@pikaa-ai/pikaa 0.2.5 → 0.3.0

package/skills/pkpd-modeling/SKILL.md

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+---
+name: pkpd-modeling
+description: Pharmacokinetic and pharmacodynamic modelling and simulation - non-compartmental analysis, compartmental and population PK, PK/PD and exposure-response, TMDD, PBPK orientation, bioequivalence, allometric scaling and first-in-human dose, drug interaction prediction, and Bayesian therapeutic drug monitoring. Use when analysing concentration-time data, deriving exposure metrics, fitting PK or PD models, or evaluating dosing regimens. Triggers include "pharmacokinetics", "pharmacodynamics", "PK/PD", "NCA", "non-compartmental", "AUC", "Cmax", "lambda z", "half-life", "clearance", "volume of distribution", "compartmental model", "population PK", "popPK", "NONMEM", "nlmixr2", "Pharmpy", "Monolix", "exposure-response", "Emax", "EC50", "indirect response", "effect compartment", "TMDD", "PBPK", "bioequivalence", "RSABE", "ABEL", "allometric scaling", "first-in-human", "MABEL", "drug-drug interaction", "DDI", "ICH M12", "concentration-QTc", "therapeutic drug monitoring", "MIPD", and "dosing regimen".
+license: MIT
+compatibility: Requires Python 3.11+ with numpy and scipy. No network access and no proprietary software. The estimation tools this skill orients you towards (NONMEM, Monolix, Phoenix, Simcyp, GastroPlus) are licensed separately and are never invoked by these scripts.
+allowed-tools: Read Write Edit Bash
+metadata:
+  version: "1.1"
+  skill-author: K-Dense Inc.
+  last-reviewed: "2026-07-27"
+---
+
+# Pharmacokinetic and Pharmacodynamic Modelling
+
+## When to use
+
+Any question about what the body does to a drug or what the drug does to the body: deriving
+exposure metrics from concentration-time data, fitting a structural model, building or checking a
+population analysis, choosing a dose or a regimen, relating exposure to effect, comparing
+formulations, or scaling to a new population.
+
+## The three rules
+
+**1. Fix the exposure metric and the analysis population before computing anything.** AUC(0-t),
+AUC(0-inf), AUC(0-tau) at steady state, and Cavg are different quantities and answer different
+questions. So do AUCinf based on observed versus predicted Clast. Choosing after seeing the
+numbers is how a negative study becomes positive.
+
+**2. Structural model, variability model, and covariate model are three separate decisions.** They
+get conflated constantly — an extra compartment added to absorb what is really unmodelled
+between-occasion variability, a covariate added to fix what is really a misspecified absorption
+model. Diagnose which one is wrong before changing any of them.
+
+**3. Convergence is not identifiability.** A fit that converges with 200% relative standard error
+on a parameter, or a correlation of 0.99 between two, has told you the data cannot separate them.
+Every fitting script here reports both and flags them, because the parameter table alone looks
+fine in exactly this situation.
+
+## Scope
+
+This skill computes, diagnoses, and structures. It does **not** decide that a formulation is
+bioequivalent, select a dose for a trial, recommend a dose for a patient, conclude that a drug has
+no QT liability, or replace a qualified pharmacometrician, clinical pharmacologist, or the
+regulatory review. The scripts report; none of them concludes. `tdm_bayes.py` in particular is a
+modelling aid — any change to a patient's regimen is the treating clinician's decision.
