caa a22 4500 605534012 CHVBK 20210128100840.0 cr unu---uuuuu 210128e20150801xx s 000 0 eng 10.1007/s10928-015-9426-0 doi (NATIONALLICENCE)springer-10.1007/s10928-015-9426-0 The method of averaging applied to pharmacokinetic/pharmacodynamic indirect response models [Elektronische Daten] [Adrian Dunne, Willem de Winter, Chyi-Hung Hsu, Shiferaw Mariam, Martine Neyens, José Pinheiro, Xavier de Trixhe] The computational effort required to fit the pharmacodynamic (PD) part of a pharmacokinetic/pharmacodynamic (PK/PD) model can be considerable if the differential equations describing the model are solved numerically. This burden can be greatly reduced by applying the method of averaging (MAv) in the appropriate circumstances. The MAv gives an approximate solution, which is expected to be a good approximation when the PK profile is periodic (i.e. repeats its values in regular intervals) and the rate of change of the PD response is such that it is approximately constant over a single period of the PK profile. This paper explains the basis of the MAv by means of a simple mathematical derivation. The NONMEM® implementation of the MAv using the abbreviated FORTRAN function FUNCA is described and explained. The application of the MAv is illustrated by means of an example involving changes in glycated hemoglobin (HbA1c%) following administration of canagliflozin, a selective sodium glucose co-transporter 2 inhibitor. The PK/PD model applied to these data is fitted with NONMEM® using both the MAv and the standard method using a numerical differential equation solver (NDES). Both methods give virtually identical results but the NDES method takes almost 8h to run both the estimation and covariance steps, whilst the MAv produces the same results in less than 30s. An outline of the NONMEM® control stream and the FORTRAN code for the FUNCA function is provided in the appendices. Springer Science+Business Media New York, 2015 Pharmacokinetic/pharmacodynamic model nationallicence Method of averaging nationallicence Computational efficiency nationallicence Dunne Adrian Model Based Drug Development, Janssen Research & Development, A Division of Janssen Pharmaceutica NV, Beerse, Belgium aut de Winter Willem Model Based Drug Development, Janssen Research & Development, A Division of Janssen Pharmaceutica NV, Beerse, Belgium aut Hsu Chyi-Hung Model Based Drug Development, Janssen Research & Development LLC, Raritan, NJ, USA aut Mariam Shiferaw Model Based Drug Development, Janssen Research & Development LLC, Raritan, NJ, USA aut Neyens Martine Model Based Drug Development, Janssen Research & Development, A Division of Janssen Pharmaceutica NV, Beerse, Belgium aut Pinheiro José Model Based Drug Development, Janssen Research & Development LLC, Raritan, NJ, USA aut de Trixhe Xavier Model Based Drug Development, Janssen Research & Development, A Division of Janssen Pharmaceutica NV, Beerse, Belgium aut Journal of Pharmacokinetics and Pharmacodynamics Springer US; http://www.springer-ny.com 42/4(2015-08-01), 417-426 1567-567X 42:4<417 2015 42 10928 https://doi.org/10.1007/s10928-015-9426-0 text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s10928-015-9426-0 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Dunne Adrian Model Based Drug Development, Janssen Research & Development, A Division of Janssen Pharmaceutica NV, Beerse, Belgium aut NATIONALLICENCE 700 1- de Winter Willem Model Based Drug Development, Janssen Research & Development, A Division of Janssen Pharmaceutica NV, Beerse, Belgium aut NATIONALLICENCE 700 1- Hsu Chyi-Hung Model Based Drug Development, Janssen Research & Development LLC, Raritan, NJ, USA aut NATIONALLICENCE 700 1- Mariam Shiferaw Model Based Drug Development, Janssen Research & Development LLC, Raritan, NJ, USA aut NATIONALLICENCE 700 1- Neyens Martine Model Based Drug Development, Janssen Research & Development, A Division of Janssen Pharmaceutica NV, Beerse, Belgium aut NATIONALLICENCE 700 1- Pinheiro José Model Based Drug Development, Janssen Research & Development LLC, Raritan, NJ, USA aut NATIONALLICENCE 700 1- de Trixhe Xavier Model Based Drug Development, Janssen Research & Development, A Division of Janssen Pharmaceutica NV, Beerse, Belgium aut NATIONALLICENCE 773 0- Journal of Pharmacokinetics and Pharmacodynamics Springer US; http://www.springer-ny.com 42/4(2015-08-01), 417-426 1567-567X 42:4<417 2015 42 10928