Basic Pharmacology - Assignment Example

EFALIZUMAB: Basic Pharmacology Common Trade s (See Complete Trade Listing) Raptiva C l a s s Immune Suppressant Dosage, Adult (usual) Plaque psoriasis, chronic (Moderate to Severe), For patients who are candidates for systemic or phototherapy: conditioning/loading dose, 0.7 mg/kg SC once; do not exceed 200 mg in a single dose Plaque psoriasis, chronic (Moderate to Severe), For patients who are candidates for systemic or phototherapy: maintenance, 1 mg/kg/week SC; safety and efficacy of therapy greater than 1 year has not been established; do not exceed 200 mg in a single dose Dosage, Pediatric, (usual) Safety and efficacy in pediatric patients has not been studied A d m i n i s t r a t i o n If appropriate, patients may self-inject efalizumab after proper training For subcutaneous administration, reconstitute efalizumab with 1.3 mL of non-USP sterile water for injection provided by the manufacturer; do not shake M o n i t o r i n g Complete blood counts with differential periodically; platelet counts should be performed monthly during initiation and then periodically (i.e. every three months) thereafter H o w   S u p p l i e d KIT: (Efalizumab, Water, Sterile) 125 MG Indications F D A   l a b e l e d   i n d i c a t i o n s Plaque psoriasis, chronic (Moderate to Severe), For patients who are candidates for systemic or phototherapy Contraindications Hypersensitivity to efalizumab or any of its components P r e c a u t i o n s Arthritis; recurrent or new onset arthritis events have been reported Combination therapy with phototherapy or other immunosuppressive agents; safety/efficacy has not been determined First dose reactions, dose-related; headache, fever, nausea, and vomiting have been reported Hemolytic anemia, immune-mediated; serious cases have been reported Immunizations, do not administer acellular, live, live-attenuated vaccines during therapy; immunosuppressive agents may decrease the vaccines immune response Malignancy, at risk for or history of; increased risk of malignancy Pre-existing infection, chronic or history of recurrent infections, do not administer to patients with clinically significant infections; increased risk of of serious infections Psoriasis, worsening/variants; erythrodermic psoriasis cases have been reported Thrombocytopenia, immune-mediated; severe cases have been reported Adverse Effects C O M M O N Dermatologic: Acne (4% ) Hematologic: Leukocytosis (26% ), Lymphocytosis (40% ) Musculoskeletal: Back pain Neurologic: Headache (32% ) Other: Influenza-like illness, Influenza-like symptoms (7% ) S E R I O U S Dermatologic: Cellulitis (rare ), Drug-exacerbated psoriasis, Worsening or Variants, Necrotizing fasciitis (rare ) Gastrointestinal: Infectious gastroenteritis Hematologic: Autoimmune hemolytic anemia, Bacterial septicemia (rare ), Immune thrombocytopenia (0.3% ) Immunologic: Bacterial septicemia (rare ), Hypersensitivity reaction (8% ), Infectious disease (29% ), Tuberculous pneumonia (rare ) Musculoskeletal: Arthritis, Osteomyelitis, Vertebral Neurologic: Aseptic meningitis Respiratory: Bronchitis, Interstitial pneumonia, Legionnaires disease, Tuberculous pneumonia (rare ) Other: Cancer Pregnancy Category Efalizumab: C Water, Sterile: Unknown Breast Feeding Efalizumab: Infant risk cannot be ruled out. Water, Sterile: Unknown (Thomson MICROMEDEX). EFALIZUMAB – Drug Development Leonardi (2003) has stated that the importance of T cell activation, T cell migration into the dermis, and T cell binding to keratinocytes has been demonstrated as key steps in the pathogenesis of psoriasis. Two adhesion molecules are thought to play important roles in this process: lymphocyte function-associated antigen -1 (LFA-1) and intercellular adhesion molecule – 1 (ICAM). LFA -1 expression is increased on memory T cells and ICAM-1 is expressed on vascular endothelial cells at the sites of inflammation as well as on keratinocytes in variety of T cell-mediated disorders. These observations provide the rationale for blocking LFA-1/ICAM-1 binding in the treatment of psoriasis. Efalizumab (Raptiva, and anti-CD11a) is a humanised form of a murine antibody directed against CD11a, the ά subunit of LFA-1. Multiple key pathogenic steps like T cell activation, cutaneous T cell trafficking, and T cell adhesion to keratinocytes are inhibited by efalizumab on binding to Cd11a as demonstrated by in vitro studies. These findings suggests that efalizumab exerts its clinical activity via several distinct mechanisms. Phase I/II Clinical Trials Phase I/II studies confirmed the biologic activity of efalizumab in patients with moderate to severe plaque psoriasis. These studies demonstrated that intravenous (IV) efalizumab administered as a single dose or as multiple weekly doses resulted in histologic and immunobiologic activities that contributed to its