Protease Inhibitors
Amprenavir
Atazanavir
Lopinavir
Indinavir
Nelfinavir
Ritonavir
Saquinavir

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AMPRENAVIR
Other names: AMP, Agenerase
Form: 50, 150 mg caps; 15 mg/mL solution
Dosing:
     Normal: 1200 mg BID caps; 1400 mg BID solutiion
     Renal failure: No change; not dialized
     Liver failure: Moderate - 450 mg BID; severe - 300 mg BID
     Pediatric: 20 mg/kg BID, age > 4 days (max: 2.4 gm/day); 1.5 mL/kg BID (max: 2.8 gm/day)
Food Effect: Avoid taking with high fat meals.
Oral bioavailability:
Serum half-life:
Intracellular half-life:
Elimination:
Adverse Events: Nausea, vomiting, diarrhea, rash, oral paresthesias, dysgeusia, mood disorder.
FDA Pregnancy Category: C
Combination Regimens:
     AMP (800 mg TID) + FTV (800 mg TID)
     AMP (800 mg TID) + IDV (800 mg TID)
     AMP (800 mg TID) + NFV (750 mg TID)
     AMP (1200 mg TID) + NFV (1250 mg BID)
     AMP (600-750 mg BID) + LPV (3 caps BID)
     AMP (600 mg BID) + RTV (200 mg BID) + EFV
Comments: Has 109 IU Vit E per 150 mg caps (46 IU/mL). Prodrug with less pills under study. Take 1 hour apart from antacids or ddI. Liquid form is 15% less bioavailable and has propylene glycol. RTV + AMP (100+600 BID; 200 + 1200 QD). RTV can reverse EFV-induced decrease in AMP. Do not use in pregnancy, age <4y. liver or renal failure. N88S sensitizes to AMP.

ATAZANAVIR
Other names: TAZ, Zrivida
Form: 200 mg cap
Dosing:
     Normal: 400 mg QD
     Renal failure: NA
     Liver failure: NA
     Pediatric: NA
Food Effect: Take with food
Oral bioavailability:
Serum half-life:
Intracellular half-life:
Elimination:
Adverse Events: unconjugatede hyperbilirubinemia, similar to Gilbert's syndrome; GI symptoms
FDA Pregnancy Category:
Combination Regimens:
     TAZ (400 mg QD) + FTV (1200 mg QD)
     TAZ (400 mg QD) + EFV +RTV (200 QD)
Comments: Also known as BMS-232632. Causes a dose-dependent hyperbilirubinemia with no associated transaminitis; rarely necessitating discontinuance. Low potential for insulin resistance and dyslipidemias. Loses activity against strains resistant to >3 PIs. EFV reduces TAZ levels significantly.

LOPINAVIR
Other names: LPV, ABT378/RTV
Form: 133/33.3 mg ABT-378/RTV per cap; 80/20 mg pel mL solution
Dosing:
     Normal: 3 caps or 5 mL BHID (6 caps or 10 mL QD in PI-naive patients)
     Renal failure: No change
     Liver failure: Use with caution
     Pediatric: 7-15 kg: 12 mg/kg BID; 15-40 kg: 10 mg/kg BID; >40 kg, >12y: adult dose
Food Effect: Take with meals
Oral bioavailability:
Serum half-life:
Intracellular half-life:
Elimination:
Adverse Events: nausea, diarrhea, asthenia
FDA Pregnancy Category: C
Combination Regimens:
     LPV (3 caps/5 mL BID) + AMP (750 mg BID)
     LPV (3 caps/5 mL BID) + IDV ((600 mg BID)
     LPV (4 caps/6.5 mL BID) + EFV (600 mg QD)
     LPV (4 caps/6.5 mL BID) + NVP (400 mg QD)
Comments: Also known as ABT-378/r. Active against other PI-resistant HIV. Orange cotton-candy flavor solution has 40% alcohol. Take ddI and ddI-EC 1.5 H apart from LPV.

