Jonathan Chauvin (1), Geraldine Ayral (1), Pauline Traynard (1)
Lixoft, Antony, France
Introduction:
Multiple peaks in plasma concentration-time curves are quite common, and can be explained by different physiological processes, such as enterohepatic recycling, delayed gastric emptying, or variability of absorption [1]. If not modelled properly, they can create difficulties in the estimation of PK parameters.
Modelling such profiles is sometimes attempted with mechanistic models that provide a physiological explanation, but they usually have the drawback of requiring many model parameters, which can cause poor accuracy of the estimates [2]. A simpler approach relies on multiple absorption models, assuming simultaneous or sequential inputs via parallel pathways.
We have developed a library of double absorption models implemented in the MonolixSuite that simplifies the selection and testing of different types of absorptions and delays.
We illustrate the performance of such models on an experimental data set for the pharmacokinetics of veralipride, a benzamide neuroleptic. Veralipride plasma concentrations exhibit double peaks after oral absorption [3], and site-specific absorption has been suggested to be the major mechanism [4]. Several modelling attempts for veralipride have been published that assume simultaneous absorptions or sequential absorption windows [3, 5], that showed the need to keep a reasonable number of parameters due to the small size of the dataset.
Methods:
The developed library of double absorption models allows to choose for each absorption a zero-order or first-order absorption process, and an optional delay with a lag time or transit compartments. The absorptions can be either simultaneous or sequential. Different number of compartmentsand linear and non-linear eliminations are available.
The library is used to easily test different hypotheses and find the appropriate model for the veralipride dataset.
The step-by-step modelling workflow set up with the MonolixSuite includes visualizing the data set to characterize the double peaks with Datxplore, exploring double absorptions model in Mlxplore, setting up and estimating a model in Monolix, assessing the uncertainty of the parameter estimates, and simulations of different models with Simulx to investigate the influence of the exact model on endpoints such as the AUC.
Results:
The model libraries in Monolix permit to easily fit stepwise the double peaks in the pharmacokinetics of veralipride, starting with a single absorption model, before moving to a delayed absorption model, to end up with double delayed absorptions. Different hypotheses were tested for each process, and the possibility to estimate inter-individual variability was precisely assessed for each parameter. The final model shows a good predictive power, and we have verified with a convergence assessment (i.e several runs from different initial values) that there is no over-parameterization.
Simulations of the model with Simulx were made to assess the variability in a large population and showed that the double peaks phenomenon strongly affects relevant endpoints such as the AUC or the time spent in a therapeutic window.
Conclusions:
The MonolixSuite and the new double absorption library allow an efficient modeling and diagnosis of the double peaks, as shown with the example of veralipride pharmacokinetics.
The double absorption model library has been made available in the 2019R1 MonolixSuite release.
References:
[1] Davies, NM, Takemoto, JK, Brocks, DR, Yáñez, JA (2010). Multiple peaking phenomena in pharmacokinetic disposition. Clin Pharmacokinet, 49, 6:351-77.
[2] Ibarra, M, Vázquez, M, Fagiolino, P (2014). Population pharmacokinetic model to analyze nevirapine multiple-peaks profile after a single oral dose. J Pharmacokinet Pharmacodyn, 41, 4:363-73.
[3] Plusquellec, Y, Campistron, G, Staveris, S, Barre, J, Jung, L, Tillement, JP, Houin, G (1987). A double-peak phenomenon in the pharmacokinetics of veralipride after oral administration: a double-site model for drug absorption. J Pharmacokinet Biopharm, 15, 3:225-39.
[4] Staveris, S, Plusquellec, Y, Campistron, G, Barre, J, Rochas, MA, Jung, L, Tillement, JP, Koffell, JC, Houin, G (1988). Pharmacokinetics of veralipride after chronic administration in humans. J Pharm Sci, 77, 1:64-7.
[5] Godfrey, KR, Arundel, PA, Dong, Z, Bryant, R (2011). Modelling the Double Peak Phenomenon in pharmacokinetics. Comput Methods Programs Biomed, 104, 2:62-9.
Reference: PAGE 28 (2019) Abstr 9055 [www.page-meeting.org/?abstract=9055]
Poster: Methodology - Other topics