Covariate modeling in pharmacometrics: General points for consideration.

Modeling the relationships between covariates and pharmacometric model parameters is a central feature of pharmacometric analyses. The information obtained from covariate modeling may be used for dose selection, dose individualization, or the planning of clinical studies in different population subgroups. The pharmacometric literature has amassed a diverse, complex, and evolving collection of methodologies and interpretive guidance related to covariate modeling. With the number and complexity of technologies increasing, a need for an overview of the state of the art has emerged. In this article the International Society of Pharmacometrics (ISoP) Standards and Best Practices Committee presents perspectives on best practices for planning, executing, reporting, and interpreting covariate analyses to guide pharmacometrics decision making in academic, industry, and regulatory settings.

Generation and application of avatars in pharmacometric modelling.

Simulations from population models have critical applications in drug discovery and development. Avatars or digital twins, defined as individual simulations matching clinical criteria of interest compared to observations from a real subject within a predefined margin of accuracy, may be a better option for simulations performed to inform future drug development stages in cases where an adequate model is not achievable. The aim of this work was to (1) investigate methods for generating avatars with pharmacometric models, and (2) explore the properties of the generated avatars to assess the impact of the different selection settings on the number of avatars per subject, their closeness to the individual observations, and the properties of the selected samples subset from the theoretical model parameters probability density function. Avatars were generated using different combinations of nature and number of clinical criteria, accuracy of agreement, and/or number of simulations for two examples models previously published (hemato-toxicity and integrated glucose-insulin model). The avatar distribution could be used to assess the appropriateness of the models assumed parameter distribution. Similarly it could be used to assess the models ability to properly describe the trajectories of the observations. Avatars can give nuanced information regarding the ability of a model to simulate data similar to the observations both at the population and at the individual level. Further potential applications for avatars may be as a diagnostic tool, an alternative to simulations with insurance to replicate key clinical features, and as an individual measure of model fit.

Comparison of Seven Non-Linear Mixed Effect Model-Based Approaches to Test for Treatment Effect.

Analyses of longitudinal data with non-linear mixed-effects models (NLMEM) are typically associated with high power, but sometimes at the cost of inflated type I error. Approaches to overcome this problem were published recently, such as model-averaging across drug models (MAD), individual model-averaging (IMA), and combined Likelihood Ratio Test (cLRT). This work aimed to assess seven NLMEM approaches in the same framework: treatment effect assessment in balanced two-armed designs using real natural history data with or without the addition of simulated treatment effect. The approaches are MAD, IMA, cLRT, standard model selection (STDs), structural similarity selection (SSs), randomized cLRT (rcLRT), and model-averaging across placebo and drug models (MAPD). The assessment included type I error, using Alzheimer's Disease Assessment Scale-cognitive (ADAS-cog) scores from 817 untreated patients and power and accuracy in the treatment effect estimates after the addition of simulated treatment effects. The model selection and averaging among a set of pre-selected candidate models were driven by the Akaike information criteria (AIC). The type I error rate was controlled only for IMA and rcLRT; the inflation observed otherwise was explained by the placebo model misspecification and selection bias. Both IMA and rcLRT had reasonable power and accuracy except under a low typical treatment effect.

Assessing Treatment Effects with Pharmacometric Models: A New Method that Addresses Problems with Standard Assessments.

Longitudinal pharmacometric models offer many advantages in the analysis of clinical trial data, but potentially inflated type I error and biased drug effect estimates, as a consequence of model misspecifications and multiple testing, are main drawbacks. In this work, we used real data to compare these aspects for a standard approach (STD) and a new one using mixture models, called individual model averaging (IMA). Placebo arm data sets were obtained from three clinical studies assessing ADAS-Cog scores, Likert pain scores, and seizure frequency. By randomly (1:1) assigning patients in the above data sets to "treatment" or "placebo," we created data sets where any significant drug effect was known to be a false positive. Repeating the process of random assignment and analysis for significant drug effect many times (N = 1000) for each of the 40 to 66 placebo-drug model combinations, statistics of the type I error and drug effect bias were obtained. Across all models and the three data types, the type I error was (5th, 25th, 50th, 75th, 95th percentiles) 4.1, 11.4, 40.6, 100.0, 100.0 for STD, and 1.6, 3.5, 4.3, 5.0, 6.0 for IMA. IMA showed no bias in the drug effect estimates, whereas in STD bias was frequently present. In conclusion, STD is associated with inflated type I error and risk of biased drug effect estimates. IMA demonstrated controlled type I error and no bias.

