2.1.1. Pharmacokinetic Parameters
For monoclonal antibodies, particularly those that demonstrate
time-dependent PK, the selection of the appropriate exposure metric to
use for E-R analyses is critical. An E-R analysis simulation for
nivolumab, for example, tested 3 different exposure metrics and resulted
in different E-R conclusions. The exposure metrics used were: (1)
average concentration at steady state (Cavgss), (2)
average concentration at cycle 1 (Cavg1st-dose), and (3)
trough concentration at cycle 1
(Cmin1st-dose).12 When
Cavgss was used as the exposure metric there was a steep
E-R relationship with a hazards ratio (HR) of 0.92 and 0.14 between
quartiles 1 and 4, and the case-matched control arm, respectively.
However, when Cavg1st-dose and
Cmin1st-dose were used the apparent E-R relationship was
flat. The flat E-R relationship is consistent with the lack of
dose-response relationship derived from the randomized dose-ranging
trial for nivolumab.13 The observed inconsistency in
E-R relationship between the different exposure metrics used
(Cavgss, Cavg1st-dose, and
Cmin1st-dose) can be attributed to the dependence of
Cavgss on concentrations from later post-treatment time
points. Patients with improving disease status have reduced drug
clearance, so at later time points there is an apparent correlation
between exposure and response. Using exposure metrics derived from
earlier time points reduces the change in disease status influencing PK,
and allows for more accurate assessment of the impact of treatment
exposure on clinical response.14
In addition to using exposure metrics derived from early time points
consideration should be placed on whether observed or model-derived
exposure metrics are used in the E-R analysis. In the E-R analysis for
trastuzumab emtansine (T-DM1) the results of Cox proportional-hazards
modeling (CPH) were not consistent between model-derived and observed
exposure metrics. After adjusting for baseline risk factors in the
analyses for both metrics the model-predicted
Cmin1st-dose and area under the curve at cycle 1
(AUC1st-dose) were significantly associated with OS
though the observed Cmin1st-dose and
AUC1st-dose were not.15 Due to the
limited understanding of this discrepancy a strong recommendation could
not be made regarding the selection of observed or model-derived
metrics, and it would be prudent for an E-R analysis to examine both.
Upon examining both metrics if either of them is significantly
associated with OS further investigation into the population PK model
and E-R analysis is warranted.