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. 2019 Nov 21;107(3):650–661. doi: 10.1002/cpt.1672

Table 1.

Summary of biopharmaceutical properties and metabolizing CYP enzymes

Parameters Imatinib mesylate M1 Crizotinib Trametinib Dabrafenib mesylate Gefitinib Erlotinib HCl Lapatinib ditosylate Vemurafenib Pazopanib HCl
Measured solubility in FaSSIF pH 6.5 (mg/mL) ≥ 5 0.0728 0.7430 N.A. 0.0037 0.0887 0.0124 0.0350 0.0054 0.0012
Measured solubility in SGF pH 1.6 (mg/mL) N.A. 0.0213 N.A. N.A. 0.0117 N.A. 0.1665 0.0055 0.0003 1.0779
Measured Caco‐2 Papp passive (10−6 cm/second) 25.90 14.70 15.35 15.44 12.45 10.41 40.43 0.21 0.11 28.46
cPeff [10−4 cm/second] 2.61 6.19 2.22 1.07 2.38 5.23 3.58 1.84 2.54 0.85
pKa values (basic) 8.07, 1.5235 9.5, 2.8 9.4, 5.620 N.A. 2.2, 1.536 7.2, 5.437 5.4238 4.6, 6.739 N.A. 6.4, 2.118
pKa values (acidic) N.A. N.A. N.A. N.A. 6.636 N.A. N.A. N.A. 7.9, 11.140 10.218
Clinical dose in food effect study (mg)a 400 Clinical dose is yet to be established 250 2 150 250 150 1,500 960 800
BCS classification II10 Likely IV IV20 II24 II36 II41 II38 IV42 IV40 II18
Dose number 0.38 > 1 1.35 11.43 193.55 11.27 53.10 277.78 711.11 2,909.09
SLAD (mg)a 6,527.96 > dose in food effect study 985.72 0.45b 4.41 227.43 24.18 23.75 8.20 0.55
DCS classification Ila Likely IV IV Ilb Ilb Ila Ilb IV IV Ilb
Major metabolizing CYP enzymes CYP3A443

CYP3A4

CYP2C8

CYP3A4

CYP3A520

—

CYP2C8

CYP3A436

CYP3A4

CYP2D644

CYP3A438

CYP3A4

CYP3A542

CYP3A440 CYP3A418

Dose number: dose number < 1 indicates that the dose is soluble in 250 mL FaSSIF, solubility criterion for BCS classification (Eq. 2).

BCS, Biopharmaceutical Classification System; Caco‐2 Papp passive, apparent passive permeability determined in Caco‐2 assay; cPeff, calculated effective intestinal permeability; DCS, Developability Classification System; FaSSIF, fasted state intestinal fluid; N.A., not applicable; pKa, acid dissociation constant; SGF, simulated gastric fluid; SLAD, solubility limited absorbable dose (amount of drug soluble in 500 mL FaSSIF, solubility criterion for DCS IIa/IIb classification (Eq. 3)).

a

Dose given as free base. bCalculated using literature solubility from the US Food and Drug Administration Clinical Pharmacology and Biopharmaceutics Review.24