INDINAVIR
Other names: IDV, Crixivan
Form: 200 mg caps, 400 mg caps
Dosing:
     Normal: 800 mg Q 8H (1200 mg Q 12H is OK when combined with other PIs)
     Renal failure: No change (19% of metabolites excreted in urine)
     Liver failure: Mild to moderate: decrease to 600 mg Q 8H; severe: avoid.
     Pediatric: 250-500 mg/m2 Q 8H
Food Effect: Take 1 H before or 2 H after meals or with low fat/protein snack
Oral bioavailability: 65%
Serum half-life: 1.5 - 2 hours
Route of metabolism: P450 cytochrome; 3A4 inhibitor (less than ritonavir)
Storage: Room temperature
Adverse Events: Nephrolithiasis, nausea, dysgeusia, benign hyperbilirubinemia (inconsequential); headache, asthenia, dizziness, rash, metallic taste, fat distribution abnomalities, possible increased bleeding in patients with hemophilia.
FDA Pregnancy Category: C
Combination Regimens:
     IDV (800 mg BID) + RTV (100-200 mg BID)
     IDV (1200 mg BID) + NFV (1250 mg BID)
     IDV (800 mg TID) + AMP (800 mg TID)
     IDV (1200 mg BID) + DLV (600 mg BID)
     IDV (800 mg TID) + DLV (400 mg TID)
     IDV (600 mg BID) + LPV (3 caps/5mL BID)
     IDV (800 mg Q 8H) + NVP (200 mg BID)
     IDV (1000 mg Q8H) + EFV (600mg QD)
Comments:  Drink 48 oz (1.5L) water per day. Grapefruit juice may reduce IDV levels by 25%. Can be taken with skim milk, coffee, tea. Can take IDV and RTV together with meals; take ddI and IDV 2H apart, but VidexEC and IDV can be taken together. IDV and SQV may be mutually antagonistic. IDV+RTV (800-1200+100-200 mg) once daily under study. CNS penetration is low but > IC95% for HIV. Has anti-HIV2 activity.

NELFINAVIR
Other names: NFV, Viracept
Form: 250 mg tabs; 50 mg/gm oral powder
Dosing:
     Normal: 1250 mg BID; 750 mg TID
     Renal failure: No change. Not dialyzed
     Liver failure: Use with caution
     Pediatric: 25 mg/kg TID; 40-55 mgKg BID
Food Effect: Take with meals or snacks
Storage: Room temperature
Oral bioavailability: 20-80%
Serum half-life:3.5 - 5 hours
Intracellular half-life:
Route of Metabolism: P450 cytochrome; 3A4 inhibitor (less than ritonavir)
Elimination:
Adverse Events: Diarrhea, hyperglycemia, fat redistribution and lipid abnormalities, possible increased bleeding episodes in patients with hemophilia
FDA Pregnancy Category: B
Combination Regimens:
     NFV (750 mg BID) + RTV (400 mg BID)
     NFV (1250 mg BID) + FTV (1200 mg BID)
     NFV (1250 mg BID) + AMP (1200 mg BID)
     NFV (1250 mg BID) + DLV (600 mg BID)
     NFV (1250 mg BID) + IDV (1200 mg BID)
     NFV (1250 mg BID) + EFV (600 mg QD)
Comments: Mix oral powder in small amounts of water, soy milk, or dietary supplement, avoid acidic juices (which causes bitter taste): 1 NFV scoop=50 mg. Reduces methadone by 40% but does not cause withdrawal. Of PIs, has highest intracellular accumulation. Potent at VL>300K and on HIV2. 1250 mg BID better than 750 mg TID. RTV(200) + NFV (2000) QD under study.

RITONAVIR
Other names: RTV, Norvir
Form: 100 mg caps; 80 mg/mL in 240 mL bottle (with 7.5 mg cap).
Dosing:
     Normal: 600 mg Q 12H; 7.5 mL Q 12H (400mg=5 mL)
     Renal failure: No change. Not dialyzed
     Liver failure: Avoid; use with caution.
     Pediatric: 400 mg/m2 BID (Begin at 250 mg/m2; then increase by 50 mg/m2 Q 3 days.
Food Effect: Levels increase by 15%; take with food if possible, this may improve tolerability
Storage: Refrigerate capsules; oral solution should not be refrigerated
Route of Metabolism: P450 cytochrome, 3A4>2D6; potent 3A4 inhibitor
Oral bioavailability:
Serum half-life:3-5 hours
Intracellular half-life:
Route of Metabolism: P450 cytochrome, 3A4>2D6; potent 3A4 inhibitor
Elimination:
Adverse Events: Dysgeusia, nausea, vomiting, diarrhea, circumoral and peripheral paresthesias, increase LFTs, uric acid, CPK; hyperglycemia, fat redistribution and lipid abnormalities.
FDA Pregnancy Category: B
Combination Regimens:
     RTV (1000 mg BID) + FTV (800-1000 mg BID)
     RTV (100-200 mg BID) + IDV (800 mg BID)
     RTV (400 mg BID) + NFV (750 mg BID)
     RTV (600 mg BID) + NVP (200 mg BID)
     RTV (500 mg BID) + EFV (600 mg QD)
     RTV (100 mg BID) + FTV (800 mg BID) + EFV
     RTV (100 mg BID) + AMP (600 mg BID) + EFV or NVP
Comments: Used in low doses to enhance other potent agents. Light sensitive. Can mix liquid with chocolate milk, peanut butter, candy, BBX sauce before and after RTV helps. Take ddI and RTV 2.5 hours apart, but IDV and RTV together with meals. Has anti-HIV2 activity. Under study: RTV+FTV(100+1600)QD; RTV+IDV(100-200+1200)QD; RTV+AMP(100-200+900-1200)QD. Can try higher doses and titrate down as dictated by ADRs (or TDM), beforre changing whole regimen. May cause methadone withdrawal.

