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LIBRIS Formathandbok  (Information om MARC21)
FältnamnIndikatorerMetadata
00004753naa a2200445 4500
001oai:DiVA.org:uu-181835
003SwePub
008121001s2012 | |||||||||||000 ||eng|
0247 a https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-1818352 URI
0247 a https://doi.org/10.1111/j.1365-2125.2012.04205.x2 DOI
040 a (SwePub)uu
041 a engb eng
042 9 SwePub
072 7a ref2 swepub-contenttype
072 7a art2 swepub-publicationtype
1001 a Svensson, Elinu Uppsala universitet,Institutionen för farmaceutisk biovetenskap,Farmakometri4 aut0 (Swepub:uu)elisv718
2451 0a Integration of data from multiple sources for simultaneous modelling analysis :b experience from nevirapine population pharmacokinetics
264 c 2012-08-06
264 1b Wiley,c 2012
338 a print2 rdacarrier
520 a WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT Integrating individual data from multiple sources in one simultaneous population analysis (sometimes called a mega-model) can address novel research questions and add power for covariate detection without requiring new clinical studies. However, the development of this type of model can be challenging and time consuming. Nevirapine is a non-nucleoside reverse transcriptase inhibitor commonly used for treatment of human immunodeficiency virus infection in resource-limited settings.WHAT THIS STUDY ADDS This study outlines a strategy for integration of data from multiple sources for modelling analysis. It provides suggestions on handling of missing covariates in the context of several data sources and a starting point for development of a multinational nevirapine mega-model. AIMS To propose a modelling strategy to efficiently integrate data from different sources in one simultaneous analysis, using nevirapine population pharmacokinetic data as an example.METHODS Data from three studies including 115 human immunodeficiency virus-infected South African adults were used. Patients were on antiretroviral therapy regimens including 200 mg nevirapine twice daily and sampled at steady state. A development process was suggested, implemented in NONMEM7 and the final model evaluated with an external data set.RESULTS A stepwise approach proved efficient. Model development started with the intensively sampled data. Data were added sequentially, using visual predictive checks for inspecting their compatibility with the existing model. Covariate exploration was carried out, and auxiliary regression models were designed for imputation of missing covariates. Nevirapine pharmacokinetics was described by a one-compartment model with absorption through two transit compartments. Body size was accounted for using allometric scaling. The model included a mixture of two subpopulations with different typical values of clearance, namely fast (3.12 l h-1) and slow metabolizers (1.45 l h-1), with 17% probability of belonging to the latter. Absorption displayed large between-occasion variability, and food slowed the absorption mean transit time from 0.6 to 2.5 h. Concomitant antitubercular treatment including rifampicin typically decreased bioavailability by 39%, with significant between-subject variability. Visual predictive checks of external validation data indicated good predictive performance.CONCLUSIONS The development strategy succeeded in integrating data from different sources to produce a model with robust parameter estimates. This work paves the way for the creation of a nevirapine mega-model, including additional data from numerous diverse sources.
653 a missing covariates
653 a nevirapine
653 a NONMEM
653 a population pharmacokinetics
653 a prediction and variability corrected visual predictive check
653 a simultaneous modelling analysis
7001 a van der Walt, Jan-Stefanu Uppsala universitet,Institutionen för farmaceutisk biovetenskap,Farmakometri4 aut0 (Swepub:uu)janva857
7001 a Barnes, Karen I.4 aut
7001 a Cohen, Karen4 aut
7001 a Kredo, Tamara4 aut
7001 a Huitema, Alwin4 aut
7001 a Nachega, Jean B.4 aut
7001 a Karlsson, Mats O.u Uppsala universitet,Institutionen för farmaceutisk biovetenskap,Farmakometri4 aut0 (Swepub:uu)matskarl
7001 a Denti, Paolo4 aut
7102 a Uppsala universitetb Institutionen för farmaceutisk biovetenskap4 org
7730 t British Journal of Clinical Pharmacologyd : Wileyg 74:3, s. 465-476q 74:3<465-476x 0306-5251x 1365-2125
8564 u https://bpspubs.onlinelibrary.wiley.com/doi/pdfdirect/10.1111/j.1365-2125.2012.04205.x
8564 8u https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-181835
8564 8u https://doi.org/10.1111/j.1365-2125.2012.04205.x

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