Journal of Pharmacokinetics and Pharmacodynamics

, Volume 42, Issue 6, pp 627–637 | Cite as

A pharmacometric case study regarding the sensitivity of structural model parameter estimation to error in patient reported dosing times

  • Jonathan KnightsEmail author
  • Shashank Rohatagi
Original Paper


Although there is a body of literature focused on minimizing the effect of dosing inaccuracies on pharmacokinetic (PK) parameter estimation, most of the work centers on missing doses. No attempt has been made to specifically characterize the effect of error in reported dosing times. Additionally, existing work has largely dealt with cases in which the compound of interest is dosed at an interval no less than its terminal half-life. This work provides a case study investigating how error in patient reported dosing times might affect the accuracy of structural model parameter estimation under sparse sampling conditions when the dosing interval is less than the terminal half-life of the compound, and the underlying kinetics are monoexponential. Additional effects due to noncompliance with dosing events are not explored and it is assumed that the structural model and reasonable initial estimates of the model parameters are known. Under the conditions of our simulations, with structural model CV % ranging from ~20 to 60 %, parameter estimation inaccuracy derived from error in reported dosing times was largely controlled around 10 % on average. Given that no observed dosing was included in the design and sparse sampling was utilized, we believe these error results represent a practical ceiling given the variability and parameter estimates for the one-compartment model. The findings suggest additional investigations may be of interest and are noteworthy given the inability of current PK software platforms to accommodate error in dosing times.


Population pharmacokinetics Simulation Dosing inaccuracies Reporting error Parameter Estimation 



The authors would like to thank Timothy Goggin for his valuable comments during the editorial process.

Compliance with ethical standards

Conflict of interest

The authors declare that there are no conflicts of interest.

Supplementary material

10928_2015_9428_MOESM1_ESM.docx (2.5 mb)
Supplementary material 1 (DOCX 2554 kb)
10928_2015_9428_MOESM2_ESM.pdf (80 kb)
Supplementary material 2 (PDF 80 kb)


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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  1. 1.Otsuka Pharmaceutical Development & Commercialization, Inc.PrincetonUSA

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