Tipranavir

602.66400

602.66

ZZT404XD09

DTXSID6048622

C66603

White solid from ethyl acetate + heptane

J05AE09|J - Antiinfectives for systemic use

113.97000

8.47930

White Solid

1.313g/cm3

86-89 °C

680ºC

365.1ºC

1.579

Insoluble|In water, 7.17X10-6 mg/L at 25 °C (est)|Freely soluble in dehydrated alcohol, propylene glycol. Insoluble in aqueous buffer, pH 7.5

0mmHg at 25°C

Henry's Law constant = 2.63X10-14 atm-cu m/mol at 25 °C (est)

pKa = 5.86 (hydroxyl) (est)

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.|SRP: At the time of review, regulatory criteria for small quantity disposal are subject to significant revision, however, household quantities of waste pharmaceuticals may be managed as follows: Mix with wet cat litter or coffee grounds, double bag in plastic, discard in trash.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including tipranavir, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

|H411 (100%): Toxic to aquatic life with long lasting effects [Hazardous to the aquatic environment, long-term hazard]|P273, P391, and P501|The GHS information provided by 1 company from 1 notification to the ECHA C&L Inventory.

Local irritation studies in rabbits indicated that tipranavir powder was minimally irritating to the eye and mildly irritating to abraded skin with open wounds.

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.

Some degree of serum aminotransferase elevations occur in a high proportion of patients taking tipranavir containing antiretroviral regimens. Moderate-to-severe elevations in serum aminotransferase levels (>5 times the upper limit of normal) are found in 3% to 10% of patients, although rates may be higher in patients with HIV-HCV coinfection. These elevations are usually asymptomatic and self-limited and can resolve even with continuation of the medication. Clinically apparent liver injury from tipranavir is rare, and the clinical pattern of liver injury, latency and recovery have not been well defined. Several protease inhibitors have been associated with acute liver injury arising 1 to 8 weeks after onset, with variable patterns of liver enzyme elevation, from hepatocellular to cholestatic. Immunoallergic features (rash, fever, eosinophilia) are uncommon, as is autoantibody formation. The acute liver injury due to tipranavir is usually self-limited, but it can be severe, and isolated cases of acute liver failure have been reported to the sponsor. In HBV or HCV coinfected patients, some instances appear to be due to exacerbation of the underlying chronic liver disease, perhaps as a result of sudden immune reconstitution. Tipranavir therapy has not been clearly linked to lactic acidosis and acute fatty liver that is reported in association with several nucleoside analogue reverse transcriptase inhibitors. Thus, tipranavir is associated with a high rate of serum enzyme elevations which is generally higher than with other protease inhibitors, for which reason it is considered a second-line HIV protease inhibitor.

Pharmacokinetic interaction with fluconazole (increased tipranavir concentrations; no change in fluconazole concentrations and AUC). If ritonavir-boosted tipranavir and fluconazole are used concomitantly, fluconazole dosage does not need to be adjusted but fluconazole dosage exceeding 200 mg daily is not recommended. If high fluconazole dosage is indicated, an alternative HIV PI or antiretroviral agent from another class should be considered.|Possible pharmacokinetic interaction with carbamazepine, phenobarbital, or phenytoin (decreased tipranavir concentrations and possible decreased antiretroviral efficacy; altered carbamazepine concentrations). If used with carbamazepine or phenytoin, some experts suggest that anticonvulsant and tipranavir concentrations be monitored; alternatively, use of another anticonvulsant can be considered. Possible pharmacokinetic interaction with valproic acid (decreased plasma concentrations of valproic acid); possibility that the anticonvulsant may be less effective.|Possible pharmacokinetic interaction with warfarin (altered warfarin concentrations). International normalized ratio (INR) should be monitored if warfarin is used concomitantly with ritonavir-boosted tipranavir, especially when initiating or discontinuing the antiretroviral agents; warfarin dosage should be adjusted as needed. Concomitant use of ritonavir-boosted tipranavir and an anticoagulant may increase the risk for bleeding;1 the drugs should be used concomitantly with caution.|Possible pharmacokinetic interactions with amiodarone, bepridil (no longer commercially available in the US), flecainide, propafenone, or quinidine (increased plasma concentrations of the antiarrhythmic agent). Potential for serious and/or life-threatening adverse effects (e.g., cardiac arrhythmias). Concomitant use with ritonavir-boosted tipranavir is contraindicated.|For more Interactions (Complete) data for Tipranavir (35 total), please visit the HSDB record page.

