Nursing Pharmacology: Antiviral Drugs

Protease Inhibitors

• Antiretroviral Drugs Used in Treating HIV Infection

  • →Protease Inhibitors

    • Darunavir (Prezista)

      • Overview and Pharmacokinetics: 

        • Of the five recommended regimens for antiretroviral therapy (ART) one regimen is a ritonavir-boosted protease inhibitor:4  Darunavir/ritonavir plus TDF/FTC [darunavir + ritonavir + tenofovir disoproxil fumarate/emtricitabine] is the protease inhibitor-based recommended protocol. This regimen has been classified as AI (A: Strong recommendation for the statement and I: one or more randomized trials with clinical outcomes and/or validated laboratory endpoints).4  The HIV protease is dimeric, consisting of two monomers, each containing one of two conserved aspartate amino acids that the active site.6   Agents that inhibit the HIV protease have been described as "transition-state" analogues which alignment the active site of the enzyme. This analysis was dependent on description of protein structure utilizing three-dimensional crystallography. Some of these analogues are oligopeptide-like and selectively inhibit viral aspartic proteases. HIV-1 protease inhibitors may be either peptide or nonpeptide agents.6

        • Darunavir is an HIV-1 and HIV-2 protease inhibitor.² 

          • The concentration of darunavir required to inhibit protease activity to the 50% level is about 2.5 nM (range: 1-5 nM).

            • The underlying mechanism of action may involve both reversible binding to the HIV protease catalytic site and prevention of protease dimerization.²

        • Following oral administration, darunavir/ritonavir are rapidly absorbed (darunavir is coadministered with ritonavir).^2,3 

          • Peak concentrations are observed about three hours following dosing.

          • Darunavir bioavailability is increased by ritonavir and ritonavir also increases the darunavir area-under-the-curve (AUC) up to 14 times.

            • This drug should be taken with food since food increases darunavir AUC by about a third.^2,3   

        • Darunavir is oxidatively metabolized by the hepatic (liver) microsomal metabolizing system, mainly depending on the cytochrome P450 isoform, CYP3A4.^2,3   

          • About 10% of the parent darunavir agent is excreted unchanged by the kidney.

          • In combination with ritonavir, darunavir half-life (t_½) is about 15 hours.

          • Darunavir is also an inhibitor of the CYP3A and ritonavir is considered a "potent inhibitor" of CYP3A and CYP2D6 forms as well as being and inducer of other hepatic enzyme systems.^2,3 

           

      • Mutations:

        • Locations of HIV Reverse Transcriptase Gene  and Resistance to the Antiretroviral Drug Darunavir¹⁴

          Several mutations associated with darunavir administration have been shown to confer darunavir resistance. The most frequently noted mutations include: V3I  L33F  I47V I54L and  L89V. Usually a minimum of three darunavir-related resistance mutations are needed for clinical drug resistance. Most of the time pretreatment resistance to darunavir is rarely observed (<10%) in treatment-naïve individuals.

          Amino acid abbreviations: A:  Alanine C:  Cysteine D:  Aspartate E:  Glutamate F:  Phenylalanine G:  Glycine H:  Histidine I:  isoleucine K:  Lysine L:  Leucine

          M:  Methionine N:  Asparagine P:  Proline Q:  Glutamine R:  Arginine S:  Serine T:  Threonine V:  Valine W:  Tryptophan Y:  Tyrosine

        •  

        • Adverse Effects/Side Effects:

          • The combination of darunavir and ritonavir (ritonavir-boosting) results in a side effect profile that incorporates both effects due to darunavir and effects associated with ritonavir.^2,3,4 

            • Gastrointestinal side effects may present in up to 1/5 of patients.

              • These G.I. effects include diarrhea and nausea.

            • Other effects noted in laboratory workups include dyslipidemia and increases in both hepatic transaminase and amylase levels.

          • Darunavir (like fosamprenavir) contains a sulfonamide group likely responsible for rash, a hypersensitivity reaction, noted in up to 10% of patients taking this combination.^2,3,4   

            • Accordingly, darunavir should be used with caution in patients with documented severe sulfonamide allergies.

              • However, in clinical trials their frequency and rash severity were comparable in patients independent of their history of sulfonamide allergy.

              • Most patients with sulfonamide allergy did tolerate darunavir.

          • Hepatic toxicity may be associated with darunavir and manifests as hepatitis.^2,3,4   

            • The likelihood of hepatotoxicity may be elevated in those patients with hepatitis B, hepatitis C or in the presence of other chronic liver pathology.

          • About 3% of patients in randomized clinical trials discontinue taking darunavir due to side effects.^2,3,4 

        • Therapeutic Use: 

          • Darunavir (Prezista) in combination with ritonavir has been FDA-approved in treating HIV-infected adults.² 

            • Darunavir/ritonavir is available in either a once-daily or twice-daily protocol which includes nucleosides for managing HIV infection in treatment-naïve adults.

              • The twice-daily regimen may be appropriate in treating treatment-experienced adults.

              • Twice-daily darunavir/ritonavir has also been approved for administration to pediatric patients >6 years of age (dosing based on weight).² 

          • Of the five recommended regimens for antiretroviral therapy (ART) one regimen is a ritonavir-boosted protease inhibitor:⁴ 

          • Darunavir/ritonavir plus TDF/FTC [darunavir + ritonavir + tenofovir disoproxil fumarate/emtricitabine] is the protease inhibitor-based recommended protocol.

