Effect of tildrakizumab (MK‐3222), a high affinity, selective anti‐IL23p19 monoclonal antibody, on cytochrome P450 metabolism in subjects with moderate to severe psoriasis

• Published in: British journal of clinical pharmacology Vol. 84; no. 10; pp. 2292 - 2302
• Main Authors: Khalilieh, Sauzanne, Hussain, Azher, Montgomery, Diana, Levine, Vanessa, Shaw, Peter M., Bodrug, Inga, Mekokishvili, Lally, Bailey‐Smith, Candice, Glasgow, Xiaoli S., Cheng, Amy, Martinho, Monika, Iwamoto, Marian
• Format: Journal Article
• Language: English
• Published: England John Wiley and Sons Inc 01.10.2018
• Subjects: Administration, Oral; Adult; Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal - pharmacokinetics; Antibodies, Monoclonal - therapeutic use; Antibodies, Monoclonal, Humanized; Caffeine - administration & dosage; Caffeine - pharmacokinetics; Cytochrome P-450 Enzyme System - metabolism; cytochrome P450; Dextromethorphan - administration & dosage; Dextromethorphan - pharmacokinetics; disease–drug interaction; Drug Interactions; Female; high‐affinity humanized IgG1k antibody; Humans; Injections, Subcutaneous; Interleukin-23 Subunit p19 - antagonists & inhibitors; Interleukin-23 Subunit p19 - immunology; interleukin‐23; Male; Midazolam - administration & dosage; Midazolam - pharmacokinetics; Middle Aged; Omeprazole - administration & dosage; Omeprazole - pharmacokinetics; Original; psoriasis; Psoriasis - diagnosis; Psoriasis - drug therapy; Psoriasis - immunology; Psoriasis - metabolism; Severity of Illness Index; tildrakizumab; Treatment Outcome; Warfarin - administration & dosage; Warfarin - pharmacokinetics; Young Adult; high-affinity humanized IgG1k antibody; tildrakizumab; disease-drug interaction; cytochrome P450; psoriasis; interleukin-23
• ISSN: 0306-5251; 1365-2125; 1365-2125
• DOI: 10.1111/bcp.13670

Aims Tildrakizumab, an interleukin (IL)‐23 inhibitor, is indicated for the treatment of moderate to severe chronic plaque psoriasis. Although tildrakizumab is not metabolized by, and does not alter, cytochrome P450 (CYP) expression in vitro, clinically significant pharmacokinetic effects through changes in systemic inflammation, which alters CYP metabolism, have been well documented. At the time of study conduct, the effect of modulation of inflammation/cytokines, including IL‐23 inhibition with tildrakizumab, on CYP metabolism, and therefore the potential for disease–drug interactions, in psoriasis patients was unknown. We therefore assessed whether tildrakizumab alters CYP metabolism in subjects with moderate to severe psoriasis. Methods This was an open‐label, fixed‐sequence, two‐period trial. In Period 1 (Day 1), subjects received an oral CYP probe cocktail of up to five drugs (midazolam 2 mg [3A4], caffeine 200 mg [1A2], warfarin 10 mg [2C9], omeprazole 40 mg [2C19] and dextromethorphan 30 mg [2D6]), followed by a 7‐day washout. In Period 2, subjects received tildrakizumab 200 mg subcutaneously on Days 1 and 29 and a second CYP probe cocktail on Day 57. Substrate or metabolite pharmacokinetics, safety and changes in Psoriasis Severity Area Index (PASI), interleukin‐6 (IL‐6) and high‐sensitivity C‐reactive protein (hs‐CRP), were assessed. Results Twenty subjects (13 men, 7 women) were enrolled. Tildrakizumab had no clinically relevant effect on the pharmacokinetics of any of the probe substrates tested. On Day 57 of Period 2, the median percentage decrease from baseline in PASI score following tildrakizumab was ~93%. There were no clinically relevant changes in IL‐6 or hs‐CRP. Treatment with tildrakizumab was generally well tolerated. Conclusion In subjects with moderate to severe psoriasis, tildrakizumab 200 mg did not have a discernible effect on CYP metabolism. The potential for clinically significant drug–drug interactions (DDIs) with tildrakizumab in patients with psoriasis is low. The difference in the occurrence of DDIs seen with anti‐inflammatory agents in rheumatoid arthritis patients compared with psoriasis patients may be due to the much greater extent of systemic inflammation in rheumatoid arthritis as compared to psoriasis.