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Prezista (darunavir)

Company: Tibotec
Approval Status: Approved June 2006
Treatment for: HIV Infections
Areas: Immune System

| General Information | Clinical Results | Side Effects | Mechanism of Action | Literature References | Additional Information |


General Information

Prezista (darunavir) is a HIV-1 protease inhibitor (PI). It is designed to disrupt formation of HIV viral particles in infected patients.

Prezista is specifically indicated for the treatment of HIV-1 infections in combination with ritonavir and other antiviral agents in treatment-experienced patients, including patients who have failed prior courses of treatment with other PIs.

Prezista is supplied as an orange, oval-shaped, film-coated tablet for oral administration. The recommended initial dosing regimen is 600 mg twice daily, in combination with 100 mg ritonavir twice daily, with food.


Clinical Results

FDA Approval
Trials TMC114-C213 and -C202
The accelerated approval of Prezista for the treatment of HIV-1 infections was based on 24-week data from a pair of ongoing, randomized phase IIb trials, dubbed TMC114-C213 and TMC114-C202, which were ongoing at the time of approval. Both trials investigated the efficacy of the drug in antiretroviral treatment-experienced HIV-1 infected adult subjects. In both studies, all subjects demonstrated at least 1 primary PI resistance mutation (D30N, M46I/L, G48V, I50L/V, V82A/F/S/T, I84V, L90M) at patient screening. Subjects in both studies received 600 mg Prezista plus 100 mg ritonavir twice daily plus an optimized background regimen (OBR), including at least 2 nucleoside reverse transcriptase inhibitors (NRTI) with or without enfurvirtide, or a control regimen consisting of an investigator-selected PI regimen plus OBR. The 24 week data set included 318 subjects in TMC114-C213 and 319 subjects in TMC114-C202 who had completed 24 weeks of treatment or discontinued earlier. Pooled data from the two studies indicated that 69.5% of subjects receiving the Prezista regimen achieved virologic response, as measured by a reduction of HIV-1 RNA of at least 1log10 from baseline at week 24, compared to a 21.0% reduction for the control regimen. Mean change from baseline was -1.89 log10 copies/mL for Prezista vs. -0.48 log10 copies/mL for control. In addition, 63% of subjects achieved HIV-1 RNA levels <400 copies/mL, and 45.0% achieved levels < 50 copies/mL at week 24, vs. 19% and 12.1% for control, respectively. 26.0% of subjects were failed to sufficiently respond to treatment on the Prezista regimen, vs. 71% for control. Increase from basline in mean CD4+ cell counts were greater for Prezista (92 cells/mm3) than control 17 cells/mm3).

Trials TMC114-C215 and -C208
Additional data supporting the approval of Prezista were ontained from a pair of non-randomized clinical trials, dubbed TMC114-C215 and TMC114-C208. These data included 24-week results from 246 subjects receiving the 600 mg Prezista/100 mg ritonavir twice daily regimen. These data indicated that 65% of subjects achieved a reduction in HIV-1 RNA of at least 1log10, 57% achieved levels <400 copies/mL, and 40% achieved levels <50 copies/mL, compared to baseline; mean reduction was 1.65log10 copies/mL. Mean CD4+ counts increased by 80 cells/mm3 from baseline at week 20.

