Table 9. Characteristics of protease inhibitors (PIs)

Generic Name	Indinavir	Ritonavir	Saquinavir		Nelfinavir
Trade name	Crixivan	Norvir	Invirase	Fortovase	Viracept
Form	200,400 mg caps	100 mg caps 600mg/7.5ml po solution	200 mg caps	200 mg caps	250 mg tablets 50mg/g oral powder
Dosing Recommendations	800 mg q8h Take 1 hr before or 2 hrs after meals; may take with skim milk or low fat meal	600 mg q12h* Take with food if possible	600 mg TID* Take with large meal	1,200 mg TID Take with large meal	750 mg TID Take with food (meal or light snack)
Oral Bioavailability	65%	(not determined)	hard gel capsule: 4%, erratic	soft gel capsule (not determined)	20-80%
Serum half-life	1.5-2 hours	3-5 hours	1-2 hours	1-2 hours	3.5-5 hours
Route of Metabolism	P450 cytochrome 3A4	P450 cytochrome 3A4 > 2D6	P450 cytochrome 3A4	P450 cytochrome 3A4	P450 cytochrome 3A4
Storage	Room temperature	Refrigerate capsules; refrigeration for oral solution is preferred but not required if used within 30 days	Room temperature	Refrigerate or store at room temperature (up to 3 mos.)	Room temperature
Adverse Effects	Nephrolithiasis GI intolerance, nausea Lab: Increased indirect bilirubinemia (inconsequential) Misc: Headache, asthenia, blurred vision, dizziness, rash, metallic taste, thrombocytopenia Hyperglycemia+ Fat redistribution and lipid abnormalities++ Possible increased bleeding episodes in patients with hemophilia	GI intolerance, nausea, vomiting, diarrhea Paresthesias - circumoral and extremities Hepatitis Asthenia Lab: Triglycerides increase>200%, transaminase elevation, elevated CPK and uric acid Hyperglycemia+ Fat redistribution and lipid abnormalities++ Possible increased bleeding episodes in patients with hemophilia	GI intolerance, nausea and diarrhea Headache Elevated transaminase enzymes Hyperglycemia+ Fat redistribution and lipid abnormalities++ Possible increased bleeding episodes in patients with hemophilia	GI intolerance, nausea, diarrhea, abdominal pain and dyspepsia Headache Elevated transaminase enzymes Hyperglycemia+ Fat redistribution and lipid abnormalities++ Possible increased bleeding episodes in patients with hemophilia	Diarrhea Hyperglycemia* Fat redistribution and lipid abnormalities++ Possible increased bleeding episodes in patients with hemophilia
Drug Interactions	Inhibits cytochrome P450 (less than ritonavir) Not recommended for concurrent use: rifampin, terfenadine, astemizole, cisapride, trazolam, midazolam, ergot alkaloids Indinavir levels increased by: ketoconazole***, delavirdine, nelfinivir Indinavir levels reduced by: rifampin, rifabutin, grapefruit juice, nevirapine Didanosine: reduces indinavir absorption unless taken > 2 hrs apart	Inhibits cytochrome P450 (potent inhibitor) Ritonavir increases levels of multiple drugs that are not recommended for concurrent use** Didanosine: may cause reduced absorption of both drugs; should be taken > 2 hours apart Ritonavir decreases levels of ethinyl estradiol, theophylline, sulfamethoxazole and zidovudine Ritonavir increases levels of clarithromycin and desipramine	Inhibits cytochrome P450 Saquinavir levels increased by: ritonavir, ketoconazole, grapefruit juice, nelfinavir, delavirdine Saquinavir levels reduced by: rifampin, rifabutin and possibly the following: phenobarbital, phenytoin, dexamethasone and carbamezepine, nevirapine Not recommended for concurrent use: rifampin, rifabutin, terfenadine, astemizole, cisapride, ergot alkaloids, triazolam, midazolam	Inhibits cytochrome P450 Saquinavir levels increased by: ritonavir, ketoconazole, grapefruit juice, nelfinavir, delavirdine Saquinavir levels reduced by: rifampin, rifabutin and possibly the following: phenobarbital, phenytoin, dexamethasone and carbamezepine, nevirapine Not recommended for concurrent use: rifampin, rifabutin, terfenadine, astemizole, cisapride, ergot alkaloids, triazolam, midazolam	Inhibits cytochrome P450 (less than ritonavir) Nelfinavir levels reduced by rifampin, rifabutin Contraindicated for concurrent use: triazolam, midazolam, ergot alkaloids, terfenadine, astemizole, cisapride Nelfinavir decreases levels of ethinyl, estradiol and norethindrone Nelfinavir increases levels of rifabutin, saquinavir and indinavir Not recommended for concurrent use: rifampin

* Dose escalation for Ritonavir: Day 1-2: 300 mg bid; day 3-5: 400 mg bid; day 6-13: 500 mg bid; day 14: 600 mg bid
Combination treatment regimen with Saquinavir (400-600 mg po bid) plus Ritonavir (400-600 mg po bid)

+ Cases of worsening glycemia control in patients with pre-existing diabetes, and cases of new-onset diabetes including diabetic ketoacidosis have been reported with the use of all protease inhibitors (50 – 52).

++ Fat redistribution and lipid abnormalities have become increasingly recognized with the use of protease inhibitors. Discontinuation of PIs may be required to reverse fat redistribution. Patients with hypertriglyceridemia or hypercholesterolemia should be evaluated for risks for cardiovascular events and pancreatitis. Possible interventions include dietary modification, lipid lowering agents, or discontinuation of PIs.

** Drugs contraindicated for concurrent use with Ritonavir: amioderone (Cordonrone), astemizole (Hismanal), bepridil (Vascar), bupropion (Wellbutin), cisapride (Propulsid), clorazepate (Tranxene), clozapine (Clozaril),diazepam (Valium), encainide (Enkaid), estazolam (ProSom), flecainide (Tambocor), flurazepam (Dalmane), meperidine (Demerol), midazolam (Versed), piroxicam (Feldene), propoxyphene (Darvon), propafenone (Rythmol), quinidine, rifabutin, terfenadine (Seldane), triazolam (Halcion), zolpidem (Ambien), ergot alkaloids.

*** Decrease indinavir to 600 mg q8h