Table 1.
Inputs for the olanzapine (OLZ) compound file in Simcyp®
| Parameter | Value | Reference |
|---|---|---|
| Physicochemical a | ||
| Molecular weight | 312.43 | |
| log P o:w | 3.0 | |
| pK a (monoprotic base) | 7.24 | |
| Blood binding | ||
| B : P | 0.83 | Simcyp predictedb |
| fu p | 0.07 | 65 |
| Absorption (first‐order model) | ||
| f a | 0.6 | 65 |
| k a (r −1 ) | 0.52c | |
| fu gut | 1.0 | |
| Q gut (l h −1 ) | 15.02 | Simcyp predictedb |
| P eff ,man (10 −4 cm s −1 ) | 8.02 | Simcyp predictedb |
| Distribution (minimal PBPK model) | ||
| V ss (l kg −1 ) | 4.14 | Simcyp predictedb |
| Elimination | ||
| N ‐demethylation, rCYP1A2 | ||
| V max (pmol min −1 pmol P450 −1) | 1.34 | 23 |
| K m (μM) | 61 | 23 |
| 2‐hydroxylation, rCYP1A2 | ||
| V max (pmol min −1 pmol P450 −1 ) | 1.92 | 23 |
| K m (μM) | 592 | 23 |
| 7‐hydroxylation, rCYP1A2 | ||
| CL int (pmol min −1 pmol P450 −1 ) | 0.00324 | 23 |
| N ‐demethylation, rCYP2C8 | ||
| V max (pmol min −1 pmol P450 −1 ) | 1.37 | 23 |
| K s (μM) | 30 | 23 |
| 10‐ N ‐glucuronidation, rUGT1A4 | ||
| V max (pmol min −1 mg −1 ) | 216 | 23 |
| K s (μM) | 183 | 23 |
| rUGT scalar d | 2.24 | 23 |
| Additional liver clearance, FMO3 | ||
| HLM CL int (μL min −1 mg −1 ) | 0.439 | 23 |
| Biliary clearance | ||
| CL int (μl min −1 mg −1 ) | 0.0 | 23 |
| CL R for 20–30‐year‐old healthy male (l h −1 ) e | 1.8 | |
B : P, blood‐to‐plasma partition ratio; CLint, intrinsic clearance; CLR, renal clearance; fa, fraction absorbed from dosage form; FMO3, flavin‐containing monooxygenase 3; fugut, fraction unbound in the gut; fup, fraction unbound in the plasma; HLM, human liver microsomes; ka, first‐order absorption rate constant; Km, michaelis‐menten constant; PBPK, physiologically based pharmacokinetic; Peff,man, effective permeability in man; pKa acid dissociation constant; Po:w, neutral species octanol : buffer partition coefficient; Qgut, gut blood flow; rCYP1A2, recombinant cytochrome P450 1A2; rUGT, recombinant UDP‐glucuronosyltransferase; Vmax, maximum rate of metabolism; Vss, volume of distribution at steady state
Physicochemical data were obtained from the ChEMBL database (https://www.ebi.ac.uk)
These parameters were predicted using previously validated functions in Simcyp®. The B : P was predicted from the log Po:w and pKa (monoprotic base) of OLZ. The value of Qgut was predicted from the equation CLperm × Qent/Qent + CLperm, where Qent is the average enterocytic blood flow (18 l h–1) and CLperm is the product of intestinal surface area (defined in Simcyp®) and apparent permeability 66. The value for Peff,man was predicted using physicochemical data and the equation Log (Peff,man) = 4–2.546 – 0.011PSA – 0.278HBD, where PSA is polar surface area and HBD is hydrogen bond donors. The predicted Vss for OLZ was determined using the corrected Poulin and Theil method 67
Back calculated based on the clinically observed time to maximum concentration in Shirley et al. [13], according to the method described by Yamazaki et al. 68
Based on differences in Vmax between user recombinant expression system [HEK293T cells; 216 (pmol min−1 mg−1) and HLM (486 pmol min−1 mg−1)]
fe, fraction excreted unchanged in urine (0.09); CLiv, intravenous clearance (20 l h−1)