indication

For combination antiretroviral treatment of HIV-1 infected adult patients with evidence of viral replication, who are highly treatment-experienced or have HIV-1 strains resistant to multiple protease inhibitors.

pharmacology

Tipranavir is a non-peptidic protease inhibitor (PI) of HIV. Protease inhibitors block the part of HIV called protease. HIV-1 protease is an enzyme required for the proteolytic cleavage of the viral polyprotein precursors into the individual functional proteins found in infectious HIV-1. Nelfinavir binds to the protease active site and inhibits the activity of the enzyme. This inhibition prevents cleavage of the viral polyproteins resulting in the formation of immature non-infectious viral particles. Protease inhibitors are almost always used in combination with at least two other anti-HIV drugs.

mechanism of action

Tipranavir (TPV) is a non-peptidic HIV-1 protease inhibitor that inhibits the processing of the viral Gag and Gag-Pol polyproteins in HIV-1 infected cells, thus preventing formation of mature virions. Two mechanisms are suggested in regards to the potency of tipranavir: 1. Tipravanir may bind to the active site of the protease enzyme with fewer hydrogen bonds than peptidic protease inhibitors, which results in increased flexibility, allowing it to fit into the active site of the enzyme in viruses that have become resistance to other protease inhibitors. This also enables tipranavir to adjust to amino acid substitutions at the active site. 2. Tipranavir's strong hydrogen bonding interaction with the amide backbone of the protease active site Asp30 may lead to its activity against resistant viruses.

toxicity

Oral LD₅₀ in rat is over 5,000 mg/kg. Side effects include thirst and hunger, unexplained weight loss, increased urination, fatigue, and dry, itchy skin.

biotransformation

Hepatic. In vitro metabolism studies with human liver microsomes indicated that CYP 3A4 is the predominant CYP enzyme involved in tipranavir metabolism.

absorption

Absorption is limited, although no absolute quantification of absorption is available.

half life

5-6 hours

drug interactions

Abacavir: The serum concentration of Abacavir may be decreased by protease inhibitors such as Tipranavir. The antiviral response should be closely monitored.

Alprazolam: Tipranavir may decrease the metabolism and clearance of Alprazolam. Consider alternate therapy or monitor for Alprazolam toxic effects if Tipranavir is initiated or dose increased.

Amiodarone: Tipranavir, co-administered with Ritonavir, may increase the plasma concentration of Amiodarone. Concomitant therapy is contraindicated.

Amlodipine: Tipranavir may decrease the metabolism and clearance of the calcium channel blocker, Amlopidine. Monitor for changes in Amlopidine therapeutic and toxic effects if Tipranavir is initiated, discontinued or dose changed.

Astemizole: Tipranavir, co-administered with Ritonavir, may increase the plasma concentration of Astemizole. Concomitant therapy is contraindicated.

Atazanavir: Tipranavir, co-administered with Ritonavir, may decrease the plasma concentration of Atazanavir. Consider alternate therapy.

Atorvastatin: Tipranavir, co-administered with Ritonavir, increases the adverse/toxic effects of Atorvastatin. Concomitant therapy should be avoided.

Bepridil: Tipranavir, co-administered with Ritonavir, may increase the plasma concentration of Bepridil. Concomitant therapy is contraindicated.

Bromazepam: Tipranavir may increase the serum concentration of bromazepam by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of bromazepam if tipranavir is initiated, discontinued or dose changed.

Bromocriptine: Tipranavir may increase the plasma concentration of Bromocriptine. Concomitant therapy should be avoided.

Budesonide: Tipranavir may increase the plasma concentration of Budesonide. Monitor for toxic Budesonide effects during concomitant administration.

Carbamazepine: Concomitant use may result in decreased Tipranavir and increased Carbamazepine concentrations.

Chlordiazepoxide: Tipranavir may decrease the metabolism and clearance of Chlordiazepoxide. Consider alternate therapy or monitor for Alprazolam toxic effects if Tipranavir is initiated or dose increased.

Cisapride: Tipranavir, co-administered with Ritonavir, may increase the plasma concentration of Cisapride. Concomitant therapy is contraindicated.

Clarithromycin: The concentrations of Tipranavir and Clarithromycin increase during concomitant therapy. Dose adjustments are required for patients with renal impairment.

Clobazam: Tipranavir may decrease the metabolism and clearance of Clobazam. Consider alternate therapy or monitor for Clobazam toxic effects if Tipranavir is initiated or dose increased.

