Ritonavir
|
|
| Systematic (IUPAC) name |
|
1,3-thiazol-5-ylmethyl N-[(2S,3S,5S)-3-hydroxy-5-[(2S)-3-methyl-2-{[methyl({[2-(propan-2-yl)-1,3-thiazol-4-yl]methyl})carbamoyl]amino}butanamido]-1,6-diphenylhexan-2-yl]carbamate
|
| Clinical data |
| Trade names |
Norvir |
| AHFS/Drugs.com |
monograph |
| MedlinePlus |
a696029 |
Pregnancy
category |
- AU: B3
- US: B (No risk in non-human studies)
|
| Legal status |
- AU: Prescription Only (S4)
- CA: ℞-only
- UK: Prescription-only (POM)
- US: ℞-only
|
Routes of
administration |
oral |
| Pharmacokinetic data |
| Protein binding |
98-99% |
| Metabolism |
Hepatic |
| Biological half-life |
3-5 hours |
| Excretion |
mostly fecal |
| Identifiers |
| CAS Registry Number |
155213-67-5 Y |
| ATC code |
J05AE03 |
| PubChem |
CID: 392622 |
| DrugBank |
DB00503 Y |
| ChemSpider |
347980 Y |
| UNII |
O3J8G9O825 Y |
| KEGG |
D00427 Y |
| ChEBI |
CHEBI:45409 N |
| ChEMBL |
CHEMBL163 Y |
| NIAID ChemDB |
028478 |
| Chemical data |
| Formula |
C37H48N6O5S2 |
| Molecular mass |
720.946 g/mol |
SMILES
-
CC(C)c4nc(CN(C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc2ccccc2)NC(=O)OCc3cncs3)cs4
|
InChI
-
InChI=1S/C37H48N6O5S2/c1-24(2)33(42-36(46)43(5)20-29-22-49-35(40-29)25(3)4)34(45)39-28(16-26-12-8-6-9-13-26)18-32(44)31(17-27-14-10-7-11-15-27)41-37(47)48-21-30-19-38-23-50-30/h6-15,19,22-25,28,31-33,44H,16-18,20-21H2,1-5H3,(H,39,45)(H,41,47)(H,42,46)/t28-,31-,32-,33-/m0/s1 Y
-
Key:NCDNCNXCDXHOMX-XGKFQTDJSA-N Y
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| N (what is this?) (verify) |
Ritonavir, with trade name Norvir (AbbVie, Inc.), is an antiretroviral drug from the protease inhibitor class used to treat HIV infection and AIDS.
Ritonavir is frequently prescribed with a highly active antiretroviral therapy (HAART), not for its antiviral action, but as it inhibits the same host enzyme that metabolizes other protease inhibitors. This inhibition leads to higher plasma concentrations of these latter drugs, allowing the clinician to lower their dose and frequency and improving their clinical efficacy.
It is on the World Health Organization's List of Essential Medicines, a list of the most important medication needed in a basic health system.[1]
Contents
- 1 Side effects
- 2 Drug interactions
- 3 Mechanism of action
- 4 History
- 5 Polymorphism and temporary market withdrawal
- 6 References
- 7 Further reading
- 8 External links
Side effects
When administered at doses effective for anti-HIV therapy, the side effects of ritonavir are those shown below. It is currently (2015) much more widely used at lower doses as a pharmacokinetic inhibitor. The adverse effects of these lower doses of ritonavir do not appear to have been extensively characterized.[2]
- asthenia, malaise
- diarrhea
- nausea and vomiting
- abdominal pain
- dizziness
- insomnia
- sweating
- taste abonormality
- metabolic
- hypercholesterolemia
- hypertriglyceridemia
- elevated transaminases
- elevated CPK
One of ritonavir's side effects is hyperglycemia. It appears that ritonavir directly inhibits the GLUT4 insulin-regulated transporter, keeping glucose from entering fat and muscle cells.[citation needed] This can lead to insulin resistance and cause problems for Type Ⅱ diabetics.
Drug interactions
Concomitant therapy of ritonavir with a variety of medications may result in serious and sometimes fatal drug interactions.[3] Ritonavir induces CYP 1A2 and inhibits the major P450 isoforms (3A4 and 2D6).
