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P460 Early use of therapeutic drug monitoring to individualize infliximab therapy in paediatric IBD: a multicentre prospective COHORT study

Crowley E.*1, Carman N.1, Arpino V.1, Frost K.1, Ricciuto A.1, Sherlock M.2, Critch J.3, Mack D.4, Benchimol E.5, Jacobson K.6, Lawrence S.6, deBruyn J.7, El-Matary W.8, Otley A.9, Huynh H.10, Church P.1, Walters T.1, Griffiths A.1

1Hospital for Sick Children, Division of Gastroenterology, Hepatology and Nutrition, Department of Paediatrics, Toronto, Canada 2McMaster Children's Hospital, Hamilton Health Sciences, Division of Gastroenterology & Nutrition, Hamilton, Canada 3Memorial University of Newfoundland, Division of Gastroenterology, Janeway Children's Health and Rehabilitation Centre, St. John's, Canada 4Children's Hospital of Eastern Ontario IBD Centre, University of Ottawa, Department of Pediatrics, Ottawa, Canada 5University of Ottawa, Children's Hospital of Eastern Ontario IBD Centre, Department of Pediatrics, Ottawa, Canada 6B.C. Children's Hospital, Division of Gastroenterology, Vancouver, Canada 7Faculty of Medicine, University of Calgary, Alberta Children's Hospital, Division of Pediatric Gastroenterology, Department of Pediatrics, Alberta, Canada 8Max Rady College of Medicine, University of Manitoba, Section of Gastroenterology, Department of Pediatrics, Manitoba, Canada 9IWK Health Centre, Department of Pediatrics, Dalhousie University, 5980 University Avenue, Division of Gastroenterology & Nutrition, Halifax, Canada 10Department of Pediatrics, University of Alberta, Edmonton, Edmonton, Canada

Background

Therapeutic drug monitoring (TDM) during infliximab (ifx) maintenance therapy is regularly used in Canada to assess loss of response and to aid in dose optimization, with pre-infusion trough levels in the range of 5–10ug/ml recommended as targets. Levels achieved early following standard induction dosing among pediatric patients are highly variable, and often inadequate even at week 12. Limited data exist in adults or children concerning the role of TDM and target levels during induction. Within the Canadian children IBD Network, we proposed to measure ifx levels during induction, aiming to determine the optimal levels required to achieve target 5–10 ug/ml at the start of maintenance.

Methods

Beginning in May 2016, children initiating ifx at SickKids Hospital and at other centres within the CIDsCANN inception cohort study had trough levels measured by ELISA at the time of the of final induction and first maintenance infusions (doses 3 and 4). Induction regimens were at the discretion of the treating physician, but often intensified among patients with severe UC. Influence of patient demographics and baseline disease activity (PGA, wPCDAI/PUCAI) on early trough levels were assessed.

Results

From May to December 2016 at 9 participating sites, 66 children (median age 11.8 years, 53% male, 52% CD, 48% UC/IBD-U; IBD duration at start of biologic 4.3mos (IQR 14.02–13.02 mos). Induction regimen was “standard” (0, 2, 6 weeks) in 77% and intensified in 23% (O, 1, 4 weeks; all steroid refractory colitis). Table 1 gives characteristics of those receiving standard vs intensified regimens As shown in Table 1, IFX levels were highly variable prior to 3rd induction dose. Within the standard induction dosing cohort, the interval between dose 3 and 4 was shortened to 6 weeks in 50%. 41% attained targeted 5–10 dose 4 levels. Despite higher dosing per kg during induction and shorter interval prior to dose 4 in the intensified regimen, IFX levels at start of maintenance were comparable to patients receiving standard induction.

Table 1. Basic demographic data Induction Infliximab TDM Study

Standard inductionIntensified induction
Population (n)5115
Gender (% male)53%23%
Age in yrs (median, IQR)12.0 (7.9–14.3)9.4 (6.5–13.8)
Type of IBD60% CD; 40% UC/IBD-U86% UC/IBD-U; 14% CD
PGA at first infusion30% severe; 16% moderate; 38% mild; 16% none60% severe; 20% moderate; 20% mild
Mean dose (mg/kg)6.04 mg/kg7.95 mg/kg
Induction duration (weeks)64
Pre-dose 3 level (median, IQR)16.4 μg/ml (10.1–26.7)16.2 μg/mL (IQR 11.9–28.8)

Conclusion

Variability in infliximab exposure is evident during induction. Adjusting dose intervals based on pre 3rd dose induction levels, increases the likelihood of entering maintenance dosing on target. An intensified regimen is necessary for patients with active colitis to achieve comparable post induction levels. The results suggest that the use of TDM during induction to individualize dosing more consistently ensures adequate drug exposure at start of maintenance.