Pharmacokinetic–pharmacodynamic assessment of topiramate dosing regimens for children with epilepsy 2 to &lt;10 years of age

Girgis, Ihab; Nandy, Partha; Nye, Jeffrey S.; Ford, Lisa; Mohanty, Surya; Wang, Steven; Ochalski, S. J.; Eerdekens, Mariëlle; Cox, Eugène

doi:10.1111/j.1528-1167.2010.02598.x

Cited by 39 publications

(69 citation statements)

References 21 publications

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“…PK‐PD CTS provides a favorable tool to integrate prior information on drug disposition and effect to evaluate the performance of candidate study designs. In this work, we underpinned CTS with a PK‐PD model, which was separately identified from both pediatric and adult data . This further enabled us to formalize CTS of BDs by using prior information from adults' data.…”

Section: Discussionmentioning

confidence: 99%

Model‐Based Assessment of Alternative Study Designs in Pediatric Trials. Part II: Bayesian Approaches

Smania

Baiardi

Ceci

et al. 2016

CPT Pharmacom & Syst Pharma

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This study presents a pharmacokinetic‐pharmacodynamic based clinical trial simulation framework for evaluating the performance of a fixed‐sample Bayesian design (BD) and two alternative Bayesian sequential designs (BSDs) (i.e., a non‐hierarchical (NON‐H) and a semi‐hierarchical (SEMI‐H) one). Prior information was elicited from adult trials and weighted based on the expected similarity of response to treatment between the pediatric and adult populations. Study designs were evaluated in terms of: type I and II errors, sample size per arm (SS), trial duration (TD), and estimate precision. No substantial differences were observed between NON‐H and SEMI‐H. BSDs require, on average, smaller SS and TD compared to the BD, which, on the other hand, guarantees higher estimate precision. When large differences between children and adults are expected, BSDs can return very large SS. Bayesian approaches appear to outperform their frequentist counterparts in the design of pediatric trials even when little weight is given to prior information from adults.

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Section: Discussionmentioning

confidence: 99%

Model‐Based Assessment of Alternative Study Designs in Pediatric Trials. Part II: Bayesian Approaches

Smania

Baiardi

Ceci

et al. 2016

CPT Pharmacom & Syst Pharma

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“…Models describing the adult and pediatric PK of carbamazepine (CBZ), clobazam (CLBZ), clonazepam (CLNZ), lamotrigine (LMT), levetiracetam (LVT), oxcarbazepine (OXC), phenobarbital (PHB), phenytoin (PHT), topiramate (TPM), valproic acid (VPA), and zonisamide (ZNS) were collected from the published literature. Models were transcribed into the appropriate format in R v. 3.1.1, along with the parameter estimates and combined with analytical solutions of the mathematical equations describing the concentration over time profiles (Eqs.…”

Section: Methodsmentioning

confidence: 99%

Individualized Dosing Algorithms and Therapeutic Monitoring for Antiepileptic Drugs

Dijkman

Wicha

Danhof

et al. 2017

Clin Pharma and Therapeutics

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Pharmacokinetic (PK) models exist for most antiepileptic drugs (AEDs). Yet their use in clinical practice to assess interindividual differences and derive individualized doses has been limited. Here we show how model-based dosing algorithms can be used to ensure attainment of target exposure and improve treatment response in patients. Using simulations, different treatment scenarios were explored for 11 commonly used AEDs. For each drug, five scenarios were considered: 1) all patients receive the same dose. 2) Individual clearance (CL), as predicted by population PK models, is used to personalize treatment. 3-5) Individual CL, obtained by therapeutic drug monitoring (TDM) according to different sampling schemes, is used to personalize treatment. Attainment of steady-state target exposure was used as the performance criterion to rank each scenario. In contrast to current clinical guidelines, our results show that patient demographic and clinical characteristics should be used in conjunction with TDM to personalize the treatment of seizures.

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“…To simplify the presentation of our methods, we shall assume throughout that the pharmacodynamic response of interest is normally distributed and that a generalized linear model is an adequate description of the underlying E – R ‐relationship:

Y = γ_{0} + {false\sum}_{k = 1}^{K} γ_{k} x_{k} + γ_{C} C + γ_{A} A + γ_{normalI} C A + ϵ

where ε ∼ N (0, σ 2 ) is a random error term. Linear models have been used to analyse E – R ‐data for the antiepileptic drugs oxcarbazepine (Nedelman et al ., ) and topiramate (Girgis et al ., ) setting Y = log ( Z +110), where Z is the percentage change from baseline in seizure frequency and C represents the steady state trough concentration under repeated dosing ( C min ).…”

Section: Using Existing Data To Inform An Extrapolation Decisionmentioning

confidence: 99%

A Quantitative Framework to Inform Extrapolation Decisions in Children

Wadsworth

Jaki

Sills

et al. 2019

Journal of the Royal Statistical Society Series A: Statistics in Society

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Summary When developing a new medicine for children, the potential to extrapolate from adult efficacy data is well recognized. However, significant assumptions about the similarity of adults and children are needed for extrapolations to be biologically plausible. One such assumption is that of similar exposure–response (E–R‐) relationships. Motivated by applications to antiepileptic drug development, we consider how data that are available from existing trials of adults and adolescents can be used to quantify prior uncertainty about whether E–R‐relationships are similar in adults and younger children. A Bayesian multivariate meta‐analytic model is fitted to existing E–R‐data and adjusted for external biases that arise because these data are not perfectly relevant to the comparison of interest. We propose a strategy for eliciting expert prior opinion on external biases. From the bias‐adjusted meta‐analysis, we derive prior distributions quantifying our uncertainty about the degree of similarity between E–R‐relationships for adults and younger children. Using these we calculate the prior probability that average pharmacodynamic responses in adults and younger children, both on placebo and at an effective concentration, are sufficiently similar to justify a complete extrapolation of efficacy data. A simulation study is performed to evaluate the operating characteristics of the approach proposed.

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Pharmacokinetic–pharmacodynamic assessment of topiramate dosing regimens for children with epilepsy 2 to <10 years of age

Cited by 39 publications

References 21 publications

Model‐Based Assessment of Alternative Study Designs in Pediatric Trials. Part II: Bayesian Approaches

Model‐Based Assessment of Alternative Study Designs in Pediatric Trials. Part II: Bayesian Approaches

Individualized Dosing Algorithms and Therapeutic Monitoring for Antiepileptic Drugs

A Quantitative Framework to Inform Extrapolation Decisions in Children

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