Validation Benchmark

Automated NCA computation validation using the Theophylline Subject 1 standard dataset. All tests compare computed parameters against published reference values from established pharmacokinetic textbooks.

Methodology

This benchmark validates the PK-NCA Suite computation engine against established pharmacokinetic reference values. The validation approach follows standard bioanalytical method principles:

  • Dataset: Theophylline Subject 1 — an 11-point oral PK profile (Dose = 319.992 mg), widely used as a standard reference in pharmacokinetic textbooks.
  • Integration Method: Linear-up Log-down trapezoidal rule. Ascending segments use the linear trapezoidal formula; descending segments use the log-linear formula, as described in Gabrielsson & Weiner (2016, §10.1.2).
  • AUMC Calculation: Log-linear AUMC uses the exact integral formula: AUMC = Δt·(t₁C₁ − t₂C₂)/lnDiff + Δt²·(C₁ − C₂)/lnDiff² where lnDiff = ln(C₁) − ln(C₂).
  • λz Selection: Best Fit algorithm with adjusted R² maximization, minimum 3 points, exclusion of Cmax.
  • Scoring: Each test parameter receives an accuracy score: Accuracy = max(0, 1 − |Δ|/Expected) × 100%. The overall benchmark score is the geometric mean of individual accuracies.
  • Tolerance-based pass/fail: Each parameter has an absolute tolerance threshold derived from published rounding conventions and inter-software variability (typically <1% relative).

References

  1. Gabrielsson J, Weiner D. Pharmacokinetic & Pharmacodynamic Data Analysis: Concepts and Applications. 5th ed. Stockholm: Swedish Pharmaceutical Press; 2016. — Primary reference for trapezoidal integration formulae (§10.1.2), AUMC calculation, and MRT derivation.
  2. Rowland M, Tozer TN. Clinical Pharmacokinetics and Pharmacodynamics: Concepts and Applications. 4th ed. Philadelphia: Lippincott Williams & Wilkins; 2010. — Standard textbook definitions of NCA parameters (Cmax, Tmax, AUC, CL/F, Vd/F).
  3. Gibaldi M, Perrier D. Pharmacokinetics. 2nd ed. New York: Marcel Dekker; 1982. — Classical derivation of linear-up log-down trapezoidal method and extrapolation formulae.
  4. Wagner JG. Fundamentals of Clinical Pharmacokinetics. Hamilton, IL: Drug Intelligence Publications; 1975. — Terminal phase regression methodology and Best Fit λz algorithm foundations.
  5. FDA Guidance for Industry. Bioanalytical Method Validation. U.S. Department of Health and Human Services; 2018. — Regulatory context for analytical validation and acceptable tolerance criteria.
  6. Zhang Y, Huo M, Zhou J, Xie S. PKSolver: An add-in program for pharmacokinetic and pharmacodynamic data analysis in Microsoft Excel. Comput Methods Programs Biomed. 2010;99(3):306-314. — Cross-validation reference for NCA implementations.