Ritonavir

Article Author:
Bilal Talha
Article Editor:
Amit Dhamoon
Updated:
8/27/2019 4:04:38 PM
PubMed Link:
Ritonavir

Indications

In the United States, the Food and Drug Administration (FDA) approved ritonavir in 1996 for the treatment of HIV. After saquinavir, it was the second approved protease inhibitor in the United States. Although ritonavir was initially designed to inhibit HIV protease, studies have found that it also inhibits cytochrome P450-3A4 (CYP450-3A4), which is its chief mechanism of action. It is currently used to augment HIV treatment by increasing the bioavailability of co-administered anti-retroviral (ARV) drugs. Initial results of ritonavir, when combined with triple therapy, showed increased CD4+ count and a decrease in HIV RNA levels in treatment naïve patients.[1] 

Lopinavir/ritonavir, in combination with other standard ARV medications, has provided significant virological suppression and better immune outcomes in both treatment-naive and treatment-experienced patients.[2]

Because of its mechanism of action, ritonavir is currently under investigation for its use in the treatment of some forms of cancer.[3] In 2014, the FDA approved a combination drug of ombitasvir/paritaprevir/ritonavir and dasabuvir for the treatment of hepatitis C virus (HCV) genotype 1.[4] It is highly efficacious with minimal side effects. Additionally, lopinavir/ritonavir was FDA approved in early 2000.

Mechanism of Action

Ritonavir works by binding to HIV-1 protease. HIV-1 protease causes cleavage of protein precursors generating new viral particles. Protease inhibitors disrupt this cleavage process, hence interrupting the production of new viral particles.[5]

Perhaps the more important mechanism of action of ritonavir for the treatment of HIV and HCV is its inhibition of the liver enzyme cytochrome P450 3A4 (CYP450-3A4).[6]  This cytochrome pathway metabolizes other protease inhibitors. When ritonavir inhibits CYP450-3A4, the bioavailability of other antiretroviral (ARV) drugs increases. Inhibition of this CYP450 pathway causes a decrease in the breakdown of ARVs, hence increasing serum drug levels. Ritonavir should be used carefully with other drugs metabolized through this pathway, including statins, anti-arrhythmic agents, anti-epileptic drugs, and anti-fungal agents.[6]

Administration

Lopinavir/ritonavir is a combination drug used for HIV. The small amount of ritonavir increases the bioavailability of the lopinavir.[1] The standard route of administration is oral. It comes as a tablet, soft gel capsule or an oral suspension, both for adult and pediatric population.[2] The typical regimen is 400 mg/100 mg orally twice per day or (400/100 mg)/5 mL oral solution.

Adults:                                                          

Tablet:     

100 mg/25 mg                                                                       

200 mg/50 mg

Oral solution:

(400 mg/100 mg)/5 mL

HIV-1:

400 mg/100 mg orally twice daily, or

800 mg/200 mg by mouth daily in patients with less than three lopinavir resistance-associated substitutions

Increase the dose to 500 mg/125 mg orally twice daily or 520 mg/130 mg solution by mouth twice daily if used with efavirenz, fosamprenavir, nelfinavir, or nevirapine.

Pregnant patients:

400 mg/100 mg oral dosing twice daily

Increase the dose to 500 mg/125 mg orally twice daily when used with efavirenz, fosamprenavir, nelfinavir, or nevirapine.

HIV post-exposure prophylaxis:

400 mg/100 mg orally twice daily

Pediatrics:

HIV infection:

(14 days- 12 months):

16 mg/4 mg/kg orally twice daily

Treatment naïve patients, age over 13 months, less than 15 kg:

12 mg/3 mg/kg orally twice daily or 230 mg/57.5mg/m^2

Increase the dose to 300 mg/75 mg/m^2 when used with efavirenz, fosamprenavir, nelfinavir, or nevirapine.

