Medical Pharmacology Chapter 36:  Antiviral Drugs

Protease Inhibitors

• Antiretroviral Drugs Used in Treating HIV Infection

  • →Protease Inhibitors

    • Metabolism:

      • Antiretroviral protease inhibitors are metabolized by the cytochrome P450 hepatic and intestinal microsomal metabolizing system.^3,4 

        • The primary isoform responsible for metabolism is CYP3A4, except for nelfinavir, although its major metabolite is dependent on CYP3A4.

        • Protease inhibitors also inhibit CYP3A4 with the most significant inhibitory effect noted with ritonavir and the least with saquinavir.

          • However, some protease inhibitors including amprinavir and ritonavir can induce particular cytochrome P450 isoforms.

            • HIV protease inhibitors exhibit variable pharmacokinetic properties probably due to interindividual differences likely due to variation in hepatic and intestinal CYP isoform enzymatic activities.

              • HIV protease inhibitor half-lives range from about 2 to 10 hours, usually allowing for 12 once- to twice-daily dosing.

      • Since protease inhibitors may inhibit CYP3A4 or induce cytochrome P450-mediated hepatic drug oxidation, drug-drug interactions are numerous.^3,4 

        • Examples of drug interactions include: dihydroergotamine, depridil and some benzodiazepines.⁸ 

          • Enhanced pharmacologic activity may be associated with amiodarone, quinidine, lidocaine (systemic effects), tricyclic antidepressants and warfarin administration.

          • Additional drug-drug interactions have been noted with rifampin, phenobarbital, rifabutin, dexamethasone, phenytoin, and carbamazepine.⁸ 

      • Accordingly, dosage adjustments are often needed and some drug combinations may be contraindicated.^3,4 

      • Boosting pharmacological efficacy of some protease inhibitors may be noted when the inhibitor is given in combination with ritonavir, taking advantage of ritonavir-mediated CYP3A4 inhibition.

        • As a result of this ritonavir-caused inhibition of the cytochrome P450 isoform responsible for protease inhibitor metabolism, the other protease inhibitor's half-life is lengthened.

          • Extending the drug half-life permits both reduces dosing frequency and makes the development of drug resistance more difficult.^3,4 

  • Some protease inhibitor structures:

    • Examples of HIV-1 Protease Inhibitors

      Ritonavir	Saquinavir	Amprenavir

   

  • Side-Effect/Toxicities: 

    • Administration of protease inhibitors, as a class, may result in nausea, diarrhea, and dyslipidemia.

    • Furthermore, body fat redistribution and accumulation result in central obesity, "dorsocervical" fat enlargement (Buffalo hump), peripheral and facial wasting and breast enlargement.⁴ 

      •  

        Posterior Cervical Enlargement (Hump) likely associated with nelfinavir, as part of multidrug HIV Protocol¹⁶

        This 35-year-old female patient had been HIV-positive for about eight years. The patient had used zidovudine, didanosine, d4T and lamivudine. For a year and a half the patient had been then treated with lamivudine, zidovudine, and nelfinavir (protease inhibitor) and centripetal fat accumulation with posterior cervical region enlargement (hump) was noted.

      • Less frequently, a cushingoid presentation may occur.⁴

      • Elevated triglycerides and low-density lipoprotein levels are associated with protease inhibitor administration.

      • Hyperglycemia and insulin resistance may also occur.

      • Various types of lipodystrophies associated with protease inhibitor administration have been described.18,3 In patients exhibiting significant fat loss, unaffected fat depots contain limited triglycerides. However, this reduction in fat depot triglycerides may cause elevated triglyceride levels in the liver and skeletal muscle. This effect appears contributory to the development of insulin resistance. Hyperinsulinemia provides early compensation for insulin resistance, thus maintaining the euglycemic state (normal glucose levels). However, islet amyloidosis and ß-cell atrophy may cause in demonstrable hyperglycemia, paralleling observations and type 2 diabetes mellitus. Protease inhibitor treatment may cause in insulin resistance by another mechanism, a reduction in glucose transporter 4 activity. Morbidity and mortality associated with lipodystrophies appear due to: (1) Complications associated with diabetes mellitus (2) Acute pancreatitis occurring episodically, secondary to extreme hypertriglyceridemia (3) Cirrhosis due to chronic hepatic steatosis and (4) Atherosclerotic valvular pathology. Adverse psychological effects resulting from reduced facial and subcutaneous fat elsewhere as well as increased fat accumulation in nonlipodystrophic regions have been described.18,3

      • In some studies (not all) administration of abacavir, lopinavir + ritonavir, fosamprenavir + ritonavir may elevate cardiovascular disease risk.

        • Protease inhibitors generally may induce myocardial conduction abnormalities, such as PR or QT interval prolongation (or both).

      • Protease inhibitor treatment related hepatitis and rarely severe hepatotoxicity have also been found.

        • The likelihood of hepatic adverse effects appears higher with tipranavir + ritonavir compared to other protease inhibitors.

      • In patients with hemophilia A or B may be at risk for increased spontaneous bleeding associated with protease inhibitor administration.⁴

  • Mutations:

    • Identified genetic alterations resulting in resistance to protease inhibitor antiretroviral activity frequently occur, suggesting that protease inhibitor-based monotherapy is likely inappropriate.

      • Codon sites associated with extensive resistance to protease inhibitors are located at positions 10, 46, 54, 82, 84 and 90, although other mutation sites have also been identified.

      •  

        Locations of HIV Reverse Transcriptase Gene Mutations and Resistance to the Antiretroviral Drug Combination Fosamprenavir + Ritonavir¹⁷

        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

      • • Some protease inhibitors, such as darunavir and tipranavir, show enhanced virologic activity in individuals exhibiting HIV-1 resistance to other protease inhibitors.

  Abbreviations:  Antiretroviral Drugs, Combinations, and Classifications⁵

  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