Aptivus®, TPV, PNU-140690
non-peptidic protease inhibitor
In vitro EC50 0.03-0.07 uM, EC90 0.07-0.18 uM. In vivo EC90 0.28-0.72 uM.
250 mg soft gel capsules, DIN 02273322; 100 mg/mL oral solution (US only; not in Canada).
Capsules contain alcohol.
100 mg/mL oral solution (US only; not in Canada); contains 116 IU/mL vitamin E.
250 mg capsule: Avoid splitting or crushing capsule.
500 mg po BID + ritonavir 200 mg po BID with food
Neonate/Infant:
Pediatric (2-18 years):
Adult/Adolescent:
Patients taking tipranavir oral solution should be advised not to take supplemental vitamin E greater than a standard multivitamin, the oral solution contains 116 IU/mL of vitamin E which is higher than the Reference Daily Intake (adults 30 IU, pediatrics approximately 10 IU).
Dosage adjustment not required since tipranavir is extensively metabolized.
CrCl (mL/min) for men: 〈(140 - age) (weight kg) x 60〉 / 〈(serum creatinine umol/L) (50)〉 CrCl (mL/min) for women: as above multiplied by 0.85 |
No dosage recommendation; use with caution in patients with hepatic impairment; TPV/RTV is contraindicated in pts with moderate to severe (Child - Pugh Class B & C) hepatic insufficiency.
Plasma tipranavir concentrations are increased in patients with significant liver fibrosis (Metavir score ≥ 2) [Morello et al. 2007]
Bioavailability of older formulation of tipranavir increased 2-fold with high-fat meal.
Tipranavir capsules:
When tipranavir 500 mg/ritonavir 200 mg BID was administered with food, tipranavir bioavailability was not altered compared to when TPV/r was administered in a fasting state.[La Porte, 2007]
Tipranavir oral solution:
When tipranavir 500 mg/ritonavir 200 mg BID as oral solution was administered with food, tipranavir Cmax ↑ 21% relative to fasting, with no change in AUC or Cmin.]La Porte, 2007]
Tipranavir/ritonavir may be taken with or without food. May take with food to decrease potential for nausea and vomiting.
Tipranavir induces CYP3A, glucuronosyl transferase in vivo. Tipranavir is a slight inducer of CYP2C9, moderate inducer of CYP1A2, and potent inhibitor of CYP2D6. [Vourvahis, 2007]
Tipranavir also induces p-glycoprotein activity. Tipranavir has been shown to significantly ↓ concentrations of several co-administered protease inhibitors.
Tipranavir capsules contain alcohol; use with caution with metronidazole (may produce disulfiram-like reaction).
> 99.9%
7.7 L (female), 10.2 L (male)
2.9-3 hours
5.5-6 hours
Substrate of CYP3A4 and P-gp. Inducer of CYP3A4, P-gp, glucuronyl transferase, slight inducer of CYP2C9, moderate inducer of CYP1A2, and potent inhibitor of CYP2D6. When co-administered with ritonavir, net effect is CYP3A inhibition.
4.4% dose excreted in urine.
Median steady-state tipranavir plasma concentrations with 500/200mg ritonavir BID: Ctrough 21.01-29.1 uM, Cmax 123.4 uM, AUC 855.6 h.uM.
Peak RNA reduction is correlated with Cmin.
Significantly higher tipranavir Ctrough and lower inter-individual variability observed in women versus men [Solas et al. 2007].
20 uM (preliminary target)
2010 CNS Penetration Effectiveness (CPE) Score: 1 [Letendre S et al. 2010]
Note: For more complete information and the most current safety data on antiretrovirals in pregnancy refer to the current US DHHS Perinatal Guidelines.
Pregnancy category C. No studies or experience in human pregnancy. Safety and pharmacokinetic in pregnancy data are insufficient to recommend use in pregnancy.
Pregnancy category C. No studies or experience in human pregnancy. Safety and pharmacokinetic in pregnancy data are insufficient to recommend use in pregnancy.