+
+## Scripts
+
+```bash
+cd skills/pkpd-modeling/scripts
+```
+
+| Script | Question answered |
+| --- | --- |
+| `nca.py` | What are the exposure metrics, and is the terminal phase good enough to report them? |
+| `fit_compartmental.py` | Which structural model do these data support, and are its parameters identifiable? |
+| `simulate_regimen.py` | What does this regimen do at steady state, and to what fraction of the population? |
+| `check_popk_dataset.py` | Will NONMEM read this dataset the way I think it will? |
+| `exposure_response.py` | Is there an exposure-response relationship, and is the plateau in the data? |
+| `bioequivalence.py` | Does the 90% CI meet the criterion, and which criterion applies? |
+| `allometry_and_fih.py` | What is the starting dose, or the dose in a smaller/younger population? |
+| `ddi_static.py` | Does the in vitro data trigger a clinical DDI study under ICH M12? |
+| `tdm_bayes.py` | What are this patient's individual parameters from their measured levels? |
+
+All take `--format table|tsv|json`. Data goes to stdout, provenance and findings to stderr, so
+`> out.tsv` keeps them separate. Exit code is `0` for no findings, `1` when findings were raised,
+`2` for bad input, so any of them can gate a workflow.
+
+Two private modules carry the shared machinery: `_models.py` (analytical solutions for linear
+mammillary models, plus integrated Michaelis-Menten, TMDD and indirect-response structures) and
+`_common.py` (I/O and reporting). Import them rather than re-deriving a Bateman function.
+
+## Workflow
+
+### 1. Non-compartmental analysis
+
+```bash
+python3 nca.py -i profile.csv --dose 100 --route extravascular --partial-auc 0-24
+```
+
+Four choices decide the answer and are usually left implicit. This script makes all four explicit:
+`--auc-method` (default `linup-logdown`), `--blq-rule`, `--lambda-z-points` or an explicit
+`--lambda-z-window`, and whether you report `auc_inf_obs` or `auc_inf_pred`.
+
+Lambda_z selection uses the standard rule: start from the last three quantifiable points, extend
+backwards, keep the longer window only if **adjusted** r-squared improves by more than 0.0001.
+Plain r-squared can only rise as points are added, so it would always pick the longest window.
+Points at or before Tmax are never eligible — including Tmax fits the tail of absorption and
+biases half-life, Vz and AUCinf downward.
+
+On a noiseless simulated one-compartment oral profile with CL/F = 5, V/F = 20, ka = 1.2:
+
+```
+id  cmax     tmax  auc_last  lambda_z  t_half   r2_adj  auc_inf_obs  pct_auc_extrap  cl_f     vz_f
+1   3.29678  1.5   19.8737   0.25      2.77259  1       19.8739      0.000781037     5.03173  20.1269
+```
+
+The 0.6% overestimate of CL/F is the trapezoidal rule on a sparsely sampled absorption phase, not
+an error — it is the irreducible bias of NCA on that sampling schedule, and it is why NCA and
+compartmental estimates of clearance never agree exactly.
+
+The findings are the point. A steady-state profile truncated at tau produces:
+
+```
+finding: subject A: 25.2% of AUCinf is extrapolated (above 20%); AUCinf is driven by the
+         lambda_z fit, not by data
+finding: subject A: lambda_z window spans 0.58 half-lives (below 2.0); the terminal phase may
+         not have been reached
+```
+
+Both are correct and both are routinely ignored. At steady state the reportable exposure metric is
+AUC(0-tau), not AUCinf; the script computes AUCinf anyway and tells you not to trust it.
+
+### 2. Compartmental fitting and model selection
+
+```bash
+python3 fit_compartmental.py -i profile.csv --dose 500 --route iv-bolus --compare 1cmt,2cmt,3cmt
+```
+
+Parameters are estimated on the log scale, so they cannot go negative and their confidence
+intervals come out asymmetric. Weighting defaults to `1/y2` (constant CV), which is the right
+default for PK and the wrong one for a homoscedastic PD endpoint.
