Combination Therapy With Immunomodulators Improves the Pharmacokinetics of Infliximab But Not Vedolizumab or Ustekinumab

• Published in: Clinical gastroenterology and hepatology Vol. 21; no. 11; pp. 2908 - 2917.e10
• Main Authors: Yarur, Andres J., McGovern, Dermot, Abreu, Maria T., Cheifetz, Adam, Papamichail, Konstantinos, Deepak, Parakkal, Bruss, Alexandra, Beniwal-Patel, Poonam, Dubinsky, Marla, Targan, Stephan R., Melmed, Gil Y.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.10.2023
• Subjects: 6-Thioguanine Nucleotide; Azathioprine; Infliximab; Mercaptopurine; Methotrexate; Therapeutic Drug Monitoring, Remission; Ustekinumab; Vedolizumab; CRP; CD; SFDR; Ustekinumab; 6-TGN; IBD; IQR; TNF; UC; 6-Thioguanine Nucleotide; RBC; Infliximab; Vedolizumab; Azathioprine; Methotrexate; Therapeutic Drug Monitoring, Remission; TDM; ADA; Mercaptopurine
• ISSN: 1542-3565; 1542-7714
• DOI: 10.1016/j.cgh.2022.10.016

The aim of this study was to assess how 6-thioguanine nucleotide (6-TGN) levels and use of oral methotrexate relate to the pharmacokinetics of biologics. This was a prospective cohort study including patients with inflammatory bowel diseases on maintenance doses of infliximab, vedolizumab, or ustekinumab on monotherapy or combination with a thiopurine or oral methotrexate. We collected 6-TGN concentrations, biomarker levels, and clinical and endoscopic disease activity. The primary outcomes were infliximab, vedolizumab, and ustekinumab concentrations as well as anti-drug antibodies (ADAs). A total of 369 patients were recruited (113 infliximab, 133 vedolizumab, and 123 ustekinumab). Patients with 6-TGN levels ≥146 pmol per 8 × 108 red blood cells (RBCs), and those receiving combination therapy with thiopurine or oral methotrexate had significantly higher infliximab concentrations when compared with monotherapy (median levels of 17.4 μg/mL on thiopurine with 6-TGN ≥146 pmol per 8 × 108 RBCs, 17.1 on methotrexate, and 3.9 on infliximab monotherapy; P = .001 for both comparisons). However, there was no association between the use of immunomodulators and 6-TGN concentrations with vedolizumab (median levels of 8.8 on thiopurine with 6-TGN ≥152 pmol per 8 × 108 RBCs, 6.8 on methotrexate, and 10.5 on vedolizumab monotherapy; P > .05 for both comparisons) or ustekinumab median concentrations (median levels of 5.0 on thiopurine with 6-TGN ≥154 pmol per 8 × 108 RBCs, 5.2 on methotrexate and 7.0 on ustekinumab monotherapy; P > .05 for both comparisons). Fourteen (12%) patients had anti-infliximab antibodies, while 1 patient had ADAs in each of the other drug cohorts. Achieving higher 6-TGN levels or the use of methotrexate improved the pharmacokinetics of infliximab. Conversely, these data do not support the use of combination therapy to augment pharmacokinetics with vedolizumab or ustekinumab. ▪