155213-67-5

Norvir was launched in Germany, the UK and US for treatment of advanced HIV in combination with antiretroviral nucleoside analogs in a record 72 days by the FDA. It is an inhibitor of HIV aspartic protease which is critical in the processing of a propeptide into the gag, gag-pol gene products and the protease itself. This inhibition results in the release of non-infectous immature virus particles. It is greater than 500-fold more selective for viral aspartic protease than the human version, has good oral bioavailability and may increase the bioavailability of other protease inhibitors. Ritonavir was able to increase the CD4 and CD8 lymphocyte count as well as reduce viral RNA. It is more potent than saqunavir and comparible in potency to zidovudine and lamivudine.

White or almost white powder.

Abbott (USA)

A selective HIV protease inhibitor

Protease inhibitor; antiviral (HIV).

Ritonivir is an HIV protease inhibitor (EC50 = 25 nM) that also inhibits CYP3A4, the primary cytochrome P450 isoform that metabolizes protease inhibitors. Through CYP3A4 inhibition, low doses of ritonivir can reduce the metabolism of concomitantly administered protease inhibitiors, enhancing their bioavailability and efficacy.[Cayman Chemical]

ChEBI: An L-valine derivative that is an antiretroviral drug from the protease inhibitor class used to treat HIV infection and AIDS, it is often used as a fixed-dose combination with another protease inhibitor, lopinavir. Also used in combination with dasabuvir sodium hydrate, ombitasvir and paritaprevir (under the trade name Viekira Pak) for treatment of chronic hepatitis C virus genotype 1 infection as well as cirrhosis of the liver.

Although ritonavir (Norvir) is a potent inhibitor of HIV-1 and HIV-2 protease, it is not well tolerated in higher doses. It is mainly used in low doses to increase blood levels of other protease inhibitors and to extend their dosing interval. Ritonavir is more commonly associated with gastrointestinal side effects, altered taste sensation, paresthesias, and hypertriglyceridemia than are other protease inhibitors. Pancreatitis may occur in the presence or absence of hypertriglyceridemia.

Norvir (Abbott).

Ritonavir is active against HIV-1 and, to a lesser extent, HIV-2.

At antiretroviral doses resistance is associated with the presence of specific amino acid substitutions in the HIV protease at positions 82 and 84. Concern about the risk for selection of ritonavir resistance when used at a subtherapeutic ‘booster’ dose has so far not been borne out by clinical experience.

A synthetic chemical available for oral use as soft capsules and a liquid formulation. It is now almost exclusively used as a pharmacokinetic enhancer to ‘boost’ the pharmacokinetic properties of HIV protease inhibitors in the treatment of HIV-1 infection in patients over 1 month in age.

Ritonavir is an HIV protease inhibitor. It inhibits recombinant HIV-1 protease by 79% when used at a concentration of 0.5 nM. It inhibits HIV-1_3B-induced cell death in MT-4 human T cell leukemia cells (EC₅₀ = 25 nM) as well as cell death induced by HIV-1_LAI, HIV-2_ROD, and HIV-2_EHO in human MT-2 cells (IC₅₀s = 0.045, 0.13, and 0.24 μM, respectively). Ritonavir also inhibits the cytochrome P450 (CYP) isoform CYP3A (IC₅₀ = 0.14 μM). It inhibits CYP-mediated oxidative metabolism of the HIV protease inhibitors saquinavir , indinavir , nelfinavir , and amprenavir in rat and human liver microsomes in a concentration-dependent manner. Ritonavir (10 mg/kg) also prevents decreases in plasma levels of these four compounds in rats. Formulations containing ritonavir have been used in the treatment of HIV-1 infection.

Ritonavir is an HIV protease inhibitor now used frequently as a booster of other protease inhbitors. Ritonavir inhibits cytochrome P450-3A4 (CYP3A4), a liver enzyme that normally metabolizes protease inhibitors. It has also been investigated as a possible anti-cancer agent.

Because of the strong CYP450-inhibiting effects of ritonavir, the drug has found value when used in fixed-dosage combinations with other PIs to block their metabolism and act as a booster for these drugs (lopinavir/ritonavir and tipranavir/ritonavir). In these cases, ritonavir is used in a subtherapeutic dose but boosts the effectiveness of the coadministered drug. The utilization of ritonavir in a therapeutic dose for treating HIV infections appears to be decreasing, but its utilization as a booster drug is finding favor.