+
+Fitting simulated two-compartment data (CL 4, V1 12, Q 6, V2 40, 8% proportional error):
+
+```
+model  parameters  wssr       aic       bic       f_vs_simpler  f_p_value    compared_with
+1cmt   2           3.13201    -19.4956  -18.0795  n/a           n/a          n/a
+2cmt   4           0.0309579  -84.7477  -81.9155  550.936       9.38016e-12  1cmt
+3cmt   6           0.0232859  -85.0193  -80.771   1.4826        0.27762      2cmt
+```
+
+**AIC picks the three-compartment model. BIC and the F test both reject it.** AIC's fixed penalty
+of 2 per parameter is weak at this sample size, and it selects the overparameterised model more
+often than practitioners expect. The parameter table settles it:
+
+```
+finding: fit: Q3 has 98% RSE - not estimable from these data at this model size
+finding: fit: V3 has 71% RSE - not estimable from these data at this model size
+```
+
+The one-compartment fit meanwhile earns:
+
+```
+finding: fit: residual signs are not random (runs test p = 0.0036) - a structural
+         misspecification, which no amount of reweighting will fix
+```
+
+That distinction — structural misspecification versus a wrong error model — is the one to get
+right. A residual-versus-time plot with runs of the same sign means the *model shape* is wrong.
+Heteroscedastic residuals with random signs mean the *weighting* is wrong. Reweighting the first
+case hides it without fixing it.
+
+### 3. Population PK
+
+Check the dataset before running anything. This is where the time actually goes.
+
+```bash
+python3 check_popk_dataset.py -i nmdata.csv --covariates WT,CRCL --time-varying WT
+```
+
+The defects that matter are the silent ones. NM-TRAN does not reject a non-numeric DV — it reads
+`BLQ` as zero and fits it as a genuine zero concentration. A blank covariate becomes 0, so a
+missing body weight becomes a 0 kg patient. `ADDL` without `II` places no additional doses.
+Records sharing a timestamp are applied in file order, so whether a level is pre- or post-dose
+depends on which row came first. None of these stop a run.
+
+```
+severity  check                            detail
+error     non-numeric DV                   DV contains text... NM-TRAN reads them as 0
+error     subject with no dose             1 subject(s) have observations but no dose: 2
+error     TIME not sorted                  1 subject(s) have out-of-order TIME: 1
+error     covariate WT missing             1 record(s) have no value...
+warning   duplicate TIME within a subject  NONMEM applies them in file order...
+```
+
+For the estimation itself, this skill does not reimplement NLME — see
+`references/population-pk.md` for estimation methods, the BLQ M1-M7 methods, covariate model
+building, and the diagnostics that decide whether a model is acceptable, and
+`references/software-ecosystem.md` for which tool to reach for.
+
+### 4. Simulation and regimen selection
+
+```bash
+python3 simulate_regimen.py --cl 5 --v 40 --dose 500 --interval 12 --n-doses 10 --steady-state
+python3 simulate_regimen.py --cl 5 --v 40 --dose 500 --interval 12 --n-doses 10 \
+    --simulate 2000 --omega-cl 0.35 --omega-v 0.25 --target-trough 4.0
+```
+
+Deterministic simulation answers "what does the typical patient look like", which is almost never
+the question:
+
+```
+metric             p5        p25      median   p75      p95      geo_mean
+peak               11.861    14.6018  16.6702  19.1476  22.9339  16.6453
+trough             0.863226  2.15191  3.64412  5.49655  9.21053  3.27035
+
+target       fraction_attaining
+trough >= 4  0.444
+```
+
+The typical trough is 3.6 and the target is 4, so **44% of the population attains it**. A regimen
+tuned on the typical patient leaves about half the population on the wrong side of the target.
+Reported attainment is still optimistic here: this is between-subject variability only, with no
+residual or between-occasion component.
+
+Linear models are solved analytically and superposed, which is exact. `--nonlinear` switches to
+integrated Michaelis-Menten elimination, where superposition is invalid and multiple-dose
+behaviour cannot be inferred from a single dose at all.
+
+### 5. Exposure-response
+
+```bash
+python3 exposure_response.py --emax -i er.csv --sigmoid
+python3 exposure_response.py --cqtc -i qt.csv --cmax 250
+```
+
+The Emax fit reports `fraction_of_emax_reached` and flags a fit whose plateau is outside the data.
