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

Background: The amprenavir (APV) early or expanded access program was desig ned to provide open-label APV to patients who would potentially receive ben efit beyond that expected from currently available protease inhibitors (PIs ) and who were at risk of disease progression before the drug's expected ti me of regulatory approval. Objective: This study was conducted as part of an early access program to a ssess the safety profile and tolerability of APV in adults and children (gr eater than or equal to4 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 lo ad limits were not imposed by this early access protocol. Methods: This open-label, nonrandomized study was conducted at multiple sit es 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 fo r 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 du ration of 85 days (range, 2-218 days). Patients in the intent-to-treat popu lation (n = 1427) had extensive experience with antiretroviral therapy. Dru g-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 a bnormalities were graded for severity on a scale of 1 to 4 in accordance wi th AIDS Clinical Trials Group guidelines. Grade 3 treatment-emergent abnorm al laboratory values regardless of causality occurring in >3% of patients w ere neutropenia in 69 of 1887 patients (3.7%; grade 3 toxicity = 500-749/mm (3)) and elevated triglycerides in 80 of 1593 patients (5.0%: grade 3 toxic ity = 751-1200 mg/dL). Most common grade 4 treatment-emergent laboratory ab normalitieswere elevated serum creatine phosphokinase levels in 36 of 1266 patients (2.8%; grade 4 = >6 times upper normal limit), elevated triglyceri des 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-experien ced, heterogeneous patient population.