Bojan Lalovic, Matthew M Hutmacher, Bill Frame, Kaori Ito, Raymond Miller Pfizer
Background: Dizziness and somnolence are the predominant adverse events (AEs) reported in the treatment of Generalized Anxiety Disorder (GAD) with pregabalin, representing a major
determinant of study withdrawal (dropout). Various ad-hoc administration regimens (titration schemes) have been implemented throughout the development of this compound to reduce the incidence and severity of AEs and dropout rates, based on clinical considerations.
Objectives: To execute a quantitative, model-based titration schedule optimization, we modeled patient withdrawal resulting from reported AEs across all dose escalation regimens. The model is to be used to provide prospective clinical trial simulations of titration schedules to select an optimal scheme to minimize AEs and resulting study withdrawal.
Methods: We developed a parametric, discrete-time model of dropout (study withdrawal) based on individual daily self-reported AE (dizziness and somnolence) information. Adverse events were reported as none, mild, moderate or severe (ordered categorical data) across six 4-6 week studies.
The dropout model focused on AEs due to considerable withdrawal during the initial, titration phase week. Graphics of nonparametric estimates of survival (plots of hazard probabilities vs. time and Kaplan Meier plots of observed vs. model predicted survivorship probabilities) were used as a guide in the selection of appropriate probability distribution model. Exponential, Weibull, log-logistic, linear-exponential and Gompertz parametric hazard probability distributions were examined to describe the time course of dropout risk as a function of the maximum adverse event by day. The hazard varied as a linear or exponential function of time for the linear-exponential and Gompertz models, respectively. The maximum adverse event severity (MAXAE) across dizziness or somnolence resulted in a more parsimonious model compared to the use of either measure of AE alone.
Results: The best fit to the data was achieved using the Gompertz model for hazard probabilities.
This two term log-linear hazard function was comprised of invariant (intercept) and a time-dependent parameter (slope) allowing for a monotonically decreasing, time-time-dependent changes in discrete conditional dropout (hazard). Additionally, initial hazard was larger with higher severity of
References:
[1] Feltner DE, Crockatt JG, Dubovsky SJ, et al. A randomized, double-blind, placebo-controlled, fixed-dose, multicenter study of pregabalin in patients with generalized anxiety disorder. J Clin Psychopharmacol 2003 Jun; 23 (3): 240-9
[2] Pohl RB, Feltner DE, Fieve RR, et al. Efficacy of pregabalin in the treatment of generalized anxiety disorder: double-blind, placebo-controlled comparison of BID versus TID dosing. J Clin Psychopharmacol 2005; 25: 151-8
[3] Rickels K, Pollack MH, Feltner DE, et al. Pregabalin for treatment of generalized anxiety disorder: a 4-week, multicenter, double-blind, placebo-controlled trial of pregabalin and alprazolam.
Arch Gen Psychiatry 2005; 62: 1022-30
[4] Montgomery SA, Tobias K, Zornberg GL, et al. Efficacy and safety of pregabalin in the treatment of generalized anxiety disorder: a 6-week, multicenter, randomized,
double-blind,placebo-controlled comparison of pregabalin and venlafaxine. J Clin Psychiatry 2006; 67:
771-82
[5] Pande AC, Crockatt JG, Feltner DE, et al. Pregabalin in generalized anxiety disorder: a placebo-controlled trial. Am J Psychiatry2003 Mar; 160 (3): 533-40
Poster: Applications- CNS
Laura Iavarone Population PK/PD of Alprazolam in the Attenuation of ACTH
Activation Induced by Cognitive Performance in Metyrapone-treated Healthy
Volunteers
L. Iavarone(1), R. Gomeni(1), E. Merlo-Pich(2)
(1) CPK&MS, GSK, Verona, Italy; (2) CPDM, GSK, Verona, Italy;
Objectives: The control of ACTH release from the pituitary is under hormonal controls.
Stimulating effects are produced by the peptide CRH released from the hypothalamus under stress.
Inhibiting effects are produced by circulating cortisol, whose release from the adrenal glands is in ACTH-dependent. Metyrapone, an inhibitor of the cortisol synthesis, attenuate the cortisol negative feedback on ACTH release, resulting in an enhanced sensitivity to the stimulating effects of CRH.
