PK, PD, and interactions: the new scenario with JAK inhibitors and S1P receptor modulators, two classes of small molecule drugs, in IBD

ABSTRACT

Introduction

Inflammatory bowel diseases (IBDs) are immune-mediated chronic inflammatory disorders of the gastrointestinal tract whose pathogenesis is not yet fully understood. Despite the advent of biological agents, there are still unmet needs for IBD patients, due to suboptimal rate of sustained remission achieved. Small molecule drugs (SMDs), the next generation of selective drugs in IBD, show promising results in ongoing trials.

Areas covered

We describe the pharmacodynamics and pharmacokinetic features of novel SMDs and their main differences with biologic agents.

Expert opinion

Small molecule drugs are a promising class of drugs for the treatment of ulcerative colitis and Crohn’s disease with good results in inducing and maintaining remission. Hence, over the next few years physicians will have numerous options of small molecule drugs for the treatment of patients with IBD. This group of drugs are potentially easier to use over biological agents due to pharmacokinetic features such as oral administration, short half-life, high volume of distribution, and lack of immunogenicity. On the other hand, drug–drug interactions can happen with small-molecule drugs, principally due to competitive metabolic and clearance mechanisms.

KEYWORDS:

• Cytochrome P450s
• drug–drug interactions
• Janus Kinase inhibitors
• Small Molecule Drugs
• Sphingosine-1-Phosphate Receptor Modulators
• pharmacokinetics
• pharmacodynamics
• inflammatory bowel disease

Article highlights

• Small molecule drugs represent the next generation of selective drugs, which have the capacity to interfere with crucial intracellular signaling pathways in ulcerative colitis and Crohn’s disease pathogenesis.

• Due to the low molecular weight of small molecule drugs, they are administered orally with a rapid absorption and a good bioavailability. The oral route of administration can also improve patients’ satisfaction.

• Other features of small-molecule drugs include the lack of immunogenicity and a short half-life, allowing a rapid interruption when needed (e.g. adverse events, pregnancy).

• Small molecule drugs are metabolized in the liver and the gut mainly by cytochrome P450s. Many other drugs are metabolized by cytochrome P450s so that it is important to be aware of potential drug–drug interactions with small molecule drugs, which could result in toxicity or failure of the therapy.

• An increased exposure to small molecule drugs could happen in patients with hepatic or renal impairment; in these situations, small molecule drugs should be used carefully.

Declaration of interest

D Gilardi received consulting fees from Nikkiso GMBH, Sofar Spa, Biofer Spa, Roche, Pfizer, and lecture fees from J&J, Pfizer, and Takeda. M Allocca received consulting fees from Nikkiso Europe and lecture fees from Janssen, Abbvie, and Pfizer. G Fiorino as a consultant and a member of Advisory Boards for MSD, Takeda Pharmaceuticals, AbbVie, Pfizer, Celltrion, Amgen, Sandoz, Samsung, and Janssen Pharmaceuticals. F Furfaro received consulting fees from Amgen, Abbvie, and lecture fees from Janssen and Pfizer. L Peyrin-Biroulet reports personal fees from AbbVie, Janssen, Genentech, Ferring, Tillots, Pharmacosmos, Celltrion, Takeda, Boerhinger Ingelheim, Pfizer, Index Pharmaceuticals, Sandoz, Celgene, Biogen, Samsung Bioepis, Alma, Sterna, Nestle, Enterome, Allergan, MSD, Roche, Arena, Gilead, Hikma, Amgen, BMS, Vifor, Norgine; Mylan, Lilly, Fresenius Kabi, Oppilan Pharma, Sublimity Therapeutics, Applied Molecular Transport, OSE Immunotherapeutics, Enthera, Theravance; grants from Abbvie, MSD, Takeda; stock options: CTMA. S Danese reports personal fees from Abbvie, Ferring, Hospira, Johnson & Johnson, Merck, Millennium Takeda, Mundipharma, Pfizer, Tigenix, UCB Pharma, and Vifor.

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed in the Author Disclosure Form.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.