openpkpd 0.3.3

Open-source Python toolkit for population PK/PD analyses

OpenPKPD

Open-source Python toolkit for population PK/PD analysis, with a native Python API, NONMEM-style control-stream support, a CLI, and a Qt desktop GUI.

Contents

• Features
• Installation
• Desktop GUI
• Quick start
• Validation and benchmarking
• Running a NONMEM control stream
• HTML / PDF reports
• Diagnostic plots
• Parallel estimation and simulation
• Parallel bootstrap
• SBML / QSP model import
• Delay Differential Equations
• Examples
• Comparison with Other Tools
• Development
• Selected references
• Licence

Features

• Python API, NONMEM-style control streams, CLI, and desktop GUI on the same estimation engine
• FO/FOCE/FOCEI/Laplacian plus SAEM, IMP/IMPMAP, BAYES(Laplace), NUTS, and nonparametric estimation
• analytical ADVAN routes, numerical ODE solvers, DDE support, and broad PK/PD model families
• simulation, VPC/pcVPC, NPC, NPDE, NCA, sparse-sampling NCA, bootstrap, and optimal design
• NONMEM-compatible outputs, HTML/PDF reporting, SBML import, and parallel execution hooks
• 34 shipped examples, marimo notebooks, and extensive automated validation against exact references and external tools

Installation

pip install openpkpd                   # core library + CLI + SymPy analytical path
pip install "openpkpd[plots]"          # + matplotlib plotting/diagnostics
pip install "openpkpd[gui]"            # + Qt desktop GUI + matplotlib plot output
pip install "openpkpd[jit]"            # + Numba JIT (10–30× ODE speedup)
pip install "openpkpd[bayes]"          # + PyMC backend for BAYES
pip install "openpkpd[notebooks]"      # + marimo notebook runtime
pip install "openpkpd[r]"             # + optional rpy2 Python-R bridge
pip install "openpkpd[full]"           # + optimagic + matplotlib

With uv:

uv add openpkpd
uv add "openpkpd[plots]"
uv add "openpkpd[gui]"                 # GUI + plotting support
uv add "openpkpd[jit]"                 # Numba JIT — 10–30× ODE speedup
uv add "openpkpd[notebooks]"           # marimo notebooks

Optional extras:

• pip install dask[distributed] — distributed parallel execution
• pip install ray — Ray cluster execution
• pip install mpi4py — MPI backend
• pip install python-libsbml — SBML/QSP model import

openpkpd[full] does not include the GUI or Bayesian extras; install [gui] and/or [bayes] separately as needed. SymPy is part of the core dependency set because the symbolic analytical-kernel path is now treated as a first-class tested route.

The detailed “which extra should I install, and why?” guidance lives in docs/getting_started/installation.md.

Desktop GUI

Install the GUI extra (Qt/PySide6 + matplotlib), then launch the desktop application with:

pip install "openpkpd[gui]"   # one-time: installs PySide6 + matplotlib
openpkpd-gui                   # launch the desktop application

From a development checkout, these shortcuts are also supported:

uv run openpkpd-gui
just run-gui

The current GUI is organized around a workspace / project / scenario tree:

• selecting the Workspace root opens the workspace home page
• selecting a Project opens a project-details editor
• selecting a Scenario opens its Dashboard page
• scenario workflows branch into Data, Model, Fit, NCA, Covariate, Advanced, Results, and Diagnostics

The menu bar now carries the main shell actions:

• File for opening/saving .opkpd project snapshots
• Workspace for creating, duplicating, renaming, and snapshotting projects/scenarios
• Navigate for switching workflows
• Inputs for dataset import and NONMEM file loading
• Results for report/plot/diagnostic shortcuts
• Settings and Help for preferences and application info

Notable GUI pages and recent improvements:

• Dashboard summarizes scenario readiness, recommended next steps, recent activity, and available follow-on workflows
• Model supports two input modes selectable via radio buttons: Builder (form-based ADVAN/TRANS/parameter editor) and Control stream (plain-text .ctl editor). When a control stream is opened, its $DATA CSV is loaded onto the Data screen automatically. A dataset loaded on the Data screen takes priority over the control stream's $DATA path at fit time. Bundled example control streams are listed in a searchable dropdown (visible in Control stream mode). Every control group has a ? button showing an informative tooltip.
• Fit shows a "Fit in progress" status while an estimation job is running, preventing ambiguity with "Ready to start fit".
• Results keeps common actions visible and places secondary actions under More actions menus. CSV artifacts are now displayed as a rendered interactive table rather than raw text, and the page can jump directly to a strong sibling comparison scenario. Bayesian review actions are shown when the current run produced Bayesian posterior artifacts.
• Plots and Diagnostics provide focused artifact browsers and preview panes
• Advanced provides VPC, Bootstrap, Design, and Artifacts tabs, with secondary settings/log/preview panels hidden behind collapsible sections by default. The current Design tab fronts the implemented PFIM path, whose support boundary is intentionally narrower than the broadest residual-error structures advertised by some external tools; see the validation matrix and optimal-design example docs for the current envelope.

Quick start

from openpkpd import ModelBuilder

built = (
    ModelBuilder()
    .problem("Theophylline 1-cmt oral FOCE")
    .data("theo.csv")
    .subroutines(advan=2, trans=2)
    .pk("""
        KA = THETA(1) * EXP(ETA(1))
        CL = THETA(2) * EXP(ETA(2))
        V  = THETA(3) * EXP(ETA(3))
    """)
    .error("Y = F * (1 + EPS(1))")
    .theta([(0.01, 1.5, 20),
            (0.001, 0.08, 5),
            (0.1, 30, 500)])
    .omega([0.5, 0.3, 0.3])
    .sigma(0.1)
    .estimation(method="FOCE", interaction=True, maxeval=9999)
    .covariance()
    .build()
)

result = built.fit()
print(result.summary())
print("OFV:", result.ofv)
print("THETA:", result.theta_final)

See examples/ for 34 runnable examples covering FO/FOCE, control streams, FOCEI optimizer controls, VPC, NCA, optimal design, Bayesian estimation, SBML import, DDE, IOV, PBPK, advanced PD, IMP/IMPMAP warm-start comparison, nonparametric support-point estimation, TMDD, multidose steady-state NCA, and phenobarbital population PK. The Sphinx example section documents a curated subset of those scripts in more detail; shipped examples outnumber annotated worked-example pages.

The repository also ships a marimo notebook library under notebooks/; install openpkpd[notebooks] to run them locally.

Validation and benchmarking

The repository includes public cross-tool benchmarks under tests/external_validation/, including:

• Monolix-backed theophylline SAEM checks
• nlmixr2-backed FOCEI checks for theophylline and warfarin
• nlmixr2-backed SAEM checks for warfarin PK (32 subjects)
• Grasela & Donn (1985) SAEM checks for neonatal phenobarbital (59 subjects)
• nlmixr2 FOCEI basin anchor for warfarin BAYES(Laplace)
• NONMEM 402 empirical BAYES(Laplace) benchmark
• Pharmpy pheno and theophylline nonparametric empirical benchmarks
• PKNCA / Phoenix-style theophylline NCA checks
• WinNonlin-backed Indometh NCA checks from a published NonCompart validation paper
• PFIM-backed optimal-design checks and FOCEI diagnostic parity harnesses

Start with:

• docs/user_guide/validation_matrix.md
• docs/user_guide/external_validation_benchmarks.md
• docs/user_guide/testing.md
• docs/user_guide/validation.md

Running a NONMEM control stream

openpkpd run model.ctl
openpkpd run model.ctl --method FOCE --verbose
openpkpd parse model.ctl --json

from openpkpd.parser.control_stream import ControlStream
from openpkpd.cli.runner import run_model

cs = ControlStream.from_file("model.ctl")
result = run_model("model.ctl")

HTML / PDF reports

from openpkpd import export_html_report_to_pdf, write_pdf_report

result.to_html("report.html", params=built.params, title="My model")
result.to_pdf("report.pdf", params=built.params, title="My model")

write_pdf_report("report-copy.pdf", result, built.params, title="My model")
export_html_report_to_pdf("report.html", "report-from-html.pdf")

PDF export uses the optional Qt-based GUI runtime. Install openpkpd[gui] to enable result.to_pdf(...), write_pdf_report(...), and export_html_report_to_pdf(...).

Diagnostic plots

from openpkpd.plots.diagnostics import compute_diagnostics
from openpkpd.plots.gof import diagnostic_panel
from openpkpd.plots.pk import spaghetti_plot

diag_df = compute_diagnostics(built.population_model, result)

fig = diagnostic_panel(diag_df, title="My model — GOF")
fig.savefig("gof.png", dpi=150)

Parallel estimation and simulation

FOCE/FOCEI, IMP, and SimulationEngine accept n_parallel to distribute work across CPU cores. SAEM accepts n_workers directly on its constructor:

from openpkpd.estimation import get_estimation_method

# FOCE inner loop across 8 processes (true multi-core via ProcessPoolExecutor)
method = get_estimation_method("FOCE", n_parallel=8)
result = method.estimate(pop_model, params)

# IMP uses ThreadPoolExecutor (numpy releases the GIL)
imp = get_estimation_method("IMP", n_parallel=8)

# SAEM: pass n_workers (not n_parallel) for thread-based E-step parallelism
from openpkpd.estimation.saem import SAEMMethod
saem = SAEMMethod(n_iter_phase1=200, n_iter_phase2=100, n_workers=8)

# Simulation replicates in parallel
from openpkpd.simulation.engine import SimulationEngine
sim = SimulationEngine(pop_model, result, seed=42, n_parallel=8)
vpc_data = sim.simulate(n_replicates=500)

n_parallel=0 auto-selects the number of workers based on os.cpu_count(). n_parallel=1 (default) runs serially for reproducibility and debugging.

The GUI Preferences dialog exposes a CPU cores spinner that applies this setting globally to all fit and VPC jobs.

Parallel bootstrap

from openpkpd.parallel import get_backend

backend = get_backend(n_jobs=8)          # auto-selects Dask → Ray → multiprocessing
with backend:
    boot_results = backend.map(fit_replicate, bootstrap_datasets)

SBML / QSP model import

from openpkpd.io import load_sbml
from openpkpd.model.parameters import ParameterSet
from openpkpd.pk.ode.advan6 import ADVAN6

model = load_sbml("tumor_growth.xml")    # requires python-libsbml
advan = ADVAN6(n_compartments=model.n_compartments)
sol   = advan.solve(model.default_pk_params, dose_events, obs_times,
                    des_callable=model.des_callable)

# Fit SBML parameters
params = ParameterSet.from_specs(model.to_theta_specs(), [], [])

Delay Differential Equations

from openpkpd.pk.ode.dde import DDESubroutine

def my_dde(t, A, pk_params, theta, eta):
    hist = pk_params["_AHISTORY"]        # history function
    tau  = pk_params["TAU"]
    A_lag = hist(max(t - tau, 0.0))
    return [-(pk_params["CL"] / pk_params["V"]) * A_lag[0]]

dde = DDESubroutine(n_compartments=1)
sol = dde.solve({"CL": 2.0, "V": 10.0, "TAU": 0.5},
                dose_events, obs_times, des_callable=my_dde)

Examples

#	Topic	#	Topic
01	Theophylline 1-cmt oral — FO	18	Parallel bootstrap resampling
02	Warfarin FOCE with covariance step	19	Count and categorical PD models
03	Two-compartment IV bolus	20	SAEM estimation with OFV convergence history
04	Emax PD model	21	Laplacian estimation and prior augmentation
05	Indirect response model (IDR types 1–4)	22	5-organ PBPK model (lung, liver, kidney, gut, central)
06	From NONMEM control stream	23	Inter-occasion variability (IOV) modelling
07	Diagnostic plots	24	Advanced PD models: effect compartment, turnover, TGI, placebo
08	ODE transit absorption	25	FOCEI optimizer controls: L-BFGS-B, Powell fallback, multi-start, retry logic
09	Three-compartment ADVAN11/12	26	Control-stream optimizer extension inspection
10	Below-limit-of-quantification handling	27	Phenobarbital neonatal population PK — weight-based allometric scaling
11	Time-to-event survival model	28	Indometh NCA (Phoenix WinNonlin reference)
12	Non-compartmental analysis (NCA)	29	Optimal design (PFIM-backed sampling-time optimization)
13	Stepwise covariate modelling (SCM)	30	Four-compartment ADVAN5 (micro-rate) model
14	Simulation and VPC	31	IMP vs IMPMAP warm-start comparison on warfarin PK
15	Bayesian estimation via MAP and Laplace posterior approximation	32	Nonparametric support-point estimation on phenobarbital
16	Delay differential equation (DDE) model	33	TMDD / QSSA / Michaelis-Menten approximation comparison
17	SBML / QSP model import	34	Multi-dose steady-state NCA

Comparison with Other Tools

OpenPKPD is a pure-Python, open-source population PK/PD toolkit with native NONMEM-style control-stream parsing and an in-process estimation/simulation stack.

At a glance

Feature	OpenPKPD	NONMEM 7.6	Monolix 2024R1	WinNonLin 8.7	mrgsolve 1.5	Pumas.jl 2.5	Pharmpy 2.0
Open source	✓	—	—	—	✓	partial	✓
Pure Python / no install fee	✓	—	—	—	—	—	partial
NONMEM .ctl compatibility	✓	—	—	—	—	—	✓
FO / FOCE / FOCEI	✓	✓	✓	✓	—	✓	via NONMEM
SAEM	partial	✓	✓	—	—	✓	via NONMEM
Full Bayesian (NUTS/MCMC)	partial	✓	—	—	—	✓	—
Analytical PK (ADVAN1–4,11,12)	✓	✓	✓	✓	✓	✓	via NONMEM
ODE PK (ADVAN6/8/10)	✓	✓	✓	—	✓	✓	via NONMEM
Delay differential equations	✓	✓	—	—	—	✓	via NONMEM
PBPK / large ODE systems	✓	—	—	—	✓	✓	via NONMEM
NONMEM-compatible output (.lst/.ext/.phi/.cov)	✓	✓	—	—	—	—	✓
HTML report	✓	—	✓	✓	—	✓	✓
NCA (AUC, Cmax, t½, BE)	✓	—	✓	✓	—	✓	✓
Sparse sampling NCA	✓	—	✓	✓	—	✓	—
CDISC PP / ADPPK output	partial	—	—	✓	—	—	—
Missing covariate imputation	✓	✓	✓	✓	—	✓	✓
BLQ handling M1/M3/M4	✓	✓	✓	✓	—	✓	via NONMEM
IOV (inter-occasion variability)	✓	✓	✓	✓	—	✓	✓
Stepwise covariate modelling (SCM)	partial	via PsN	✓	—	—	✓	✓
VPC / bootstrap	✓	via PsN	✓	✓	—	✓	✓
SBML / QSP model import	✓	—	—	—	—	—	—
Parallel execution (multi-core / Dask / Ray)	✓	✓	✓	—	✓	✓	✓
GUI	partial	—	✓	✓	—	partial	—
R integration	✓	via PsN	—	✓	✓	—	✓

Legend: ✓ = primary / broadly validated support; partial = real but narrower, selectively benchmarked, or less mature than the strongest alternatives; via NONMEM = supported through NONMEM as a required backend; — = not available.

Note on Pharmpy: Pharmpy is a model manipulation and workflow library (Uppsala University). It reads, writes, and transforms NONMEM/nlmixr2 models and orchestrates tools such as SCM, VPC, and bootstrap, but delegates all parameter estimation to an external engine (NONMEM or nlmixr2). Rows marked "via NONMEM" require a separate NONMEM licence.

For the method-by-method support classification behind these labels, see docs/user_guide/validation_matrix.md.

Where OpenPKPD leads

• Native NONMEM-style control-stream parsing plus a built-in engine: inspect, run, and translate .ctl workflows without depending on a commercial backend.
• SBML/QSP import: load systems-biology models from BioModels / libSBML directly into the estimation pipeline.
• Delay differential equations: DDESubroutine (ADVAN16) with history-interpolation — unique among Python tools.
• NONMEM-format output: .lst, .ext, .phi, .cov, .cor files readable by Xpose, PsN, and Certara tools.
• CDISC output: PP domain (NCA) and ADPPK-style CSV for regulatory data exchange.
• Sparse sampling NCA: model-informed profile reconstruction for 2–5-sample-per-subject designs.
• Broad feature coverage in one repository: estimation, NCA, simulation, bootstrap, SCM, reporting, and a desktop GUI live together in the same codebase.

Where OpenPKPD trails

• Speed: Pure-Python inner loops are slower than compiled C++ (mrgsolve) or Julia (Pumas) for large simulations. The optional openpkpd[jit] extra closes much of this gap for ODE models (10–30× speedup via Numba LLC tier), but estimation outer loops and analytical ADVAN subroutines remain Python-speed.
• SAEM convergence: functional but less mature than specialized SAEM software; Monolix and Pumas have deeper convergence diagnostics and tuning options.
• Advanced-estimator breadth: SAEM, IMP/IMPMAP, BAYES(Laplace), native NUTS, and nonparametric estimation are real surfaces, but most still have narrower external-validation envelopes than FO/FOCEI.
• GUI scope: OpenPKPD ships a working desktop GUI, but it is narrower and less mature than the commercial GUI-first workflows in WinNonLin and Monolix.
• Regulatory validation: NONMEM and WinNonLin are GxP-validated commercial products; OpenPKPD is research-grade.

Full feature comparison: docs/user_guide/comparison.md

Development

git clone https://github.com/breisfeld/OpenPKPD.git
cd openpkpd
uv sync --all-extras
uv run pytest -q

If you specifically want the symbolic analytical-kernel path active in a source checkout, use:

uv sync --extra dev --extra symbolic
just prewarm-symbolic-caches

For common source-checkout workflows, the repository also includes a cross-platform justfile that selects the needed uv extras automatically:

just run-tests-unit
just lint
just build-docs-html
just install-hooks

See docs/contributing.md for the fuller contributor workflow.

Notes: Much of the code in the code base was created by Claude AI under careful guidance and review. As with all PRs, those using AI will be considered if they have been carefully vetted and tested by the human submitter.

Selected references

A complete, annotated bibliography is in docs/user_guide/citations.md. Key primary sources for the implemented algorithms are listed below.

Estimation

• Sheiner LB, Beal SL (1980, 1983). Evaluation of methods for estimating population pharmacokinetic parameters. J Pharmacokinet Biopharm 8:553–571; 11:303–319. (FO / FOCE foundation.)
• Delyon B, Lavielle M, Moulines E (1999). Convergence of a stochastic approximation version of the EM algorithm. Ann Stat 27:94–128. (SAEM.)
• Kuhn E, Lavielle M (2004). Coupling a stochastic approximation version of EM with an MCMC procedure. ESAIM Probab Stat 8:115–131. (SAEM Rao–Blackwellisation.)
• Mallet A (1986). A maximum likelihood estimation method for random coefficient regression models. Biometrika 73:645–656. (Nonparametric NPML.)
• Byrd RH, Lu P, Nocedal J, Zhu C (1995). A limited memory algorithm for bound constrained optimization. SIAM J Sci Comput 16:1190–1208. (L-BFGS-B outer optimizer.)

Covariance step

• White H (1982). Maximum likelihood estimation of misspecified models. Econometrica 50:1–25. (Sandwich R⁻¹SR⁻¹ estimator.)

PK/PD models

• Savic RM, Jonker DM, Kerbusch T, Karlsson MO (2007). Implementation of a transit compartment model for describing drug absorption. J Pharmacokinet Pharmacodyn 34:711–726.
• Sheiner LB, Stanski DR, Vozeh S, Miller RD, Ham J (1979). Simultaneous modeling of pharmacokinetics and pharmacodynamics. Clin Pharmacol Ther 25:358–371. (Effect compartment / link model.)
• Dayneka NL, Garg V, Jusko WJ (1993). Comparison of four basic models of indirect pharmacodynamic responses. J Pharmacokinet Biopharm 21:457–478. (IDR types I–IV.)
• Mager DE, Jusko WJ (2001). General pharmacokinetic model for drugs exhibiting target-mediated drug disposition. J Pharmacokinet Pharmacodyn 28:507–532. (TMDD full model.)
• Simeoni M, et al. (2004). Predictive pharmacokinetic-pharmacodynamic modeling of tumor growth kinetics. Cancer Res 64:1094–1101.

NCA and diagnostics

• Schuirmann DJ (1987). A comparison of the two one-sided tests procedure for assessing bioequivalence. J Pharmacokinet Biopharm 15:657–680.
• Karlsson MO, Holford N (2008). A tutorial on visual predictive checks. PAGE 17, Abstr 1434.
• Brendel K, Comets E, Laffont C, Laveille C, Mentré F (2006). Metrics for external model evaluation. Pharm Res 23:2036–2049. (NPDE.)

Covariate modelling and optimal design

• Jonsson EN, Karlsson MO (1998). Automated covariate model building within NONMEM. Pharm Res 15:1463–1468. (SCM.)
• Mentré F, Mallet A, Baccar D (1997). Optimal design in random-effects regression models. Biometrika 84:429–442. (Population FIM / PFIM.)

Licence

AGPLv3 — see LICENSE for details.