Mutations in the protease gene associated with resistance to protease inhibitors (IAS-USA Fall 2017 Resistance Mutations):
*as major & minor mutations accumulate, susceptibility to PIs decreases
Phenotypic data on clinical virus isolates associated with various mutations using ViroLogic PhenoSenseTM (http://hivdb.stanford.edu/):
32, 33, 45, 82, 84: 14-fold ↑
Approx. 3-fold ↑ IC90 after serial passage of virus in presence of tipranavir
Only mild (6-fold ↑) in IC90 with ritonavir-resistance virus that is highly cross-resistant to indinavir, nelfinavir, and saquinavir.
GI: diarrhea, nausea, vomiting. Diarrhea occurs 4-5 days after starting; most cases improve over time. No trend of dose-dependence observed.
Rash: Mild to moderate rashes including urticarial rash, maculopapular rash, and possible photosensitivity have been reported (8-14% in phase 2 and 3 trials). Female gender associated with increased frequency of skin rash. Additionally, in one drug interaction trial in healthy female volunteers given a single dose of ethinyl estradiol followed by tipranavir/ritonavir, 33% of subjects developed a rash. Rash accompanied by joint pain or stiffness, throat tightness, or generalized pruritus (itching) has been reported in both men and women receiving tipranavir/ritonavir.
Hepatotoxicity (Black Box warning): Tipranavir co-administered with low dose ritonavir has been associated with reports of clinical hepatitis and hepatic decompensation, including some fatalities. All patients should be followed closely with clinical and laboratory monitoring, especially those with chronic hepatitis B or C co-infection, as these patients have an increased risk of hepatotoxicity. Liver function tests should be performed at baseline and frequently through treatment. In addition, tipranavir is contraindicated in patients with moderate and severe (Child-Pugh Class B and C, respectively) hepatic insufficiency.
Intracranial Hemorrhage (ICH) - Black Box Warning:
Further investigations are ongoing to assess the role of TPV in ICH.
Sulfa Allergy: Tipranavir should be used with caution in patients with a known sulfonamide allergy. Tipranavir contains a sulfonamide component. The potential for cross-sensitivity between drugs in the sulfonamide class and tipranavir is unknown.
TPV/r did not prolong the QTc interval, exhibit QT prolongation or clinically important ECG effects with therapeutic dosing (TPV/r 500/200mg BID) or supra-therapeutic dosing (TPV/r 750/200mg BID) in 80 healthy subjects [Huettner et al. ICAAC 2007]
Protease class effects include: hyperlipidemia, hypertriglyceridemia, hyperglycemia, fat maldistribution, weight gain, increase in LFTs, hepatitis, increased bleeding in hemophiliacs, osteonecrosis.
Assess risk factors for diabetes, coronary artery disease, osteonecrosis (i.e. steroids, ETOH, diabetes, hyperlipidemia), and hepatic dysfunction (i.e. HBV/HCV, ETOH use). CBC/diff, LFTs, glucose, fasting cholesterol profile.
CBC/diff, LFTs, glucose q 3 mos. Fasting lipids (8-12 hr level) q 3-6 months post-therapy, then annually. If TG > 2.3 mmol/L at baseline, repeat after 1-2 months.
Capsules stable under refrigeration for at least 18 months; when stored unopened at room temperature, capsules are stable for up to 90 days. When stored at room temperature and opened twice daily, capsules are stable for up to 60 days. Tightly cap bottles after each use.
Store oral solution and room temperature (25ºC). Use solution within 60 days of opening the bottle.
Boehringer Ingelheim (Canada) Ltd.
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The information in this website/app is intended for use by and with experienced physicians and pharmacists. The information is not intended to replace sound professional judgment in individual situations, and should be used in conjunction with other reliable sources of information. Due to the rapidly changing nature of information about HIV treatment and therapies, users are advised to recheck the information contained herein with the original source before applying it to patient care. Decisions about particular medical treatments should always be made in consultation with a qualified medical practitioner knowledgeable about HIV-related illness and the treatments in question.
Neither Toronto General Hospital, Alberta Health Services, the Ottawa Hospital, nor the authors and contributors are responsible for deletions or inaccuracies in information or for claims of injury resulting from any such deletions or inaccuracies. Mention of specific drugs, drug doses or drug combinations within this website does not constitute endorsement by the authors, Toronto General Hospital, Alberta Health Services or the Ottawa Hospital.
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Last updated: January 10, 2016
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