Skill Tracer
Skills › Scientific Agent Skills › pkpd-modeling › source-ledger.md

source-ledger.md

57 lines · skills/pkpd-modeling/references/source-ledger.md at 5f2bc03

Open on GitHub
1# Source ledger — reviewed 2026-10-01
2

Source ledger — reviewed 2026-10-01

Raw lines 1 to 2
3## Execution evidence
4
5The bundled CLI suite and synthetic smoke examples were run in isolated Python with NumPy 2.5.3
6and SciPy 1.18.1. Tests cover analytical linear-PK identities, NCA, individual fitting, ordinary BE,
7DDI arithmetic, TDM, scaling, event validation and PD helpers. Analytical and synthetic agreement
8is numerical verification, not clinical validation or qualification for a regulatory application.
9
10Pharmpy 2.2.0 was installed in a separate isolated environment. Seven transformations on the bundled
11pheno model executed: QSS TMDD, indirect/direct/effect-compartment PD, allometry, transit absorption
12and Michaelis-Menten elimination. Signatures for those methods, annotate_unit and
13calculate_eta_shrinkage were inspected. Nineteen run_* tools were enumerated. No licensed NLME
14estimation, R workflow or PBPK simulation was executed.

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.

Raw lines 3 to 15
16## Current interfaces and package metadata
18- [Pharmpy changelog](https://pharmpy.github.io/latest/changelog.html):2.2.0, Python>=3.12 except 3.14.1,
19 annotate_unit rename; [tools](https://pharmpy.github.io/latest/tools.html),
20 [TMDD API](https://pharmpy.github.io/latest/api/pharmpy.modeling.set_tmdd.html),
21 [shrinkage API](https://pharmpy.github.io/latest/api/pharmpy.modeling.calculate_eta_shrinkage.html).
22- [NumPy trapezoid](https://numpy.org/doc/stable/reference/generated/numpy.trapezoid.html),
23 [SciPy least_squares](https://docs.scipy.org/doc/scipy/reference/generated/scipy.optimize.least_squares.html),
24 [solve_ivp](https://docs.scipy.org/doc/scipy/reference/generated/scipy.integrate.solve_ivp.html).
25- [nlmixr2 CRAN](https://cran.r-project.org/web/packages/nlmixr2/index.html):7.0.1, R>=4.1,
26 rxode2>=5.0.0; [rxode2 changes](https://nlmixr2.github.io/rxode2/news/index.html).
27- [OSP releases](https://github.com/Open-Systems-Pharmacology/Suite/releases):Suite 12 Update 3;
28 [R interface news](https://github.com/Open-Systems-Pharmacology/OSPSuite-R/blob/main/NEWS.md):12.3.2.
29- [ICON NONMEM](https://www.iconplc.com/solutions/technologies/nonmem):7.6 capabilities. Vendor
30 legacy guide endpoints could not be fully fetched; no installed licensed engine was available.
31- [PKPy authors](https://github.com/Gumgo91/PKPy); PyPI pkpy returned 404 at review. PyPI JSON
32 metadata confirmed chi-drm1.0.3, pints0.6.1 and lmfit1.3.4; their APIs were not exercised.

Current interfaces and package metadata

Raw lines 16 to 33
34## Scientific/regulatory corrections and primary evidence
36- [ICH M12 full text](https://www.pmda.go.jp/files/000268574.pdf): TDI5×Cmax,u, distinct MATE/systemic
37 efflux cutoffs, fu reliability, inlet/enterocyte concentrations and separate mechanism evaluation.
38 Per-minute/per-hour consistency and full-inhibition ceilings were checked algebraically.
39- [FDA BE May 2026](https://www.fda.gov/media/163638/download): design-specific replicate models,
40 squared-contrast bias correction and upper chi-square quantile. The CLI now rejects unsupported
41 raw replicate/scaled analysis. [PowerTOST](https://cran.r-project.org/web/packages/PowerTOST/vignettes/vignette.html)
42 informs planning comparisons; the bundled quantile-grid method remains an approximation.
43- [Phoenix8.4 guide](https://onlinehelp.certara.com/phoenix/8.4/responsive_html5_%21MasterPage%21/WinNonlin_Guide.pdf):
44 automatic terminal selection differs from the helper's strict extension-improvement rule.
45- [Vancomycin consensus](https://www.idsociety.org/practice-guideline/vancomycin/): serious MRSA,
46 total AUC24 400–600 mg·h/L with MIC 1 mg/L assumption; not a universal antimicrobial index target.
47- E11A, E14/S7B, FIH, M13A/B/C and M15 primary sources and regional dates are listed in
48 [regulatory guidance](regulatory-guidance.md). M13B is now EMA Step 5, not draft Step 2b.

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.
Raw lines 34 to 49
50## Deliberate boundaries
52No script calls a remote clinical/data API; it reads local CSV/CLI values. External URLs are
53primary documentation links, not service/authentication endpoints. Phantom endpoints were not
54introduced. No patient data, outcome validation, licensed engine run, prospective clinical workflow
55or submission review was performed. Product-specific guidance is not enumerated. Sparse-data
56identifiability, priors, censoring assumptions, parameter uncertainty and extrapolation remain the
57analyst's responsibility; the supplied tools cannot resolve them from convergence alone.

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.

Raw lines 50 to 57