Clinical Pharmacokinetic and Pharmacodynamic Considerations in the Treatment of Ulcerative Colitis

Sophie E Berends, Anne S Strik, Mark Löwenberg, Geert R D'Haens, Ron A A Mathôt, Sophie E Berends, Anne S Strik, Mark Löwenberg, Geert R D'Haens, Ron A A Mathôt

Abstract

Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) of unknown etiology, probably caused by a combination of genetic and environmental factors. The treatment of patients with active UC depends on the severity, localization and history of IBD medication. According to the classic step-up approach, treatment with 5-aminosalicylic acid compounds is the first step in the treatment of mild to moderately active UC. Corticosteroids, such as prednisolone are used in UC patients with moderate to severe disease activity, but only for remission induction therapy because of side effects associated with long-term use. Thiopurines are the next step in the treatment of active UC but monotherapy during induction therapy in UC patients is not preferred because of their slow onset. Therapeutic drug monitoring (TDM) of the pharmacologically active metabolites of thiopurines, 6-thioguanine nucleotide (6-TGN), has proven to be beneficial. Thiopurine S-methyltransferase (TMPT) plays a role in the metabolic conversion pathway of thiopurines and exhibits genetic polymorphism; however, the clinical benefit and relevance of TPMT genotyping is not well established. In patients with severely active UC refractory to corticosteroids, calcineurin inhibitors such as ciclosporin A (CsA) and tacrolimus are potential therapeutic options. These agents usually have a rather rapid onset of action. Monoclonal antibodies (anti-tumor necrosis factor [TNF] agents, vedolizumab) are the last pharmacotherapeutic option for UC patients before surgery becomes inevitable. Body weight, albumin status and antidrug antibodies contribute to the variability in the pharmacokinetics of anti-TNF agents. Additionally, the use of concomitant immunomodulators (thiopurines/methotrexate) lowers the rate of immunogenicity, and therefore the concomitant use of anti-TNF therapy with an immunomodulator may confer some advantage compared with monotherapy in certain patients. TDM of anti-TNF agents could be beneficial in patients with primary nonresponse and secondary loss of response. The potential benefit of applying TDM during vedolizumab treatment has yet to be determined.

Conflict of interest statement

Sophie Berends has received lecture fees from Merck Sharp & Dohme, Johnson & Johnson and Tillotts. Anne Strik has received lecture fees from Biogen, Johnson and Johnson, Merck Sharp & Dohme, Mundipharma, Takeda, and Tillotts. Mark Löwenberg has received speaker fees from Abbvie, Covidien, Dr. Falk Pharma, Ferring Pharmaceuticals, Merck Sharp & Dohme, Receptos, Takeda, Tillotts and Tramedico, and has also received research grants from AbbVie, Merck Sharp & Dohme, Achmea Healthcare and ZonMW. Geert D’Haens has served as an advisor for Abbvie, Ablynx, Amakem, AM Pharma, Avax- ia, Biogen, Bristol-Myers Squibb, Boerhinger Ingelheim, Celgene, Celltrion, Cosmo, Covidien, Ferring, Dr. Falk Pharma, Engene, Galapagos, Gilead, GlaxoSmithKline, Hospira, Immunic, Johnson and Johnson, Lycera, Medimetrics, Millenium/Takeda, Mitsubishi Pharma, Merck Sharp & Dohme, Mundipharma, Novonordisk, Pfizer, Prometheus Laboratories/Nestle, Protagonist, Receptos, Robarts Clinical Trials, Salix, Sandoz, Setpoint, Shire, Teva, Tigenix, Tillotts, Topivert, Versant and Vifor, and has also received speaker fees from Abbvie, Ferring, Johnson and Johnson, Merck Sharp & Dohme, Mundipharma, Norgine, Pfizer, Shire, Millenium/Takeda, Tillotts and Vifor. Ron Mathôt has no conflicts of interest to declare.

Figures

Fig. 1
Fig. 1
Classical step-up approach for ulcerative colitis
Fig. 2
Fig. 2
Thiopurine metabolism. 6-TG thioguanine, 6-TGN 6-thioguanine nucleotide, 6-MMP 6-methylmercaptopurine, 6-MP 6-mercaptopurine, 6-TIMP 6-thioinosine monophosphate, 6-TUA 6-thiouric acid, GST glutathione S-transferase, HPRT hypoxanthine–guanine phosphoribosyltransferase, IMPDH inosine 5-monophosphate dehydrogenase, TPMT thiopurine S-methyltransferase, XO xanthine oxidase
Fig. 3
Fig. 3
Therapeutic drug monitoring strategy for thiopurines. 6-TGN 6-thioguanine nucleotide, 6-MMP 6-methylmercaptopurine
Fig. 4
Fig. 4
FcRn recycling mechanism. IgG immunoglobulin G, FcRn neonatal Fc receptor

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Source: PubMed

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