Reporting guidelines for population pharmacokinetic analyses.

The purpose of this work was to develop a consolidated set of guiding principles for the reporting of population pharmacokinetic (PK) analyses based on input from a survey of practitioners as well as discussions between industry, consulting, and regulatory scientists. The survey found that identification of population covariate effects on drug exposure and support for dose selection (in which population PK frequently serves as preparatory analysis for exposure-response modeling) are the main areas of influence for population PK analysis. The proposed guidelines consider 2 main purposes of population PK reports: (1) to present key analysis findings and their impact on drug development decisions, and (2) as documentation of the analysis methods for the dual purpose of enabling review of the analysis and facilitating future use of the models. This work also identified 2 main audiences for the reports: (1) a technically competent group responsible for in-depth review of the data, methodology, and results; and (2) a scientifically literate but not technically adept group, whose main interest is in the implications of the analysis for the broader drug development program. We recommend a generalized question-based approach with 6 questions that need to be addressed throughout the report. We recommend 8 sections (Synopsis, Introduction, Data, Methods, Results, Discussion, Conclusions, Appendix) with suggestions for the target audience and level of detail for each section. A section providing general expectations regarding population PK reporting from a regulatory perspective is also included. We consider this an important step toward industrialization of the field of pharmacometrics such that a nontechnical audience also understands the role of pharmacometric analyses in decision making. Population PK reports were chosen as representative reports to derive these recommendations; however, the guiding principles presented here are applicable for all pharmacometric reports including pharmacokinetics/pharmacodynamics and simulation reports.

Reporting guidelines for population pharmacokinetic analyses.

The purpose of this work was to develop a consolidated set of guiding principles for reporting of population pharmacokinetic (PK) analyses based on input from a survey of practitioners as well as discussions between industry, consulting and regulatory scientists. The survey found that identification of population covariate effects on drug exposure and support for dose selection (where population PK frequently serves as preparatory analysis to exposure-response modeling) are the main areas of influence for population PK analysis. The proposed guidelines consider two main purposes of population PK reports (1) to present key analysis findings and their impact on drug development decisions, and (2) as documentation of the analysis methods for the dual purpose of enabling review of the analysis and facilitating future use of the models. This work also identified two main audiences for the reports: (1) a technically competent group responsible for in-depth review of the data, methodology, and results, and (2) a scientifically literate, but not technically adept group, whose main interest is in the implications of the analysis for the broader drug development program. We recommend a generalized question-based approach with six questions that need to be addressed throughout the report. We recommend eight sections (Synopsis, Introduction, Data, Methods, Results, Discussion, Conclusions, Appendix) with suggestions for the target audience and level of detail for each section. A section providing general expectations regarding population PK reporting from a regulatory perspective is also included. We consider this an important step towards industrialization of the field of pharmacometrics such that non-technical audience also understands the role of pharmacometrics analyses in decision making. Population PK reports were chosen as representative reports to derive these recommendations; however, the guiding principles presented here are applicable for all pharmacometric reports including PKPD and simulation reports.

Grey-box pharmacokinetic/pharmacodynamic modelling of a euglycaemic clamp study.

Grey-box pharmacokinetic/pharmacodynamic (PK/PD) modelling is presented as a promising way of modelling the pharmacokinetics and pharmacodynamics of the in vivo system of insulin and glucose and to estimate model and derived PK/PD parameters. The concept behind grey-box modelling consists in using a priori physiological knowledge along with information from data in the estimation of model parameters. The PK/PD properties of two types of insulin are investigated in a euglycaemic clamp study where a single bolus of insulin is injected subcutaneously. The effect of insulin on the glucose disappearance is investigated by artificially maintaining a blood glucose concentration close to the normal fasting level. The infused glucose needed to maintain the clamped blood glucose concentration can therefore be used as a measure for the glucose utilization. The PK and PD parameters are successfully estimated simultaneously thereby describing the uptake, distribution, and effect of the two different types of insulin.