Tipranavir (PNU-140690) exhibits strong action against a broad range of wild-type and multi-PI-resistant HIV-1 variants, inhibits the enzymatic activity of HIV-1 protease, and prevents the dimerization of protease subunits. HIV11MIX, a mixture of 11 multi-PI-resistant (but TPV-sensitive) clinical isolates (including HIVB and HIVC), quickly develops high-level Tipranavir (PNU-140690) resistance and replicates at high concentrations of Tipranavir (PNU-140690) after being selected against Tipranavir (by 10 passages [HIV11MIXP10]). With IC50s of 2.9 and 3.2 μM, respectively, which represent 11- and 12-fold increases in comparison to the IC50 against cHIVB, cHIVBI54V and cHIVBI54V/V82T are considerably resistant to Tipranavir (PNU-140690)[1].

To increase the bioavailability of dipranavir (PNU-140690), it is necessary to combine it with low-dose ritonavir (RTV) when given orally twice a day. The abundance of Tipranavir (PNU-140690) in the liver, spleen, and eyes is considerably higher in Tipranavir/r-cotreated mice than in Tipranavir-treated animals. In the Tipranavir-alone group, 31 and 38% of the serum and liver, respectively, are made up of metabolites of tipranavir (PNU-140690). In the serum and liver of mice cotreated with tipranavir (PNU-140690) and tipranavir (TPV/r), respectively, only 1 and 2% of metabolites are found. One dose of [14C]Tipranavir (PNU-140690) is given to Sprague-Dawley rats in conjunction with RTV. Feces include a lot of oxidation-related metabolites. There isn't a single metabolite that is discovered to be substantially present in urine[2].

Absorption, Distribution and Excretion
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.

---

Metabolism / Metabolites
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.

---

Biological Half-Life
5-6 hours

Hepatotoxicity
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.
Likelihood score: E* (unproven but suspected cause of clinically apparent liver injury).

---

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
No published information is available on the use of tipranavir during breastfeeding. Tipranavir is not recommended during breastfeeding. Achieving and maintaining viral suppression with antiretroviral therapy decreases breastfeeding transmission risk to less than 1%, but not zero. Individuals with HIV who are on antiretroviral therapy with a sustained undetectable viral load and who choose to breastfeed should be supported in this decision. If a viral load is not suppressed, banked pasteurized donor milk or formula is recommended.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Gynecomastia has been reported among men receiving highly active antiretroviral therapy. Gynecomastia is unilateral initially, but progresses to bilateral in about half of cases. No alterations in serum prolactin were noted and spontaneous resolution usually occurred within one year, even with continuation of the regimen. Some case reports and in vitro studies have suggested that protease inhibitors might cause hyperprolactinemia and galactorrhea in some male patients, although this has been disputed. The relevance of these findings to nursing mothers is not known. The prolactin level in a mother with established lactation may not affect her ability to breastfeed.

---

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

---

Interactions
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.

[1]. Loss of the protease dimerization inhibition activity of tipranavir (TPV) and its association with the acquisition of resistance to TPV by HIV-1. J Virol. 2012 Dec;86(24):13384-96.

[2]. Metabolism-mediated drug interactions associated with ritonavir-boosted tipranavir in mice. Drug Metab Dispos. 2010 May;38(5):871-8.

[3]. Bardoxolone and bardoxolone methyl, two Nrf2 activators in clinical trials, inhibit SARS-CoV-2 replication and its 3C-like protease. Signal Transduct Target Ther. 2021 May 29;6(1):212.

Therapeutic Uses
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/

---

Drug Warnings
/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.

---

Pharmacodynamics
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.

C31H33N2O5F3S

602.66432

602.206

174484-41-4

Tipranavir-d4;1217819-15-2

54682461

White to off-white solid powder

1.313g/cm3

680ºC at 760mmHg

86-89ºC

365.1ºC

0mmHg at 25°C

1.579

8.479

2

10

11

42

1050

2

CCC[C@]1(CC(=C(C(=O)O1)[C@H](CC)C2=CC(=CC=C2)NS(=O)(=O)C3=NC=C(C=C3)C(F)(F)F)O)CCC4=CC=CC=C4

SUJUHGSWHZTSEU-FYBSXPHGSA-N

InChI=1S/C31H33F3N2O5S/c1-3-16-30(17-15-21-9-6-5-7-10-21)19-26(37)28(29(38)41-30)25(4-2)22-11-8-12-24(18-22)36-42(39,40)27-14-13-23(20-35-27)31(32,33)34/h5-14,18,20,25,36-37H,3-4,15-17,19H2,1-2H3/t25-,30-/m1/s1

N-[3-[(1R)-1-[(2R)-4-hydroxy-6-oxo-2-(2-phenylethyl)-2-propyl-3H-pyran-5-yl]propyl]phenyl]-5-(trifluoromethyl)pyridine-2-sulfonamide

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~200 mg/mL (~331.86 mM)
Ethanol :≥ 50 mg/mL (~82.97 mM)

Solubility in Formulation 1: 5 mg/mL (8.30 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 50.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

---

Solubility in Formulation 2: ≥ 5 mg/mL (8.30 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 50.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

---

View More

Solubility in Formulation 3: 2.5 mg/mL (4.15 mM) in 10% EtOH + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear EtOH stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

---

Solubility in Formulation 4: 2.5 mg/mL (4.15 mM) in 10% EtOH + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear EtOH stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix well.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

---

Solubility in Formulation 5: ≥ 2.5 mg/mL (4.15 mM) (saturation unknown) in 10% EtOH + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear EtOH stock solution to 900 μL of corn oil and mix evenly.

---

Solubility in Formulation 6: 2.5 mg/mL (4.15 mM) in 5% DMSO + 40% PEG300 + 5% Tween80 + 50% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

---

 (Please use freshly prepared in vivo formulations for optimal results.)