There have been reports of increased bleeding, including spontaneous skin hematomas and hemarthrosis in patients with hemophilia type A and B treated with protease inhibitors. In some patients additional Factor VIII was given. In more than half of the reported cases, treatment with protease inhibitors was continued or reintroduced if treatment had been discontinued. A causal relationship between protease inhibitors and these events has not been established.|New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus and hyperglycemia have been reported during post-marketing surveillance in HIV-1 infected patients receiving protease inhibitor therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events. In some cases, diabetic ketoacidosis has occurred. In those patients who discontinued protease inhibitor therapy, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and a causal relationship between protease inhibitor therapy and these events has not been established.|Clinical hepatitis and hepatic decompensation, including some fatalities, have been reported. Extra vigilance is warranted in patients with chronic hepatitis B or hepatitis C co-infection, as these patients have an increased risk of hepatotoxicity.

Extensive (> 99.9%), to both human serum albumin and α-1-acid glycoprotein.

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.|FDA Label|Aptivus, co-administered with low-dose ritonavir, is indicated for combination antiretroviral treatment of HIV-1 infection in highly pretreated adults and adolescents 12 years of age or older with virus resistant to multiple protease inhibitors.Aptivus should only be used as part of an active combination antiretroviral regimen in patients with no other therapeutic options.This indication is based on the results of two phase-III studies, performed in highly pretreated adult patients (median number of 12 prior antiretroviral agents) with virus resistant to protease inhibitors and of one phase-II study investigating pharmacokinetics, safety and efficacy of Aptivus in mostly treatment-experienced adolescent patients aged 12 to 18 years.In deciding to initiate treatment with Aptivus, co-administered with low dose ritonavir, careful consideration should be given to the treatment history of the individual patient and the patterns of mutations associated with different agents. Genotypic or phenotypic testing (when available) and treatment history should guide the use of Aptivus. Initiation of treatment should take into account the combinations of mutations which may negatively impact the virological response to Aptivus, co-administered with low-dose ritonavir.

Tipranavir is an antiretroviral protease inhibitor used in the therapy and prevention of human immunodeficiency virus (HIV) infection and the acquired immunodeficiency syndrome (AIDS). Tipranavir can cause transient and usually asymptomatic elevations in serum aminotransferase levels and is a rare cause of clinically apparent, acute liver injury. In coinfected patients, hepatic injury during highly active antiretroviral therapy including tipranavir may be a result of exacerbation of the underlying chronic hepatitis B or C, rather than a direct effect of the medication.

Antiviral Agents

Anti-HIV Agents|Tipranavir with low-dose ritonavir (ritonavir-boosted tipranavir) is used in conjunction with other antiretroviral agents for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults, adolescents, and pediatric patients 2 years of age and older with evidence of viral replication who are antiretroviral-experienced and infected with HIV-1 strains resistant to multiple HIV protease inhibitors (PIs). /Included in US product labeling/

/BOXED WARNING/ WARNING: HEPATOTOXICITY and INTRACRANIAL HEMORRHAGE. Hepatotoxicity: Clinical hepatitis and hepatic decompensation, including some fatalities, have been reported. Extra vigilance is warranted in patients with chronic hepatitis B or hepatitis C co-infection, as these patients have an increased risk of hepatotoxicity. Intracranial Hemorrhage: Both fatal and non-fatal intracranial hemorrhage have been reported.|New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus and hyperglycemia have been reported during post-marketing surveillance in HIV-1 infected patients receiving protease inhibitor therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events. In some cases, diabetic ketoacidosis has occurred. In those patients who discontinued protease inhibitor therapy, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and a causal relationship between protease inhibitor therapy and these events has not been established.|Aptivus should be used with caution in patients with a known sulfonamide allergy. Tipranavir contains a sulfonamide moiety. The potential for cross-sensitivity between drugs in the sulfonamide class and Aptivus is unknown.|Rash, including maculopapular rash, urticarial rash, and possible photosensitivity reaction, has been reported in patients receiving ritonavir-boosted tipranavir. Rash occurred in 10% of women, 8% of men, and 21% of children receiving ritonavir-boosted tipranavir in clinical studies. The median time to onset of rash was 53 days and the median duration of rash was 22 days in adults. Rash accompanied by joint pain or stiffness, throat tightness, or generalized pruritus also has been reported. Discontinue tipranavir if severe rash develops.|For more Drug Warnings (Complete) data for Tipranavir (16 total), please visit the HSDB record page.

