Safety profile and tolerability of amprenavir in patients enrolled in an early access program

BACKGROUND: The amprenavir (APV) early or expanded access program was designed to provide open-label APV to patients who would potentially receive benefit beyond that expected from currently available protease inhibitors (PIs) and who were at risk of disease progression before the drug's expected time of regulatory approval. OBJECTIVE: This study was conducted as part of an early access program to assess the safety profile and tolerability of APV in adults and children (> or =4 years of age) who were either intolerant to or, in the opinion of the patient's physician, virologically failing a previous PI-containing antiretroviral regimen. Specific CD4+ cell count and viral load limits were not imposed by this early access protocol. METHODS: This open-label, nonrandomized study was conducted at multiple sites throughout the United States. Adults received APV at a dosage of 1200 mg BID. Patients weighing <50 kg received APV at a dosage of 20 mg/kg BID for the solid formulation or 1.5 mL/kg BID for the liquid formulation. RESULTS: A total of 489 physicians registered for this program; 364 (74.4%) enrolled patients. The safety population of 2217 patients (2048 males [92.4%] and 169 females [7.6%] aged 2 to 74 years) received APV for a median duration of 85 days (range, 2-218 days). Patients in the intent-to-treat population (n = 1427) had extensive experience with antiretroviral therapy. Drug-related treatment-emergent adverse events reported in >3% of patients in the safety population were nausea in 279 patients (12.6%), diarrhea in 197 patients (8.9%), rash in 177 patients (8.0%), vomiting in 148 patients (6.7%), and fatigue in 89 patients (4.0%). Adverse events and laboratory test abnormalities were graded for severity on a scale of 1 to 4 in accordance with AIDS Clinical Trials Group guidelines. Grade 3 treatment-emergent abnormal laboratory values regardless of causality occurring in >3% of patients were neutropenia in 69 of 1887 patients (3.7%; grade 3 toxicity = 500-749/mm3) and elevated triglycerides in 80 of 1593 patients (5.0%; grade 3 toxicity = 751-1200 mg/dL). Most common grade 4 treatment-emergent laboratory abnormalities were elevated serum creatine phosphokinase levels in 36 of 1266 patients (2.8%; grade 4 = >6 times upper normal limit), elevated triglycerides in 39 of 1593 patients (2.4%), and neutropenia in 41 of 1887 patients (2.2%). CONCLUSIONS: The results of this large cohort of patients support the data from the phase II/III clinical development program and suggest that APV has an acceptable safety profile and is generally well tolerated when used in combination with other antiretroviral drugs in a heavily treatment-experienced, heterogeneous patient population.     

T cell-based therapies for EBV-associated malignancies

Epstein-Barr virus (EBV) is associated with a number of human malignancies. The cells of these tumours express a range of EBV latent cycle gene products that have the potential to be exploited as targets for T cell-mediated immunological therapies. Considerable progress has been made in developing adoptive T cell transfer for EBV-associated post-transplant lymphoproliferative disease (PTLD) and clinical experience clearly demonstrates that EBV-specific T cell responses can be used to treat this EBV-associated malignancy. Adoptive T cell therapies for other EBV-associated malignancies are less advanced, although encouraging data are starting to emerge. Adoptive T cell transfer, however, does require significant levels of specialist laboratory support. Large-scale treatment of patients in geographical areas with a high prevalence of EBV-associated malignancy is likely to require the development of therapeutic vaccination strategies, a number of which are in development at present. Although it remains to be seen whether long-lasting sterilising immunity to EBV could be achieved, an alternative vaccine-based approach would be to develop a prophylactic vaccine to protect against primary EBV infection.     

Noninvasive chemical methods of estimating pharmacokinetic parameters

Two noninvasive methods have been advocated for pharmacokinetic and bioavailability studies. The measurement of the salivary and urinary excretion of drugs and their metabolites may avoid sampling blood, particularly in introductory studies. The measurement of the salivary concentrations of drugs is of most value in studies on compounds which are little ionized at physiological pH values. Well studied examples where there is a good parallelism between salivary and plasma drug concentrations include the neutral drug, ethanol, the weakly acidic drugs, phenytoin and sulphapyridine, and the weakly basic drugs, carbamazepine and antipyrine. Data on the salivary secretion of more strongly acidic or basic drugs are often conflicting and further work is required to determine the usefulness of measuring the salivary secretion of such drugs in pharmacokinetic and biopharmaceutical studies. Studies on the rate of excretion or cumulative excretion of drugs and their metabolites in urine may provide good estimates of the terminal half lives of drugs. However, accurate determinations of the kinetic parameters of rapid processes are not obtainable from studies on urinary excretion. Reliable data can only be obtained if the timing of urine collections is precise and if there are no significant losses of urine.