Pharmacokinetics of anti-TNFα agents in paediatric IBD: Is there any difference at all compared with adults?
Amit Assa, P-ECCO Member
Anti-tumor necrosis factor alpha (TNFα) therapy is frequently used in the treatment of Crohn’s Disease (CD) and Ulcerative Colitis (UC) in both adult and paediatric patients. Nevertheless, primary or secondary treatment failure of anti-TNFα treatment is not uncommon . Both primary and secondary treatment failures are attributed either to pharmacokinetic, pharmacodynamic and immunogenic factors or to adverse events in response to the specific agent . In recent years, loss of response (LOR) during anti-TNFα treatment has commonly been approached through the use of therapeutic drug monitoring involving measurement of infliximab or adalimumab trough concentrations (TC) and anti-drug antibodies (ADAs). Therapeutic drug monitoring of anti-TNFα agents enables proper stratification of LOR into a specific type of LOR, with corresponding adjustment of treatment. In children, in line with findings in adults, it has consistently been shown that higher drug TC is associated with higher efficacy  and that LOR is most commonly attributable to either low TC or the development of anti-drug antibodies .
Kang et al.  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.  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 . 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  (or 10.4 mg/mL, IQR 9.1–14.4, according to Naviglio et al. ). It was clearly shown that low TCs and high ADAs are the most frequent causes of non-response during induction .
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.  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 .
One of the more striking findings of the PAILOT trial  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 , 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.  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 , 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 . 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) . , 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 . Finally, target-mediated clearance is also affected by increased inflammatory burden (termed a ‘‘sink effect’’) , 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.
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