Table 2.
Safety margins of loperamide in preclinical models, relative to its maximum human free therapeutic plasma concentration (FTPC).
| Test System | Parameter | Tested Dose | Margin |
|---|---|---|---|
| X FTPC | |||
| IKr (hERG) | IC50 | 390 nM | 1560 |
| INa | IC50 | 526 nM | 2104 |
| ICa | IC50 | 4091 nM | 16,364 |
| In Silico Modelling | NE on APs | 150 nM | 600 |
| Significant effects on APs | 200 nM | 800 | |
| Rabbit ventricular wedge | NE | 100 nM | 400 |
| ↑ QRS | 300 nM | 1200 | |
| ↓ iCEB | 1000 nM | 4000 | |
| Cardiac arrhythmias | 3000 nM | 12,000 | |
| Anesthetized guinea pig | NE | 1.25 mg/kg i.v. (FPC = 36 ng/mL) | 304 |
| ↑iCEB, QRS | 2.5 mg/kg i.v. (FPC = 105 ng/mL) | 879 | |
| ↑ QTcB, Incidence of AV Block (type II/III). | 2.5 mg/kg i.v. (FPC = 105 ng/mL) | 879 |
Loperamide’s free TPC (unbound plasma concentration) 0.25 nM drug concentrations in human plasma at steady state Cmax after 16 mg orally q.d. (Doser et al., 1995 [65]) was used for margin calculations; xFTPC: fold over human FTPC. FPC: free plasma concentration. NE: no relevant effects; APs: cardiac action potentials. ↓↑: significant increase or decrease.