Clinical study design strategies to mitigate confounding effects of time-dependent clearance on dose optimization of therapeutic antibodies.

Time-dependent pharmacokinetics (TDPK) is a frequent confounding factor that misleads exposure-response (ER) analysis of therapeutic antibodies, where a decline in clearance results in increased drug exposure over time in patients who respond to therapy, causing a false-positive ER finding. The object of our simulation study was to explore the influence of clinical trial designs on the frequency of false-positive ER findings. Two previously published population PK models representative of slow- (pembrolizumab) and fast-onset (rituximab) TDPK were used to simulate virtual patient cohorts with time-dependent clearance and the frequency of false-positive ER findings. The impact of varying the number of dose groups, dose range, and sample size was evaluated over time. Study designs with a single tested dose level showed a high probability of showing a false-positive ER finding. When TDPK has a slow onset, use of exposure measures from early timepoints in ER analysis significantly reduces the risk of a false-positive, while with fast onset it did not. Randomization of patients to two dose levels greatly reduced the risk, with a threefold or greater dose range offering the greatest benefit. The likelihood of false-positive increases with a larger sample size, where greater care should be taken to identify confounding factors. Clinical trial simulation supports that appropriate clinical study design and analysis with adequate dose exploration can reduce but cannot entirely eliminate the risk of misleading ER findings.