2008 - Marseille - France

PAGE 2008: Methodology- Design
Massimo Cella

Randomisation to exposure in early paediatric trials: an analysis on the influence of the dose on the heterogeneity in the response to abacavir.

Massimo Cella(1), Meindert Danhof(1), Oscar Della Pasqua(1,2)

(1)Division of Pharmacology, LACDR, Leiden University, Leiden, The Netherlands, (2)Clinical Pharmacology & Discovery Medicine, GlaxoSmithKline, Greenford, UK

Introduction: The efficacy of a pharmacological treatment is usually described by a function that relates the effect with the dose of the drug that has been administered. However, plasma concentration or exposure (e.g., AUC) are known to be better descriptors of the pharmacological effect. Neverthless, efficacy evaluation in clinical trials still imposes the use of the same dose to all the patients involved, leading to large variability in drug concentration and exposure. This variability increases even further when one considers the response to treatment, which yields misleading information about efficacy, toxicity and variability itself. This issue is particularly important in paediatric pharmacology, where differences in response may occur and no clear relationship between dose and exposure is assessed before the start of the trials.

Objectives: To assess whether an adaptive design in early clinical trials based on "variable dosing - controlled exposure" can provide better dosing recommendations compared to the standard fixed dose approach.

Methods: Using Trial Simulator v. 2.0, two paediatric studies (n=60) have been simulated for abacavir. In the first study, plasma concentrations following a 600 mg abacavir administration were taken at standard sampling times. The data were fitted with a one compartment model that included the effect of weight on clearance and volume of distribution (NONMEM v.6). In the second study, an adaptive design was used in which patients were randomised to exposure, with a target of 6.02 mg*h/L (efficacious exposure in adults). Patients were administered with the starting dose of 600 mg. Plasma concentrations were modelled and clearance and systemic exposure estimated (AUC). Based on these results, the dosage strength for the remaining duration of treatment was recalculated to achieve target exposure. †Final parameters estimates and dosing recommendations were compared between the 2 approaches.

Results and conclusions: Preliminary results show that adaptive randomisation can be used to optimise dosing regimens in early paediatric research. This approach increases the probability of demonstrating efficacy (i.e., study power) as compared to dose-controlled trials. Furthermore, it contributes to further understanding of the role of dose on the total heterogeneity in clinical response.

Reference: PAGE 17 (2008) Abstr 1297 [www.page-meeting.org/?abstract=1297]
Poster: Methodology- Design
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