Pharmacokinetics of anti-TNFα agents in paediatric IBD: Is there any difference at all compared with adults?

Kang et al. [3] demonstrated a linear TC response curve in children with CD treated with infliximab and reported that a threshold of  ≥5 µg/mL is strongly associated with mucosal healing. Similarly, van Hoeve et al. [5] showed that median infliximab TC is significantly higher in children with Inflammatory Bowel Disease (IBD) who achieve clinical remission. The optimal threshold for predicting endoscopic remission was ≥5.4 µg/mL. Adalimumab requires higher TC for similar outcomes, as was demonstrated in the PAILOT randomised controlled trial, in which a threshold of 10 µg/mL performed better than lower TCs in terms of clinical and biological remission [6]. Infliximab pharmacokinetic studies were also performed in children with IBD during induction [7, 8]. Clinical response was associated with a median TC of 27.8 μg/mL (IQR 19.5–40) before the second infusion and 18.8 μg/mL (IQR 9.5–23) before the third infusion [7] (or 10.4 mg/mL, IQR 9.1–14.4, according to Naviglio et al. [8]). It was clearly shown that low TCs and high ADAs are the most frequent causes of non-response during induction [4].

Post-induction TCs (week 14 for infliximab and weeks 4–8 for adalimumab) are predictive of clinical outcomes at 1 year also in children. Singh et al. [9] reported that an infliximab TC at week 14 of >3, >4 and >7 µg/mL had positive predictive values of 64%, 76% and 100%, respectively, for predicting sustained response at 1 year in children with IBD, whereas a recent study demonstrated that a median TC of 6.0 mg/mL (IQR 3.2–12.0) at week 14 was associated with better one-year outcomes [10].

One of the more striking findings of the PAILOT trial [6] is that the vast majority of TC-monitored patients (87%) required adalimumab intensification in order to maintain a modest target of 5 µg/mL. These observations raise the question of whether anti-TNFα pharmacokinetics in children are distinct from those in adults.

As mentioned previously, recent trials clearly demonstrated that an inadequate serum infliximab concentration (pharmacokinetic failure) is the main cause of treatment failure among paediatric patients with IBD [4, 8] and that, in most children, standard dosing of anti-TNFα agents is not sufficient to achieve a therapeutic TC [12], particularly in the context of hypoalbuminaemia. was achieved by only 21% and 41% of children at albumin levels of 3 and 4 g/dl, respectively. Kelsen et al. [13] found that patients with CD, aged seven years or younger, showed lower infliximab response rates compared to those in older patients. In a more recent study [14], young children (less than 10 years of age) required much higher doses of infliximab per kilogram (almost twofold) in order to maintain clinical remission and achieve an adequate TC. Younger patients were also at greater risk for the development of ADAs, which was plausibly attributed to subtherapeutic TC during induction and early maintenance.

It has consistently been shown that the pharmacokinetics of anti-TNFα agents is affected by multiple variables, including immunogenicity (the presence of ADAs), hypoalbuminaemia, target-mediated clearance (high disease burden), intestinal losses and concomitant use of immunomodulators [15]. Nevertheless, in children other factors may also be involved.

Patients with low weight are more likely to have low infliximab TC because of clearance, which is not linearly weight related [16, 17]. Patients with infantile-onset IBD have the lowest weight among paediatric IBD patients, making them most susceptible to under-dosing. Another factor affecting the pharmacokinetics of anti-TNFα agents is body surface area (BSA) [18]. , particularly in younger children, in whom the BSA to weight ratio is higher. Additionally, it has been shown that infliximab distribution in children differs from that in adults as more drug is distributed to the peripheral compartment, leading to a lower TC [19]. Finally, target-mediated clearance is also affected by increased inflammatory burden (termed a ‘‘sink effect’’) [20], which may further contribute to low anti-TNFα TC in children, as both paediatric-onset CD and UC have been shown to present with significant inflammatory burden (CD) and more extensive disease (UC).

In summary, anti-TNFα TC targets in children with IBD do not differ significantly from those in adults. Nevertheless, it is more difficult to achieve these targets, particularly in young children, due to distinct pharmacokinetic properties. Consequently, in this vulnerable population it is advisable to use more intensified regimens up-front and/or to intensify treatment early, according to clinical response, as well as to use early and frequent therapeutic drug monitoring.

