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Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection

Protease Inhibitors (PIs)

Tipranavir

(Last updated: March 5, 2015; last reviewed: March 5, 2015)

Tipranavir (TPV, APTIVUS)

Tipranavir (TPV, APTIVUS)

For additional information see Drugs@FDA: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm
Formulations

Oral Solution: 100 mg tipranavir/mL, with 116 International Units (IU) vitamin E/mL
Capsules: 250 mg
Dosing Recommendations

Note: Tipranavir must be used with ritonavir boosting. The ritonavir boosting dose used for tipranavir is higher than that used for other protease inhibitors.

Pediatric Dose (Aged <2 Years):
  • Not approved for use in children aged <2 years
Pediatric Dose (Aged 2–18 Years):
Note:
Not recommended for treatment-naive patients

Body Surface Area Dosing:
  • Tipranavir 375 mg/m2 plus ritonavir 150 mg/m2, both twice daily
Maximum Dose:
  • Tipranavir 500 mg plus ritonavir 200 mg, both twice daily
Weight-Based Dosing:
  • Tipranavir 14 mg/kg plus ritonavir 6 mg/kg, both twice daily
Maximum Dose:
  • Tipranavir 500 mg plus ritonavir 200 mg, both twice daily
Adult Dose:
Note:
Not recommended for treatment-naive patients
  • Tipranavir 500 mg (two 250-mg capsules) plus ritonavir 200 mg, both twice daily
Selected Adverse Events
  • Rare cases of fatal and non-fatal intracranial hemorrhage
  • Skin rash (more common in children than adults)
  • Nausea, vomiting, diarrhea
  • Hepatotoxicity
  • Hyperlipidemia
  • Hyperglycemia
  • Fat maldistribution
  • Possible increased bleeding episodes in patients with hemophilia
Special Instructions
  • Administer tipranavir and ritonavir together with food.
  • Tipranavir oral solution contains 116 IU vitamin E/mL, which is significantly higher than the reference daily intake for vitamin E. Patients taking the oral solution should avoid taking any form of supplemental vitamin E that contains more vitamin E than found in a standard multivitamin.
  • Tipranavir contains a sulfonamide moiety and should be used with caution in patients with sulfonamide allergy.
  • Store tipranavir oral solution at room temperature, 25° C (77° F); do not refrigerate or freeze. Oral solution must be used within 60 days after the bottle is first opened.
  • Store unopened bottles of oral tipranavir capsules in a refrigerator at 2° C to 8° C (36° F to 46° F). Once bottle is opened, capsules can be kept at room temperature (maximum of 77° F or 25° C) if used within 60 days.
  • Use tipranavir with caution in patients who may be at increased risk of intracranial hemorrhage, including individuals with brain lesion, head trauma, recent neurosurgery, coagulopathy, hypertension, or alcoholism, or who use anticoagulant or antiplatelet agents (including vitamin E).
  • Use of tipranavir is contraindicated in patients with moderate or severe hepatic impairment.
Metabolism
  • Cytochrome P450 3A4 (CYP3A4) inducer and substrate
  • Dosing in patients with renal impairment: No dose adjustment required
  • Dosing in patients with hepatic impairment: No dose adjustment required for mild hepatic impairment; use contraindicated for moderate-to-severe hepatic impairment.

Drug Interactions (see also the Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents and http://www.hiv-druginteractions.org/)

  • Tipranavir (TPV) has the potential for multiple drug interactions. Co-administration of tipranavir/ritonavir (TPV/r) with drugs that are highly dependent on CYP3A for clearance or are potent CYP3A inducers is contraindicated.
  • Before tipranavir is administrated, a patient’s medication profile should be carefully reviewed for potential drug interactions.
  • Tipranavir should be used with caution in patients who are receiving medications known to increase the risk of bleeding, such as antiplatelet agents, anticoagulants, or high doses of supplemental vitamin E.

Major Toxicities

  • More common: Diarrhea, nausea, fatigue, headache, rash (more frequent in children than in adults), and vomiting. Elevated transaminases, cholesterol, and triglycerides.
  • Less common (more severe): Lipodystrophy. Hepatotoxicity: clinical hepatitis and hepatic decompensation, including some fatalities. Patients with chronic hepatitis B or hepatitis C coinfection or elevations in transaminases are at increased risk of developing further transaminase elevations or hepatic decompensation (approximately 2.5-fold risk). Epistaxis.
  • Rare: New-onset diabetes mellitus, hyperglycemia, ketoacidosis, exacerbation of preexisting diabetes mellitus, spontaneous bleeding in hemophiliacs. Increased risk of intracranial hemorrhage. Tipranavir should be used with caution in patients who may be at risk of increased bleeding from trauma, surgery, or other medical conditions.

Resistance

The International Antiviral Society-USA (IAS-USA) maintains a list of updated resistance mutations (see https://www.iasusa.org/sites/default/files/tam/22-3-642.pdf) and the Stanford University HIV Drug Resistance Database offers a discussion of each mutation (see http://hivdb.stanford.edu/DR/).

Pediatric Use

Approval and General Considerations
TPV is Food and Drug Administration (FDA)-approved for use in children aged ≥2 years who are treatment-experienced and infected with HIV strains resistant to more than one protease inhibitor (PI).1 The use of TPV is limited by the high pill burden imposed on patients taking TPV capsules, including the burden of taking a higher dose of boosting ritonavir than is required with other PIs. This increased dose of ritonavir is associated with greater potential for drug interactions and increased toxicity. In addition, TPV is associated with serious adverse events that limit its use to patients with few treatment options. However, TPV is approved for use in children as young as 2 years and is available in a liquid formulation.

Efficacy

FDA approval of tipranavir was based on a multicenter, pediatric study of the safety, efficacy, and pharmacokinetics (PKs) of TPV/r in HIV-infected children (PACTG 1051/BI-1182.14).2 This study enrolled treatment-experienced children (with the exception of three treatment-naive patients) aged 2 to 18 years (median age 11.7 years) with baseline HIV RNA ≥1,500 copies/mL. Children in three age strata were randomized to two different doses of tipranavir/ritonavir: TPV/r 290 mg/115 mg per m2 body surface area (low dose, 58 patients) or TPV/r 375 mg/150 mg/m2 body surface area (high dose, 57 patients) twice daily, plus optimized background therapy. At baseline, resistance to all commercially available PIs was present in greater than 50% of patient isolates, and the TPV/r mutation scores increased with age.2 At 48 weeks, 39.7% of patients receiving the low dose and 45.6% of those receiving the high dose had viral loads <400 copies/mL. The groups did not differ in percentage of patients who achieved viral loads <50 copies/mL. HIV RNA levels <400 copies/mL tended to be seen in a greater proportion of the youngest patients (70%), who had less baseline resistance. TPV treatment was associated with a mean increase in CD4 T lymphocyte count of 100 cells/mm3 and 59 cells/mm3 in low- and high-dose groups, respectively, at week 48. Recently, the 5-year long-term follow-up to evaluate safety, efficacy, and tolerability of patients enrolled in PACTG 1051 was reported.3 At week 288, most children were no longer receiving TPV/r. Reasons for discontinuation included adverse events, virologic failure, and non-adherence. The youngest patients who were stable at week 48 were more likely to still be on treatment after 5 years with continued efficacy.3

Pharmacokinetics

PK evaluation of the liquid formulation at steady state in children was assessed.4 In children aged 2 to <12 years, at a dosage of TPV/r 290/115 mg/m2 body surface area, TPV trough concentrations were consistent with those achieved in adults receiving standard TPV/r 500 mg/200 mg dosing. However, children aged 12 to 18 years required a higher dose (375/150 mg/m2 body surface area, 30% higher than the directly scaled adult dose) to achieve drug exposure similar to that in adults receiving the standard TPV/r dose. Population PK analysis demonstrated that TPV clearance can be affected by body weight and that volume of distribution can be affected by age.4 Based on these studies, the final dose of TPV/r 375/150 mg/m2 body surface area twice daily is recommended.

Toxicity

Adverse effects were similar between treatment groups in the multicenter, pediatric study.2 Twenty-five percent of children experienced a drug-related serious adverse event (AE), and 9% of patients discontinued study drugs because of AEs. The most common AEs were gastrointestinal disturbances; 37% of participants had vomiting and 24% had diarrhea. Moderate or severe laboratory toxicity (primarily increase in gamma glutamyl transpeptidase and creatine phosphokinase) was seen in 11% of children. In the long-term follow-up report for PACTG 1051, incidence of AEs defined as drug-related was 55% to 65% regardless of age at entry, with higher discontinuation rates due to AEs in the older age groups.3

Vitamin E is an excipient in the TPV oral solution, with a concentration of 116 IU of vitamin E and 100 mg tipranavir/mL of solution. The recommended dose of TPV (14 mg/kg body weight) results in a vitamin E dose of 16 IU/kg body weight per day, significantly higher than the reference daily intake for vitamin E (10 IU) and close to the upper limit of tolerability for children. In PACTG 1051, bleeding events were reported more commonly in children receiving TPV oral capsules (14.3%) than in children taking TPV oral solution (5.75%).2 Overall, the incidence of bleeding episodes (primarily epistaxis) in pediatric patients observed in clinical trials was 7.5%.5

References

  1. Courter JD, Teevan CJ, Li MH, Girotto JE, Salazar JC. Role of tipranavir in treatment of patients with multidrug-resistant HIV. Ther Clin Risk Manag. 2010;6:431-441. Available at http://www.ncbi.nlm.nih.gov/pubmed/20957134.
  2. Salazar JC, Cahn P, Yogev R, et al. Efficacy, safety and tolerability of tipranavir coadministered with ritonavir in HIV-1-infected children and adolescents. AIDS. 2008;22(14):1789-1798. Available at http://www.ncbi.nlm.nih.gov/pubmed/18753862.
  3. Salazar JC, Cahn P, Della Negra M, et al. Efficacy and safety of tipranavir coadministered with ritonavir in HIV-1-infected children and adolescents: 5 years of experience. Pediatr Infect Dis J. 2014;33(4):396-400. Available at http://www.ncbi.nlm.nih.gov/pubmed/23995585.
  4. Sabo J, Cahn P, Della Negra M, et al. Population pharmacokinetic (PK) assessment of systemic steady-state tipranavir (TPV) concentrations for HIV+ pediatric patients administered tipranavir/ritonavir (TPV/r) 290/115 mg/m2 and 375/150 mg/m2 BID (BI 1192.14 and PACTG 1051 study team). Presented at: 13th Conference on Retroviruses and Opportunistic Infections. 2006. Denver, CO.
  5. APTIVUS [package insert]. Boehringer Ingelheim. 2012. Available at http://bidocs.boehringer-ingelheim.com/BIWebAccess/ViewServlet.ser?docBase=renetnt&folderPath=/Prescribing+Information/PIs/Aptivus/10003515+US+01.pdf.

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