+When the highest observed exposure reaches only a third of the estimated Emax, Emax and EC50 are
+extrapolations that are strongly correlated with each other; quoting them as independent estimates
+is not supportable, and a "linear" exposure-response is simply the low-concentration limb of the
+same curve.
+
+`--cqtc` evaluates the **upper bound of the two-sided 90% confidence interval** of predicted
+placebo-corrected change-from-baseline QTc against the 10 ms threshold, which is the question ICH
+E14 actually asks. A point estimate, or a 95% interval, answers a different one. The bundled model
+is an ordinary linear regression for screening; a submission-grade C-QTc analysis needs a mixed
+model with random intercept and slope per subject.
+
+Every mode carries the same caveat, because it is the one that gets forgotten: patients are
+randomised to **dose**, not to **exposure**. Exposure-response across quantiles is observational
+even inside a randomised trial, and can reflect the covariates that drive clearance.
+
+### 6. Bioequivalence
+
+```bash
+python3 bioequivalence.py -i be.csv --design 2x2 --metric AUC
+python3 bioequivalence.py -i be.csv --design replicate --metric Cmax --scaling both
+python3 bioequivalence.py --power --cv 0.30 --gmr 0.95 --target-power 0.80
+```
+
+Three criteria share the word "bioequivalence" and are not interchangeable: average BE (90% CI
+inside 80.00-125.00%), EMA's ABEL (limits widened as a function of CVwR, capped at
+69.84-143.19%, point estimate still within 80-125%), and FDA's RSABE (a scaled linearised bound
+via Hyslop's method, not an interval at all). `--scaling` refuses to run on a 2x2 design:
+
+```
+error: reference-scaling requires --design replicate. High observed variability in a 2x2 study
+does not license widening: without replicated reference administrations there is no estimate of
+within-subject reference variability to scale to.
+```
+
+Sample size reproduces the published tables exactly (CV 30%, GMR 0.95, 80% power → N = 40 for a
+2x2). Power is computed by integrating over the sampling distribution of the estimated standard
+deviation rather than treating the standard error as known — the normal approximation overstates
+power at realistic sample sizes. Note that **N is driven far more by the assumed GMR than by CV**;
+assuming 1.00 instead of 0.95 roughly halves the calculated N and is the usual reason a BE study
+comes in underpowered.
+
+### 7. Scaling, paediatrics, and first-in-human
+
+```bash
+python3 allometry_and_fih.py --scale --cl 5 --weight-from 70 --weight-to 6 --pma-weeks 44
+python3 allometry_and_fih.py --fih --noael rat=50,dog=10 --safety-factor 10
+```
+
+Scaling by size alone below about 2 years of age overpredicts clearance, in a neonate by several
+fold, because clearance is limited by enzyme and renal maturation rather than by size. Supplying
+`--pma-weeks` adds the Anderson-Holford sigmoidal maturation term; omitting it below 20 kg raises
+a finding.
+
+```
+parameter  reference  exponent  size_scaled  maturation_factor  final
+CL         5          0.75      0.792063     0.30634            0.242641
+V          40         1         3.42857      1                  3.42857
+```
+
+Size alone would predict 0.79 L/h; with maturation at 44 weeks post-menstrual age it is 0.24 L/h,
+a 3.3-fold difference. Volume is not matured — maturation describes eliminating capacity, not
+distribution space.
+
+`--fih` uses the body-surface-area conversion from FDA's 2005 maximum-safe-starting-dose guidance
+and always emits a finding that a NOAEL-derived MRSD is not sufficient on its own for agonist
+immunomodulators: compute MABEL with `--mabel` and take the lower value.