Oral absorption: Not known/available
C_max 600 mg twice daily: c. 11.2 mg/L
C_min 600 mg twice daily: c. 3.7 mg/L
Plasma half-life: c. 3–5 h
Volume of distribution: c. 0.3–0.6 L/kg
Plasma protein binding: c. 97%
Absorption and distribution
Fasting and high-fat meals had no appreciable effect on oral absorption. It penetrates poorly into the CNS. The semen:plasma ratio is <0.04. It is distributed into breast milk.
Metabolism and excretion
Four oxidized metabolites have been identified, the major of which retains antiretroviral activity. Around 11% of the dose is excreted in urine, 4% as unchanged drug. The remainder is found in feces. Metabolites are eliminated primarily via the feces.
No dose adjustment is recommended in mild to moderate hepatic impairment. It should not be given to patients with severe hepatic impairment, nor should it be given as a pharmacokinetic enhancer to patients with decompensated liver disease.

Treatment of HIV infection in adults and children >1 month old (in combination with other antiretroviral agents)

Full (antiretroviral) doses are associated with nausea, vomiting, diarrhea and fatigue in >20% of subjects. The degree to which ritonavir at low dose is associated with specific adverse events is uncertain. In HIV-negative healthy volunteers given ‘booster’ doses of 100 mg every 12 h, the concentration of total cholesterol, low-density cholesterol and triglycerides all increased, and the concentration of high-density cholesterol concentration fell.