Treatment naïve patients, greater than 13 months, 15 to 40 kg:

10mg/2.5 mg/kg by mouth twice daily OR 230 mg/57.5 mg/m^2

Increase the dose to 300 mg/75 mg/m^2 when used with efavirenz, fosamprenavir, nelfinavir, or nevirapine.

Treatment-experienced patients, older than 13 months, under 15 kg:

13 mg/3.25 mg/kg orally twice a day. Max dose is 400 mg/100 mg twice daily or 300 mg/75 mg/m^2

Increase the dose to 300 mg/75 mg/m^2 when used with efavirenz, fosamprenavir, nelfinavir or nevirapine

Treatment-experienced patients, over 13 months, 15 to 45 kg:

11 mg/2.75 mg/kg by mouth two times daily. Max dose is 400 mg/100 mg twice daily or 300 mg/75 mg/m^2

Increase the dose to 300 mg/75 mg/m^2 when used with efavirenz, fosamprenavir, nelfinavir, or nevirapine.

Treatment experienced patients, older than 13 months, weight greater than 45 kg:

400 mg/100 mg/kg orally twice daily

Increase to 500 mg/125 mg orally twice daily or 520 mg/130 mg solution twice per day with efavirenz, fosamprenavir, nelfinavir, or nevirapine.

Adverse Effects

Ritonavir has several constitutional side effects including malaise, dizziness, and insomnia, gastrointestinal side effects including nausea, vomiting, abdominal pain, and diarrhea, metabolic side effects such as hyperlipidemia, hypertriglyceridemia, transaminitis, and rhabdomyolysis.[2] Although there are reports of QT prolongation with the use of protease inhibitors, studies have not established them as independent culprits.[7]

Because of the metabolic side effects of ritonavir, lipid-lowering agents might also be indicated along with protease inhibitors to reduce cardiovascular disease risk. Other serious adverse effects are pancreatitis, diabetes mellitus, renal failure, hypersensitivity reactions, Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN), hepatotoxicity, leukopenia, and neutropenia.[5]

Contraindications

Ritonavir contraindications include patients who have a previously known allergic reaction either to ritonavir or any of its components. Such a hypersensitivity reaction includes Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN). It requires cautious use with other medications that inhibit the CYP450-3A4 enzyme, causing an increase in serum drug levels. Ritonavir should also not be given to patients on pharmacological agents that act as CYP inducers. These can cause drastically reduced levels of ritonavir, which can consequently result in potential drug resistance.[5]

Monitoring

Because ritonavir use correlates with hepatotoxicity, monitoring of liver function tests before initiation of therapy, 2 to 8 weeks after starting treatment and subsequently every 3 to 6 months is recommended. Ritonavir has also demonstrated associations with hypercholesterolemia, so a lipid profile is a recommendation, at baseline, and then every 6 to 12 months. Because a rise in lipids increases the risk for cardiovascular disease, lipid-lowering agents may be required. Patients on ritonavir are also susceptible to diabetes mellitus, so recommendations include baseline fasting glucose levels followed by screening every 12 months. Although there is weak evidence of QT prolongation and Torsades de Pointes in patients on ritonavir, the measurement of electrolyte levels including magnesium should take place at baseline, 2 to 8 weeks after starting treatment, and every 3 to 6 months after that.[7] The pediatric population should also have similar screening.

Oral solution of lopinavir/ritonavir contains alcohol so it should be avoided in neonates less than 42 weeks postmenstrual age and less than 14 days old. Infants, particularly premature infants, are at increased risk of central nervous system complications.

