Table 1.
Overview of the composition of PK/PD models used for modeling of ECG intervals in preclinical species and human, indicating selected concentration–effect relationship, model for capturing potential time delays and baseline function
| Variable | Species | Concentration–effect relationship | Baseline function | Time delay model |
|---|---|---|---|---|
| QTc | Human | Linear: disopyramide,1,2 quinidine,3–5 sotalol,6–8 N-acetylprocainamide,9 sematilide,10 dofetilide,11 citalopram,12 lamotrigine,13a prulifloxacin,14a moxifloxacin,8,13,14 grepafloxacin,8 mifepristone,15a cabazitaxel,16a AZD1386,17 NCE01-0318 Exponential: AZD383919 Emax: disopyramide,20 N-acetylprocainamide,9 sematilide,10 azimilide,21 AZD130517 Emax sigmoidal: dofetilide,11 vernacalant22 Operational agonism: dofetilide23 |
Constant: sotalol,3,7 sematilide,10 dofetilide,11 citalopram,12 mifepristone,15 cabazitaxel,16 azimilide,21 AZD1305,17 vernacalant22 1x cosine: sotalol,8 moxifloxacin,8 grepafloxacin,8 NCE01-0318 3x cosine: AZD383919 Unknown cosine: lamotrigine,13 moxifloxacin,13 AZD138617 |
Effect compartment: disopyramide,1 quinidine,3,4 sotalol,7 N-acetylprocainamide,9 sematilide,10 dofetilide,11 citalopram,12 AZD1305,17 AZD383919 |
| QTc | Rat | Linear: quinidine,24 roxithromycin,25 azithromycin25 Emax: terfenadine,24 clarithromycin,25 erythromycin,26 ebastine27 |
Effect compartment: roxithromycin,25 azithromycin,25 clarithromycin,25 erythromycin,26 ebastine27 | |
| QTc | Guinea pig | Linear: Imipramine,28 fluvoxamine28 Emax: tacrolimus29 |
Effect compartment: Imipramine,28 fluvoxamine28 Myocardial compartment: tacrolimus29 |
|
| QTc | Dog | Linear: AZD1305,17 AZD1386,17 cisapride,30 sotalol,30 moxifloxacin,30 Compound 2,31 quinidine,32 NCE01-0318 Emax: AZD383919 Emax sigmoidal: dofetilide,33 cisapride,34,35 moxifloxacin,34 terfenadine,35 E-403135 |
Constant: cisapride,34,35 moxifloxacin34 Linear: dofetilide33 Unknown cosine: AZD1305,17 AZD138617 1x cosine: cisapride,30 sotalol,30 moxifloxacin,30 NCE01-0318 3x cosine: AZD383919 |
Effect compartment: AZD1305,17 quinidine,32 dofetilide,33 cisapride,35 terfenadine,35 E-4031,35 AZD383919 |
| QTc | Monkey | Linear: Compounds 1,8,9,31 Moxifloxacin36 | Model Cmax-Emax: Compounds 8–931 | |
| QRS | Human | Linear: quinidine,3,5 cabazitaxel,16a flecainide37,38 | Constant: cabazitaxel,16 flecainide37,38 | Effect compartment: quinidine3 |
| QRS | Dog | Linear: R155139 Emax sigmoidal: Compounds 3–731 HR-dependent: flecainide40 |
Constant: R155139 HR-dependent: flecainide40 |
Effect compartment: R155139 |
| QRS | Monkey | Linear: R1551 | Constant: R155139 | |
| PQ | Human | Linear: quinidine3 | Effect compartment: quinidine3 | |
| PR | Human | Linear: cabazitaxel16a | Constant: cabazitaxel16 | |
| PR | Dog | Linear: R1551 | Constant: R155139 | Effect compartment: R155139 |
| PR | Monkey | Linear: R1551 | Constant: R155139 | Effect compartment: R155139 |
| ERP | Rabbit | Exponential: AZ13395438,41 Compound A and 2f42 | Constant: AZ13395438,41 Compound A and 2f42 | Effect compartment: AZ13395438,41 Compound A and 2f42 |
a
Studies where no ECG effect was found. References contained in Supplementary Material.
ERP, effective refractory period.