The list of clinically significant interactions of ritonavir includes but is not limited to following drugs:
- amiodarone - decreased metabolism, possible toxicity
- midazolam and triazolam - contraindicated
- carbamazepine - decreased metabolism, possible toxicity
- cisapride - decreased metabolism, possible prolongation of Q-T interval and life-threatening arrythmias
- disulfiram (with ritonavir oral preparation) - decreased metabolism of ritonavir
- eplerenone
- etravirine
- flecainide - decreased metabolism, possible toxicity
- MDMA - decreased metabolism, can sometimes result in toxic outcomes like serotonin syndrome which can be life-threatening[4][5]
- mescaline
- meperidine (pethidine) - build-up of toxic concentrations of norpethidine possible
- nilotinib
- nisoldipine
- phenytoin - the proposed mechanism involves ritonavir induction of phenytoin metabolism via CYP450 2C9
- pimozide
- quinidine
- ranolazine
- salmeterol
- St John's wort
- statins - decreased metabolism, without dosage modification increased risk of rhabomyolisis
- thioridazine
- topotecan
- voriconazole - ritonavir increases metabolism of voriconazole
Mechanism of action
Ritonavir (center) bound to the active site of HIV protease.
Ritonavir was originally developed as an inhibitor of HIV protease. It is one of the most complex inhibitors. It is now rarely used for its own antiviral activity, but remains widely used as a booster of other protease inhibitors. More specifically, ritonavir is used to inhibit a particular liver enzyme that normally metabolizes protease inhibitors, cytochrome P450-3A4 (CYP3A4).[6] The drug's molecular structure inhibits CYP3A4, so a low dose can be used to enhance other protease inhibitors. This discovery, which has drastically reduced the adverse effects and improved the efficacy of protease inhibitors and HAART, was first communicated in an article published in the journal AIDS in 1997 by researchers at the University of Liverpool.[7] This effect does come with a price: it also affects the efficacy of numerous other medications, making it difficult to know how to administer them concurrently.
History
HIV deaths in the United States fell from approximately 50,000 per year to 18,000 in the two years following the FDA approval of ritonavir
[8]
Ritonavir is manufactured as Norvir by AbbVie, Inc.. The Food and Drug Administration (FDA) approved ritonavir on March 1, 1996, making it the seventh approved antiretroviral drug and the second approved protease inhibitor in the United States. Within 2 years of the approval of ritonovir (and of saquinavir a few months earlier), the U.S. HIV-associated death rate fell from over 50,000 per year to about 18,000. [9]
In 2003, Abbott (now AbbVie, Inc.) raised the price of a Norvir course from USD $1.71 per day to $8.57 per day, leading to claims of price gouging by patients' groups and some members of Congress. Consumer group Essential Inventions petitioned the NIH to override the Norvir patent, but the NIH announced on August 4, 2004 that it lacked the legal right to allow generic production of Norvir.[10]
In 2014, FDA approved Viekira Pak which ritonavir is one of its components.[11]
Polymorphism and temporary market withdrawal
Norvir was originally dispensed as an ordinary capsule, which did not require refrigeration. This was as a crystal of what is now called form I.[12] However, like many drugs, ritonavir exhibits polymorphism, i.e., the same molecule crystallizes into more than one type of crystal. The different crystals, or polymorphs, are made of the same molecules but in different crystalline arrangements. The solubility and hence the bioavailability is very different in the two different arrangements.[13]
During development (it was introduced in 1996), only the polymorph now called form I was found, but in 1998, a lower free energy, more stable polymorph (form II) appeared. This more stable (and so less soluble) crystal form compromised the oral bioavailability of the drug. This caused the removal of the oral capsule formulation from the market.[13]
Even a trace of form II can catalyse the transformation from the more bioavailable form I to form II. Thus form II threatened existing supplies of ritonavir as the lower solubility polymorph caused the therapeutically effective polymorph to convert to form II. Form II, which was not therapeutically effective because of poor solubility and resulting much lower bioavailability, entered production lines and effectively halted production processes.[12]
After this discovery in the late 1990s, Abbott (now AbbVie) withdrew the original capsules from the market, and recommended patients switch to Norvir suspension while researchers worked to solve the problem. The capsules have been replaced with refrigerated gelcaps, to solve the crystallization problem of the original capsules.
In 2000 Abbott (now AbbVie) was awarded approval by the FDA for a tablet (called Kaletra) which contains Ritonavir that does not require refrigeration.[14]
References
- ^ "WHO Model List of EssentialMedicines" (PDF). World Health Organization. October 2013. Retrieved 22 April 2014.