+
+### 8. Drug interactions
+
+```bash
+python3 ddi_static.py --basic --ki 0.5 --imax 2.0 --fu 0.05 --dose 0.4
+python3 ddi_static.py --msm --ki 0.5 --imax 2.0 --fu 0.05 --dose 0.4 --fm 0.9 --fg 0.7
+```
+
+ICH M12 basic models with their cut-offs (R1 ≥ 1.02 hepatic, ≥ 11 intestinal; R2 ≥ 1.25 for TDI;
+R3 ≤ 0.8 for induction; transporter cut-offs by site), plus the mechanistic static model. The
+basic models are deliberately conservative: a negative is meaningful, a positive is a trigger for
+further work, not a prediction of clinical magnitude.
+
+The mechanistic static model reports the ceiling alongside the prediction:
+
+```
+note: With fm = 0.9, no inhibitor of this pathway can raise the victim AUC above 10.00-fold. If
+the prediction approaches that ceiling, fm is doing more work than the inhibition constants.
+```
+
+`fm` and `Fg` dominate the answer far more than the inhibition constants, and are usually the
+least well established numbers in the calculation.
+
+### 9. Therapeutic drug monitoring
+
+```bash
+python3 tdm_bayes.py --model vancomycin-adult --weight 80 --crcl 75 \
+    --dose 1500 --interval 12 --level 18.2@11.5 --level 42@2 --target-auc24 500
+```
+
+MAP Bayesian estimation shrinks towards the population when the data are uninformative and follows
+the data when they are not, which is why it beats both a trough read against population parameters
+and log-linear regression on two points. A single level raises a finding: it cannot separate
+clearance from volume, and whichever parameter the sample is uninformative about has simply
+returned its prior.
+
+The bundled vancomycin parameterisation is explicitly labelled illustrative. Substitute a model
+validated in your population before the output means anything.
+
+## Software ecosystem
+
+Verified against live sources on 2026-07-27; see `references/software-ecosystem.md` for the full
+map and `references/source-ledger.md` for provenance.
+
+- **Pharmpy 2.1.1** (2026-05-19) is the practical Python entry point — model-agnostic, drives
+  NONMEM/nlmixr2/rxode2, and ships 19 `run_*` tools including `run_amd`, `run_modelsearch`,
+  `run_covsearch`, `run_structsearch`, `run_pdsearch`, `run_modelrank`, `run_vpc` and `run_qa`.
+  Two breaking changes are recent enough to catch you out: **2.0.0 (2026-02-12) changed dataset
+  row indices to start at 1**, and **2.1.0 (2026-05-08) renamed `add_placebo_model` to
+  `set_placebo_model`** and now requires numpy ≥ 2.
+- **NONMEM 7.6** (user guides dated November 2025) remains the regulatory default. New since 7.5:
+  ADVAN16 (RADAR5 implicit Runge-Kutta for stiff delay differential equations), ADVAN17 (stiff
+  delay differential-algebraic), NUTS Bayesian sampling, and SAEM storage of individual samples.
+- **nlmixr2** (requires rxode2 ≥ 5.0.0) is the credible open-source NLME alternative;
+  `babelmixr2` and `monolix2rx` translate models between it, NONMEM and Monolix.
+- **PKPy** (PeerJ, 2025) is a Python popPK framework but is **GitHub-only — not on PyPI**, so
+  `uv pip install pkpy` fails. `chi-drm` (1.0.3) is on PyPI for Bayesian PKPD.
+- **Open Systems Pharmacology Suite v12** (PK-Sim/MoBi) is the open-source PBPK platform; Simcyp
+  and GastroPlus are the commercial ones. `ospsuite` is R-only and needs .NET 8.
+
+Python has no mature NCA or NLME package of regulatory standing. That gap is why this skill ships
+its own validated NCA and fitting implementations rather than wrapping one.
+
+## What this skill exists to prevent
+
+1. Lambda_z chosen by plain r-squared, or fitted through Tmax.
+2. AUCinf reported from a profile where 25% of it was extrapolated.
+3. AIC allowed to select a compartment whose intercompartmental clearance has 98% RSE.