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.

Agents used to treat AIDS and/or stop the spread of the HIV infection. These do not include drugs used to treat symptoms or opportunistic infections associated with AIDS. (See all compounds classified as Anti-HIV Agents.)

Absorption is limited, although no absolute quantification of absorption is available.|Tipranavir is extensively bound to plasma proteins (>99.9%). It binds to both human serum albumin and a-1-acid glycoprotein. The mean fraction of tipranavir (dosed without ritonavir) unbound in plasma was similar in clinical samples from healthy volunteers and HIV-1 positive patients. Total plasma tipranavir concentrations for these samples ranged from 9 to 82 uM. The unbound fraction of tipranavir appeared to be independent of total drug concentration over this concentration range.|Administration of (14)C-tipranavir to subjects (n=8) that received Aptivus/ritonavir 500/200 mg dosed to steady-state demonstrated that most radioactivity (median 82.3%) was excreted in feces, while only a median of 4.4% of the radioactive dose administered was recovered in urine. In addition, most radioactivity (56%) was excreted between 24 and 96 hours after dosing. The effective mean elimination half-life of tipranavir/ritonavir in healthy volunteers (n=67) and HIV-1 infected adult patients (n=120) was approximately 4.8 and 6.0 hours, respectively, at steady state following a dose of 500/200 mg twice daily with a light meal.|The pharmacokinetic and metabolite profiles of the antiretroviral agent tipranavir (TPV), administered with ritonavir (RTV), in nine healthy male volunteers were characterized. Subjects received 500-mg TPV capsules with 200-mg RTV capsules twice daily for 6 days. They then received a single oral dose of 551 mg of TPV containing 90 uCi of [(14)C]TPV with 200 mg of RTV on day 7, followed by twice-daily doses of unlabeled 500-mg TPV with 200 mg of RTV for up to 20 days. Blood, urine, and feces were collected for mass balance and metabolite profiling. Metabolite profiling and identification was performed using a flow scintillation analyzer in conjunction with liquid chromatography-tandem mass spectrometry. The median recovery of radioactivity was 87.1%, with 82.3% of the total recovered radioactivity excreted in the feces and less than 5% recovered from urine. Most radioactivity was excreted within 24 to 96 hr after the dose of ((14)C)TPV. Radioactivity in blood was associated primarily with plasma rather than red blood cells. Unchanged TPV accounted for 98.4 to 99.7% of plasma radioactivity. Similarly, the most common form of radioactivity excreted in feces was unchanged TPV, accounting for a mean of 79.9% of fecal radioactivity. The most abundant metabolite in feces was a hydroxyl metabolite, H-1, which accounted for 4.9% of fecal radioactivity. TPV glucuronide metabolite H-3 was the most abundant of the drug-related components in urine, corresponding to 11% of urine radioactivity. In conclusion, after the coadministration of TPV and RTV, unchanged TPV represented the primary form of circulating and excreted TPV and the primary extraction route was via the feces.|The in vitro plasma protein binding of tipranavir was very high (> 99.9%) in all species including humans, with only a slight trend towards saturation over the concentration range of 10 to 100 um. Tipranavir with or without ritonavir co-administration, distributed primarily in the liver, small intestine, large intestine, kidney and lung. Tipranavir did not cross the blood-brain barrier and did not readily partitioning into red blood cells.|Following intravenous dosing, tipranavir demonstrated low clearance ranging from 0.08 L/hr/kg in dogs to 1.15 l/h/kg in mice. The Vss ranged from 0.13 L/kg in dogs to 0.51 L/kg in rats. TPV was eliminated rapidly with a terminal t1/2 ranging from 0.93 hr in dogs to 5.43 hr in rats. Following oral dosing, tipranavir exhibited a mean Tmax ranging from 0.5 to 8 hr in all species. In all species a moderate or poor oral bioavailability of tipranavir was revealed, due to a lack of absorption and/or intestinal metabolism. Whereas the bioavailability in rats showed moderately levels of 28.0%, the bioavailability in dogs (6.5% and 7.7%) and also in mice (11%) and rabbits (9.9%) was minimal. Food had no significant effect on tipranavir oral bioavailability in dogs. Ritonavir co-administration studies were performed to investigate the benefit gained by the combination. However the use of different doses of ritonavir for oral and intravenous PK of tipranavir does not allow a clear comparison of tipranavir bioavailability with or without ritonavir. With ritonavir co-administration, following intravenous dosing, tipranavir demonstrated low to moderate clearance ranging from 0.0182 L/hr/kg in rats to 3.00 L/hr/kg in mice. In rats and dogs, co-administration of ritonavir resulted in a 4- to 5-fold decrease in clearance for tipranavir, which would be consistent with inhibition of drug-metabolising enzymes by ritonavir.

