ArticleClinical pharmacology and therapeutics2026
Time-Dependent Bias and Prognostic Confounding in Exposure-Response Analysis of Targeted Therapies: Lessons from Sunitinib in Metastatic Renal Cancer.
Article in Clinical pharmacology and therapeutics, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
0 citing papers in PubMed.
No citing paper in PubMed yet.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
2 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Exposure-response (E-R) analyses of sunitinib in metastatic renal cell carcinoma (mRCC) have supported concentration-guided dose escalation. However, such analyses may be biased when exposure metrics incorporate post-baseline dose modifications, time-varying apparent clearance, or baseline factors that influence both pharmacokinetics and clinical outcomes. We re-evaluated the E-R relationship of sunitinib in mRCC with explicit assessment of these biases. A population pharmacokinetic analysis of 294 patients from four clinical trials identified time-dependent declines in apparent clearance for sunitinib and SU12662. E-R analyses were performed in 165 cytokine-refractory patients treated with the approved 50 mg 4-weeks-on/2-weeks-off regimen, using time to progression (TTP), overall survival (OS), and tolerability-related outcomes. Baseline albumin and age were identified as shared covariates of exposure and outcome and incorporated as confounders in multivariable multistate survival models. The apparent positive association between higher exposure and improved TTP and OS was attenuated when exposure was defined using early, baseline-anchored metrics rather than time-averaged apparent clearance. It was no longer evident after adjustment for albumin and age. Consistently, simulations with confounders fixed at cohort medians showed overlapping TTP and OS profiles across exposure groups. In contrast, higher exposure remained associated with poorer tolerability, including increased risks of dose reduction and treatment discontinuation driven by adverse-events. These findings indicate that previously reported positive E-R relationships for sunitinib were largely due to time-dependent bias and confounding. The results do not support exposure-guided dose escalation based on total plasma concentrations, but instead suggest the use of therapeutic drug monitoring to identify patients at risk of excessive exposure and toxicity.
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.