          • This regimen has been classified as AI (A: Strong recommendation for the statement and I: one or more randomized trials with clinical outcomes and/or validated laboratory endpoints).⁴ 

References

Wang F Kieff E Medical Viriology, Chapter 177 Section 11:  Viral Diseases:  General Considerations (in Harrison's Principles of Internal Medicine, 18th edition, Longo DF Fauci AS Kasper DL Hauser SL Jameson JL Loscalzo J, eds) McGraw-Hill, New York, 2012, pp 1432-1433. Flexner C Chapter 59.  Antiretroviral Agents and Treatment of HIV Infection (in Goodman & Gilman's The Pharmacological Basis of Therapeutics, 12 e, Brunton LL Chabner BA Knollmann BC, eds) The McGraw-Hill Companies, Inc, 2011. Safrin S Chapter 49:  Antiviral Agents:  Antiretroviral Agents in Basic & Clinical Pharmacology 13e (Katzung BG Trevor AJ, eds) 2015, online edition. AIDSinfo:  Guidelines for the Use of Antriretroviral Agents in HIV-1-Infected Adults and Adolescents https://aidsinfo.nih.gov/guidelines (2015) Tsibris AMN Hirsch MS Chapter 130 Antiretroviral Therapy for Human Immunodeficiency Virus Infection in Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases, 8e (Bennett JE Bolin R Blaser, eds) Elsevier, Inc/Saunders 2015, online version. Woster PM Antiviral Agents and Protease Inhibitors.  Chapter 43  in Foye's Principles of Medicinal Chemistry, 6e Lemke TL; Williams DA, eds; Roche VF Zito SW, asst. eds), Lippincott Williams & Wilkins, a Wolters Kluwer business, 1219, 2008. Swaminathan J and MSD staff at the European Bioinformatics Institute  (http://www.ebi.ac.uk/) Renin:  molecular structure registered with 2rn code. https://commons.wikimedia.org/wiki/File:PDB_2ren_EBI.jpg Flexner C HIV-Protease Inhibitors The New England Journal of Medicine 338(18) 1281-1292, April 30, 1998. http://www.ncbi.nlm.nih.gov/pubmed/9562584 Billah Z Drug Resistance in HIV Protease Mutant with Darunavir https://www.youtube.com/watch?v=ou7-b5WRVjM (Published May 21, 2014) Liu F Kovalevsky AY Tie Y Ghosh AK Harrison RW Weber IT Effect of flap mutations on structure of HIV-1 Protease and  inhibition by saquinavir and darunavir J. Mol. Biol 381:  102-115, 2008. http://www.ncbi.nlm.nih.gov/pubmed/18597780 (second sourced from reference 9) Tie Y Boross PI Wang Y-F Gaddis L Hussain AK Leshchenko S Ghosh AK Louis JM Harrison RW Weber IT High resolution crystal structures of HIV-1 protease with a potent non-peptide inhibitor (UIC-94017) active against multi-drug-resistant clinical strains.  J. Mol. Biol. 338:  341-252, 2004. http://www.ncbi.nlm.nih.gov/pubmed/15066436 (second sourced from reference 9). HIV-1 protease (https://en.wikipedia.org/wiki/HIV-1_protease);  Graphic contributed by  Boghog https://en.wikipedia.org/wiki/File:HIV_protease_1KJF.png Stellbrink JH Pulik P Szlvik J Murphy D Lazzarin A Portilla J Rinehart A Le Fevre E Fang A Valluri S Mukwaya G Heera J  Maraviroc (MVC) dosed once daily with darunavir/ritonavir (DRV/r) in a 2 drug-regimen compared to emtricitabing/tenofovir (TDF/FTC) with DRV/r; 48-week results from MODERN (Study A4001095). AIDS 2014; published July 29, 2014) https://www.youtube.com/watch?v=JMMqkXx4YrU Wensing AM Calvez V Gunthard JF Johnson VA Paredes R Pillay D Shafer RW Richman DD Special Contribution:  2014 Update of the Drug Resistance Multations in HIV-1 Topics in Antivral Medicine 22(3)  June/July 2014, https://www.iasusa.org/sites/default/files/tam/22-3-642.pdf

 

Disclaimer

This Web-based pharmacology and disease-based integrated teaching site is based on reference materials, that are believed reliable and consistent with standards accepted at the time of development. Possibility of human error and on-going research and development in medical sciences do not allow assurance that the information contained herein is in every respect accurate or complete. Users should confirm the information contained herein with other sources. This site should only be considered as a teaching aid for undergraduate and graduate biomedical education and is intended only as a teaching site. Information contained here should not be used for patient management and should not be used as a substitute for consultation with practicing medical professionals. Users of this website should check the product information sheet included in the package of any drug they plan to administer to be certain that the information contained in this site is accurate and that changes have not been made in the recommended dose or in the contraindications for administration.  Advertisements that appear on this site are not reviewed for content accuracy and it is the responsibility of users of this website to make individual assessments concerning this information.  Medical or other information  thus obtained should not be used as a substitute for consultation with practicing medical or scientific or other professionals.