SAQUINAVIR
Other names: FTV, Fortovase, INV, Invirase
Form: 200 mg caps soft gel, FTV; 200 mg caps, hard gel, INV
Dosing:
     Normal: 1200 mg TID (FTV), 1600 mg BID, FTV; 600 mg TID, INV.
     Renal failure: No change. Not dialyzed.
     Liver failure: Use with caution in severe liver disease.
     Pediatric: 50 mg/kg TID
Food Effect: Take with high fat meals
Storage: (I) Room temperature (F) Refrigerate or store at room temperature (up to 3 months)
Oral bioavailability:
Serum half-life: (I) 1-2 hours (F) 1-2 hours
Intracellular half-life:
Route of Metabolism: (I) P450 cytochrome; 3A4 inhibitor (less than ritonavir); (F) P450 cytochrome, 3A2 inhibitor (less than ritonavir)
Elimination:
Adverse Events: Nausea, vomiting, diarrhea, headache; elevated transaminases, hyperglycemia, fat redistribution and lipid abnormalities.
FDA Pregnancy Category: B
Combination Regimens:
     FTV (1600 mg QD) + RTV (100 mg QD)
     FTV (1000 mg BID) + RTV (1000 mg BUD)
     FTV (800 mg TID) +NFV (750 mg TID)
     FTV (1200 mg TID) + DLV (400 mg TID)
     FTV (1400 mg BID) + DLV (600 mg BID)
     FTV (1200 mg QD) + RTV (100 mgQD) + EFV
     FTV (1200 mg QD) + TAZ (400 mg QD)
Comments: RTV +FTV (100+1600QD in Rx-naive; 100+1000 BID in PI-experienced patients) effective. RTV+INV is better tolerated than FTV and achieves viricidal blood levels; same dosing as with FTV. Grapefruit juice increases and garlic supplement decreases FTV level, but RTV+FTV (100+1200QD or 100+800BID) OK with EFV or garlic; SQV and IDV may be mutually antagonistic. RTV can reverse EPV-induced decrease in FTV. Anti-HIV2 activity unclear.

Cross-resistance:
Unfortunately, cross-resistance in the PI class is extremely common. The resistance patterns of indinavir and ritonavir are almost identical, and saquinavir resistance also leads to resistance to other PIs.
D30N and I50V - Early resistance to nelfinavir and amprenavir usually occurs as a result of unique mutations (D30N and I50V, respectively), and in the case of nelfinavir, there are clinical data suggesting that patients failing nelfinavir often respond to other PIs. However, recent data suggest that a substantial proportion of patients develop resistance to nelfinavir as a result of alternate genotypic pathways, such as L90M, and that such patients are more likely to have cross-resistance to other PIs.
Dual PI regimens: RTV/SQV, RTV/IDV, NFV/SQV are frequently used as salvage therapy after initial PI-containing combination. This approach has generally been associated with poor results in patients with indinavir resistance. However, patients who begin the salvage regimen when their viral load is still low may have a better outcome. The data also has been more encouraging in nelfinavir-resistant patients. The role of amprenavir after failure of a first PI remains to be determined.
3TC resistance? A number of studies have demonstrated the counterintuitive finding that patients failing PI-containing regimens may not always have PI resistance. Many patients failing IDV monotherapy or triple-therapy with AZT/3TC/IDV had 3TC resistance (M184V) but no resistance to indinavir. For these cases, intensification may be an option with resistance testing determining what drugs should be changed . However, currently available resistance assays are known to be insensitive to resistant mutants present in small quantities.