Use population approach to characterize PK time-course with erratic absorption

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Objectives: Characterization of population pharmacokinetics of a new CNS compound explored in neurological and psychiatric disorder accounting for intra and inter-subjects variability from a single ascending dose study.

Methods: Twenty subjects received a single dose from 10 to 250 mg. Each subject received ascending doses up to four different occasions. High intra-subjects variability (40-60%) mainly due to PH-dependent absorption was observed in the majority of subjects. Concentration-time data were analyzed using nonlinear mixed-effect modeling (NONMEM) assuming a variable rate and extent of absorption from occasion-to-occasion.

Results: Initially, a two compartmental model with first order absorption accounting only for inter-individual variability (IIV) has been used. Then, the same structural model including also inter-occasions variability (IOV) in both ka (rate of absorption) and extent of absorption has been developed. Different models including IOV on absorption rate and/or extent of absorption have been tested. The model selection has been done using diagnostic plots and statistical criteria (log-likelihood and posterior predictive check). The comparison between all the different models led to select the one accounting for IOV in both rate and extent of absorption. Moreover, the highest source of variability has been identified in the inter-occasion variability for the extent of absorption suggesting the critical role of relative bioavailability for the future development of this compound.   

Conclusions: An appropriate population PK model was successfully developed to characterize plasma concentration-time data of the drug after oral administration. Based on the results, the influence of the erratic absorption profiles on the PK after repeat dose has been predicted using a simulation approach assuming time independent behaviour.