Ongoing Study Commitments

  • Tibotec commits to submit the final study reports and datasets of the 96-week data for the ongoing Phase 2b studies TMC114-C202, TMC114-C213, TMC 114-C208, and TMC114-C215.
    Final Study Report: by December 31, 2007
  • Tibotec commits to submit the final study reports and datasets of the 48 week data for the ongoing Phase 3 studies TMC114-C211 and TMC114-C214.
    Final Study Report: by December 31, 2007
  • Deferred pediatric study under PREA for the treatment of HIV-1 infection in pediatric patients ages 6 to 17 years. Designed to assess the pharmacokinetics, safety, tolerability and antiviral activity of two alternative doses of a suitable pediatric formulation in combination with ritonavir, in treatment-experienced pediatric children and adolescents between 6 and 17 years of age.
    Protocol Submission: Completed
    Final Report Submission: 24 week data by June 30, 2008
  • Deferred pediatric study under PREA for the treatment of HIV-1 infection in pediatric patients less than 6 years of age. Designed to evaluate dose requirements and safety in pediatric patients less than 6 years of age with HIV-1 infection after preliminary review of data from the 6 to 17 year olds in trial TMC114-C212 with the Division of Antiviral Products (DAVP).
    Protocol Submission: by December 31, 2008
    Final Report Submission: by June 30, 2011
  • Tibotec commits to conduct an in vivo drug-drug interaction study between darunavir/rtv b.i.d. and rifabutin.
    Protocol Submission: by July 31, 2006
    Final Report Submission: by June 30, 2007
  • Tibotec commits to conduct an in vivo drug-drug interaction study between darunavir/rtv b.i.d. and buprenorphine/naloxone.
    Protocol Submission: by December 31, 2006
    Final Report Submission: by January 31, 2008
  • Tibotec commits to conduct an in vivo drug-drug interaction study between darunavir/rtv b.i.d. and carbamazepine.
    Protocol Submission: by December 31, 2006
    Final Report Submission: by January 31, 2008
  • Tibotec commits to complete the ongoing carcinogenicity study in mice and submit the final report.
    Protocol Submission: Completed
    Final Report Submission: by December 31, 2007
  • Tibotec commits to complete the ongoing carcinogenicity study in rats and submit the final report.
    Protocol Submission: Completed
    Final Report Submission: by December 31, 2007
  • Tibotec commits to conduct a cocktail study to determine the effects of steady state darunavir/rtv 600/100 mg b.i.d. on the metabolism of CYP450 probe substrates for the following enzymes: CYP2C9, CYP2C19, and CYP2D6.
    Protocol Submission: by December 31, 2006
    Final Report Submission: by January 31, 2008
  • Tibotec commits to evaluate the pharmacokinetics of darunavir/rtv in HIV-negative subjects with Child-Pugh A and Child-Pugh B liver disease in order to determine dosing recommendations.
    Protocol Submission: by July 31, 2006
    Final Report Submission: by March 31, 2007
  • Tibotec commits to conduct a study of darunavir in treatment-experienced female patients to elucidate any potential gender differences in efficacy and safety.
    Protocol Submission: by December 31, 2006
    Final Report Submission: 24 week data by December 31, 2008
  • Tibotec is asked to submit the results from their planned study TMC114-C127, a drug-drug interaction study between darunavir/rtv b.i.d. and methadone.
    Final Report Submission: Not Specified
  • In addition to the required periodic adverse drug experience reports [21 CFR 314.80(c)(2)], Tibotec is asked to submit a separate periodic adverse drug experience report for rash.
    Final Report Submission: Not Specified
  • Tibotec is asked to determine response rates based upon presence of specific cleavage site mutations at baseline and submit this analysis with the Prezista traditional approval application.
    Final Report Submission: Not Specified
  • Tibotec is asked to determine the protease cleavage site mutations that occur most frequently (>10%) in virologic failure isolates and submit this analysis with the Prezista traditional approval application.
    Final Report Submission: Not Specified
  • Tibotec is asked to determine if the most frequently occurring protease cleavage site mutations contributed to decreases in darunavir susceptibility through site-directed mutagenesis and submit this analysis with the Prezista traditional approval application.
    Final Report Submission: Not Specified

Side Effects

Adverse events associated with the use of Prezista may include, but are not limited to, the following:

  • Diarrhea
  • Nausea
  • Headache
  • Nasopharyngitis
  • Rash

Administration of Prezista has been associated with incidence of rare, severe, potentially life threatening skin reactions, including erythema multiforme and Stevens-Johnson Syndrome. Patients are advised to monitor their skin for signs of rash while taking Prezista, and treatment should be discontinued if severe rash develops.