Potentially hazardous interactions with other drugs
Alpha-blockers: concentration of alfuzosin increased - avoid.
Aminophylline: concentration of aminophylline reduced.
Analgesics: buprenorphine and NSAID levels may be increased (risk of toxicity) - avoid dextropropoxyphene and piroxicam; methadone, pethidine and possibly morphine concentration reduced; increased alfentanil, fentanyl and toxic pethidine metabolite concentration - avoid with pethidine.
Anthelmintics: possibly reduces active metabolite of albendazole, consider increasing albendazole dose.
Anti-arrhythmics: increased concentration of amiodarone, flecainide and propafenone (increased risk of ventricular arrhythmias) - avoid; possible increased risk of arrhythmias with disopyramide; avoid with dronedarone.
Antibacterials: rifabutin concentration increased (risk of uveitis) - reduce rifabutin dose; concentration of clarithromycin and other macrolides increased - reduce dose of clarithromycin in renal impairment; concentration reduced by rifampicin; concentration of both drugs may be increased in combination with fusidic acid - avoid; AUC of bedaquiline increased by 22%, avoid if ritonavir given for >14 days; concentration of delamanid increased.
Anticoagulants: anticoagulant effect of coumarins and phenindione possibly increased; effect of warfarin may be enhanced or reduced; avoid with apixaban; concentration of rivaroxaban increased - avoid.
Antidepressants: SSRIs and tricyclic concentrations possibly increased; concentration reduced by St John’s wort - avoid; possibly reduced paroxetine concentration; increased side effects with trazodone.
Antiepileptics: carbamazepine fosphenytoin and phenytoin concentration may be increased; concentration reduced by fosphenytoin, phenytoin; concentration of lamotrigine and valproate reduced.
Antifungals: in combination with itraconazole or ketoconazole concentration of both drugs may be increased; concentration increased by fluconazole; voriconazole concentration reduced - avoid.
Antimalarials: use artemether/lumefantrine with caution; concentration possibly reduced by mefloquine; concentration of quinine increased.
Antimuscarinics: avoid with darifenacin and tolterodine; reduce dose of fesoterodine; concentration of solifenacin possibly increased.
Antipsychotics: concentration of lurasidone, pimozide, quetiapine, clozapine and possibly other antipsychotics may be increased (risk of toxicity) - avoid; possibly inhibits metabolism of aripiprazole - reduce aripiprazole dose; olanzapine concentration reduced.
Antivirals: concentration of both drugs reduced with boceprevir; didanosine and ritonavir should be taken 2.5 hours apart; indinavir, maraviroc and saquinavir levels increased; increased risk of toxicity with efavirenz - monitor LFTs, avoid high dose ritonavir with atripla; concentration of simeprevir increased - avoid; possibly reduces telaprevir concentration.
Anxiolytics and hypnotics: levels of many of them increased (risk of extreme sedation and respiratory depression) - avoid alprazolam, diazepam, flurazepam, midazolam, zolpidem; concentration of buspirone increased.
Avanafil: concentration of avanafil significantly increased - avoid.
Bosentan: increases bosentan concentration.
Calcium-channel blockers: levels of calciumchannel blockers possibly increased - avoid with lercanidipine.
Ciclosporin: levels possibly increased by ritonavir.
Cilostazol: possibly increases cilostazol concentration.
Colchicine: possibly increases risk of colchicine toxicity, avoid in hepatic or renal impairment.
Corticosteroids: possibly increased corticosteroid concentration; increased concentration of inhaled/ intranasal budesonide and fluticasone.
Cytotoxics: increases concentration of afatinib (separate ritonavir by 6-12 hours); possibly increases concentration of axitinib, panobinostat and pazopanib, reduce dose of axitinib, panobinostat and pazopanib; possibly increases concentration of bosutinib, cabazitaxel, ceritinib and olaparib - avoid or reduce dose of bosutinib, cabazitaxel, ceritinib and olaparib; possibly increases concentration of cabozantinib and vinblastine; possibly increases concentration of crizotinib, everolimus, nilotinib, simeprevir and vinflunine - avoid; avoid with dasatinib and lapatinib; concentration of ibrutinib possibly increased - reduce dose of ibrutinib; concentration of docetaxel possibly increased - avoid or reduce docetaxel dose; reduce dose of ruxolitinib; possibly increases concentration of ponatinib - consider reducing initial dose of ponatinib; concentration of paclitaxel increased.
Dapoxetine: avoid concomitant use.
Diuretics: eplerenone concentration increased - avoid.
Domperidone: possible increased risk of ventricular arrhythmias - avoid.
Ergot alkaloids: risk of ergotism - avoid.
Guanfacine: possibly increases guanfacine dose - halve guanfacine dose.
5HT1 agonists: concentration of eletriptan increased - avoid.
Ivabradine: ivabradine concentration possibly increased - avoid.
Lipid-lowering drugs: increased risk of myopathy with rosuvastatin and simvastatin - avoid; possibly increased risk of myopathy with atorvastatin; avoid with lomitapide.
Naloxegol: possibly increases naloxegol concentration - avoid.
Oestrogens and progestogens: metabolism accelerated (contraceptive effect reduced).
Orlistat: absorption of ritonavir possibly reduced.
Ranolazine: possibly increases ranolazine concentration - avoid.
Sildenafil: concentrations of sildenafil significantly increased - avoid.
Tacrolimus: levels possibly increased by ritonavir.
Tadalafil: concentrations of tadalafil increased - avoid.
Theophylline: metabolism accelerated, theophylline levels reduced.
Ticagrelor: possibly increases concentration of ticagrelor - avoid.
Ulipristal: contraceptive effect reduced - avoid.
Vardenafil: possibly increased vardenafil concentration - avoid.

Ritonavir is extensively metabolised in the liver mainly by cytochrome P450 isoenzymes CYP3A4 and to a lesser extent by CYP2D6. Five metabolites have been identified and the major metabolite has antiviral activity, but concentrations in plasma are low.
About 86% of a dose is eliminated through the faeces (both as unchanged drug and as metabolites) and about 11% is excreted in the urine.

Store at -20°C

1) Lea and Faulds (2018)?Ritonavir;?Drugs?52?541 2) Koudriakova?et al.?(1998)?Metabolism of the Human Immunodeficiency Virus Protease Inhibitors Indinavir and Ritonavir by Human Intestinal Microsomes and Expressed Cytochrome P4503A4/3A5: Mechanism-Based Inactivation of Cytochrome P3503A by Ritonavir;?Drug Metab. Dispos.?26?552 3) Rock?et al.?(2014)?Characterization of Ritonavir-Mediated Inactivation of Cytochrome P450 3A4;?Mol. Pharmacol.?86?665