Prezista (darunavir ethanolate)

Infection with the HIV virus has reached worldwide epidemic proportions. Around 40 million people currently suffer from AIDS, the mortality rate is 3 million each year and since the first reported case in the early 1980’s, an estimated 30 million have already died of it (Josephson et al, 2007). The urgency of developing treatments to cure or manage this disease cannot be overemphasized. Many drugs with different modes of action have since been developed, a recent one being Prezista – a protease inhibitor indicated for patients exhibiting resistance to other drugs of the same type (Josephson et al, 2007).

Prezista, submitted for review by Tibotec Inc. , was issued an accelerated approval by the FDA in 2006 based on the results of two controlled studies of 24-weeks duration ongoing at that time and then traditional approval in 2008 by virtue of a 48-week Phase III study in non-resistant patients and another 2 controlled trials that lasted 96 weeks involving resistant patients (Mary Ann Liebert Inc. , 2008).

Accelerated approval was given specifically for investigational new drugs which address life-threatening illnesses and are deemed as more effective than existing drugs. In the case of Prezista, initial approval was because of both its promising therapeutic effects and the absence of serious side effects directly correlated with use of the drug at the time of approval (EMEA, 2006).

Based on the 2006 approval, Prezista was allowed post marketing but required Tibotec to conduct pertinent studies including in vivo studies of interaction between this drug and rifabutin as well as carbamazepine, conduct studies on the effects of the drug on the activity of certain enzymes, conduct dose reformulation in patients below 6 years old to mediate noted toxic side effects among patients in this group and continue studies for carcinogenicity (Birnkrant, 2008). Studies conducted among females to rule out differences in responses to the drug based on gender and pediatric studies above 6 years old are still currently under FDA review.

Based on the communications between Tibotec and the FDA since submission of investigational new drug application, the former is regarded as a client of review and approval services provided by the FDA. Initial approval was given with less than a year of Phase II studies and drug to drug interaction as well as carcinogenicity in mice not even completed. After FDA approval and prior to 2008, Canada, Scotland and the European Union granted conditional approval to the drug pending further evidence of benefits compared to risks (Hosein, 2006). The accelerated approval failed to consider the toxicity of Prezista in utero.

It was only in 2008 during Phase III trials where toxic side effects were found to be significant among pregnant women and the unborn prompting the FDA to require Tibotec to conduct reproductive toxicity studies and to issue new safety information (Birnkrant, 2008). The development of liver and pancreas damage including drug-induced hepatitis, in some cases fatal, has been noted in previous clinical trials and also after FDA approval (Health Canada, 2008). However, the warning of hepatoxicity has been issued by Tibotec only in 2008, two years after approval and after Phase III trials have been conducted (Tennenburg, 2008).

With regard to clinical research protocol, Tibotec Inc. adhered to that prescribed by the FDA in terms of number of participants in clinical trials and the average time period for completion of the phases I to III of the clinical research process. Studies were conducted by Tibotec Inc. and the results were forwarded to the FDA for review in terms of the following areas: chemistry, pharmacology and toxicology, clinical pharmacology, microbiology, medical, statistics and environmental assessment (Gibbs & Kendall, 2006). Each area decided for or against approval based on the results of their review.

Overall, accelerated approval was based on the effectiveness of Prezista in decreasing viral count while increasing CD4+ cell count in the clinical studies (Gibbs & Kendall, 2006). Studies that are lacking and need to be conducted are forwarded to Tibotec Inc. including the deadline for submission. List of References Birnkrant, D. (2008). Department of Health and Human Services Letter to Susan Fiordeliso of Tibotec Inc. Retrieved 28 May 2009 from http://www. accessdata. fda. gov/drugsatfda_docs/appletter/2008/021976s006ltr. pdf. Busse, K. and Penzak, S. (2007).

“Darunavir: A Second-Generation Protease Inhibitor”. American Journal of Health-System Pharmacy 64(1). Retrieved 28 May 2009 from Academic Search Premier Database. EMEA (2006). Scientific Discussion. Retrieved 29 May 2009 from http://www. emea. europa. eu/humandocs/PDFs/EPAR/prezista/0770707en6. pdf. Gibbs, N. and Kendall, M. (2006). Center for Drug Evaluation and Research: Application No. 21-976. Retrieved 29 May 2009 from http://www. accessdata. fda. gov/drugsatfda_docs/nda/2006/021976s000_Sprycel_MedR. pdf. Health Canada (2008).

Association of Prezista (darunavir) with Hepatoxicity. Retrieved 29 May 2009 from http://www. hc-sc. gc. ca/dhp-mps/medeff/advisories-avis/prof/_2008/prezista_hpc-cps-eng. php. Hosein, S. R. (2006). New Protease Inhibitor – darunavir (Prezista) – Approved in Canada. Retrieved 28 May 2009 from http://www. catie. ca/catienews. nsf/c1213b02193fa85a85256f10006e9f7e/7ca418d794e8ff32852571ca005619fd! OpenDocument. Johnson and Johnson (2008). http://files. shareholder. com/downloads/JNJ/0x0x256161/6abf8b4e-4c92-4ec7-9004-529d54836c0d/JNJ_News_2008_12_3_Financial_Releases. pdf.

Josephson, F. , Albert, J. , Flamholc, L. Gisslen, M. , Karlstrom, O. , Lindgren, S. et. al. (2007). “Antiretroviral Treatment of HIV Infection: Swedish Recommendations 2007”. Scandinavian Journal of Infectious Diseases 39. Retrieved 28 May 2009 from Academic Search Premier Database. Mary Ann Liebert Inc. (2008). “Antiviral Briefs”. AIDS Patient Care and STD’s 22(12). Retrieved 28 May 2009 from Academic Search Premier Database. Tenenburg, A. (2008). Important Drug Warning. Retrieved 28 May 2009 from http://www. hivguidelines. org/admin/files/other/hot%20topics/DRV. pdf.

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