Overview of model-building strategies in population PK/PD analyses: 2002-2004 literature survey

Abstract

Aims: A descriptive survey of published population pharmacokinetic and/or pharmacodynamic (PK/PD) analyses from 2002 to 2004 was conducted and an evaluation made of how model building was performed and reported.

Methods: We selected 324 articles in Pubmed using defined keywords. A data abstraction form (DAF) was then built comprising two parts: general characteristics including article identification, context of the analysis, description of clinical studies from which the data arose, and model building, including description of the processes of modelling. The papers were examined by two readers, who extracted the relevant information and transmitted it directly to a MySQL database, from which descriptive statistical analysis was performed.

Results: Most published papers concerned patients with severe pathology and therapeutic classes suffering from narrow therapeutic index and/or high PK/PD variability. Most of the time, modelling was performed for descriptive purposes, with rich rather than sparse data and using NONMEM software. PK and PD models were rarely complex (one or two compartments for PK; E(max) for PD models). Covariate testing was frequently performed and essentially based on the likelihood ratio test. Based on a minimal list of items that should systematically be found in a population PK-PD analysis, it was found that only 39% and 8.5% of the PK and PD analyses, respectively, published from 2002 to 2004 provided sufficient detail to support the model-building methodology.

Conclusions: This survey allowed an efficient description of recent published population analyses, but also revealed deficiencies in reporting information on model building.

Figure 1

Screening of the articles selected in Pubmed using exclusion criteria (exclusion criteria were not mutually exclusive)

Figure 2

(A) Journals in which articles on population PK/PD (n = 324) were most frequently published; other: journals in which <5% of the papers were found. (B) Therapeutic classes most frequently studied in population PK/PD articles (n = 324); other: therapeutic classes found in <5% of the papers

Figure 3

Number of compartments of each PK model (n = 360, left side) and PD model types (n = 118, right side). The different types of PD models are defined by: E_max models (1), indirect models (2), physiological models (3), other models for continuous data (including linear, exponential, power and log linear models) (4), or models for noncontinuous data (including Cox, logistic and time to event models, and models for count or ordered categorical data) (5). The percentage is indicated if only = 5%

Figure 4

Description level of PK (n = 360) and PD (n = 118) model building. The grey part of each column represents the percentage of models with reported information; the white part, models with no reported information. Information is defined by the number of subjects and number of observations (total or per patient) included in the model, in respective columns (1) and (2), type of Inter-Individual Variability model in column (3), nature of error model in column (4), and description of criteria used in model building in column (5). The percentage is indicated only if = 5%. (Yes, (); No, (□))