正文
获取原文件references/source-ledger.md
Execution evidence
The bundled CLI suite and synthetic smoke examples were run in isolated Python with NumPy 2.5.3 and SciPy 1.18.1. Tests cover analytical linear-PK identities, NCA, individual fitting, ordinary BE, DDI arithmetic, TDM, scaling, event validation and PD helpers. Analytical and synthetic agreement is numerical verification, not clinical validation or qualification for a regulatory application.
Pharmpy 2.2.0 was installed in a separate isolated environment. Seven transformations on the bundled pheno model executed: QSS TMDD, indirect/direct/effect-compartment PD, allometry, transit absorption and Michaelis-Menten elimination. Signatures for those methods, annotate_unit and calculate_eta_shrinkage were inspected. Nineteen run_* tools were enumerated. No licensed NLME estimation, R workflow or PBPK simulation was executed.
Current interfaces and package metadata
- Pharmpy changelog:2.2.0, Python>=3.12 except 3.14.1, annotate_unit rename; tools, TMDD API, shrinkage API.
- NumPy trapezoid, SciPy least_squares, solve_ivp.
- nlmixr2 CRAN:7.0.1, R>=4.1, rxode2>=5.0.0; rxode2 changes.
- OSP releases:Suite 12 Update 3; R interface news:12.3.2.
- ICON NONMEM:7.6 capabilities. Vendor legacy guide endpoints could not be fully fetched; no installed licensed engine was available.
- PKPy authors; PyPI pkpy returned 404 at review. PyPI JSON metadata confirmed chi-drm1.0.3, pints0.6.1 and lmfit1.3.4; their APIs were not exercised.
Scientific/regulatory corrections and primary evidence
- ICH M12 full text: TDI5×Cmax,u, distinct MATE/systemic efflux cutoffs, fu reliability, inlet/enterocyte concentrations and separate mechanism evaluation. Per-minute/per-hour consistency and full-inhibition ceilings were checked algebraically.
- FDA BE May 2026: design-specific replicate models, squared-contrast bias correction and upper chi-square quantile. The CLI now rejects unsupported raw replicate/scaled analysis. PowerTOST informs planning comparisons; the bundled quantile-grid method remains an approximation.
- Phoenix8.4 guide: automatic terminal selection differs from the helper's strict extension-improvement rule.
- Vancomycin consensus: serious MRSA, total AUC24 400–600 mg·h/L with MIC 1 mg/L assumption; not a universal antimicrobial index target.
- E11A, E14/S7B, FIH, M13A/B/C and M15 primary sources and regional dates are listed in regulatory guidance. M13B is now EMA Step 5, not draft Step 2b.
Deliberate boundaries
No script calls a remote clinical/data API; it reads local CSV/CLI values. External URLs are primary documentation links, not service/authentication endpoints. Phantom endpoints were not introduced. No patient data, outcome validation, licensed engine run, prospective clinical workflow or submission review was performed. Product-specific guidance is not enumerated. Sparse-data identifiability, priors, censoring assumptions, parameter uncertainty and extrapolation remain the analyst's responsibility; the supplied tools cannot resolve them from convergence alone.