Clonazepam: Tipranavir may decrease the metabolism and clearance of Clonazepam. Consider alternate therapy or monitor for Clonazepam toxic effects if Tipranavir is initiated or dose increased.

Clorazepate: Tipranavir may decrease the metabolism and clearance of Clorazepate. Consider alternate therapy or monitor for Clorazepate toxic effects if Tipranavir is initiated or dose increased.

Conjugated Estrogens: Conjugated estrogens may increase the adverse dermatological effects (i.e. skin rash) of Tipranavir. Tipranavir may decrease the serum concentration Conjugated estrogens. Monitor for estrogen deficiency during concomitant therapy.

Cyclosporine: Tipranavir may affect the efficacy/toxicity of Cyclosporine.

Dabigatran etexilate: P-Glycoprotein inducers such as tipranavir may decrease the serum concentration of dabigatran etexilate. This combination should be avoided.

Delavirdine: Concomitant use may result in increased Tipranavir and decreased Delavirdine concentrations. Monitor for altered therapeutic and adverse effects of both agents if either agent is initiated, discontinued or dose changed.

Desipramine: Tipranavir, co-administered with Ritonavir, may increase the concentration of Desipramine. Monitor Desipramine concentration and efficacy/toxicity and adjust dose as required.

Diazepam: Tipranavir may decrease the metabolism and clearance of Diazepam. Consider alternate therapy or monitor for Diazepam toxic effects if Tipranavir is initiated or dose increased.

Didanosine: Tipranavir may decrease the concentration of Didanosine.

Diethylstilbestrol: Diethylstilbestrol may increase the adverse dermatological effects (i.e. skin rash) of Tipranavir. Tipranavir may decrease the serum concentration Diethylstilbestrol. Monitor estrogen levels during concomitant therapy.

Dihydroergotamine: Tipranavir, co-administered with Ritonavir, may increase the plasma concentration of Dihydroergotamine. Concomitant therapy is contraindicated.

Diltiazem: Tipranavir, co-administered with Ritonavir, may alter the concentration of Diltiazem. Monitor for efficacy and adverse/toxic effects of Diltiazem.

Disulfiram: Disulfiram may cause Tipranavir (Aptivus brand) toxicity by inhibiting alcohol metabolism. Aptivus capsules contain alcohol.

Efavirenz: Efavirenz may alter the serum concentration Tipranavir. Monitor for changes in Tipranavir therapeutic and adverse effects if Efavirenz is initiated, discontinued or dose changed.

Ergoloid mesylate: Tipranavir may increase the plasma concentration of Ergoloid mesylates. Concomitant therapy should be avoided.

Ergonovine: Tipranavir, co-administered with Ritonavir, may increase the plasma concentration of Ergonovine. Concomitant therapy is contraindicated.

Ergotamine: Tipranavir, co-administered with Ritonavir, may increase the plasma concentration of Ergotamine. Concomitant therapy is contraindicated.

Esomeprazole: Tipranavir, co-administered with Ritonavir, may decrease the plasma concentration of Esomeprazole. Consider alternate therapy or increase the dose of Esomeprazole based on the therapeutic response.

Estazolam: Tipranavir may decrease the metabolism and clearance of Estazolam. Consider alternate therapy or monitor for Estazolam toxic effects if Tipranavir is initiated or dose increased.

Estradiol: Estradiol may increase the adverse dermatological effects (i.e. skin rash) of Tipranavir. Tipranavir may decrease the serum concentration Estradiol. Use an alternate form of contraception or monitor for estrogen deficiency if Estradiol is used for hormone replacement therapy.

Estrone: Estropipate may increase the adverse dermatological effects (i.e. skin rash) of Tipranavir. Tipranavir may decrease the serum concentration Estropipate. Monitor for estrogen deficiency during concomitant therapy.

Ethinyl Estradiol: Tipranavir, co-administered with Ritonavir, decreases Ethinyl estradiol concentrations. Ethinyl estradiol may increase the adverse dermatological effects (i.e. skin rash) of Tipranavir. Use an alternate form of contraception or monitor for estrogen deficiency if Ethinyl estradiol is used for hormone replacement therapy.

Felodipine: Tipranavir, co-administered with Ritonavir, may alter the concentration of Felopidine. Monitor for efficacy and adverse/toxic effects of Felopidine.

Flecainide: Tipranavir, co-administered with Ritonavir, may increase the plasma concentration of Flecainide. Concomitant therapy is contraindicated.

Fluconazole: Fluconazole may increase the serum concentration of Tipranavir. Dose adjustments are not required.

Fluoxetine: Tipranavir increases the concentration of Fluoxetine. The Fluoxetine dose may require an adjustment.

Flurazepam: Tipranavir may decrease the metabolism and clearance of Flurazepam. Consider alternate therapy or monitor for Flurazepam toxic effects if Tipranavir is initiated or dose increased.

Fluticasone Propionate: Tipranavir, co-administered with Ritonavir, may increase the plasma concentration of Fluticasone propionate. Concomitant therapy should be avoided if possible.

Fosamprenavir: Tipranavir, co-administered with Ritonavir, may decrease the plasma concentration of Fosamprenavir. Consider alternate therapy.

Fusidic Acid: Concomitant therapy of Tipranavir with Fusidic acid may result in increased serum concentrations of both agents. Consider alternate therapy or monitor for increased serum concentrations and toxocity of both agents.

Isradipine: Tipranavir may decrease the metabolism and clearance of the calcium channel blocker, Isradipine. Monitor for changes in Isradipine therapeutic and adverse effects if Tipranavir is initiated, discontinued or dose changed.

Itraconazole: Tipranavir may increase the serum concentration of Itraconazole.

Ketoconazole: Tipranavir may increase the serum concentration of Ketoconazole.

Lopinavir: Tipranavir, co-administered with Ritonavir, may decrease the plasma concentration of Lopinavir. Consider alternate therapy.

Lovastatin: Tipranavir, co-administered with Ritonavir, may increase the plasma concentration of Lovastatin. Concomitant therapy is contraindicated.

Meperidine: Tipranavir may increase the adverse/toxic effects of Meperidine. Consider alternate therapy or monitor for Meperidine toxicity during concomitant use.

Mestranol: Mestranol may increase the adverse dermatological effects (i.e. skin rash) of Tipranavir. Tipranavir may decrease the serum concentration Mestranol. Use an alternate form of contraception or monitor for estrogen deficiency if Mestranol is used for hormone replacement therapy.

Methadone: Tipranavir, co-administered with Ritonavir, decreases the Methadone concentration. Monitor for symptoms of opiate withdrawal.

Methylergonovine: Tipranavir, co-administered with Ritonavir, may increase the plasma concentration of Methylergonovine. Concomitant therapy is contraindicated.

Midazolam: Tipranavir, co-administered with Ritonavir, may increase the plasma concentration of Midazolam. Concomitant therapy is contraindicated.

Nevirapine: Nevirapine, a CYP3A4 inducer, may decrease the serum concentration of Tipranavir, a CYP3A4 substrate. Monitor for changesin Tipranavir effect if Nevirapine is initiated, discontinued or dose changed.

Nicardipine: Tipranavir, co-administered with Ritonavir, may alter the concentration of Nicardipine. Monitor for efficacy and adverse/toxic effects of Nicardipine.

Nifedipine: Tipranavir may decrease the metabolism and clearance of the calcium channel blocker, Nifedipine. Monitor for changes in Nifedipine therapeutic and adverse effects if Tipranavir is initiated, discontinued or dose changed.

Nimodipine: Tipranavir may decrease the metabolism and clearance of the calcium channel blocker, Nimodipine. Monitor for changes in Nimodipine therapeutic and adverse effects if Tipranavir is initiated, discontinued or dose changed.

Nisoldipine: Tipranavir, co-administered with Ritonavir, may alter the concentration of Nisoldipine. Monitor for efficacy and adverse/toxic effects of Nisoldipine.

Nitrendipine: Tipranavir may decrease the metabolism and clearance of the calcium channel blocker, Nitrendipine. Monitor for changes in Nitrendipine therapeutic and adverse effects if Tipranavir is initiated, discontinued or dose changed.

Omeprazole: Tipranavir, co-administered with Ritonavir, may decrease the plasma concentration of Omeprazole. Consider alternate therapy or increase the dose of Omeprazole based on the therapeutic response.

Paroxetine: Tipranavir increases the concentration of Paroxetine. The Paroxetine dose may require an adjustment.

Pergolide: Tipranavir may increase the plasma concentration of Pergolide. Concomitant therapy should be avoided.

Phenobarbital: Phenobarbial decreases the concentration of Tipranavir. Monitor for decreased Tipranavir efficacy.

Phenytoin: Phenytoin decreases the concentration of Tipranavir. Monitor for decreased Tipranavir efficacy.

Pimozide: Tipranavir, co-administered with Ritonavir, may increase the plasma concentration of Pimozide. Concomitant therapy is contraindicated.

Posaconazole: Tipranavir may increase the serum concentration of Posaconazole. Posaconazole may increase the serum concentration of Tipranavir.

Pravastatin: Tipranavir may increase the plasma concentration of Pravastatin. Consider alternate therapy.

Prazepam: Tipranavir may decrease the metabolism and clearance of Prazepam. Consider alternate therapy or monitor for Prazepam toxic effects if Tipranavir is initiated or dose increased.

Propafenone: Tipranavir, co-administered with Ritonavir, may increase the plasma concentration of Propafenone. Concomitant therapy is contraindicated.

Quazepam: Tipranavir may decrease the metabolism and clearance of Quazepam. Consider alternate therapy or monitor for Quazepam toxic effects if Tipranavir is initiated or dose increased.

Quinidine: Tipranavir, co-administered with Ritonavir, may increase the plasma concentration of Quinidine. Concomitant therapy is contraindicated.

Ranolazine: Increased levels of ranolazine - risk of toxicity

Rifabutin: Tipranavir increases the concentration of Rifabutin. Adjust Rifabutin dose and monitor for adverse/toxic effects.

Rifampin: Rifampin may decrease the plasma concentration of Tipranavir. Concomitant use is not recommended.

Rifapentine: Concomitant therapy may cause decreased Tipranavir and increased Rifapentine plasma concentrations.

Rosuvastatin: Concomitant therapy of Rosuvastatin and Tipranavir/Ritonavir may increase Rosuvastatin and Tipranavir concentrations. Consider alternate therapy.

Saquinavir: Tipranavir, co-administered with Ritonavir, may decrease the plasma concentration of Saquinavir. Consider alternate therapy.

Sertraline: Tipranavir increases the concentration of Sertraline. The Sertraline dose may require an adjustment.

Sildenafil: Tipranavir, co-administered with Ritonavir, may increase the concentration of Sildenafil. Alternate therapy should be considered.

Simvastatin: Tipranavir, co-administered with Ritonavir, may increase the plasma concentration of Simvastatin. Concomitant therapy is contraindicated.

Sirolimus: Tipranavir may affect the efficacy/toxicity of Sirolimus.

Sodium bicarbonate: Sodium bicarbonate may decrease the absorption of Tipranavir. Separate administration of the agents and monitor for decreased efficacy of Tipranavir.

St. John's Wort: St. John's Wort may decrease the concentration and efficacy of Tipranavir. Concomitant therapy should be avoided.

Tacrolimus: Tipranavir may decrease the metabolism and clearance of Tacrolimus. Dose adjustments may be required. Monitor for Tacrolimus efficacy and toxicity during concomitant therapy.

Tadalafil: Tipranavir may reduce the metabolism of Tadalafil. Concomitant therapy should be avoided if possible due to high risk of Tadalafil toxicity.

Temsirolimus: Tipranavir may affect the efficacy/toxicity of Temsirolimus.

Terfenadine: Tipranavir, co-administered with Ritonavir, may increase the plasma concentration of Terfenadine. Concomitant therapy is contraindicated.

Theophylline: Tipranavir, co-administered with Ritonavir, may decrease the concentration of Theophylline.

Trazodone: The protease inhibitor, Tipranavir, may increase the efficacy/toxicity of Trazodone by inhibiting Trazodone metabolism and clearance. Monitor for changes in Trazodone efficacy/toxicity if Tipranavir is initiated, discontinued or dose changed.

Triazolam: Tipranavir, co-administered with Ritonavir, may increase the plasma concentration of Triazolam. Concomitant therapy is contraindicated.

Valproic Acid: Tipranavir decreases the concentration of Valproic acid. Monitor Valproid acid efficacy.

Vardenafil: Tipranavir, co-administered with Ritonavir, may increase the plasma concentration of Vardenafil. Concomitant therapy is contraindicated.

Verapamil: Tipranavir, co-administered with Ritonavir, may alter the concentration of Verapamil. Monitor for efficacy and adverse/toxic effects of Verapamil.

Voriconazole: Voriconazole may increase the serum concentration of tipranavir by decreasing its metabolism. Tipranavir may increase the serum concentration of voriconazole. Monitor for changes in the therapeutic and adverse effects of both agents if concomitant therapy is initiated, discontinued or if doses are changed.

Zidovudine: Tipranavir decreases the concentration of Zidovudine.