Table 1.
Input parameters for the canagliflozin physiologically‐based pharmacokinetic model
| Input parameter | Value | Comment | |
|---|---|---|---|
| Molecular weight | 444.52 g mol–1 | CAS # 842 133–18‐0 | |
| Canagliflozin Structure |
(1S)‐1,5‐anhydro‐1‐[3‐[[5‐(4‐fluorophenyl)‐2‐thienyl]methyl]‐4‐methylphenyl]‐D‐glucitol hemihydrate |
||
| Molecular weight | 444.52 g mol–1 | Molecular weight of free base (i.e. without hemihydrate) | |
| LogP | 3.8 | Internal dataa | |
| Compound Type | Neutral | Internal dataa | |
| pKa1 | unionized | Internal dataa | |
| B/P | 0.69 | Reference: 8 | |
| Fraction of drug unbound (Fu) plasma | 0.017 | Internal dataa | |
| Absorption model | ADAM | ||
| Solubility (Fessif at pH 5) | 5.01 mg ml−1 | Predicted value from GastroPlus | |
| Peff, man | 3.66 10−4 cm s–1 | Predicted value from GastroPlus | |
| Particle size (monodispersed) | 17 μm | Internal dataa | |
| Dosage form | 300 mg QD | ||
| Fraction of drug unbound in gut (Fugut) | 0.06 | Fitted parameter in Simcyp v11.1 | |
| Distribution | Full PBPK | Method 2, Simcyp v11.1 | |
| Observed Rat tissue/plasma Kp (partition coefficient) values at Cmax after oral dose of 5 mg kg–1 | Radiolabelled rat tissue distribution study (Internal dataa) | ||
| Adipose | 0.268 | Radiolabelled rat tissue distribution study (Internal dataa) | |
| Liver | 7.68 | ||
| Muscle | 2.10 | ||
| Skin | 1.02 | ||
| Other tissue Kps | 0.05 | Fitting of Kp values on the basis of observed canagliflozin intravenous pharmacokinetic profile 13. | |
| Percentage UD available for reabsorption | 0% | No evidence of enterohepatic recirculation 4 | |
| Renal clearance (ClR) | 0 l h–1 | l h–1 | In human mass balance study <1% of the dose was excreted in urine as unchanged 8 |
| Ki for CYP2B6, CYP3A4, CYP2C8, CYP2C9 | 8, 13.5, 37.5, 40 μmol l–1 | CYP inhibition experiments in human liver microsomes (data from Table 4) | |
| Fraction of drug unbound in microsomes‐ Fumic b (0.2 mg) | 0.735 | Predicted from Simcyp v 11.1 | |
a
Internal data on file, Janssen Research & Development. Data can be provided on request to the corresponding author
b
Predictive performance of the Fumic calculator in the Simcyp has been published by Turner et al. 14.
CYP, cytochrome P450