MOTIVATE trials showed no clinically relevant differences in safety between the maraviroc and placebo groups.^[10]

References

^ Abel S, Russell D, Whitlock LA, Ridgway CE, Nedderman AN, Walker DK (April 2008). "Assessment of the absorption, metabolism and absolute bioavailability of maraviroc in healthy male subjects". British Journal of Clinical Pharmacology 65 (Suppl 1): 60–7. doi:10.1111/j.1365-2125.2008.03137.x. PMC 2311408. PMID 18333867.
^ Abel S, Back DJ, Vourvahis M (2009). "Maraviroc: pharmacokinetics and drug interactions". Antiviral Therapy 14 (5): 607–18. PMID 19704163.
^ http://www.uphs.upenn.edu/news/News_Releases/2012/07/hiv/
^ Blocade of lymphocyte chemotaxis in visceral graft-versus-host disease, Ran Reshef et al., New England Journal of Medicine, 367:135 (July 12, 2012)
^ Levy JA (January 2009). "HIV pathogenesis: 25 years of progress and persistent challenges". AIDS 23 (2): 147–60. doi:10.1097/QAD.0b013e3283217f9f. PMID 19098484.
^ Biswas P, Tambussi G, Lazzarin A (May 2007). "Access denied? The status of co-receptor inhibition to counter HIV entry". Expert Opinion on Pharmacotherapy 8 (7): 923–33. doi:10.1517/14656566.8.7.923. PMID 17472538.
^ Gay News From 365Gay.com
^ Krauskopf, Lewis (August 6, 2007). "Pfizer wins U.S. approval for new HIV drug". Reuters. Retrieved 2007-08-06.
^ Reuters, Europe gives final approval to Pfizer HIV drug
^ ^a ^b Stephenson J (April 2007). "Researchers buoyed by novel HIV drugs: will expand drug arsenal against resistant virus". JAMA 297 (14): 1535–6. doi:10.1001/jama.297.14.1535. PMID 17426263.
^ Emmelkamp JM, Rockstroh JK (October 2007). "CCR5 antagonists: comparison of efficacy, side effects, pharmacokinetics and interactions--review of the literature". European Journal of Medical Research 12 (9): 409–17. PMID 17933722.
^ "Maraviroc reduces viral load in naive patients at 48 weeks". AIDS Patient Care and STDs 21 (9): 703–4. September 2007. PMID 17941136.

External links

BBC News story: Drug 'stops HIV's entry to cells'
Maraviroc data at aidsmap
Maraviroc early access program
New HIV Drug Recommended for Approval
maraviroc at the US National Library of Medicine Medical Subject Headings (MeSH)

UpToDate Contents

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1. HIV抗レトロウイルス療法に関する臨床試験：CCR5アンタゴニスト clinical trials of hiv antiretroviral therapy ccr5 antagonists
2. HIV薬剤耐性検査の解釈についての手引 primer on interpretation of hiv drug resistance testing
3. 抗レトロウイルス療法の潜在的副作用に関するHIV感染患者を対象としたカウンセリング counseling hiv infected patients regarding potential side effects of antiretroviral therapy
4. HIV薬剤耐性検査アッセイの概要 overview of hiv drug resistance testing assays
5. HIV-1感染の免疫学 immunology of hiv 1 infection

English Journal

Response to "Clinical Relevance of CYP3A5 Genotype on Maraviroc Exposures".

Lu Y1, Fuchs EJ1, Hendrix CW1, Bumpus NN2.
Drug metabolism and disposition: the biological fate of chemicals.Drug Metab Dispos.2015 May;43(5):773. doi: 10.1124/dmd.115.064188.
PMID 25838403

Clinical Relevance of CYP3A5 Genotype on Maraviroc Exposures.

Vourvahis M1, McFadyen L2, Heera J2, Clark A2.
Drug metabolism and disposition: the biological fate of chemicals.Drug Metab Dispos.2015 May;43(5):771-2. doi: 10.1124/dmd.115.063321.
PMID 25838402

Performance of commonly used genotypic assays and comparison with phenotypic assays of HIV-1 coreceptor tropism in acutely HIV-1-infected patients.

Ceresola ER1, Nozza S2, Sampaolo M3, Pignataro AR3, Saita D3, Ferrarese R3, Ripa M2, Deng W4, Mullins JI4, Boeri E3, Tambussi G2, Toniolo A5, Lazzarin A6, Clementi M1, Canducci F7.
The Journal of antimicrobial chemotherapy.J Antimicrob Chemother.2015 May;70(5):1391-5. doi: 10.1093/jac/dku573. Epub 2015 Jan 20.
OBJECTIVES: Although founder viruses in primary HIV-1 infections (PHIs) typically use the CCR5 coreceptor (R5-tropic), 3%-19% of subjects also harbour CXCR4-using viruses (X4-tropic), making tropism determination before CCR5 antagonist usage mandatory. Genotypic methods can be used to accurately det
PMID 25608585

Japanese Journal

Impact of maraviroc-resistant mutation M434I in the C4 region of HIV-1 gp120 on sensitivity to antibody-mediated neutralization

Boonchawalit Samatchaya,Harada Shigeyoshi,Shirai Noriko,Gatanaga Hiroyuki,Oka Shinichi,Matsushita Shuzo,Yoshimura Kazuhisa
Japanese Journal of Infectious Diseases advpub(0), 2015
… We previously reported that a maraviroc (MVC) resistant HIV-1 generated using in vitro selection exhibited high sensitivity to several neutralizing monoclonal antibodies (NMAbs) and autologous plasma IgGs. …
NAID 130005086979