+4. Reweighting used to fix non-random residuals, which are a structural problem.
+5. `BLQ` left in a DV column, where NM-TRAN reads it as a real zero.
+6. A regimen chosen on the typical patient, with no attainment estimate for the population.
+7. Emax and EC50 quoted as independent estimates when the plateau was never observed.
+8. Reference-scaled bioequivalence limits applied to a 2x2 study.
+9. Allometric scaling to a neonate with no maturation term.
+10. An MRSD from a NOAEL used as the starting dose for an agonist immunomodulator.
+
+## References
+
+- `references/nca-conventions.md` — parameter definitions, lambda_z rules, BLQ handling, steady state
+- `references/structural-models.md` — closed-form solutions, parameterisations, NONMEM ADVAN/TRANS map
+- `references/population-pk.md` — NLME estimation, covariate building, BLQ M1-M7, diagnostics, VPC
+- `references/pd-and-exposure-response.md` — Emax, indirect response, effect compartment, ER analysis
+- `references/tmdd-and-biologics.md` — TMDD approximations, monoclonal antibody PK, immunogenicity
+- `references/pbpk.md` — when PBPK earns its cost, platforms, and what verification requires
+- `references/bioequivalence.md` — designs, ABE/ABEL/RSABE, ICH M13 series, highly variable drugs
+- `references/special-populations.md` — paediatrics, renal and hepatic impairment, obesity, pregnancy
+- `references/dataset-standards.md` — CDISC PC/PP and ADPC/ADPP, NONMEM data items, common defects
+- `references/ddi-and-qt.md` — ICH M12 stepwise assessment, static models, ICH E14/S7B C-QTc
+- `references/antimicrobial-and-tdm.md` — PK/PD indices, PTA/CFR, vancomycin AUC-guided dosing, MIPD
+- `references/software-ecosystem.md` — every tool, what it is for, licensing, and verified versions
+- `references/regulatory-guidance.md` — the guidance ledger with dates, status, and what each requires
+- `references/source-ledger.md` — provenance and research dates for every claim in this skill
+
+## Assets
+
+- `assets/popk-analysis-plan.md` — population analysis plan structure, with the decisions stated up front
+- `assets/nca-reporting-checklist.md` — what an NCA report has to state for the numbers to be interpretable

package/skills/pkpd-modeling/assets/nca-reporting-checklist.md

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+# NCA reporting checklist
+
+An NCA result is uninterpretable — and irreproducible — unless every item below is stated. Most
+disagreements between two analyses of the same data resolve to one of the first four.
+
+## The four conventions that change the answer
+
+- [ ] **Trapezoidal rule**: linear / linear-up-log-down / log-linear
+- [ ] **BLQ handling**, stated separately for each position:
+  - leading (before the first quantifiable sample): [ zero / excluded ]
+  - embedded: [ zero / LLOQ÷2 / excluded ]
+  - trailing: [ excluded / other ]
+- [ ] **Lambda_z selection**: the rule, the minimum number of points, whether Tmax was excluded, and
+      the window and point count actually used **for each subject**
+- [ ] **AUCinf basis**: observed Clast or predicted Clast
+
+## Data
+
+- [ ] Analyte, matrix, assay, LLOQ, and the bioanalytical validation report reference
+- [ ] Actual elapsed times used, not nominal — and nominal times used only for grouping
+- [ ] Dose actually administered per subject, including any deviations
+- [ ] Records excluded, with the reason, and confirmation the criteria were set before unblinding
+- [ ] Deviations in sampling time above [ ]% of the nominal time, and how they were handled
+
+## Parameters reported
+
+- [ ] Cmax and Tmax as **observed** values, never interpolated
+- [ ] AUClast, AUCinf (both observed- and predicted-based, or one with the basis stated)
+- [ ] % AUC extrapolated, per subject
+- [ ] lambda_z, t½, and the number of points and time span of the terminal fit, per subject
+- [ ] CL or CL/F, Vz or Vz/F — with `/F` used for every extravascular route
+- [ ] Vss **only** for intravenous data
+- [ ] At steady state: AUC(0-tau), Cavg, Cmin, PTF%, accumulation ratio — and **not** AUCinf
+- [ ] Partial AUCs, if pre-specified, with their intervals
+
+## Terminal-phase quality, per subject
+
+- [ ] Adjusted r-squared of the lambda_z regression
+- [ ] Span ratio (window duration ÷ t½); flag below 2
+- [ ] % AUC extrapolated; flag above 20%
+- [ ] Number of points in the fit; flag below 3
+- [ ] Subjects for whom lambda_z was not estimable, and how they were handled in the summary
+
+## Summary statistics
+
+- [ ] Exposure metrics (AUC, Cmax) as **geometric mean and geometric CV%**
+- [ ] Tmax as **median and range**
+- [ ] Arithmetic mean, SD and CV% alongside, if wanted, but not instead
+- [ ] n for each parameter, since it differs when lambda_z fails for some subjects
+
+## Presentation
+
+- [ ] Individual concentration-time profiles on both linear and semi-logarithmic axes
+- [ ] Mean profiles with a stated rule for handling BLQ in the mean
+- [ ] A table of individual parameters, not only summary statistics
+
+## Method and provenance
+
+- [ ] Software and version
+- [ ] Units for every parameter, and confirmation that dose and concentration units are consistent
+- [ ] Whether the analysis was pre-specified, and the reference to the plan
+- [ ] Any deviation from the plan, with its reason
+
+## The traps this checklist exists to catch
+
+1. Reporting AUCinf from a truncated steady-state profile.
+2. Interpolating Cmax, or reporting a mean Tmax.
+3. Quoting Vz as if it were Vss, or reporting Vss from oral data.
+4. Applying one BLQ rule to the test arm and another to the reference.
+5. Presenting arithmetic means for AUC and Cmax.
+6. Summarising across subjects without saying that lambda_z failed for some of them.
+7. Omitting the lambda_z window, which makes the half-life unreproducible.

package/skills/pkpd-modeling/assets/popk-analysis-plan.md

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+# Population Pharmacokinetic Analysis Plan
+
+> Template. Every bracketed field is a decision to make and record **before** the analysis starts.
+> A plan written after the modelling is not an analysis plan, and the difference is visible to a
+> reviewer.
+
+**Study/programme:** [ ]  **Compound:** [ ]  **Plan version and date:** [ ]
+**Author:** [ ]  **Reviewers:** [ ]
+
+---
+
+## 1. Objectives
+
+Primary objective: [ ]
+
+Each objective must name the decision it informs — a dose for the next study, a label statement, a
+covariate adjustment, a waiver. "Characterise the population pharmacokinetics" is not an objective;
+it is an activity.
+
+Secondary objectives: [ ]
+
+**Intended use of the model:** [ ] — regulators evaluate a model against its intended use, and the
+required rigour follows from it.
+
+## 2. Data
+
+| Item | Specification |
+| --- | --- |
+| Studies included | [ ] |
+| Analysis population | [ ] |
+| Analyte and matrix | [ ] |
+| Assay and LLOQ | [ ] (see the bioanalytical validation report) |
+| Time reference | actual elapsed time from the most recent dose |
+| Dataset specification | [ reference the document ] |
+| Derivation script | [ path / repository ] |
+
+**Exclusions**, defined now and applied blind to the model:
+
+- [ ] Records with no matching dose record
+- [ ] Concentrations flagged by the bioanalytical laboratory
+- [ ] Subjects with documented non-compliance
+- [ ] Pre-dose concentrations in a first-dose profile above [ ]% of Cmax
+- [ ] Other: [ ]
+
+**BLQ handling:** [ M1 / M3 / other ]. Justification: [ ]. Expected BLQ fraction: [ ]%.
+If the observed BLQ fraction exceeds [ ]%, the method changes to M3.