- ^ Norvir, rxlist.com
- ^ Ritonavir, Merck Manual
- ^ Henry, J. A.; Hill, I. R. (1998). "Fatal interaction between ritonavir and MDMA". Lancet 352 (9142): 1751–1752. doi:10.1016/s0140-6736(05)79824-x. PMID 9848354. edit
- ^ Papaseit, E.; Vázquez, A.; Pérez-Mañá, C.; Pujadas, M.; De La Torre, R.; Farré, M.; Nolla, J. (2012). "Surviving life-threatening MDMA (3,4-methylenedioxymethamphetamine, ecstasy) toxicity caused by ritonavir (RTV)". Intensive Care Medicine 38 (7): 1239–1240. doi:10.1007/s00134-012-2537-9. PMID 22460853. edit
- ^ Zeldin RK, Petruschke RA (2004). "Pharmacological and therapeutic properties of ritonavir-boosted protease inhibitor therapy in HIV-infected patients". Journal of Antimicrobial Chemotherapy 53 (1): 4–9. doi:10.1093/jac/dkh029. PMID 14657084.
- ^ Merry, Concepta; Barry, Michael G.; Mulcahy, Fiona; Ryan, Mairin; Heavey, Jane; Tjia, John F.; Gibbons, Sara E.; Breckenridge, Alasdair M.; Back, David J. (1997). "Saquinavir pharmacokinetics alone and in combination with ritonavir in HIV-infected patients". AIDS 11 (4): F29–F33. doi:10.1097/00002030-199704000-00001. PMID 9084785.
- ^ "www.cdc.gov" (PDF).
- ^ "HIV Surveillance --- United States, 1981--2008". Retrieved 8 November 2013.
- ^ Ceci Connolly (2004-08-05). "NIH Declines to Enter AIDS Drug Price Battle". Washington Post. Retrieved 2006-01-16.
- ^ "FDA approves Viekira Pak to treat hepatitis C". Food and Drug Administration. December 19, 2014.
- ^ a b Bauer J et al. (2001). "Ritonavir: An Extraordinary Example of Conformational Polymorphism". Pharmaceutical Research 18 (6): 859–866. doi:10.1023/A:1011052932607. PMID 11474792.
- ^ a b S. L. Morisette, S. Soukasene, D. Levinson, M. J. Cima and O. Almarsson (2003). "Elucidation of crystal form diversity of the HIV protease inhibitor ritonavir by high-throughput crystallization". Proc. Natl. Acad. Sci. USA 100 (5): 2180–84. doi:10.1073/pnas.0437744100. PMC 151315. PMID 12604798.
- ^ "KALETRA FAQ". AbbVie's Kaletra product information. AbbVie. 2011. Retrieved 5 July 2014.
Further reading
- Chemburkar, Sanjay R.; Bauer, John; Deming, Kris; Spiwek, Harry; Patel, Ketan; Morris, John; Henry, Rodger; Spanton, Stephen et al. (2000). "Dealing with the Impact of Ritonavir Polymorphs on the Late Stages of Bulk Drug Process Development". Organic Process Research & Development 4 (5): 413. doi:10.1021/op000023y.
External links
- PubPK - Ritonavir pharmacokinetics
- [1] (manufacturer's website)
- Ritonavir bound to proteins in the PDB
- Norvir Prescribing Information
|
Antiviral drugs: antiretroviral drugs used against HIV (primarily J05)
|
|
Entry/fusion inhibitors
(Discovery and development) |
- gp41 (Enfuvirtide (ENF, T-20))
- CCR5 (Maraviroc (MVC)
- Vicriviroc†, Cenicriviroc†, PRO 140†)
- CD4 (Ibalizumab†)
- gp120 (Fostemsavir†)
|
|
Reverse-transcriptase
inhibitors (RTIs) |
Nucleoside and
nucleotide (NRTI) |
- Nucleoside analogues/NRTIs: Abacavir (ABC)°#
- Emtricitabine (FTC)°#
- Lamivudine (3TC)°#
- Didanosine (ddI)#
- Zidovudine (AZT, ZDV)#
- Apricitabine†
- Stampidine†
- Elvucitabine†
- Racivir†
- Amdoxovir†
- Stavudine (d4T)#
- Zalcitabine (ddC)◊
- Festinavir†
- Nucleotide analogues/NtRTIs: Tenofovir disoproxil fumarate (TDF)°#
- Tenofovir alafenamide fumarate (TAF)†
|
|
