Cluster 1: exposure · pk · population
Automatically detected text-similarity community. Keywords are calculated from article titles and summaries; membership is recalculated when the published corpus changes.
Capivasertib rest-day placement at the same weekly dose: a public PopPK simulation
Three equal-dose weekly schedules are compared with an independent implementation of published PK equations. Weekly AUC is nearly unchanged, while minima and cutoff-dependent low-concentration times differ. Conditional sensitivity simulations do not establish clinical equivalence or predict efficacy, toxicity, or recovery.
Can maximal degradation alone set the dosing interval of a targeted protein degrader?
A review of public ER-PROTAC data and a minimal model of how assumptions about site-of-action exposure and target recovery change comparisons of dosing frequency and PD metrics. The model is not fitted to the actual drug, and no clinical dose is proposed.
- In public data, end-of-study ER degradation with vepdegestrant was at least 94% at every dose while TGI ranged from 85% to 120%, and the 24-hour tumor/plasma ratio for ERD-1233 was 9.81; end-of-study PD and plasma concentration do not stand in for efficacy or tumor exposure.
- In an assumption-based minimal model with a 6 h target half-life, Q2D gave higher maximal degradation than QD (81.1% vs 73.7%) but a lower minimum (14.3% vs 48.4%) and mean (52.2% vs 63.8%).
- Recovery rate, required degradation and the interval for an actual drug cannot be set from public data. Endpoint degradation alone does not separate effect-site retention from target recovery.
Do fixed doses of anti-PD-1 antibodies keep exposure in range at extreme body weights?
Re-implemented population PK models for pembrolizumab and nivolumab were applied to a public adult weight distribution. Fixed doses let trough exposure fall below the trial-tested range most often in heavy patients, weight-based doses in the first interval of light patients; the verdict on extended intervals depends on how the range is defined. No dose is recommended.
- With fixed doses, trough exposure fell below the lower limit of the trial range more often in heavy patients; more than 10% fell below it for pembrolizumab 200 mg at 150 kg and above (13.3%) and nivolumab 240 mg at 100 kg and above (10.7 to 18.5%).
- Weight-based doses (2 mg/kg, 3 mg/kg) were worse on the light side: at 40 kg, 26 to 31% of patients had a first-interval trough below the lower limit.
- The verdict on 400 mg Q6W and 480 mg Q4W changed with the definition of the range: 14 to 15% fell below a 5th-percentile limit but 0.06% (pembrolizumab) below a minimum-value limit. This compares exposure and recommends no dose.
Reimplementing a published mosunetuzumab population PK model: step-up dosing exposure and the limits of extrapolating to receptor occupancy and CRS
Mosunetuzumab PK recalculated from the published paper and its supplement. A paired analysis of 2,000 virtual patients examines the effects of dose and interval and how far exposure can be translated to CD20 occupancy and CRS. Figures, Python code and CSV files included.
- The published PopPK model (two compartments with time-varying CL) was reimplemented in Python, recalculating Cycle 1, 42-day and Cycle 4 AUC within about 1% of published values (Cycle 1 Cmax −4.0%); this confirms the implementation, not external validity.
- In the same 2,000 virtual patients, raising the second dose from 2 to 4 mg increased the concentration before the first 60 mg dose by 77.9%, and lengthening step-up intervals from 7 to 14 days lowered 42-day AUC by 30.8%; changing only the first or second dose moved 42-day AUC by less than 2%.
- The published RO–CRS regression takes the maximum RO over 42 days and outputs about 6.7% even when RO is near 0; it cannot predict CRS incidence or individual risk for modified regimens.
How complex does a population PK model need to be for exposure comparison? Measured nimotuzumab PK
Three population PK structures estimated from individual PK data, with internal validation, convergence and exposure differences across dosing conditions used to examine the limits of model selection.
- Linear one-compartment, linear two-compartment and nonlinear-elimination PopPK models were fitted to public data (12 subjects, 321 concentrations). AIC fell with complexity (790.42, 751.25, 747.47), but leave-one-subject-out RMSE improved by only about 4.2% and 3.3%, short of the prespecified 10%.
- The 400 to 200 mg AUC ratio was 2 in the linear models and about 2.35 in the nonlinear model, a difference above 10%: the models ranked dosing conditions alike, but absolute exposure and dose ratios depended on the model.
- Only 4.5–22% of bootstrap runs passed the convergence screen, so no 95% CIs were reported. Limitations in original records and independent validation leave both adoption of the nonlinear model and sufficiency of the linear model unresolved.
Repotrectinib escalation timing: exploring lead-in regimens with a public population PK model
An independent Python implementation of published structural equations compares 7-, 14- and 21-day lead-ins. Conditional paired simulations and sensitivity analyses separate cumulative exposure, peak-window effects and late troughs. No patient refitting, NONMEM equivalence or efficacy/safety prediction is claimed.
How far can public summary PK data evaluate a change in the tarlatamab dosing interval?
A two-compartment model estimated from published aggregate PK values, comparing Q2W, Q3W and Q4W exposure in light of identifiability and uncertainty.
- A two-compartment model fitted to six Cycle 2 PK summary values from the label explained them with a maximum error of 10.0%, but profiles showed CL, Q and Vp were poorly identified, and the terminal half-life (about 19.0 days) did not match the NCA median of 6.21 days.
- Extending the interval at the same 10 mg gives average-concentration ratios of 2/3 for Q3W and 1/2 for Q4W (fixed by mass balance under linear PK); the Q4W trough ratio was 0.371 with a wide conditional range of 0.171–0.498.
- The efficacy Emax relationship is based on first-cycle average concentration and cannot be reused as a threshold for maintenance troughs, and the per-dose fall in CRS cannot be explained by current exposure alone.
Can matching average exposure alone set the tarlatamab dosing interval?
Between-subject variability simulated from a published population PK model, with efficacy exposure–response, period-specific CRS and maintenance exposure examined separately. Matching average exposure does not preserve peaks and troughs, and the analysis shows the limits of deciding from public information.
- Recalculating the published PopPK model (FDA Tables 66–67) in 5,000 virtual subjects matched initial-dose exposure to the label means, but the steady-state trough was about 16–41% higher, so population exposure is not fully reproduced.
- Matching dose intensity to 10 mg Q2W does not preserve the profile: 20 mg Q4W kept average exposure but gave a median peak of about 1.78× and a median trough of about 0.60×.
- Efficacy saturation (Cycle 1 Cavg), CRS by period and low maintenance concentrations need separate evidence; matching average exposure alone cannot establish equivalence of maintenance regimens.
Before comparing TROP2 ADC exposure: why a reported AUC changed
An audit of sacituzumab govitecan and datopotamab deruxtecan distinguishes measured and derived analytes, label versions, exposure windows and response endpoints. The public summaries do not establish a shared payload target.