Nursing Pharmacology:  Antiviral Drugs

• Antiretroviral Drugs Used in Treating HIV Infection

  • →Non-nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NNRTI): (continued)

    • Delavirdine (Rescriptor)

      • Delavirdine (Rescriptor) is structurally described as a bisheteroarylpiperazine nonnucleoside reverse transcriptase inhibitor  (NNRTI) which targets HIV-1 viral reverse transcriptase.^1,4 

      • Mutations and Resistance to Delaviridine

        • Delavirdine exhibits the same susceptibility to mutations which confer resistance to its inhibitory actions on HIV-1 reverse transcriptase as noted earlier for efavirenz and nevirapine.¹

          • Therefore, the patient exhibiting virologic failure associated with delavirdine should not be treated with either efavirenz or nevirapine.¹

          • NNRTI Resistance¹¹

            Attribution: Sprach DH NNRTI Resistance https://www.youtube.com/watch?v=mLzMiugJAxQ (2015) HIV/AIDS (CDC) YouTube Channel:  https://www.cdc.gov/hiv/basics/whatishiv.html

      • Pharmacokinetics

        • Delavirdine shows good bioavailability (85%); however, absorption is diminished in the presence of antacids, histamine H₂-receptor antagonists, proton pump inhibitors and achlorhydria.^1,7

          •  Examples of proton pump inhibitors include:

            • Omeprazole (Prilosec),

            • Lansoprazole (Prevacid)

            • Dexlansoprazole (Kapidex)

            • Esomeprazole (Nexium)

            • Pantoprazole (Somac)

            • Rapdprazole (Pariet).

        • Delavirdine is metabolized by the cytochrome P450 microsomal drug metabolizing system, particularly by the CYP3A4 and CYP2C9 enzymic isoforms.

          • Drugs that increase (Inducers) of CYP3A4 should be avoided since these agents might reduce delavirdine plasma concentrations.

          • Examples of important and potent CYP3A4 inducers include these drugs:

            • Phenytoin

            • Phenobarbital

            • Rifabutin

            • Rifampin

            • Carbamazepine

          • Furthermore, the combination of delavirdine with rifabutin and fosamprenavir is contraindicated because of decreased delavirdine  plasma concentrations.

            • Other HIV-related medications that may change delavirdine plasma levels include didanosine, lopinavir, nelfinavir and ritonavir.

            • Also, coadministration of delavirdine along with saquinavir or indinavir extends the elimination t_½ of the protease inhibitors permitting twice-daily as opposed to three times daily dosing.

        • Less than 5% of a delavirdine dosage may be recovered in the urine unchanged.

        • Delavirdine clearance is mainly due to CYP3A4-mediated oxidative metabolism.^1,7

      • Adverse Effects:

        • A common side effect of delavirdine administration is rash, noted in about 40% of individuals receiving the drug.

          • This presentation occurs early in therapy, often within the first three weeks. Sometimes, albeit rarely, a more severe rash including erythema multiforme and Stevens-Johnson syndrome may occur.

            • Erythema multiforme¹²

              Heilman J Erythema multiforme minor (note:  blanching of lesion centers) https://commons.wikimedia.org/wiki/File:Erythema_multiforme_minor_of_the_hand.jpg

          • Other side effects, such as elevation of hepatic transaminase enzymes as well as liver failure, have also been reported.

          • Lastly, another unlikely side effect appears to be neutropenia.

      • Therapeutics:

        • Delavirdine is one of the five non-nucleoside reverse transcriptase inhibitors (nnRTIs) that is currently FDA-approved; the others being etravirine, nevirapine, efavirenz and rilpivirine.⁹  

          • However, despite favorable virologic potency and durability of non-nucleoside reverse transcriptase inhibitor-based protocols, concerns with respect to viral strain resistance represent a major issue.⁹  

            • Resistance to the NNRTIs  may already exist in antiretroviral treatment-naïve patients.

              • Additionally, these agents exhibit a "low genetic barrier" for resistance development.

              • Significant resistance to NNRTIs, with the exception of etravirine, may follow from a single mutation and within-class cross-resistance is likely.

                • As an example, in rilpivirine-treated individuals, rilpivirine resistance mutations present at virologic failure, appears to confirm cross-resistance to other NNRTIs , including etravirine. 

            • NNRTIs are more likely used in combination with other HIV antiretroviral medications.⁹

References

Flexner C Antiretroviral Agents and Treatment of HIV Infection, Chapter 59  in Goodman & Gilman's The Pharmacological Basis of Therapeutics, 12th edition (Brunton LL Chabner BA Knollmann BC, eds; Brunton LL, ed; Blumenthal DK  Murri N Hilal-Dandan R, assoc eds, Knollmann BC, consulting ed, on-line edition) The McGraw-Hill Companies, 2011. Fauci AS Lane HC Chapter 226, Human Immunodeficiency Virus Disease:  AIDS and Related Disorders, in Harrison's Online   (Kasper DL Fauci AS Hauser SL Longo DL Jameson JL Loscalzo J, Eds.),  Harrison's Principles of Internal Medicine, 19th edition, The McGraw-Hill Companies, Inc. 2015 (on-line edition) Longo DL Fauci AS  188, The Human Retroviruses, in Harrison's Online   (Dan L. Longo, Anthony S. Fauci, Dennis L. Kasper, Stephen L. Hauser, J. Larry Jameson, Joseph Loscalzo, Eds.),  Harrison's Principles of Internal Medicine, 18th edition, The McGraw-Hill Companies, Inc. 2012. Woster PM Chapter 43:  Antiviral Agents and Protease Inhibitors in Foye's Principles of Medicinal Chemistry 6e, Lemke, TL Williams DA, eds; Roche VG Zito SW, asst eds) Wolters Kluwer|Lippincott Williams & Wilkins 1214, 2008. HIV Overview:  The HIV Life Cycle, Education Materials, AIDSinfo, NIH http://aidsinfo.nih.gov/education-materials/fact-sheets/19/73/the-hiv-life-cycle 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. Safrin S Chapter 49:  Antiviral Agents:  Antiretroviral Agents in Basic & Clinical Pharmacology 13e (Katzung BG Trevor AJ, eds) 2015, online edition. 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 AIDSinfo:  Guidelines for the Use of Antriretroviral Agents in HIV-1-Infected Adults and Adolescents https://aidsinfo.nih.gov/guidelines (2015) DNA Codon Table https://en.wikipedia.org/wiki/DNA_codon_table Sprach DH NNRTI Resistance (2015) Northwest AIDS Education and Training Center NWAETC:  Project Echo https://www.youtube.com/watch?v=mLzMiugJAxQ Heilman J Erythema multiforme minor  https://commons.wikimedia.org/wiki/File:Erythema_multiforme_minor_of_the_hand.jpg

 

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