Medical Pharmacology Chapter 36:  Antiviral Drugs

Protease Inhibitors

• Antiretroviral Drugs Used in Treating HIV Infection

  • →Protease Inhibitors

    • Darunavir (Prezista)

      • 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   HIV-1 Protease Dimer12 HIV-1 protease dimer (green and cyan) with the active site (Aspartate-25) shown in red and polypeptide substrate shown in magenta. The red vertical line emphasizes that the active protease depends on association of two monomers; the association results in active site formation.

         

        • 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. The table below may be used to identify the wild type amino acid and subsequently the amino acid at the given codon describing the mutation site. For example, considering mutation V31L a Valine at position 31 is replaced by an Isolucine. 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 

  Abbreviations:  Antiretroviral Drugs, Combinations, and Classifications⁴

  3TC = lamivudine	ABC = abacavir	ARV = antiretroviral	ATV/c = cobicistat-boosted atazanavir	ATV/r = ritonavir-boosted atazanavir ear
  DRV/r= ritonavir-boosted darunavir	DTG = dolutegravir	EFV = efavirenz	EVG/c/TDF/FTC = elvitegravir/cobicistat/tenofovir DF/emtricitabine	FTC = emtricitabine
  LPV/r = ritonavir-boosted lopinavir	RAL = raltegravir	RPV =rilpivirine	RTV = ritonavir	TDF = tenofovir disoproxil fumarate
  INSTI = integrase strand transfer inhibitor	NNRTI = nonnucleoside reverse transcriptase inhibitor	NRTI = nucleoside reverse transcriptase inhibitor	PI = protease inhibitor	CrCl = creatinine clearance

   

  "Rating Scheme for Recommendation"⁴

  Strength of Recommendation	Quality of Evidence for Recommentation
  A:  Strong recommendation for the statement	I:  One or more randomized trials with clinical outcomes and/or validated laboratory endpoints
  B:  Moderate recommendation for the statement	II:  One or more well-designed, non-randomized trials or observational cohort studies with long-term clinical outcomes
  C:  Optional recommendation for the statement	III.  Expert opinion