Therapeutic drug monitoring in patients with inflammatory bowel disease

Abstract

Thiopurine analogs and anti-tumor necrosis factor (TNF) agents have dramatically changed the therapeutics of inflammatory bowel diseases (IBD), improving short and long-term outcomes. Unfortunately some patients do not respond to therapy and others lose response over time. The pharmacokinetic properties of these drugs are complex, with high inter-patient variability. Thiopurine analogs are metabolized through a series of pathways, which vary according to the patients' pharmacogenetic profile. This profile largely determines the ratios of metabolites, which are in turn associated with likelihoods of clinical efficacy and/or toxicity. Understanding these mechanisms allows for manipulation of drug dose, aiming to reduce the development of toxicity while improving the efficacy of treatment. The efficacy of anti-TNF drugs is influenced by many pharmacodynamic variables. Several factors may alter drug clearance, including the concomitant use of immunomodulators (thiopurine analogs and methotrexate), systemic inflammation, the presence of anti-drug antibodies, and body mass. The treatment of IBD has evolved with the understanding of the pharmacologic profiles of immunomodulating and TNF-inhibiting medications, with good evidence for improvement in patient outcomes observed when measuring metabolic pathway indices. The role of routine measurement of metabolite/drug levels and antibodies warrants further prospective studies as we enter the era of personalized IBD care.

Keywords: Adalimumab; Anti-tumor necrosis factor; Antibodies; Azathioprine; Drug level; Drug monitoring; Inflammatory bowel disease; Infliximab; Thioguanine; Thiopurines.

Figure 1

Metabolic pathway of azathioprine/mercaptopurine metabolism. AZA: Azathioprine; MP: Mercaptopurine; TPMT: Thiopurine methyltransferase; XO: Xanthine oxidase; IMPDH: Inosine-5-monophosphate dehydrogenase; GMPS: Guanidine- 5-monophosphate synthetase; 6-TA: 6-Thiouric acid; 6-MMP: 6-Methyl- mercaptopurine; 6-TIMP, 6-Thioinosine monophosphate; 6-MeTIMP: 6-Methylthioinosine monophosphate; 6-MeTITP: 6-Methyl thioinosine triphosphate pyrophosphate; 6-TITP: 6-Thioinosine triphos- phate pyrophosphate; TXMP: Thioxanthosine monophosphate; 6-TGN: 6-Thioguanine nucleotides; 6-TGMP: 6-Thioguanine monophosphate; 6-TGDP: 6-Thioguanine diphosphate; 6-TGTP: 6-Thioguanine triphosphate.

Figure 2

Algorithm with recommendation on how to manage patients that fail therapy with Azathioprine/Mercaptopurine. AZA: Azathioprine; MP: Mercaptopurine; 6-TGN: 6-Thioguanine nucleotides; 6-MMP: 6-Methyl-mercaptopurine.

Figure 3

Variables associated with Anti-tumor necrosis factor levels. TNF: Tumor necrosis factor.

Figure 4

Approaches to patients on infliximab in the setting of lose of response. ATI: Anti-infliximab antibody; IFX: Infliximab; TNF: Tumor necrosis factor.