Toxicity

Because there is a small quantity of ritonavir in combination lopinavir/ritonavir, there are few reports of ritonavir toxicity. However, there have been a few case reports suggesting retinal toxicity secondary to ritonavir. One such case showed an improvement after discontinuing ritonavir after 2 and 4 weeks.[8][9]

Because most of the neurological and gastrointestinal side effects are directly associated with higher ritonavir concentrations,[10] the dosage should be monitored and titrated down in patients with side effects. This titration could result in increased tolerability of the drug and a decrease in treatment failure.[10] 

Enhancing Healthcare Team Outcomes

Since ritonavir is a potent CYP450-3A4 inhibitor, physicians need to be cautious when adding it to a patient's regimen with multiple comorbidities and medications. For instance, cobicistat and ritonavir are both used as pharmacokinetic boosters with similar inhibition of CYP450-3A4. However, in the presence of inducers such as rifamycin or anti-convulsants, the inhibition of CYP450-3A4 is markedly different.[11] It might be easy to extrapolate data from ritonavir and apply it to cobicistat; however, a person on a stable dose of another medication can experience an increase or decrease in serum drug concentrations. The pharmacist should perform thorough medication reconciliation and report back to the prescribing clinician with any concerns.

In addition to standard drug monitoring for a particular regimen by the primary care provider/nurse practitioner, dose adjustment or additional monitoring might be necessary if a drug-drug interaction is suspected.[11]

Nursing is in the best position to evaluate and emphasize the importance of patient compliance with their antiretroviral regimen, as well as assess treatment progress, and monitor for adverse reaction, informing the physician of their findings.

Any antiretroviral regimen, including those with ritonavir, requires an interprofessional team approach, including physicians, specialists, specialty-trained nurses, and pharmacists, all collaborating across disciplines to achieve optimal patient results. [Level V]


References

[1] Lea AP,Faulds D, Ritonavir. Drugs. 1996 Oct;     [PubMed PMID: 8891466]
[2] Croxtall JD,Perry CM, Lopinavir/Ritonavir: a review of its use in the management of HIV-1 infection. Drugs. 2010 Oct 1;     [PubMed PMID: 20836579]
[3] Eatemadi A,Aiyelabegan HT,Negahdari B,Mazlomi MA,Daraee H,Daraee N,Eatemadi R,Sadroddiny E, Role of protease and protease inhibitors in cancer pathogenesis and treatment. Biomedicine     [PubMed PMID: 28006747]
[4] Klibanov OM,Gale SE,Santevecchi B, Ombitasvir/paritaprevir/ritonavir and dasabuvir tablets for hepatitis C virus genotype 1 infection. The Annals of pharmacotherapy. 2015 May;     [PubMed PMID: 25680759]
[5] Kemnic TR,Gulick PG, HIV Antiretroviral Therapy 2019 Jan;     [PubMed PMID: 30020680]
[6] Loelius SG,Lannan KL,Blumberg N,Phipps RP,Spinelli SL, The HIV protease inhibitor, ritonavir, dysregulates human platelet function in vitro. Thrombosis research. 2018 Sep;     [PubMed PMID: 30031293]
[7] Hunt K,Hughes CA,Hills-Nieminen C, Protease inhibitor-associated QT interval prolongation. The Annals of pharmacotherapy. 2011 Dec;     [PubMed PMID: 22128044]
[8] Tu Y,Poblete RJ,Freilich BD,Zarbin MA,Bhagat N, Retinal toxicity with Ritonavir. International journal of ophthalmology. 2016;     [PubMed PMID: 27162744]
[9] Louie AK,Jones HN, Case Report: Retinal Toxicity Secondary to Ritonavir. Optometry and vision science : official publication of the American Academy of Optometry. 2019 May;     [PubMed PMID: 31046022]
[10] Gatti G,Di Biagio A,Casazza R,De Pascalis C,Bassetti M,Cruciani M,Vella S,Bassetti D, The relationship between ritonavir plasma levels and side-effects: implications for therapeutic drug monitoring. AIDS (London, England). 1999 Oct 22;     [PubMed PMID: 10546861]
[11] Tseng A,Hughes CA,Wu J,Seet J,Phillips EJ, Cobicistat Versus Ritonavir: Similar Pharmacokinetic Enhancers But Some Important Differences. The Annals of pharmacotherapy. 2017 Nov;     [PubMed PMID: 28627229]