Nonlinear mixed effects modeling of time dependencies in drug‐free ECG data from healthy volunteers

• Published in: Clinical pharmacology and therapeutics 2004-02, Vol.75 (2), p.P97-P97
• Main Authors: Ravva, P., Gastonguay, M. R., Sweeney, K. R., Gibbs, M. A., Tensfeldt, T. G., Benincosa, L. J.
• Format: Article
• Language: English
• ISSN: 0009-9236; 1532-6535
• DOI: 10.1016/j.clpt.2003.11.371

Purpose It may be important to understand time‐dependencies in ECG data when developing models as a function of drug concentration in longitudinal studies. A model‐based analysis was employed to explore and compare the dependence of RR, QT and QTcI (individual rate‐corrected QT) on daytime temporal fluctuations. Methods Data were collected from normal, healthy volunteers (32 subjects, 4 occasions). Intercept (mean) and cosine (period, amplitude (A), mean (M) and offset (O)) models were fitted to RR, QT and QTcI data (NONMEM V, FOCE). Results The cosine model was superior to an intercept model for all endpoints. The final model included exponential inter‐individual variance on M and O, additive on A. Selected parameter estimates (% SE) are listed below. (See Table) Inter‐occasion variability (IOV) for model parameters was appreciable for all endpoints. Even after correcting for heart rate‐dependency, QTcI modeling revealed IOV of 0.9% and 67% in M and A, respectively. Conclusion Time‐dependency was not completely removed by heart rate correction and substantial IOV exists. This has direct implication when utilizing time‐matched baseline adjustments for determining drug effect. Since it may be of interest to qualify QTc changes as small as 5 msec, uncontrolled variability in time‐dependent QTcI and random IOV is of sufficient magnitude to potentially result in misinterpretation of drug‐induced QT effects. Clinical Pharmacology & Therapeutics (2004) 75, P97–P97; doi: 10.1016/j.clpt.2003.11.371 M (msec) A (msec) RR 904 (1.9) 59.5 (9.3) QT 374 (0.94) 10.3 (9.3) QTcI 386 (0.73) 3.9 (19)