Universität zu Köln

Arshad, Usman ORCID: 0000-0002-7003-5300, Chasseloup, Estelle, Nordgren, Rikard and Karlsson, Mats O. (2019). Development of visual predictive checks accounting for multimodal parameter distributions in mixture models. J. Pharmacokinet. Pharmacodyn., 46 (3). S. 241 - 251. NEW YORK: SPRINGER/PLENUM PUBLISHERS. ISSN 1573-8744

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Abstract

The assumption of interindividual variability being unimodally distributed in nonlinear mixed effects models does not hold when the population under study displays multimodal parameter distributions. Mixture models allow the identification of parameters characteristic to a subpopulation by describing these multimodalities. Visual predictive check (VPC) is a standard simulation based diagnostic tool, but not yet adapted to account for multimodal parameter distributions. Mixture model analysis provides the probability for an individual to belong to a subpopulation (IPmix) and the most likely subpopulation for an individual to belong to (MIXEST). Using simulated data examples, two implementation strategies were followed to split the data into subpopulations for the development of mixture model specific VPCs. The first strategy splits the observed and simulated data according to the MIXEST assignment. A shortcoming of the MIXEST-based allocation strategy was a biased allocation towards the dominating subpopulation. This shortcoming was avoided by splitting observed and simulated data according to the IPmix assignment. For illustration purpose, the approaches were also applied to an irinotecan mixture model demonstrating 36% lower clearance of irinotecan metabolite (SN-38) in individuals with UGT1A1 homo/heterozygote versus wild-type genotype. VPCs with segregated subpopulations were helpful in identifying model misspecifications which were not evident with standard VPCs. The new tool provides an enhanced power of evaluation of mixture models.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Arshad, Usman UNSPECIFIED orcid.org/0000-0002-7003-5300 UNSPECIFIED Chasseloup, Estelle UNSPECIFIED UNSPECIFIED UNSPECIFIED Nordgren, Rikard UNSPECIFIED UNSPECIFIED UNSPECIFIED Karlsson, Mats O. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-147324
DOI:	10.1007/s10928-019-09632-9
Journal or Publication Title:	J. Pharmacokinet. Pharmacodyn.
Volume:	46
Number:	3
Page Range:	S. 241 - 251
Date:	2019
Publisher:	SPRINGER/PLENUM PUBLISHERS
Place of Publication:	NEW YORK
ISSN:	1573-8744
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language POPULATION PHARMACOKINETICS; IRINOTECAN; METRICS Multiple languages Pharmacology & Pharmacy Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/14732