Exposure-response Analysis for Spontaneously Reported Dizziness in Pregabalin-treated Patient With Generalized Anxiety Disorder

Abstract

To describe the pregabalin exposure-adverse event (AE) (dizziness) relationship in patients with generalized anxiety disorder, separate models were developed for the incidence of AE and for the conditional severity of AE, given that an AE has occurred using patient data from six clinical studies. The incidence component was modeled using a nonlinear logistic regression model. The conditional severity component was modeled as an ordered categorical variable with a proportional odds model to capture the severity on any given day. A Markov element was introduced to account for the correlation between neighboring observations. The proportional odds model including a time course of appearance and disappearance of AE could adequately describe the time course of probability of dizziness. Incorporating a transition model including Markov elements improved the model fit and greatly improved the predictability of the time course of probability of dizziness.

Pharmacodynamic Differentiation of Lorazepam Sleepiness and Dizziness Using an Ordered Categorical Measure

“…The 2 mg dose of drug selected in this study is within the range of recommended daily doses of lorazepam for maintenance treatment of generalized anxiety disorder. Studies modeling the intensity of drug AEs over time are relatively uncommon,19, 20 and no studies have formally applied population PK/PD analyses in differentiation of AEs.…”

“…The current logistic or proportional odds model assumes independence of neighboring consecutive categorical observations as a function of time. The Markov or transition model19, 20 which determines the conditional probability of reporting an observation at time t given the previous observation, and therefore assumes dependence between these observations, would be a valid model to test because data were collected frequently and longitudinally over time. The PPC analysis of the number of different categorical transitions for both lorazepam sleepiness and dizziness simulated form the logistic models, show that the observed population mean lies within the posterior distributions for the number of the different transitions.…”

“…The current logistic model assumes independence of two consecutive categorical observations measured as a function of time. To test that this assumption is reasonable, the posterior distribution of the number of different transitions19, 20 from the logistic model were generated for both lorazepam sleepiness and dizziness and overlaid on the observed mean value.…”

The Use of Clinical Utility Assessments in Early Clinical Development

“…Occurrence of safety/tolerability events do range from very rare to frequent, and oftentimes, concurrent severity data are not available or not considered in a quantifiable manner. Additionally, due to a lack of adequate data availability, large variability and complex modeling required, there are only a few examples in literature for safety data modeling (25)(26)(27). Perhaps the most prominent safety data modeling is the PK/ PD modeling of the QTc interval prolongation (28,29) due to some very high profile drug recalls from the market.…”

Implementation and Evaluation of the SAEM Algorithm for Longitudinal Ordered Categorical Data with an Illustration in Pharmacokinetics–Pharmacodynamics

“…Mixed effect analyses are increasingly employed for the analysis of longitudinal efficacy or safety categorical data measured in clinical trials (1)(2)(3)(4)(5). For this purpose, proportional odds model are frequently used.…”