Non-nucleoside (NNRTI)
(Discovery and development) |
- (1st generation) Efavirenz (EFV)°#
- Nevirapine (NVP)#
- Delavirdine (DLV)◊
(2nd generation) diarylpyrimidines (Etravirine (ETR)- Rilpivirine (RPV)°)
- Doravirine
|
|
|
Integrase inhibitors
(Integrase strand transfer inhibitors (INSTI)) |
- Raltegravir (RAL)°
- Elvitegravir (EVG)°
- Dolutegravir (DTG)°
- Globoidnan A (experimental)
- MK-2048†
- BI 224436†
- Cabotegravir†
|
|
| Maturation inhibitors |
|
|
Protease Inhibitors (PI)
(Discovery and development) |
| 1st generation |
- Fosamprenavir (FPV)
- Lopinavir (LPV)°#
- Nelfinavir (NFV)#
- Ritonavir (RTV)#
- Saquinavir (SQV)#
- Amprenavir (APV)◊
- Indinavir (IDV)◊#
- Telinavir
- Droxinavir
|
|
| 2nd generation |
- Atazanavir (ATV)°
- Darunavir (DRV)°
- Tipranavir (TPV)
|
|
|
| Combined formulations |
- Abacavir/lamivudine°
- Abacavir/dolutegravir/lamivudine°
- Abacavir/lamivudine/zidovudine
- Atazanavir/cobicistat
- Darunavir/cobicistat
- Efavirenz/emtricitabine/tenofovir°
- Elvitegravir/cobicistat/emtricitabine/tenofovir°
- Emtricitabine/rilpivirine/tenofovir°
- Lamivudine/raltegravir
- Lamivudine/zidovudine
- Lopinavir/ritonavir°
- Tenofovir/emtricitabine°
|
|
| Pharmacokinetic boosters |
- Ritonavir (r)
- Cobicistat (c)
|
|
| Experimental agents |
| Uncoating inhibitors |
|
|
| Transcription inhibitors |
|
|
| Translation inhibitors |
|
|
| Other |
- Abzyme
- Calanolide A
- Ceragenin
- Cyanovirin-N
- Diarylpyrimidines
- Epigallocatechin gallate (EGCG)
- Foscarnet
- Fosdevirine†
- Griffithsin
- Hydroxycarbamide
- Miltefosine
- Portmanteau inhibitors
- Scytovirin
- Seliciclib†
- Synergistic enhancers
- Tre recombinase
- Zinc finger protein transcription factor
- KP-1461†
- BIT225†
|
|
| Failed agents |
- Aplaviroc
- Atevirdine
- Brecanavir
- Capravirine
- Dexelvucitabine
- Emivirine
- Lersivirine
- Lodenosine
- Loviride
|
|
|
- #WHO-EM
- ‡Withdrawn from market
- Clinical trials:
- †Phase III
- §Never to phase III
°DHHS recommended initial regimen options. ◊Formerly or rarely used agent.
|
Index of viral disease
|
|
| Description |
|
|
| Disease |
- Systemic
- Cutaneous
- Zoster
- Human papillomavirus
- Zoonotic
- Symptoms and signs
|
|
| Treatment |
|
|
|
|
RNA virus antivirals (primarily J05, also S01AD and D06BB)
|
|
| Hepatitis C |
- protease inhibitors
- Asunaprevir†
- Boceprevir
- Faldaprevir†
- Grazoprevir†
- Paritaprevir
- Ritonavir
- Telaprevir
- Simeprevir
- RNA polymerase inhibitors
- NS5A inhibitors
- ACH-3102†
- Daclatasvir
- Deleobuvir§
- Elbasvir†
- Ledipasvir
- MK-3682
- MK-8408
- Samatasvir
- Ombitasvir
combinations (Ombitasvir/paritaprevir/ritonavir)
|
|
| Picornavirus |
|
|
| Anti-influenza agents |
- adamantane derivatives/M2 inhibitors (Amantadine
- Rimantadine)
- neuraminidase inhibitors/release phase (Oseltamivir
- Zanamivir
- Peramivir, Laninamivir†)
|
|
| Multiple/general |
| Interferon |
- Interferon alfa 2b
- Peginterferon alfa-2a
|
|
| Multiple/unknown |
- BCX4430
- Ribavirin#/Taribavirin†
- Moroxydine
- Favipiravir
|
|
|
- #WHO-EM
- ‡Withdrawn from market
- Clinical trials:
- †Phase III
- §Never to phase III
|
Index of viral disease
|
|
| Description |
|
|
| Disease |
- Systemic
- Cutaneous
- Zoster
- Human papillomavirus
- Zoonotic
- Symptoms and signs
|
|
| Treatment |
|
|
|
