A Minimal Continuous-Time Markov Pharmacometric Model

作者：Schindler Emilie; Karlsson Mats O^*

来源：AAPS Journal, 2017, 19(5): 1424-1435.

DOI：10.1208/s12248-017-0109-1

• NONMEM
• non-linear mixed effects models
• ordered categorical data
• pharmacokinetic-pharmacodynamic
• serial correlations

In this work, an alternative model to discrete-time Markov model (DTMM) or standard continuous-time Markov model (CTMM) for analyzing ordered categorical data with Markov properties is presented: the minimal CTMM (mCTMM). Through a CTMM reparameterization and under the assumption that the transition rate between two consecutive states is independent on the state, the Markov property is expressed through a single parameter, the mean equilibration time, and the steady-state probabilities are described by a proportional odds (PO) model. The mCTMM performance was evaluated and compared to the PO model (ignoring Markov features) and to published Markov models using three real data examples: the four-state fatigue and hand-foot syndrome data in cancer patients initially described by DTMM and the 11-state Likert pain score data in diabetic patients previously analyzed with a count model including Markovian transition probability inflation. The mCTMM better described the data than the PO model, and adequately predicted the average number of transitions per patient and the maximum achieved scores in all examples. As expected, mCTMM could not describe the data as well as more flexible DTMM but required fewer estimated parameters. The mCTMM better fitted Likert data than the count model. The mCTMM enables to explore the effect of potential predictive factors such as drug exposure and covariates, on ordered categorical data, while accounting for Markov features, in cases where DTMM and/or standard CTMM is not applicable or conveniently implemented, e.g., non-uniform time intervals between observations or large number of categories.

• 出版日期2017-9