In this work we investigated the effects of Alprazolam on ACTH levels over time(4h) following dosing and in response to a cognitive performance test in volunteers receiving metyrapone 8 h before. The objective was to model the time-course of the inhibition produced by Alprazolam.
Methods: The relationship between ACTH and Alprazolam plasma levels was studied using an indirect PD response model. The rate of change of the ACTH response over time with no drug present can be described by dR/dt=kin-kout∙R, kin is the zero-order constant for production and kout
is the first-order rate constant for loss. The PK/PD model was developed in a stepwise fashion and described the change in ACTH over time and the effect of cognitive test at 3h post-dose. The final model represents inhibitory processes that operate according to the classical inhibitory function, I(t)=1-(Cp/(Cp+IC50) where Cp is the Alprazolam plasma levels and IC50 is the Alprazolam plasma levels producing 50% of maximum inhibition. The rate of change of R can be described by dR/dt= kin∙I(t)-kout∙R. A Mixed effect modelling (NONMEM) was used to estimate the model parameters. The circadian fluctuation of ACTH in the absence of Metyrapone was described by a cosine function over a 24h period
Results: Increase of ACTH over time was produced by metyrapone, further enhanced by the cognitive test. Alprazolam was able to decrease ACTH level in the experimental settings. The PK/PD relationships between ACTH exposure and Alprazolam plasma levels able to overall inhibit over the 24h the release of ACTH of the 50% (IC50) was estimated to be 6.22ng/mL.
Conclusions:
Poster: Applications- CNS
Maria Kjellsson Modelling Sleep Using Markov Mixed Effects Models Maria C. Kjellsson (1), Daniele Ouellet (2), Raymond Miller (2), Mats O. Karlsson (1) (1) Uppsala University, Uppsala, Sweden (2) Pfizer Global Research & Developement, Ann Arbor,
Michigan, USA
Objectives: To characterize the time course of sleep stages and the concentration-effect relationship of Drug X relative to placebo and to an active comparator using Markov models in patients with insomnia.
Methods: Sleep data were obtained in a 4-way crossover study of low and high doses of Drug X, a standard dose of an active control and placebo in 43 patients with primary insomnia. Sleep
stages were measured for 8 hrs overnight at screening (baseline) and for 2 nights of dosing following each treatment. Markov models consisting of submodels for baseline, placebo, Drug X and positive control were developed for each transition. All models were merged into a joint sleep model for simulations.
The submodels were developed sequentially, starting with baseline, followed by placebo, and in parallel for each drug. For each additional submodel, the parameters of the previous submodel were fixed. To speed up the model-building process, a number of pre-defined standard models for each submodel were tried. These standard models were chosen based on previous experience with similar data [1] and physiological plausibility.
The model development was done using a population analysis approach in NONMEM V, assessing both between subject and between occasion variability (BSV, BOV).
A posterior predictive check and simulations of 3 alternate study designs were performed.
Results: The baseline model was in most cases best described by a piece-wise linear function (PWL) of both bedtime (0 to 8 hrs) and stage time (duration within a stage). The PLW had two slopes with an internal breakpoint, which was either fixed at the median or estimated. BSV was characterized in most transitions and BOV in about half of the transitions.
Placebo effects were found on 4 transitions, all for transitions between awake, stage 1 and REM. A majority of the drug effects of Drug X were best described as a linear model as a function of drug concentration in the effect compartment. The drug effects of the positive control were described with a linear model changing with the predicted concentrations in central compartment.
The predictive performance of the joint model, assessed by simulations of the realized study design, was good, with 16 of 18 pre-defined efficacy parameters well described.
Simulations with changing the time of dosing from ½ hour to 1 hour prior to bedtime resulted in a 40% reduction in latency to persistent sleep for the higher dose of Drug X.
Conclusions: The proposed reduced model building process resulted in a model that describes the sleep pattern at baseline, and following placebo, low and high dose of Drug X and positive control.
References:
[1] Karlsson MO et al. A pharmacodynamic Markov mixed-effect model for the effect of temazepam on sleep. Clin Pharmacol Ther 2000;68(2):175-88
Poster: Applications- CNS
Frank Larsen Non-Linear Mixed Effects PK/PD Modelling of Acute Autoinhibitory