Optimize Dosing of Anti-TNF Biologics in Ulcerative Colitis
Optimize Dosing of Anti-TNF Biologics in Ulcerative Colitis
Background Acute severe ulcerative colitis (ASUC), the most aggressive presentation of ulcerative colitis (UC), occurs in 15% of adults and children with UC. First line therapy with intravenous corticosteroids is ineffective in half of adults and one-third of children. Therapeutic monoclonal antibodies against TNF (anti-TNF therapy) are emerging as a common treatment for ASUC due to their similar efficacy to calcineurin inhibitors and more favourable adverse effect profile.
Aim To comprehensively review the evidence for anti-TNF therapy for ASUC in children and adults with regard to outcomes and pharmacokinetics.
Methods PubMed and recent conference proceedings were searched using the terms 'ulcerative colitis', 'acute severe ulcerative colitis', 'anti-TNF', 'pharmacokinetics' and the generic names of specific anti-TNF agents.
Results Outcomes after anti-TNF therapy for ASUC remain suboptimal with about one half of children and adults undergoing colectomy. While several randomised controlled trials have demonstrated the efficacy of anti-TNF therapy for ambulatory patients with moderate to severely active UC, patients in these studies were less ill than those with ASUC. Patients with ASUC may exhibit more rapid clearance of anti-TNF biologics due to pharmacokinetic mechanisms influenced by disease severity.
Conclusions Conventional weight-based dosing effective in patients with moderately to severely active UC, may not be equally effective in those with acute severe ulcerative colitis. Personalised anti-TNF dosing strategies, which integrate patient factors and early measures of pharmacokinetics and response, hold promise for ensuring sustained drug exposure and maximising early mucosal healing in patients with acute severe ulcerative colitis.
Ulcerative colitis (UC) affects approximately 600 000 individuals in the USA, 20 000 of whom are children. UC is clearly a global disease, as its incidence is rising in nations around the world. Furthermore, as previously low-incident countries become more developed, the rate of inflammatory bowel disease (IBD) increases beginning with the emergence of increased UC cases. Across various cohorts, between 14% and 47% of adults with UC will develop pan-colitis and 12–15% will develop aggressive or severe disease requiring hospitalisation. In contrast, pan-colitis occurs in 80% of children with UC, a much higher frequency than in adults, with 15% exhibiting severe disease. Intravenous (IV) corticosteroids are first line treatment for acute severe UC (ASUC) requiring hospitalisation in children and adults. Approximately, one-third of children and one half of adults hospitalised for ASUC will prove refractory to IV corticosteroids. Therapeutic monoclonal antibodies against tumour necrosis factor (anti-TNF therapy) are emerging as the predominant treatment for ASUC refractory to IV corticosteroids; however, colectomy rates still remain high. Approximately, 30% of adults with ASUC undergo colectomy within 60 days of admission. In children with ASUC, 10% undergo colectomy prior to discharge, with a cumulative colectomy rate at 1 year of 20%. This review will focus on the evidence supporting the use of anti-TNF therapy for ASUC, limitations of previous large randomised clinical trials with regard to ASUC, and how understanding the pharmacokinetics (PK) and pharmacodynamics (PD) of anti-TNF biologics can lead to improvements in how we use this class of drugs to treat ASUC.
Abstract and Introduction
Abstract
Background Acute severe ulcerative colitis (ASUC), the most aggressive presentation of ulcerative colitis (UC), occurs in 15% of adults and children with UC. First line therapy with intravenous corticosteroids is ineffective in half of adults and one-third of children. Therapeutic monoclonal antibodies against TNF (anti-TNF therapy) are emerging as a common treatment for ASUC due to their similar efficacy to calcineurin inhibitors and more favourable adverse effect profile.
Aim To comprehensively review the evidence for anti-TNF therapy for ASUC in children and adults with regard to outcomes and pharmacokinetics.
Methods PubMed and recent conference proceedings were searched using the terms 'ulcerative colitis', 'acute severe ulcerative colitis', 'anti-TNF', 'pharmacokinetics' and the generic names of specific anti-TNF agents.
Results Outcomes after anti-TNF therapy for ASUC remain suboptimal with about one half of children and adults undergoing colectomy. While several randomised controlled trials have demonstrated the efficacy of anti-TNF therapy for ambulatory patients with moderate to severely active UC, patients in these studies were less ill than those with ASUC. Patients with ASUC may exhibit more rapid clearance of anti-TNF biologics due to pharmacokinetic mechanisms influenced by disease severity.
Conclusions Conventional weight-based dosing effective in patients with moderately to severely active UC, may not be equally effective in those with acute severe ulcerative colitis. Personalised anti-TNF dosing strategies, which integrate patient factors and early measures of pharmacokinetics and response, hold promise for ensuring sustained drug exposure and maximising early mucosal healing in patients with acute severe ulcerative colitis.
Introduction
Ulcerative colitis (UC) affects approximately 600 000 individuals in the USA, 20 000 of whom are children. UC is clearly a global disease, as its incidence is rising in nations around the world. Furthermore, as previously low-incident countries become more developed, the rate of inflammatory bowel disease (IBD) increases beginning with the emergence of increased UC cases. Across various cohorts, between 14% and 47% of adults with UC will develop pan-colitis and 12–15% will develop aggressive or severe disease requiring hospitalisation. In contrast, pan-colitis occurs in 80% of children with UC, a much higher frequency than in adults, with 15% exhibiting severe disease. Intravenous (IV) corticosteroids are first line treatment for acute severe UC (ASUC) requiring hospitalisation in children and adults. Approximately, one-third of children and one half of adults hospitalised for ASUC will prove refractory to IV corticosteroids. Therapeutic monoclonal antibodies against tumour necrosis factor (anti-TNF therapy) are emerging as the predominant treatment for ASUC refractory to IV corticosteroids; however, colectomy rates still remain high. Approximately, 30% of adults with ASUC undergo colectomy within 60 days of admission. In children with ASUC, 10% undergo colectomy prior to discharge, with a cumulative colectomy rate at 1 year of 20%. This review will focus on the evidence supporting the use of anti-TNF therapy for ASUC, limitations of previous large randomised clinical trials with regard to ASUC, and how understanding the pharmacokinetics (PK) and pharmacodynamics (PD) of anti-TNF biologics can lead to improvements in how we use this class of drugs to treat ASUC.
