simcyp v11.1  (Simcyp)

Journal: British Journal of Clinical Pharmacology

Article Title: In vitro and physiologically‐based pharmacokinetic based assessment of drug–drug interaction potential of canagliflozin

doi: 10.1111/bcp.13186

Figure Lengend Snippet: Input parameters for the canagliflozin physiologically‐based pharmacokinetic model

Article Snippet: Percentage UD available for reabsorption 0% No evidence of enterohepatic recirculation 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 ) Fraction of drug unbound in microsomes‐ F umic b (0.2 mg) 0.735 Predicted from Simcyp v 11.1 Open in a separate window a Internal data on file, Janssen Research & Development.

Techniques: Molecular Weight, Solubility, Inhibition

Journal: British Journal of Clinical Pharmacology

Article Title: In vitro and physiologically‐based pharmacokinetic based assessment of drug–drug interaction potential of canagliflozin

doi: 10.1111/bcp.13186

Figure Lengend Snippet: Input parameters for the canagliflozin physiologically‐based pharmacokinetic model

Article Snippet: Distribution , Full PBPK , , Method 2, Simcyp v11.1.

Techniques: Molecular Weight, Solubility, Inhibition

Journal: British Journal of Clinical Pharmacology

Article Title: In vitro and physiologically‐based pharmacokinetic based assessment of drug–drug interaction potential of canagliflozin

doi: 10.1111/bcp.13186

Figure Lengend Snippet: Input parameters for the canagliflozin physiologically‐based pharmacokinetic model

Article Snippet: The trial designs for DDI simulations are shown in Table . table ft1 table-wrap mode="anchored" t5 Table 1 caption a7 Input parameter Value Comment Molecular weight 444.52 g mol –1 CAS # 842 133–18‐0 Canagliflozin Structure (1 S )‐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 data a Compound Type Neutral Internal data a pKa1 unionized Internal data a B/P 0.69 Reference: 8 Fraction of drug unbound (Fu) plasma 0.017 Internal data a 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 data a 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 data a ) Adipose 0.268 Radiolabelled rat tissue distribution study (Internal data a ) 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 .

Techniques: Molecular Weight, Solubility, Inhibition