How to handle non-linearity in absorption: a case study in oncology
Sophie Peigné, Donato Teutonico and Marylore Chenel
Clinical Pharmacokinetics and Pharmacometrics division, Servier, France
Objectives: Drug S is an orally administered compound, with a complex absorption due to a low solubility, currently in clinical development for cancer therapy. Two dose escalation phase I clinical studies with drug S taken once per day, without food, during a 21 days cycle, are ongoing to determine the safety profile and the tolerability of this drug. In addition, the influence of food intake was assessed in a cohort of one of the 2 clinical studies after single oral administration of drug S. Using data from those 2 studies, a population pharmacokinetic (PK) model was built in order to characterize the PK of drug S and investigate potential non-linearity, to quantify its variability in patients and to identify the sources of variability.
Methods: For the 2 clinical studies, PK measurements were available for 73 patients, including 5 patients in the food interaction cohort. A total of 22 PK samples were collected at D1 and D8. Between the 2occasions, trough concentrations were also collected. A population modelling approach was used to characterize the PK of drug S in the patient population using MONOLIX version 4.3. Several absorption models were investigated as well as different elimination processes (i.e linear or non-linear elimination). A covariate analysis was also performed, investigating the impact of demographic characteristics as well as food effect. Due to the solubility issues of this compound, a dose effect was tested on absorption parameters.
Results: A 2 compartment model with a linear elimination best described the disposition of drug S. For the intestinal absorption, a model with transit compartments, parameterized with mean transit time (MTT) and transit rate constant (Ktr), was used. A large inter individual variability was observed for most of PK parameters. The effect of dose, implemented as continuous covariate, was found on absorption parameters (MTT and Ktr), indicating that a longer absorption for the higher doses, likely due to the number of tablets administered. The food intake increased the bioavailability by a 6 fold factor and the MTT parameter by a 3 fold factor.
Conclusions: The current developed model allowed a good description of the PK data for the drug S. During model building, a dose effect on absorption parameters was identified, which could be related to the solubility and the number of dosage forms administered. As soon as PD data will be available, they will be added to build a PK/PD model.
