Medical Pharmacology Chapter 36:  Antiviral Drugs

• Antiretroviral Drugs Used in Treating HIV Infection

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

    • Rilpivirine (Endurant)

      •  

        Rilpivirine

      • Rilpivirine (Endurant) is classified as a second generation NNRTI (non-nucleoside reverse transcriptase inhibitor) that has proven useful (in combination with other drugs) in HIV antiretroviral drug therapy for treatment-naïve adult individuals.¹⁰ 

        • Rilpivirine has been combined with other agents such as tenofovir disoproxil fumarate and emtricitabine for management of HIV infection.⁹

      • Rilpivirine in combination with tenofovir disoproxil fumarate and emtricitabine was until recently described as a "Recommended regimen."⁹  

        • However in the April, 2015 revision this combination was reclassified to the "Alternative or Other category."

          • The protocol, applies to patients with baseline HIV RNA <100,000 copies/cc or with CD4⁺ T lymphocytes (CD4) counts of >200 cells/mm³.⁹

    • Mutations and Resistance to Rilprivirine (Endurant):

      •  

        Locations of HIV Reverse Transcriptase Gene Mutations and Resistance to the

        Antiretroviral Drug Rilprivirine⁸

        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

      • Probably the most common rilpivirine NNRTI resistance mutation is located at codon 138 reflecting an E138K transition.^8,9  

        • This transition corresponds to a replacement of the wild-type, naturally occurring glutamate amino acid for a lysine.

        • As noted, other mutations have also been documented.

        • The E138K mutation results in a generalized NNRTIs resistance which includes a resistance to etravirine.^8,9  

          • Rilpivirine treatment may also select for K101E, Y181C and V189I resistance mutations.

          • The K101E describes a transition from the naturally occurring, wild-type lysine to a glutamate amino acid.

          • Y181C represents a transition from the naturally occurring, wild-type tyrosine to a cysteine amino acid.^8,9

    • Pharmacokinetics:

      • Rilpivirine administration should be with a high-fat meal (>400 kcal).^6.7 

        • Oral absorption of rilpivirine can be notably reduced if the patient is also taking acid-reducing drugs, including and acids and H₂-receptor blockers.

          • Accordingly, rilpivirine administration along with proton-pump inhibitor drugs is a contraindication.

          • Dosage adjustment is not recommended for patients with renal dysfunction even if the patient is requiring hemodialysis or peritoneal dialysis.

          • Furthermore in those patients with only mild-to-moderate liver insufficiency, no dosage adjustment is apparently required.

            • In those individuals with severe liver dysfunction, the issue of dosage adjustment remains to be resolved.⁷   

      • The cytochrome P450 microsomal metabolizing system is responsible for rilpivirine metabolism.^6.7   

        • The primary P450 isoform involved is CYP3A4.

          • Rilprivine plasma half-life is estimated to be approximately 2 days (t_½≈ 50 h).

            • Rilpivirine clearance is influenced by drugs which increase or decrease the concentration of CYP3A4.

              • For example, efavirenz and rifamycins reduce rilpivirine plasma concentrations.

              • By contrast, administration of protease inhibitors and azole antifungals leads to higher rilpivirine plasma levels.

          • Examples of drugs which are contraindicated for use concurrently with rilpivirine include:⁷   

            • Carbamazepine

            • Phenobarbital'

            • Phenytoin

            • Proton pump inhibitors (as noted above)

            • Dexamethasone,

            • Rifabutin

            • Rifampin

            • Rifapentine

            • St. John's wort.

    • Adverse Effects:

      • Examples of adverse effects associated with rilpivirine administration include:⁶

        • Depression

        • Headache

        • Insomnia

        • Rash

          • Rilprivirine-induced rash appears notably less common compared to efavirenz.

      • At high, "supratherapeutic" doses prolongation of cardiac QTc may occur.⁶

        • Based on two international phase 3 randomized, placebo controlled clinical trials (ECHO and THRIVE), the increase in the QT interval was about 11 ms from baseline.¹²  

        • Few adverse effects possibly related to conduction anomalies or to rate and rhythm disturbance were noted. 

          • Based on in vitro studies, the most likely mechanism accounting for rilpivirine-induced changes in the QT interval was related to potassium channel blockade.¹²  

    • Therapeutics:

      • Rilprivirine is classified as one agent in a multiagent protocol in the alternative or other category.⁹  

        • Rilprivirine may be used in treatment-naïve patients with with baseline HIV RNA <100,000 copies/cc or with CD4⁺ T lymphocytes (CD4) counts of >200 cells/mm³.⁹ 

        • Rilpivirine is thus used in combination with at least two other antiretroviral agents.⁷  

          • A fixed-dose formulation including emtricitabine, tenofovir and rilpivirine has been marketed.⁷