TABLE 1.
Main physicochemical and biopharmaceutics properties of omaveloxolone used in the model.
| Parameter | Value for crystalline drug | Value for amorphous drug | Reference/rationale |
|---|---|---|---|
| Molecular weight | 554.7 | From structure | |
| Compound nature | Crystalline | Amorphous | From FDA, chemistry review for omaveloxolone (NDA 216718) 41 |
| pKa | 7.26 (A) | Measured | |
| Log P | >5 | Measured | |
| True density (g/mL) | 1.2 | Not reported. Default value used | |
| Intrinsic solubility (μg/mL) | 0.154 | Approx. 1.1 | Measured |
| Precipitation time (s) | NA | 25,167 | Does not play a role in drug exposure per sensitivity analysis |
| In vitro degradation rate (min−1) | 0 | No measured chemical degradation for up to 24 h in biorelevant media | |
| FaSSIF‐V2 solubility (μg/mL) | 1.4 (24 h) | 14 | Measured. The value for the amorphous drug was taken as 10 times that for the crystalline drug (see page 11 of Supplementary Materials [Supplementary Results–Solubility and precipitation]) |
| FeSSIF solubility (μg/mL) | 9 (24 h) | 90 | Measured. The value for the amorphous drug was taken as 10 times that for the crystalline drug (see Supplementary Results–Solubility and precipitation) |
| Bile salt solubilization ratio | 7.3 × 105 | 9.34 × 105 | Fitted from solubility data in GastroPlus |
| Exponent for bile salt solubilization | 1.3039 | 1.2813 | Fitted from solubility data in GastroPlus |
| fu plasma (%) | 3.1 | From FDA, clinical pharmacology review for omaveloxolone (NDA 216718) 18 | |
| B/P ratio | 0.70 | ||
| DS particle size diameter (μm) | Not reported. 50 μm radius for model use on crystalline content |
D (v,0.1) = measured D (v,0.5) = measured D (v,0.9) = measured |
Measured. Typical D (v,0.9) < 30 μm for amorphous drug |
| Jejunum P eff (10−4 cm/s) | 3 | Fitted to oral monkey data from RTA‐P‐18011. Predicted to be 3.841 using APv10.3 | |
| Formulation type | Suspension (if precipitate) or same as amorphous or IR capsule (when spiked) | 50‐mg immediate‐release capsules | The recommended dose is 150 mg once daily |
| Model for dissolution | Based on Johnson model using DS PSD, adjusted for bile salt effect on solubility and diffusion. Dissolution model employed a “controlled‐release undissolved” formulation type using measured dissolution with a Weibull fit of the data | Based on mechanism of release and measured DS PSD (see Supplementary Materials and Methods–Integration of DP dissolution) | |
| Model for distribution | Full PBPK model with Lukacova parameters for K p calculation | Based on best fit to monkey IV data | |
| V max of CYP3A4 in the gut (mg/s) | 0.5 | Converted to in vivo V max from intrinsic HLM clearance and adjusted to PK data from study 1806 | |
| V max of CYP3A4 in the PBPK model (mg/s/mg‐enz) | 0.015 | Converted to in vivo V max from intrinsic HLM clearance and adjusted to PK data from study 1806 | |
| K m of CYP3A4 (μg/mL) | 1 | Rounded from 0.694 μg/mL; converted from CYP3A4 measured K m in study RTA408‐P‐1212 | |
| V max of P‐gp (mg/s) | 2.523 × 10−4 | Converted from Caco‐2‐derived data | |
| K m of P‐gp (μg/mL) | 2.9401 | Converted from Caco‐2‐derived data | |
Abbreviations: B/P, blood:plasma concentration ratio; CYP3A4, cytochrome P450 3A4; D (v,0.1/0.5/0.9), 10%/50%/90% of particles are smaller than the stated size; DP, drug product; DS, drug substance; FaSSIF‐V2, fasted‐state simulated intestinal fluid V2; FDA, US Food and Drug Administration; FeSSIF, fed‐state simulated intestinal fluid; fu, fraction unbound; HLM, human liver microsome; IR, immediate‐release; IV, intravenous; K m, Michaelis–Menten constant; K p, permeability constant; log P; partition coefficient/lipophilicity; NDA, new drug application; PBPK, physiologically based pharmacokinetic; P eff, effective permeability; P‐gp, P‐glycoprotein; PK, pharmacokinetic; pKa, acid‐dissociation constant; PSD, particle size distribution; V max, maximum rate of reaction.