References

1. Conrad MA, Kelsen JR. The treatment of pediatric inflammatory bowel disease with biologic therapies. Curr Gastroenterol Rep. 2020;22:36.
2. Ding NS, Hart A, De Cruz P. Systematic review: predicting and optimising response to anti-TNF therapy in Crohn's disease – algorithm for practical management. Aliment Pharmacol Ther. 2016;43:30–51.
3. Kang B, Choi SY, Choi YO, et al. Subtherapeutic infliximab trough levels and complete mucosal healing are associated with sustained clinical remission after infliximab cessation in paediatric-onset Crohn's disease patients treated with combined immunosuppressive therapy. J Crohns Colitis. 2018;12:644–52.
4. Ungar B, Glidai Y, Yavzori M, et al. Association between infliximab drug and antibody levels and therapy outcome in pediatric inflammatory bowel diseases. J Pediatr Gastroenterol Nutr. 2018;67:507–12.
5. van Hoeve K, Dreesen E, Hoffman I, et al. Higher infliximab trough levels are associated with better outcome in paediatric patients with inflammatory bowel disease. J Crohns Colitis. 2018;12:1316–25.
6. Assa A, Matar M, Turner D, et al. Proactive monitoring of adalimumab trough concentration associated with increased clinical remission in children with Crohn's disease compared with reactive monitoring. Gastroenterology. 2019;157:985–96.
7. Clarkston K, Tsai YT, Jackson K, et al. Development of infliximab target concentrations during induction in pediatric Crohn disease patients. J Pediatr Gastroenterol Nutr. 2019;69:68–74.
8. Naviglio S, Lacorte D, Lucafò M, et al. Causes of treatment failure in children with inflammatory bowel disease treated with infliximab: a pharmacokinetic study. J Pediatr Gastroenterol Nutr. 2019;68:37–44.
9. Singh N, Rosenthal CJ, Melmed GY, et al. Early infliximab trough levels are associated with persistent remission in pediatric patients with inflammatory bowel disease. Inflamm Bowel Dis. 2014;20:1708–13.
10. van Hoeve K, Dreesen E, Hoffman I, et al. Adequate infliximab exposure during induction predicts remission in paediatric patients with inflammatory bowel disease. J Pediatr Gastroenterol Nutr. 2019;68:847–53.
11. Assa A, Dorfman L, Shouval DS, et al. Therapeutic drug monitoring-guided high-dose infliximab for infantile-onset inflammatory bowel disease: a case series. J Pediatr Gastroenterol Nutr. 2020;71:516–20.
12. Frymoyer A, Piester TL, Park KT. Infliximab dosing strategies and predicted trough exposure in children with Crohn disease. J Pediatr Gastroenterol Nutr. 2016;62:723–7.
13. Kelsen JR, Grossman AB, Pauly-Hubbard H, et al. Infliximab therapy in pediatric patients 7 years of age and younger. J Pediatr Gastroenterol Nutr. 2014;59:758–62.
14. Jongsma MME, Winter DA, Huynh HQ, et al. Infliximab in young paediatric IBD patients: it is all about the dosing. Eur J Pediatr. 2020;179:1935–44.
15. Ordás I, Mould DR, Feagan BG, et al. Anti-TNF monoclonal antibodies in inflammatory bowel disease: pharmacokinetics-based dosing paradigms. Clin Pharmacol Ther. 2012;91:635–46.
16. Steenholdt C, Bendtzen K, Brynskov J, et al. Optimizing treatment with TNF inhibitors in inflammatory bowel disease by monitoring drug levels and antidrug antibodies. Inflamm Bowel Dis. 2016;22:1999–2015.
17. Dotan I, Ron Y, Yanai H, et al. Patient factors that increase infliximab clearance and shorten half-life in inflammatory bowel disease: a population pharmacokinetic study. Inflamm. Bowel Dis. 2014;20:2247–59.
18. Fasanmade AA, Adedokun OJ, Blank M, et al. Pharmacokinetic properties of infliximab in children and adults with Crohn’s disease: a retrospective analysis of data from 2 phase III clinical trials. Clin Ther. 2011;33:946–64.
19. Bramuzzo M, Arrigo S, Romano C, et al. Efficacy and safety of infliximab in very early onset inflammatory bowel disease: a national comparative retrospective study. United Eur Gastroenterol J. 2019;7:759–66.
20. Keizer RJ, Huitema ADR, Schellens JHM, et al. Clinical pharmacokinetics of therapeutic monoclonal antibodies. Clin Pharmacokinet. 2010;49:493–507.