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The early stages of the drug development process are often characterized by a limited number of subjects participating the study and a limited number of measurements per individual that can be collected, mainly due to technical, ethical, and cost reasons. The so-called dose escalation studies, performed during phase I, usually involve about 40 subjects or less, and feature observations at no more than three (rarely four or five) dose levels-per-subject. Depending on the complexity of the underlying pharmacokinetics, simple linear models or nonlinear ones (e.g., power, Emax models) may be appropriate to describe the relationship between the metrics of systemic exposure to the drug (Cmax, AUC ) and the administered dose. However, in such data-poor scenarios, formulating models based on parametric descriptions is generally hard, and may easily result in model misspecification. Hence, nonparametric or “model-free” solutions, borrowed from the machine learning field, are deemed appealing. We resort to Gaussian process theory to work out Bayesian posterior expectations of a population (a.k.a mixed-effects) regression problem, namely Population Smoothing Splines (PSS). We show that in seven experimental dose escalation studies, Population Smoothing Splines improve on three widely used parametric population methods. Superiority of the model-free technique is confirmed by a simulated benchmark: Population Smoothing Splines compare very favorably even with the true parametric model structure underlying the simulated data.
Date of Publication: Nov. 2011