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PK of Once Daily Regimen: Fosamprenavir/r, Tenofovir and FTC in Naives
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.....plasma levels of all four drugs remained within previously described pharmacokinetic parameters, supporting the potential for this combination to be a useful once-daily regimen for the treatment of HIV infection....
This study data was reported in a poster at IAS-Rio by David Parks, Ed Acosta et al and below is Press Release from Vertex reporting summary of data. All drugs in the combination studied are FDA approved for once daily use, but the PK interaction, clinical tolerance, and virologic response of this combination has not been previously studied in treatment-naives. Subjects in this study received:
Fosamprenavir 1400 mg (2 x 700mg tablets) qd
FIXED DOSE: Tenofovir 300 mg tablet qd+FTC 200 mg tablet qd
RTV 200 mg (2 x 100 capsules) qd
TOTAL PILL COUNT: 5 pills
SUMMARY of study:
15 subjects
mean baseline HIV RNA: 129,000 c/ml (range: 1,940-578,000)
mean week 2 HIV RNA: 84,000 (range: 234-39,000)
mean week 4 HIV RNA: 929 c/ml (range: <50 to 3390)
--TDF, FTC, and RTV AUC24 and Cmin were very similar to historical controls (see package insert)
--FosAPV AUC24 was about 22% higher than historical controls (see package insert)
--TDF & FTC Tmax was slightlt prolonged with a slight decrease in Cmax
--overall there was no profound interaction between these drugs when compared with historical controls-see package insert
--the combination appeared well tolerated by patients through week 4
--subjects will be followed for 48 weeks-the most common grade 1 adverse events were diarrhea 4 (27%) and hyperlipidemia 3 (20%).
"Study Results Presented on Pharmacokinetics of Once-Daily HIV Combination Therapy
- Combination of Lexiva/r and Truvada Evaluated -"
Rio de Janeiro, Brazil - July 26, 2005 - An open label, single-arm study conducted among 15 HIV-positive patients evaluated the pharmacokinetic parameters of a once-daily combination of LEXIVA (fosamprenavir calcium), ritonavir and Truvada (tenofovir and emtricitabine) after four weeks of treatment. Results showed that plasma levels of all four drugs remained within previously described pharmacokinetic parameters, supporting the potential for this combination to be a useful once-daily regimen for the treatment of HIV infection. However, further study is necessary to determine conclusively the safety and efficacy of LEXIVA/ritonavir in combination with Truvada.
The study, which was supported by Vertex Pharmaceuticals Incorporated, was reported today in Rio de Janeiro, Brazil at the 3rd Annual International AIDS Society (IAS) Conference on HIV Pathogenesis and Treatment.
LEXIVA is an HIV protease inhibitor that was co-discovered by GlaxoSmithKline (GSK) and Vertex Pharmaceuticals Incorporated. It is the first PI to offer flexible dosing options (for PI-naïve patients) with no food or water restrictions.
LEXIVA is indicated in combination with other antiretroviral agents for the treatment of HIV infection in adults. The following points should be considered when initiating therapy with LEXIVA boosted with ritonavir (LEXIVA/r) in PI-experienced patients: the PI-experienced patient study was not large enough to reach a definitive conclusion that LEXIVA/r and lopinavir/ritonavir are clinically equivalent. Once-daily administration of LEXIVA plus ritonavir is not recommended for PI-experienced patients.
The study examined subjects who took a combination of 1400 mg LEXIVA, 200 mg ritonavir and a fixed-dose of 300/200 mg tenofovir/emtricitabine for four weeks. Mean baseline HIV RNA and CD4 cell counts were 129,777 (1,940-578,000) copies/mL and 357 (156-476) cells/mm3. Median LEXIVA Cmax, Cmin, t1/2 and AUC24 were 8.3 mg/L, 1.7 mg/L, 10.7 hr and 84.3 mg h/L, respectively. These parameters for tenofovir were 0.2 mg/L, 0.05 mg/L, 11.9 hr and 2.4 mg h/L, respectively. Mean (range) HIV RNA after the first four weeks of therapy was 929 (<50-3390) copies/mL.
"The identification of potent, well tolerated HIV combination regimens is an important step forward in the improved management of HIV infection," said David A. Parks, Medical Director, Central West Healthcare, Inc. who conducted the study with Edward P. Acosta, Pharm.D., Assistant Professor of the Department of Pharmacology and Toxicology at the University of Alabama at Birmingham. "These study results are encouraging in that they support the potential for these products to be used together in a regimen."
Important Safety Information about LEXIVA
HIV medicines do not cure HIV infection/AIDS or prevent passing HIV to others.
LEXIVA is contraindicated in patients with previously demonstrated clinically significant hypersensitivity to any of the components of this product or to amprenavir. Hyperglycemia, new onset or exacerbations of diabetes mellitus, and spontaneous bleeding in hemophiliacs have been reported with protease inhibitors.
Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and "cushingoid appearance" have been observed in patients receiving antiretroviral therapy. The causal relationship, mechanism, and long-term consequences of these events are currently unknown.
LEXIVA should be used with caution in patients with a known sulfonamide allergy.
Severe or life-threatening skin reactions were reported in less than 1 percent of 700 patients treated with LEXIVA in clinical studies, including one case of Stevens-Johnson syndrome.
Skin rashes (all grades, without regard to causality) occurred in approximately 19 percent of patients treated with LEXIVA in the pivotal efficacy studies. This led to the discontinuation of LEXIVA in less than 1 percent of patients.
During the initial phase of treatment, patients responding to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections.
LEXIVA is contraindicated with ergot derivatives, cisapride, pimozide, midazolam, and triazolam. If LEXIVA is coadministered with ritonavir, flecainide and propafenone are also contraindicated. Caution should be used when coadministering medications that are substrates, inhibitors, or inducers of CYP3A4, or potentially toxic medications that are metabolized by CYP3A4. Serious and/or life-threatening drug interactions could occur between LEXIVA and amiodarone, lidocaine (systemic), tricyclic antidepressants, and quinidine. Concentration monitoring of these agents is recommended if these agents are used concomitantly with LEXIVA. LEXIVA should not be coadministered with rifampin, St. John's wort, lovastatin, simvastatin, or delavirdine. Particular caution should be used when prescribing phosphodiesterase (PDE-5) inhibitors for erectile dysfunction (eg, sildenafil or vardenafil) in patients receiving LEXIVA. This list of potential drug interactions is not complete.
Treatment with LEXIVA/r has resulted in increases in the concentration of triglycerides. Triglyceride and cholesterol testing should be performed prior to initiating therapy with LEXIVA and at periodic intervals during therapy. The most common adverse events seen in clinical trials with LEXIVA were diarrhea, nausea, vomiting, headache and rash.
About Vertex
Vertex Pharmaceuticals Incorporated is a global biotechnology company committed to the discovery and development of breakthrough small molecule drugs for serious diseases. The Company's strategy is to commercialize its products both independently and in collaboration with major pharmaceutical companies. Vertex's product pipeline is principally focused on viral diseases, inflammation, autoimmune diseases and cancer. Vertex co-promotes the HIV protease inhibitor, Lexiva®, with GlaxoSmithKline.
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