In addition, certain laboratory abnormalities were associated with the use of Prezista (laboratory abmormalities are a common concern with PI administration). These included, but were not limited to, eleavations of levels of triglycerides, pancreatic amylase, aspartate aminotransferase, total cholesterol, gamma glutamyl transferase, pancreatic lipase, partial thromboplastin, and alanine aminotransferase, and decreases in white blood cell counts. The magnitude of these abnormalities were generally lower for Prezista than for comparator PI regimens, though not for all measures. Careful monitoring of laboratory values is recommended while on Prezista therapy.

Pharmacokinetic changes have been noted when Prezista is co-administered with other medications, including changes in absoption, total exposure, and elimination of one or both drugs. Some of these interactions may neccessitate adjustment of dose schedule and careful monitoring of tolerability. Affected medications include but are not limited to: the NNRTI HIV medication efavirenz; the PI HIV medications lopinavir and saquinavir; the anticoagulant warfarin; certain antidepressants, including SSRIs; certain antifungal agents; certain statin cholesterol medications; and the narcotic analgesic methadone. It is recommended patients consult their physicians to discuss any potential drug interations or dosing adjustments.

Risks of adverse reactions, some of which are potentially serious or life threatening, have been identified when co-administering Prezista with a number of medications. These include, but are not limited to: the antihistamines astemizole and terfenadine; ergot derivatives including dihydroergotamine, ergonovine, ergotamine, methylergonovine; the gastrointestinal motility agent cisapride; the neuroleptic pimozide; and the hypnotic sedatives midazolam and triazolam. The risks associated with these interactions should be thoroughly discussed with a medical professional, and use of alternative therapies should be considered, as appropriate.


Mechanism of Action

Prezista is an inhibitor of HIV-1 protease, designed to selectively inhibits the cleavage of HIV encoded Gag-Pol polyproteins in infected cells, thereby preventing the formation of mature virus particles.


Literature References

Kovalevsky AY, Tie Y, Liu F, Boross PI, Wang YF, Leshchenko S, Ghosh AK, Harrison RW, Weber IT Effectiveness of nonpeptide clinical inhibitor TMC-114 on HIV-1 protease with highly drug resistant mutations D30N, I50V, and L90M. Journal of Medicinal Chemistry 2006 Feb 23;49(4):1379-87

De Meyer S, Azijn H, Surleraux D, Jochmans D, Tahri A, Pauwels R, Wigerinck P, de Bethune MP TMC114, a novel human immunodeficiency virus type 1 protease inhibitor active against protease inhibitor-resistant viruses, including a broad range of clinical isolates. Antimicrobial Agents and Chemotherapy 2005 Jun;49(6):2314-21

Arasteh K, Clumeck N, Pozniak A, Lazzarin A, De Meyer S, Muller H, Peeters M, Rinehart A, Lefebvre E; TMC114-C207 Study Team TMC114/ritonavir substitution for protease inhibitor(s) in a non-suppressive antiretroviral regimen: a 14-day proof-of-principle trial. AIDS 2005 Jun 10;19(9):943-7

Surleraux DL, Tahri A, Verschueren WG, Pille GM, de Kock HA, Jonckers TH, Peeters A, De Meyer S, Azijn H, Pauwels R, de Bethune MP, King NM, Prabu-Jeyabalan M, Schiffer CA, Wigerinck PB Discovery and selection of TMC114, a next generation HIV-1 protease inhibitor. Journal of Medicinal Chemistry 2005 Mar 24;48(6):1813-22


Additional Information

For additional information regarding Prezista or HIV-1 infections, please visit the Prezista web page.




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Prezista Drug Information

The Prezista drug information shown above is licensed from Thomson CenterWatch. The information provided here is for general educational purposes only and does not constitute medical or pharmaceutical advice which should be sought from qualified medical and pharmaceutical advisers.





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