Hepatic. In vitro metabolism studies with human liver microsomes indicated that CYP 3A4 is the predominant CYP enzyme involved in tipranavir metabolism.|Tipranavir (TPV) is the first nonpeptidic protease inhibitor used for the treatment of drug-resistant HIV infection. Clinically, TPV is coadministered with ritonavir (RTV) to boost blood concentrations and increase therapeutic efficacy. The mechanism of metabolism-mediated drug interactions associated with RTV-boosted TPV is not fully understood. In the current study, TPV metabolism was investigated in mice using a metabolomic approach. TPV and its metabolites were found in the feces of mice but not in the urine. Principal component analysis of the feces metabolome uncovered eight TPV metabolites, including three monohydroxylated, three desaturated, one dealkylated, and one dihydroxylated. In vitro study using human liver microsomes recapitulated five TPV metabolites, all of which were suppressed by RTV. CYP3A4 was identified as the primary enzyme contributing to the formation of four TPV metabolites (metabolites II, IV, V, and VI), including an unusual dealkylated product arising from carbon-carbon bond cleavage. Multiple cytochromes P450 (2C19, 2D6, and 3A4) contributed to the formation of a monohydroxylated metabolite (metabolite III). In vivo, RTV cotreatment significantly inhibited eight TPV metabolic pathways. In summary, metabolomic analysis revealed two known and six novel TPV metabolites in mice, all of which were suppressed by RTV. The current study provides solid evidence that the RTV-mediated boosting of TPV is due to the modulation of P450-dependent metabolism.|The pharmacokinetic and metabolite profiles of the antiretroviral agent tipranavir (TPV), administered with ritonavir (RTV), in nine healthy male volunteers were characterized. Subjects received 500-mg TPV capsules with 200-mg RTV capsules twice daily for 6 days. They then received a single oral dose of 551 mg of TPV containing 90 uCi of [(14)C]TPV with 200 mg of RTV on day 7, followed by twice-daily doses of unlabeled 500-mg TPV with 200 mg of RTV for up to 20 days. ... The most abundant metabolite in feces was a hydroxyl metabolite, H-1, which accounted for 4.9% of fecal radioactivity. TPV glucuronide metabolite H-3 was the most abundant of the drug-related components in urine, corresponding to 11% of urine radioactivity. ...|In vitro metabolism studies indicated that CYP3A4 is the predominant CYP isoform involved in tipranavir metabolism in humans. CYP3A isozyme was also identified in rat as the predominant CYP isoform involved in tipranavir metabolism.|Studies in rats and humans dosed by tipranavir co-administered with ritonavir were conducted to assess metabolites. The unchanged tipranavir was the predominant form in plasma (>85.7%). Unchanged tipranavir was also the major form excreted in feces and urine. Combined levels of excreted metabolites in feces and urine accounted for approximately 4.8% and 7.4% in male and female rats. Only small amounts of a glucuronide were observed in faeces.|For more Metabolism/Metabolites (Complete) data for Tipranavir (6 total), please visit the HSDB record page.

