122
Another retrospective study examined 199 CD and 42 UC patients, of which 140
were receiving infliximab and 107 were receiving adalimumab, who had lost
response underwent drug level and antibody monitoring [ 47 ]. In those with loss of
response while receiving adalimumab, the presence of trough levels >4.5 μg/mL
had a 100% positive predictive value (PPV) of response to switching to an alterna-
tive therapy and a 90% PPV for failure to respond to dose intensification. In addi-
tion, titers of anti-adalimumab drug antibodies >4 μg/mL had a PPV of 76% for
failure to dose intensification. In this retrospective study, the predictive characteris-
tics for infliximab were not as robust as those appreciated by Afif and colleagues,
with a PPV of 72% for responding to switching to another class of medication with
adequate drug levels and a 56% PPV for failure to respond to dose intensification.
Interestingly, the authors did appreciate some evidence of being able to continue
anti-TNFs in the setting of low-level antibodies. Specifically, patients with low-
level antibodies who had increases in their anti-TNF dose also had significant
increases in drug concentration and also had significantly higher clinical response
rates when combining both infliximab and adalimumab users. These data suggest
that when anti-drug antibodies are present but in low concentration, further anti-
TNF titration may be effective, consistent with the findings of Pariente and col-
leagues [ 46 ].
Reactive TDM has also recently been demonstrated to be cost-effective, both in
simulation modeling and in clinical practice. Velayos and colleagues constructed a
Markov model to simulate those individuals undergoing dose escalation guided by
drug level measurement, compared to a strategy of dose escalation based only on
symptoms. While clinical outcomes were the same for both cohorts, a significant
cost saving was realized, likely secondary to reductions in unnecessary dose escala-
tion [ 48 ]. Interestingly, the model was not sensitive to variations in test cost up to
$5700 per level measurement [ 48 , 49 ]. Similar findings were appreciated in a
prospective randomized controlled trial of dose escalation versus reactive monitor-
ing in 69 patients with secondary loss of response to infliximab [ 50 ]. Comparable
clinical response rates were appreciated in each cohort, with significant savings in
costs for those undergoing therapeutic drug level monitoring.
Proactive TDM
As opposed to reactive TDM, an alternative approach is to assess drug levels and
antibody formation in a proactive manner to ensure that drug levels are within the
appropriate proposed therapeutic range during both induction and maintenance
therapy. This approach, also known as “proactive TDM,” is designed to maximize
the clinical benefit of anti-TNF therapies with the goal of preventing flares of dis-
ease by maintaining adequate trough concentrations. In proactive TDM, trough lev-
els and anti-drug antibodies are typically assessed at the end of induction and then
at least every 6–12 months, with dose modification or immunomodulator addition
when appropriate to optimize levels within a desired therapeutic range.
F.I. Scott and M.T. Osterman