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nca-conventions.md

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1# NCA conventions and reproducibility

NCA conventions and reproducibility

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3## Define the estimand before integration

5Record dose, analyte, matrix, actual times, concentration units, assay/LLOQ and dose history.

6AUC(0-t), AUC(0-inf) after a single dose, and AUC(0-tau) at steady state are different quantities.

7The helper integrates from the first retained sample and does not extrapolate to time zero.

8For an IV bolus this omits early exposure if C0 was not sampled or independently estimated.

10| Decision | Bundled implementation | Report |

11| --- | --- | --- |

12| Trapezoids | Linear, linear-up/log-down, or log for any positive unequal endpoints | Rule and zero/equal-endpoint fallback |

13| BLQ | Global zero, half-LLOQ, or missing | Location-dependent preprocessing, if applied |

14| Missing values | Blank concentration is treated as BLQ | Remove truly missing samples before analysis |

15| Lambda_z | At least three positive non-BLQ post-Tmax points; negative slope | Selected times, count, adjusted R², span in half-lives |

16| Tail | Observed and predicted Clast alternatives | Which AUCinf drove CL/F and Vz/F |

17| Partial AUC | Interpolate only inside sampled bounds | Prespecified boundaries and interpolation rule |

19The log-down AUC segment is `dt*(C1-C2)/log(C1/C2)`. Equal endpoints require the linear limit.

20AUMC uses integration of t*C, not the trapezoidal rule on transformed log concentrations.

21Sorting is explicit: NumPy's `trapezoid` integrates in the supplied order and does not sort.

22[NumPy documentation](https://numpy.org/doc/stable/reference/generated/numpy.trapezoid.html).

Define the estimand before integration

Record dose, analyte, matrix, actual times, concentration units, assay/LLOQ and dose history. AUC(0-t), AUC(0-inf) after a single dose, and AUC(0-tau) at steady state are different quantities. The helper integrates from the first retained sample and does not extrapolate to time zero. For an IV bolus this omits early exposure if C0 was not sampled or independently estimated.

Decision	Bundled implementation	Report
Trapezoids	Linear, linear-up/log-down, or log for any positive unequal endpoints	Rule and zero/equal-endpoint fallback
BLQ	Global zero, half-LLOQ, or missing	Location-dependent preprocessing, if applied
Missing values	Blank concentration is treated as BLQ	Remove truly missing samples before analysis
Lambda_z	At least three positive non-BLQ post-Tmax points; negative slope	Selected times, count, adjusted R², span in half-lives
Tail	Observed and predicted Clast alternatives	Which AUCinf drove CL/F and Vz/F
Partial AUC	Interpolate only inside sampled bounds	Prespecified boundaries and interpolation rule

The log-down AUC segment is dt*(C1-C2)/log(C1/C2). Equal endpoints require the linear limit. AUMC uses integration of t*C, not the trapezoidal rule on transformed log concentrations. Sorting is explicit: NumPy's trapezoid integrates in the supplied order and does not sort. NumPy documentation.

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24## Terminal phase

26Automatic selection begins with the last three eligible points and extends backwards only when

27adjusted R² improves by more than 0.0001. This differs from Phoenix Best Fit, which favors a longer

28window within its tolerance of the best score. Tmax exclusion here applies even to IV bolus.

29Use a manual window when scientifically justified; it still needs three declining post-Tmax points.

30A predicted Clast is evaluated at the last quantifiable time, even if the selected window ends earlier.

31[Phoenix 8.4 guide](https://onlinehelp.certara.com/phoenix/8.4/responsive_html5_%21MasterPage%21/WinNonlin_Guide.pdf).

33A good regression can reflect absorption-limited decline, distribution or assay artifacts rather

34than elimination. Plot the fit. Screening flags (20% extrapolated AUC, adjusted R² below 0.8,

35span below two half-lives) are not universal exclusion criteria. State any exclusion rule prospectively.

Terminal phase

Automatic selection begins with the last three eligible points and extends backwards only when adjusted R² improves by more than 0.0001. This differs from Phoenix Best Fit, which favors a longer window within its tolerance of the best score. Tmax exclusion here applies even to IV bolus. Use a manual window when scientifically justified; it still needs three declining post-Tmax points. A predicted Clast is evaluated at the last quantifiable time, even if the selected window ends earlier. Phoenix 8.4 guide.

A good regression can reflect absorption-limited decline, distribution or assay artifacts rather than elimination. Plot the fit. Screening flags (20% extrapolated AUC, adjusted R² below 0.8, span below two half-lives) are not universal exclusion criteria. State any exclusion rule prospectively.

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37## Parameter identities and route

39- `t_half=log(2)/lambda_z`; `AUCinf=AUClast+Clast/lambda_z`.

40- Single-dose `CL=D/AUCinf` for IV, `CL/F=D/AUCinf` for extravascular input.

41- `Vz=CL/lambda_z` differs from `Vss=CL*MRT`.

42- IV infusion MRT needs correction for mean input time (duration/2 for constant infusion).

43- Oral MRT contains mean absorption time; it cannot directly determine Vss.

44- At demonstrated steady state, `CLss(/F)=D/AUCtau` and `Cavg=AUCtau/tau`.

46With `--tau`, provide exactly one sampled interval including its boundaries. The helper withholds

47single-dose AUCinf/CL/Vz/Vss and explicitly records the steady-state assumption. It does not test

48whether the patient or simulated system has actually reached steady state. BLQ substitution and

49unmeasured early exposure remain sensitivity analyses, not biological measurements.

Parameter identities and route

t_half=log(2)/lambda_z; AUCinf=AUClast+Clast/lambda_z.
Single-dose CL=D/AUCinf for IV, CL/F=D/AUCinf for extravascular input.
Vz=CL/lambda_z differs from Vss=CL*MRT.
IV infusion MRT needs correction for mean input time (duration/2 for constant infusion).
Oral MRT contains mean absorption time; it cannot directly determine Vss.
At demonstrated steady state, CLss(/F)=D/AUCtau and Cavg=AUCtau/tau.

With --tau, provide exactly one sampled interval including its boundaries. The helper withholds single-dose AUCinf/CL/Vz/Vss and explicitly records the steady-state assumption. It does not test whether the patient or simulated system has actually reached steady state. BLQ substitution and unmeasured early exposure remain sensitivity analyses, not biological measurements.

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