5-6 hours

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.|Tipranavir (TPV) is an HIV-1 protease inhibitor that inhibits the virus-specific processing of the viral Gag and Gag-Pol polyproteins in HIV-1 infected cells, thus preventing formation of mature virions.|Tipranavir inhibits the replication of laboratory strains of HIV-1 and clinical isolates in acute models of T-cell infection, with 50% effective concentrations (EC50) ranging from 0.03 to 0.07 uM (18-42 ng/mL). Tipranavir demonstrates antiviral activity in cell culture against a broad panel of HIV-1 group M non-clade B isolates (A, C, D, F, G, H, CRF01 AE, CRF02 AG, CRF12 BF). Group O and HIV-2 isolates have reduced susceptibility in cell culture to tipranavir with EC50 values ranging from 0.164 -1 uM and 0.233-0.522 uM, respectively. When used with other antiretroviral agents in cell culture, the combination of tipranavir was additive to antagonistic with other protease inhibitors (amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir) and generally additive with the NNRTIs (delavirdine, efavirenz, and nevirapine) and the NRTIs (abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, and zidovudine). Tipranavir was synergistic with the HIV-1 fusion inhibitor enfuvirtide. There was no antagonism of the cell culture combinations of tipranavir with either adefovir or ribavirin, used in the treatment of viral hepatitis.

Emergency and supportive measures: Maintain an open airway and assist ventilation if needed. Treat coma, seizures, hypotension or anaphylaxis if they occur. Replace fluid losses resulting from gastroenteritis with intravenous crystalloids. Maintain steady urine flow with intravenous fluids to alleviate crystalluria and reverse renal dysfunction. Treat lactic acidosis with judicious doses of sodium bicarbonate and by withdrawal of the offending drug. /Antiviral and antiretroviral agents/|Specific drugs and antidotes: There are no specific antidotes for these agents. Anecdotal cases of patients with severe lactic acidosis suggest that vitamin deficiency may be a contributor to the development of a life-threatening condition. Riboflavin ... and/or thiamine ... may be beneficial if levels are low. /Antiviral and antiretroviral agents/|Decontamination: Administer activated charcoal orally if conditions are appropriate. Gastric lavage is not necessary after small to moderate ingestions if activated charcoal can be given promptly. /Antiviral and antiretroviral agents/|/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/|For more Antidote and Emergency Treatment (Complete) data for Tipranavir (6 total), please visit the HSDB record page.

/CASE REPORTS/ A 55-year-old HIV-infected patient on antiretroviral treatment with Ritonavir-boosted Tipranavir as part of HAART developed intracranial hemorrhage during the acute phase of cryptococcal meningitis. CT scan and MRI confirmed the intracranial haemorrhage. Positive cryptococcal antigen and cultures of both blood and CSF confirmed the diagnosis of meningitis caused by Cryptococcus neoformans. There was no evidence of any bleeding disorder, use of aspirin or antiplatelet agents. The patient was treated with Liposomal Amphotericin B for cryptococcal meningitis. No special treatment was needed for the intracranial hemorrhage, but Tipranavir was discontinued and replaced by Kaletra and Saquinavir. Intracranial hemorrhage could be related to Tipranavir and cryptococcal meningitis was a predisposing factor. Headache stopped 3 days after starting antifungal treatment. ...|/GENOTOXICITY/ Tipranavir showed no evidence of mutagenicity or clastogenicity in a ... a chromosome aberration assay in human peripheral lymphocytes ... .|/OTHER TOXICITY INFORMATION/ Hepatitis and hepatic decompensation, including some fatalities, have been reported in patients receiving ritonavir-boosted tipranavir; causal relationship not established. Hepatotoxicity generally has occurred in patients with advanced HIV infection receiving multiple concomitant drugs. Increases in hepatic transaminase concentrations (grade 3 and 4) have been reported in approximately 10% of antiretroviral-experienced patients receiving ritonavir-boosted tipranavir in clinical studies.

3'-((1R)-1-((6R)-5,6-dihydro-4-hydroxy-2-oxo-6-phenethyl-6-propyl-2h-pyran-3-yl)propyl)-5-(trifluoromethyl)-2-pyridinesulfonanilide

Oral: Capsules 250 mg, Aptivus (Boehringer Ingelheim); Solution: 100 mg/mL, Aptivus (Boehringer Ingelheim)

HPLC determination in plasma

Human drugs -> Aptivus -> EMA Drug Category|Antivirals for systemic use -> Human pharmacotherapeutic group|Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients