(Last updated: March 5, 2015; last reviewed: March 5, 2015)
Tipranavir (TPV, APTIVUS)For additional information see Drugs@FDA: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm
Oral Solution: 100 mg tipranavir/mL, with 116 International Units (IU) vitamin E/mL
Capsules: 250 mg
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):
Note: Not recommended for treatment-naive patients
Body Surface Area Dosing:
Note: Not recommended for treatment-naive patients
Selected Adverse Events
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/)
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/).
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.
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
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.
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