Introduction to population pharmacokinetic/pharmacodynamic analysis with nonlinear mixed effects models.

By Joel S. Owen and Jill Fiedler-Kelly

Wiley, 2014

320 pp., hardcover, $110

ISBN 978-0-470-58229-9

My first encounter with NONMEM was some 20 years ago when, as a fresh postdoc, I had a dataset for which I wanted to develop a mechanistic pharmacokinetic–pharmacodynamic (PKPD) model. Thankfully, the software had already been installed on my computer by a predecessor and I thought it would be a good idea to have a look at it. I soon realized that my usual approach of “don’t read the manual” was not going to work since after a few hours I was still staring at a black screen with a blinking cursor and a string of DOS error messages. I started to flick through the daunting pile of yellow user manuals and became less and less clear on what to do. Thankfully, an experienced PKPD modeler was visiting the lab that day who gave me the advice that I guess many new NONMEM users have heard: “Start with User Guide V, don’t worry about the rest”. User Guide V turned out to be not only an introduction to the NONMEM software but also to non-linear mixed effects modeling and population PK, with the famous theophylline dataset as case study. It must have been the first and main reference for many NONMEM users to date, but that may now change with the publication of the first book dedicated to the most widely used pharmacometrics tool.

Although not obvious from the title, “Introduction to Population Pharmacokinetic/Pharmacodynamic Analysis with Nonlinear Mixed Effects Models” by Owen and Fiedler-Kelly is really an introductory guide to NONMEM and how to apply the software in basic PK and PKPD modeling.

The first two chapters provide a high level overview of pharmacometrics and population modeling concepts and terminology (including a table with commonly-used Greek characters for the nonstatisticians!). The next two chapters detail the nitty-gritty of writing a basic NM-TRAN control stream and compiling a NONMEM dataset. Chapter 5, Model Building: Typical Process, is the largest and covers analysis planning (with an recommended Analysis Plan content as appendix), exploratory data analysis, model development, basic diagnostic plots and covariate analysis. Chapter 6 focuses on the non-graphical interpretation of the NONMEM output file and potential error messages. Following a brief chapter on how to obtain individual parameter estimates and exposure predictions from a population PK analysis, model evaluation is covered in Chapter 8. This part is one that perhaps could be expanded in a next edition since a wide range of topics (numerical, visual and posterior predictive assessment techniques, log-likelihood profiling, leverage analysis and bootstrapping) are being covered in less then 20 pages. The same could be said about Simulation Basics, which comes after Chapters 9 and 10 with some examples of user-written PK and PKPD models. The book finishes with a short overview of the importance of quality control during every phase of a data-analysis project.

The book is richly illustrated and many topics are accompanied by example NONMEM input code and output. Additional supportive material (exercises with answers, some NONMEM control stream examples and a few SAS codes for figure generation) can be accessed online at http://booksupport.wiley.com.

Overall, given the widespread use of NONMEM in drug development and clinical practice, it is remarkable that a book like this has not been published before. I think it is a most welcome addition to the educational pharmacometrics literature and an excellent starting point for new NONMEM users. The authors never pretend that the material goes beyond introductory level (in terms of theory and more advanced NONMEM features) and point the reader to various other references aimed at those who want to study the subject in more depth.

This book may make the “User Guide V experience” a story from the good old times for the next generation of pharmacometricians.

Conflict of Interest

P.H.vd.G. is Editor-in-Chief of CPT: Pharmacometrics & Systems Pharmacology, which will publish with Wiley in 2015.