+
+**Missing covariates:** [ imputation rule, or exclusion ]. Missingness will be tabulated before
+imputation.
+
+## 3. Software
+
+| | |
+| --- | --- |
+| Estimation | [ NONMEM 7.x / Monolix / nlmixr2 ] version [ ] |
+| Orchestration and post-processing | [ Pharmpy / PsN / R ] version [ ] |
+| Estimation method | [ FOCE-I / SAEM followed by IMP ] |
+| Environment | [ container / lockfile reference ] |
+
+## 4. Structural model
+
+Starting point: [ ] compartments, [ ] absorption, [ ] elimination.
+
+Candidate structures to be evaluated: [ ]
+
+Parameterisation is clearance-based (CL, V, Q, Vp) in all candidates.
+
+Selection criteria, in this order: physiological plausibility; residual patterns; likelihood-ratio
+test for nested models (ΔOFV > [3.84] at 1 df); BIC; parameter precision. **An extra compartment
+whose intercompartmental clearance has RSE above [50]% is not retained regardless of the objective
+function.**
+
+## 5. Between-subject and between-occasion variability
+
+- IIV on: [ ] Distribution: [ exponential ]
+- Correlations estimated between: [ ]
+- IOV on: [ ], with an occasion defined as [ ]
+- Rule for removing a variance component: [ ]
+
+## 6. Residual error
+
+Candidates: [ proportional / additive / combined / log-transform-both-sides ]. Separate error
+models by [ study / assay / matrix ]: [ yes / no, with justification ].
+
+## 7. Covariate model
+
+**Covariates included a priori on mechanistic grounds, not tested:**
+
+- Body size: allometric scaling on CL (exponent [0.75], [fixed]) and V (exponent [1.0], [fixed])
+- Maturation, if paediatric subjects are included: [ function, parameters, fixed or estimated ]
+- Other: [ ]
+
+**Covariates to be evaluated:**
+
+| Covariate | Parameter(s) | Functional form | Rationale |
+| --- | --- | --- | --- |
+| [ ] | [ ] | [ ] | [ ] |
+
+**Procedure:** [ stepwise covariate modelling / full model estimation ].
+If stepwise: forward inclusion at p < [0.05] (ΔOFV > 3.84), backward elimination at p < [0.001]
+(ΔOFV > 10.83). Note that stepwise selection biases effect sizes upward and narrows intervals; a
+full-model approach is preferred where the objective is to quantify an effect.
+
+Clinical relevance threshold: a covariate effect is reported as relevant if it changes [ exposure
+metric ] by more than [ ]% across the [5th–95th] percentile of the covariate.
+
+## 8. Model evaluation
+
+- Goodness-of-fit: DV vs PRED and IPRED; CWRES vs time and vs PRED; |IWRES| vs IPRED
+- Eta shrinkage reported for every eta; covariate plots not interpreted above [30]% shrinkage
+- Prediction-corrected VPC, [ n ] replicates, stratified by [ ]
+- NPDE with tests of mean, variance and normality
+- Parameter uncertainty by [ covariance step / bootstrap (n = ) / SIR / log-likelihood profiling ]
+- Condition number reported; above 1000 is treated as ill-conditioned
+
+**Acceptance criteria for the final model:** [ ]
+
+## 9. Simulations
+
+Purpose: [ ]  Scenarios: [ ]  Replicates: [ ]  Population sampled from: [ ]
+Uncertainty in fixed effects propagated: [ yes / no ]  Endpoint summarised: [ ]
+
+## 10. Deviations
+
+Any departure from this plan is recorded in the report with its reason and the date it was decided.
+Post hoc analyses are labelled as such and reported separately from the pre-specified analysis.
+
+---
+
+**Approvals**
+
+| Role | Name | Signature | Date |
+| --- | --- | --- | --- |
+| Author | | | |
+| Reviewer | | | |
+| Clinical pharmacology | | | |