The Clinical Use of Tipranavir in HIV Infection: DRUG INTERACTIONS AND CONTRAINDICATIONS

26 Mar
2010

The Clinical Use

TPV is given with ritonavir to increase its therapeutic concentration, thereby inhibiting HIV replication.

In clinical studies, TPV was an inhibitor of CYP 1A2, CYP 2C9, CYP 2C19, and CYP 2D6, but the net effect in vivo is not known. When given with 200 mg of ritonavir, TPV is an inhibitor of CYP 3A4, and it may increase concentrations of drugs that are metabolized via this iso-enzyme. These drug interactions include:

  • an increased risk of fentanyl (Dura-gesic, Janssen) and midazolam (Versed, Roche) toxicities accompanied by CNS and respiratory depression.
  • increased serum levels (e.g., Plendil canadian, AstraZeneca) and potential toxicity (e.g., headache, peripheral edema, hypotension, and tachycardia).
  • increased concentrations  (Pfizer), (Bayer/GlaxoSmithKline), and (Cialis canadian, Eli Lilly).
  • increased risk of toxicity with canadian tacrolimus (Astellas), including nephrotoxicity, hyperglycemia, hyperkalemia, and neuropsychiatric reactions.

The concurrent use of antiarrhythmic agents, ergot derivatives, cisapride (Pro-pulsid, Janssen), rifampin, pimozide (Orap, Gate), midazolam, and triazolam (Halcion, Pfizer) is contraindicated because of the potential for serious or life-threatening reactions. Coadministra-tion of TPV with lovastatin (e.g., Meva-cor, Merck) and (Merck) is also contraindicated because of the increased risk of myopathy and rhabdomyolysis.

Because a TPV/r combination decreases the levels of abacavir sulfate (Zia-gen, GlaxoSmithKline), doses of conjugated estrogens, methadone, and zidovudine canadian (GlaxoSmithKline) must be adjusted according to the patient’s response. On the contrary, medications that increase plasma levels of TPV include clarithromycin (Biaxin, Abbott), (Canadian Diflucan, Pfizer), (Janssen), and ( Janssen).

Drugs that decrease TPV plasma levels include antacids such as aluminum and magnesium products and magal-drate. TPV should be taken separately from antacid medications; it should be taken one hour before or two hours after antacids. When coadministered with aluminum and magnesium-based liquid antacids, TPV/r causes a decrease in the area-under-the-curve concentration (AUC) and peak concentration of TPV.

As with other PIs, the concomitant use of garlic and St. John’s Wort should be avoided, because these herbal supplements may decrease the AUC concentration of TPV/r.

TPV is an intestinal P-glycoprotein (P-gp) substrate, a weak P-gp inhibitor, and a potent P-gp inducer. When TPV is taken with ritonavir, data suggest that the combination is a P-gp inducer at steady state.

DOSAGE AND ADMINISTRATION

TPV is available as 250-mg capsules. The recommended dose is 500 mg (two 250-mg capsules) with twice daily to be taken with food. Bio-availability is increased with a high-fat meal; the high-fat meal enhances the extent of bioavailability but has minimal effect on TPV peak concentrations.

TPV should be stored in the refrigerator before the bottled is opened. After that, the capsules can be stored at room temperature for 60 days. Enteric-coated didanosine (Videx, Bristol-Myers Squibb Oncology) should be taken four hours before or after the administration of TPV.

Baseline liver function assays should be performed before patients take the TPV/r combination. Liver function test results should be monitored frequently throughout therapy, because TPV can increase the chance of hepatotoxicity.

TPV/r should be used with caution in patients with hepatic impairment, hepatitis B or C infection, and elevated trans-aminase levels, because increased TPV concentrations are likely. No dosage adjustment recommendations are available for patients with impaired liver function.

PREGNANCY CATEGORY

TPV is a Pregnancy Category C medication. It crosses the placenta, and it should be used during pregnancy only if the potential benefit justifies the risks to the fetus.

Its use in pediatric patients has not been established. Women are instructed not to breast-feed while taking this medication because of the chance of passing the virus to their newborn babies.

COST

The average wholesale price (AWP) of a month’s supply of TPV 500 mg/riton­avir 200 mg is $2,376. This total may vary, depending on the acquisition cost for each hospital. Similar ritonavir-boosted PIs have the following AWPs:

  • lopinavir/ritonavir (Kaletra, Abbott), $800
  • boosted fosamprenavir calcium (Lexiva, GlaxoSmithKline/Vertex) (60 tablets), $1,200
  • boosted atazanavir sulfate (Reyataz, Bristol-Myers Squibb), 200 mg (60 capsules), $1,300

CONCLUSION

HIV-1 resistance and virological failure continue to be a thorn in the side of the clinical HIV community. The large number of patients with highly resistant HIV has become a major concern as well. HIV clinicians are constantly searching for agents that will decrease the pill burden and improve medication adherence.

TPV is the first nonpeptide PI developed for the treatment of HIV-1 infection. This agent is able to enter infected immune cells and inhibit HIV replication for many strains of HIV that are resistant to other commercially available PIs. The drug’s unique structure and design allow for improved potency. Because of the widespread prevalence of drug-resistant HIV, the addition of this new PI should improve the chances of achieving 100% virological suppression.

Although tipranavir offers a potent alternative for HIV-resistant patients, the boxed warning cannot be ignored. The health care community must pay close attention to the side-effect profile of TPV.

Pharmacists can expect a high level of success with HAART therapy that includes the PIs. Success is defined as achieving a therapeutic goal of less than 50 copies per milliliter of HIV RNA in plasma after four to six months of HAART. Pharmacists play a major role in reducing the risk of HIV resistance. They should encourage patients to take medications correctly as prescribed and to become knowledgeable about their medications, and they must verify that patients are picking up refills consistently to achieve total adherence.

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