Medical Pharmacology Chapter 36:  Antiviral Drugs

• Antiretroviral Drugs Used in Treating HIV Infection

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

    • Delavirdine (Rescriptor)

      •  

        Delaviridine

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

        • As with other agents in this class, delavirdine inhibits reverse transcriptase and DNA-directed DNA polymerases HIV-1 actions following formation of enzyme-substrate complexes.⁴ 

          • The result of this interaction is chain termination.

        • Although delavirdine is one of the five NNRTIs currently FDA-approved, delavirdine use has declined due to its multiple daily dose requirement given its short half-life (t_½ ≈ 6 hours, with an extended t_½ range of between 2-11 hours secondary to interpatient clearance variability.¹

      • 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.

          • 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