Comparison of covariate selection methods with correlated covariates: prior information versus data information, or a mixture of both?

The inclusion of covariates in population models during drug development is a key step to understanding drug variability and support dosage regimen proposal, but high correlation among covariates often complicates the identification of the true covariate. We compared three covariate selection methods balancing data information and prior knowledge: (1) full fixed effect modelling (FFEM), with covariate selection prior to data analysis, (2) simplified stepwise covariate modelling (sSCM), data driven selection only, and (3) Prior-Adjusted Covariate Selection (PACS) mixing both. PACS penalizes the a priori less likely covariate model by adding to its objective function value (OFV) a prior probability-derived constant: [Formula: see text], Pr(X) being the probability of the more likely covariate. Simulations were performed to compare their external performance (average OFV in a validation dataset of 10,000 subjects) in selecting the true covariate between two highly correlated covariates: 0.5, 0.7, or 0.9, after a training step on datasets of 12, 25 or 100 subjects (increasing power). With low power data no method was superior, except FFEM when associated with highly correlated covariates ([Formula: see text]), sSCM and PACS suffering both from selection bias. For high power data, PACS and sSCM performed similarly, both superior to FFEM. PACS is an alternative for covariate selection considering both the expected power to identify an anticipated covariate relation and the probability of prior information being correct. A proposed strategy is to use FFEM whenever the expected power to distinguish between contending models is < 80%, PACS when > 80% but < 100%, and SCM when the expected power is 100%.

Development of visual predictive checks accounting for multimodal parameter distributions in mixture models.

The assumption of interindividual variability being unimodally distributed in nonlinear mixed effects models does not hold when the population under study displays multimodal parameter distributions. Mixture models allow the identification of parameters characteristic to a subpopulation by describing these multimodalities. Visual predictive check (VPC) is a standard simulation based diagnostic tool, but not yet adapted to account for multimodal parameter distributions. Mixture model analysis provides the probability for an individual to belong to a subpopulation (IPmix) and the most likely subpopulation for an individual to belong to (MIXEST). Using simulated data examples, two implementation strategies were followed to split the data into subpopulations for the development of mixture model specific VPCs. The first strategy splits the observed and simulated data according to the MIXEST assignment. A shortcoming of the MIXEST-based allocation strategy was a biased allocation towards the dominating subpopulation. This shortcoming was avoided by splitting observed and simulated data according to the IPmix assignment. For illustration purpose, the approaches were also applied to an irinotecan mixture model demonstrating 36% lower clearance of irinotecan metabolite (SN-38) in individuals with UGT1A1 homo/heterozygote versus wild-type genotype. VPCs with segregated subpopulations were helpful in identifying model misspecifications which were not evident with standard VPCs. The new tool provides an enhanced power of evaluation of mixture models.

Phenobarbital in intensive care unit pediatric population: predictive performances of population pharmacokinetic model.

An external evaluation of phenobarbital population pharmacokinetic model described by Marsot et al. was performed in pediatric intensive care unit. Model evaluation is an important issue for dose adjustment. This external evaluation should allow confirming the proposed dosage adaptation and extending these recommendations to the entire intensive care pediatric population. External evaluation of phenobarbital published population pharmacokinetic model of Marsot et al. was realized in a new retrospective dataset of 35 patients hospitalized in a pediatric intensive care unit. The published population pharmacokinetic model was implemented in nonmem 7.3. Predictive performance was assessed by quantifying bias and inaccuracy of model prediction. Normalized prediction distribution errors (NPDE) and visual predictive check (VPC) were also evaluated. A total of 35 infants were studied with a mean age of 33.5 weeks (range: 12 days-16 years) and a mean weight of 12.6 kg (range: 2.7-70.0 kg). The model predicted the observed phenobarbital concentrations with a reasonable bias and inaccuracy. The median prediction error was 3.03% (95% CI: -8.52 to 58.12%), and the median absolute prediction error was 26.20% (95% CI: 13.07-75.59%). No trends in NPDE and VPC were observed. The model previously proposed by Marsot et al. in neonates hospitalized in intensive care unit was externally validated for IV infusion administration. The model-based dosing regimen was extended in all pediatric intensive care unit to optimize treatment. Due to inter- and intravariability in pharmacokinetic model, this dosing regimen should be combined with therapeutic drug monitoring.