clinical activity. A randomized, double-blind, placebo-controlled, multicenter phase II trial, in which patients received IV efalizumab or placebo for 8 weeks demonstrated that efalizumab at doses of 0.3 mg/kg/wk resulted in histologic improvement as observed in earlier studies and confirmed the clinical response. Efalizumab-treated patients demonstrated a significantly greater decrease in the raw PASI score at day 56 compared with baseline than did patients who received placebo _(-7.1 vs -1.8,P 132.0 and body surface area (BSA) > 10%). An identical 12-week study design, including identical subject inclusion and exclusion criteria allowed pooling of the efficacy and safety data for 1095 patients. On day 84, 29.2% of patients who received efalizumab 1.0mg/kg/wk and 27.6% who received 2.0mg/kg/wk demonstrated > 75% improvement in PASI relative to baseline compared with 3.4% of placebo-treated patients. In addition, 55.6% of patients treated with efalizumab 1.0mg/kg/wk and 54.5% of those treated with 2.0 mg/kg/wk had > 50% PASUI improvement, compared with only 15.1% of patients who received placebo. Similar improvement was noted in Overall Lesion Severity (OLS) and Physician’s Global Assessment of Change (PGA) measures. The impact of efalizumab on patient reported outcomes, as measured by Dermatology Life Quality Index (DLQI), was also assessed. The DLQI questionnaire measures the extent to which psoriasis affects quality of life. The responses on the questions range from “Not at all” (0) to’Very much’ (3) with individual scores of 0 to 3, respectively, with an overall sum of 0 to 30. The improvement in DLQI paralleled the improvement in PASI, OLS, and PGA with a greater proportion of efalizumab-treated subjects demonstrating marked improvement at day 84. Analysis of the pooled adverse events confirmed the safety profile observed in earlier studies (Table 1). The most frequently reported adverse events included headache, non-specific infection (eg., common cold), nausea, chills, pain and fever. Given the chronic nature of psoriasis, a number of trials have been conducted to evaluate the effects of continuing efalizumab therapy beyond the initial 12-week treatment period. Preliminary results from these trials suggest that patients are likely to derive optimal therapeutic benefit from prolonged efalizumab treatment. Following the initial 12 weeks of treatment in trial ACD2059g, a second 12-week treatment period (extended treatment) was conducted to characterize the effects of continued efalizumab treatment at the same dose and frequency in patients who achieved a response (> 75% PASI improvement from baseline), or a partial response (>50% and 75% PASI improvement at 12 weeks, most were able to maintain their PASI improvement during extended treatment with weekly or every-other-week dosing. Among those who had > 50% and 75% PASI improvement in responders, weekly dosing during extended treatment resulted in a better response rate among partial responders than did every-other-week dosing. Efalizumab treatment was well tolerated during the second treatment period, and the types and frequency of adverse events were consistent with that observed during the first 12- week period except for the lack of acute adverse events. Efalizumab represents a significant advance in the management of plaque psoriasis, a chronic disease that is likely to require treatment over each individual patient’s life time. In addition to the favourable impact on the disease severity and patient reported outcomes, effalizumab has a rapid onset of clinical benefits. References Leonardi, C. L., (2003) Efalizumab: An Overview, J Am Acad Dermatol, 49, S98-104. MICROMEDEX(R) Healthcare Series Vol. 131.(1974 2007 Thomson MICROMEDEX).  Table I. Adverse events* during first 12 weeks: ACD2058g and ACD2059g Adverse event Placebo (%) [n=292] Efalizumab 1.0 mg/kg/wk, (%) [n=396] 2.0 mg/kg/wk, (%) [n=407] Headache 80(27.4%) 129(32.6) 151(37.1) Infection, NOS 42(14.4) 51(12.9) 59(14.5) Nausea 27(9.2) 48(12.1) 56(13.8) Chills 13(4.5) 58(14.6) 53(13.0) Pain 20(6.8) 56(14.1) 45(11.1) Fever 15(5.1) 39(9.8) 46(11.3) Asthenia 24(8.2) 34(8.6) 38(9.3) Diarrhea 23(7.9) 28(7.1) 30(7.4) Myalgia 13(4.5) 29(7.3) 32(7.9) Pharyngitis 20(6.8) 24(6.1) 31(7.6) Accidental injury 15(5.1) 28(7.1) 27(6.6) Rhinitis 22(7.5) 31(7.8) 17(4.2) Back pain 6(2.1) 20(5.1) 25(6.1) Arthalgia 10(3.4) 28(7.1) 14(3.4) Dizziness 14(4.8) 21(5.3) 17(4.2) Peripheral edema 10(3.4) 23(5.8) 17(4.2) Pruitus 16(5.5) 15(3.8) 18(4.4) Sinusitis 7(2.4) 22(5.6) 14(3.4) Herpes simplex 15(5.1) 18(4.5) 25(6.1) Psoriasis 6(2.1) 20(5.1) 13(3.2) Adverse events are in descending order of all subjects. *includes all events occurring in >5% of any one group. Multiple occurrences of an event within a body system are counted once in the overall incidence. NOS, not otherwise specified. Read More