117patients assessing the association between drug levels of infliximab and adalim-
umab and mucosal healing conducted by Ungar and colleagues, rates of mucosal
healing were twofold higher in those with detectable drug levels compared to those
without [ 35 ]. There also appeared to be a dose-response in this study, with adalim-
umab serum concentrations >7.1 μg/mL and infliximab serum concentrations >5 μg/mL
being strongly predictive of mucosal healing. Interestingly, this effect appeared to
be less dramatic at adalimumab levels >12 μg/mL or infliximab levels >8 μg/mL,
suggesting that specific pharmacokinetic windows may exist for anti-TNFs.
Other studies have demonstrated a possible association between clinical out-
comes and serum concentrations of adalimumab. While a retrospective analysis of
the initial data from CLASSIC I and II did not clearly demonstrate a durable asso-
ciation between adalimumab levels and clinical response, more recent data have
supported this association [ 36 ]. Karmiris and colleagues assessed the association
between adalimumab levels and clinical response in 130 patients [ 25 ]. Those who
received higher loading doses (160 mg followed by 80 mg compared to 80 mg fol-
lowed by 40 mg) had higher adalimumab trough levels at week 4, which was associ-
ated with a significantly higher probability of CRP normalization, longer sustained
clinical benefit, and lower rates of primary non-response. Additionally, higher
median adalimumab levels were associated with higher early and later response
rates, while lower median drug levels were associated with therapy discontinuation.
As previously noted, Ungar and colleagues have also demonstrated an association
between serum adalimumab concentrations and mucosal healing [ 35 ].
Given the lack of commercially available assays to assess drug levels for other
anti-TNFs, the impact of drug levels of certolizumab pegol or golimumab is less
clear. In an open-label extension of the PRECISE-2 trial (PRECISE-4), higher drug
levels of certolizumab pegol were not associated with an increased probability of
clinical response after receiving an extra dose of the medication [ 37 ]. However, in a
subgroup analysis of individuals initiating the drug after failing infliximab, there
was an association between subsequent remission and having drug levels in the
upper two quintiles [ 38 ]. With regard to golimumab, a recent analysis of data from
the phase 2 and 3 PURSUIT trials demonstrated that serum golimumab levels dur-
ing induction at week 6 and during maintenance therapy (weeks 30 and 54) were
associated with increased rates of clinical response, mucosal healing, and clinical
remission [ 39 ]. Further research is required for both of these agents to better assess
the association between drug levels and clinical response.
The role of drug levels with newer anti-integrins such as vedolizumab is less
clear as that appreciated with anti-TNFs [ 40 ]. In the GEMINI 1 and 2 clinical trials,
increased dosing frequency from every 8 weeks to every 4 weeks did appear to
increase the serum concentrations of the vedolizumab (38.3 ± 24.4 μg/mL vs.
11.2 ± 7.2 μg/mL, respectively) but was not associated with significantly increased
rates of clinical response. Interestingly, regardless of dosing, ~95% of α 4 β 7
heterodimers (the target of the drug) were bound to vedolizumab when assessed;
this saturation may in part explain the disconnect between serum concentrations and
clinical response. Further research is required regarding the impact of drug levels
and this specific class of medications.
8 Therapeutic Drug Monitoring of Biologic Agents