ケモカイン標的療法

義江修
日本臨床免疫学会会誌 = Japanese journal of clinical immunology 36(4), 189-196, 2013-08-31
… を動物実験から見極めることを困難にし，また候補薬物の前臨床試験を動物で行うことを困難にしている．そのため，ケモカインレセプターを標的とした薬剤開発の可能性はいまだ十分に見極められたとは言い難い．本稿では，それぞれのケモカインレセプターの疾患関連性を検討し，さらに実際に現在臨床応用に至っているCCR5阻害薬（Maraviroc），CXCR4阻害薬（Plerixafor），抗CCR4抗体（Mogamulizmab）について紹介したい． …
NAID 10031196415

インテグラーゼ阻害薬,CCR5受容体拮抗薬 (特集抗ウイルス薬) -- (抗ウイルス薬の特性と適応・使い分け)

塚田訓久
日本臨床 70(4), 596-600, 2012-04
NAID 40019238399

Related Pictures

Maraviroc, primer medicamento oral de acción extracelular para pacientes resistentes Structure of Selzentry (maraviroc) Brand: Selzentry Generic: maraviroc Indication: Antiviral | pharmacology | Pharmacy Antiretroviral therapy _drugs,_mechanism_of_action,_adverse_effects,_… Maraviroc (para el tratamiento del VIH) | Dosificación, Efectos secundarios | infoSIDA CONCEPTO VIH-SIDA E ITS A.C.: CROI 2013: La Intensificación con Maraviroc y

★リンクテーブル★

リンク元	「マラビロック」「マラビロク」

「マラビロック」

Maraviroc
Systematic (IUPAC) name
	4,4-difluoro-N-{(1S)-3-[3-(3-isopropyl- 5-methyl-4H-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-phenylpropyl}cyclohexanecarboxamide
Clinical data
Trade names	Selzentry
AHFS/Drugs.com	monograph
MedlinePlus	a607076
Licence data	EMA:Link, US FDA:link
Pregnancy; category	AU: B1; US: B (No risk in non-human studies);
Legal status	UK: Prescription-only (POM); US: ℞-only;
Routes of; administration	Oral
Pharmacokinetic data
Bioavailability	23%
Metabolism	Liver
Biological half-life	16 h
Identifiers
CAS Registry Number	376348-65-1
ATC code	J05AX09
PubChem	CID: 3002977
IUPHAR/BPS	806
DrugBank	DB04835
ChemSpider	20078004
UNII	MD6P741W8A
ChEBI	CHEBI:63608
ChEMBL	CHEMBL1201187
NIAID ChemDB	104834
Chemical data
Formula	C29H41F2N5O
Molecular mass	513.666 g/mol
	SMILES Cc5nnc(n5[C@@H]1C[C@H]4CC[C@@H](C1)N4CC[C@H](NC(=O)C2CCC(F)(F)CC2)c3ccccc3)C(C)C ;
	InChI InChI=1S/C29H41F2N5O/c1-19(2)27-34-33-20(3)36(27)25-17-23-9-10-24(18-25)35(23)16-13-26(21-7-5-4-6-8-21)32-28(37)22-11-14-29(30,31)15-12-22/h4-8,19,22-26H,9-18H2,1-3H3,(H,32,37)/t23-,24+,25-,26-/m0/s1 ; Key:GSNHKUDZZFZSJB-QYOOZWMWSA-N ;
(what is this?) (verify)

　　[★]

英: maraviroc

エイズ治療薬
CCR5阻害薬
エイズウイルスとCCR5との結合を妨げる

「マラビロク」

　　[★]

英: maraviroc
商: シーエルセントリ
関: マラビロック

[1] Abel S, Russell D, Whitlock LA, Ridgway CE, Nedderman AN, Walker DK (April 2008). "Assessment of the absorption, metabolism and absolute bioavailability of maraviroc in healthy male subjects". British Journal of Clinical Pharmacology 65 (Suppl 1): 60–7. doi:10.1111/j.1365-2125.2008.03137.x. PMC 2311408. PMID 18333867.

[2] Abel S, Back DJ, Vourvahis M (2009). "Maraviroc: pharmacokinetics and drug interactions". Antiviral Therapy 14 (5): 607–18. PMID 19704163.

[3] ttp://www.uphs.upenn.edu/news/News_Releases/2012/07/hiv/

[4] Blocade of lymphocyte chemotaxis in visceral graft-versus-host disease, Ran Reshef et al., New England Journal of Medicine, 367:135 (July 12, 2012)

[5] Levy JA (January 2009). "HIV pathogenesis: 25 years of progress and persistent challenges". AIDS 23 (2): 147–60. doi:10.1097/QAD.0b013e3283217f9f. PMID 19098484.

[6] Biswas P, Tambussi G, Lazzarin A (May 2007). "Access denied? The status of co-receptor inhibition to counter HIV entry". Expert Opinion on Pharmacotherapy 8 (7): 923–33. doi:10.1517/14656566.8.7.923. PMID 17472538.

[7] Gay News From 365Gay.com

[8] Krauskopf, Lewis (August 6, 2007). "Pfizer wins U.S. approval for new HIV drug". Reuters. Retrieved 2007-08-06.

[9] Reuters, Europe gives final approval to Pfizer HIV drug

[JAMA-10] Stephenson J (April 2007). "Researchers buoyed by novel HIV drugs: will expand drug arsenal against resistant virus". JAMA 297 (14): 1535–6. doi:10.1001/jama.297.14.1535. PMID 17426263.

[11] Emmelkamp JM, Rockstroh JK (October 2007). "CCR5 antagonists: comparison of efficacy, side effects, pharmacokinetics and interactions--review of the literature". European Journal of Medical Research 12 (9): 409–17. PMID 17933722.

[12] "Maraviroc reduces viral load in naive patients at 48 weeks". AIDS Patient Care and STDs 21 (9): 703–4. September 2007. PMID 17941136.

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maraviroc