Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

10.2    Pharmacodynamics
Exposure-Response Relationships
Based on the data from four clinicals trials conducted in patients with advanced malignancies and systemic mastocytosis, including NAVIGATOR, EXPLORER, and PATHFINDER, higher exposure was associated with increased risk of Grade ≥ 3 related adverse effects, any Grade pooled cognitive adverse effects, Grade ≥ 2 pooled cognitive adverse effects, and Grade ≥ 2 pooled edema adverse effects over the dose range of 30 mg to 400 mg (0.1 to 1.33 times the recommended dose for GIST and 0.15 to 2 times the recommended dose for AdvSM) once daily.

Based on exposure and efficacy data from EXPLORER and PATHFINDER (n=84), higher avapritinib exposure was associated with faster time to response over the dose range of 30 mg to 400 mg (0.15 to 2 times the recommended dose for AdvSM) once daily.

Cardiac Electrophysiology
The effect of AYVAKIT on the QTc interval was evaluated in an open-label, single-arm study in 27 patients administered dose of 300 mg or 400 mg (1.33 times the recommended 300 mg dose) once daily.
No large mean increase in QTc (i.e.> 20 ms) was detected at the mean steady state maximum concentration (Cmax) of 899 ng/mL.

Pharmacokinetic Properties

10.3    Pharmacokinetics
Avapritinib Cmax and AUC increased proportionally over the dose range of 30 mg to 400 mg once daily in patients with GIST (0.1 to 1.33 times the recommended 300 mg dose). Avapritinib Cmax and AUC increased proportionally over the dose range of 200 mg to 400 mg once daily in patients with systemic mastocytosis (1 to 2 times the recommended 200 mg dose). Steady state concentration of avapritinib was reached by day 15 following daily dosing. Steady state pharmacokinetic parameters per recommended dosing regimen are described in Table 7.
Table 7. Steady State Pharmacokinetic Parameters of AYVAKIT Following Different Dosing Regimen

Dosing Regimen                                     200 mg once daily          300 mg once daily (Systemic                   (GIST)
Mastocytosis)

Geometric Mean (CV%) steady state Cmax           377 (62%, n=18)           813 (52%, n=110) (ng/mL)

Geometric Mean (CV%) steady state AUC0-24h 6600 (54%, n=16)                15400 (48%, n=110) (h•ng/mL)

Mean accumulation ratio                          6.41 (n=9)                3.82 (n=34) Absorption
The median time to peak concentration (Tmax) ranged from 2 to 4 hours following single doses of avapritinib 30 mg to 400 mg in patients with GIST and single doses of avapritinib 30 mg to 300 mg in patients with systemic mastocytosis.
Effect of Food
The Cmax of avapritinib was increased by 59% and the AUC0-INF was increased by 29% when AYVAKIT was taken with a high-calorie, high-fat meal (approximately 909 calories, 58 grams carbohydrate, 56 grams fat and 43 grams protein) compared to those in the fasted state.
Distribution
The mean apparent volume of distribution of avapritinib is 1200 L (43%) at 300 mg for patients with GIST, and 1900 L (43%) at 200 mg in patients with systemic mastocytosis. In vitro protein binding of avapritinib is 98.8% and is independent of concentration. The blood-to-plasma ratio is 0.95.
Elimination
The mean plasma elimination half-life of avapritinib was 32 hours to 57 hours following single doses of avapritinib 30 mg to 400 mg (0.1 to 1.33 times the recommended 300 mg dose) in patients with GIST, and 20 hours to 39 hours following single doses of avapritinib 30 mg to 400 mg (0.15 to 2 times the recommended 200 mg dose) in patients with systemic mastocytosis. The steady state mean apparent oral clearance of avapritinib is 21.8 L/h (12%) at 300 mg for patients with GIST, and 40.3 L/h (86%) at 200 mg in patients with systemic mastocytosis.
Metabolism
Avapritinib is primarily metabolized by CYP3A4, CYP3A5 and to a lesser extent by CYP2C9 in vitro.
Following a single oral dose of approximately 310 mg of radiolabeled avapritinib to healthy subjects, unchanged avapritinib (49%) and its metabolites M690 (hydroxy glucuronide; 35%) and M499 (oxidative deamination; 14%) were the major circulating compounds. The formation of the glucuronide M690 is catalyzed mainly by UGT1A3. Following oral administration of AYVAKIT 300 mg once daily in patients, the steady state AUC of M499 is approximately 80% of the AUC of avapritinib. M499 is not likely to contribute to efficacy at the recommended dose of avapritinib.
Excretion
Following a single oral dose of approximately 310 mg of radiolabeled avapritinib to healthy subjects, 70% of the radioactive dose was recovered in feces (11% unchanged) and 18% in urine (0.23% unchanged).
Specific Populations
No clinically significant differences in the pharmacokinetics of avapritinib were observed based on age (18 to 90 years), sex, race (White, Black, or Asian), body weight (39.5 to 156.3 kg), mild to moderate (CLcr 30 to 89 mL/min estimated by Cockcroft-Gault) renal impairment, or mild (total bilirubin ≤ ULN and AST > ULN or total bilirubin > 1 to 1.5 times ULN and any AST) to moderate (total bilirubin > 1.5 to 3 times ULN and any AST) hepatic impairment. The effect of severe renal impairment (CLcr 15 to 29 mL/min), end-stage renal disease (CLcr < 15 mL/min), or severe hepatic impairment (total bilirubin > 3 times ULN and any AST) on the pharmacokinetics of avapritinib is unknown.


Drug Interaction Studies
Clinical Studies and Model-Informed Approaches
Effect of Strong and Moderate CYP3A Inhibitors on Avapritinib: Coadministration of AYVAKIT 300 mg once daily with itraconazole 200 mg once daily (a strong CYP3A inhibitor) is predicted to increase avapritinib AUC by 600% at steady state.
Coadministration of AYVAKIT 300 mg once daily with fluconazole 200 mg once daily (a moderate CYP3A inhibitor) is predicted to increase avapritinib AUC by 210% at steady state [see Drug Interactions (7.1)].
Effect of Strong and Moderate CYP3A Inducers on Avapritinib: Coadministration of AYVAKIT 400 mg as a single dose with rifampin 600 mg once daily (a strong CYP3A inducer) decreased avapritinib Cmax by 74% and AUC0-INF by 92%.
Coadministration of AYVAKIT 300 mg once daily with efavirenz 600 mg once daily (a moderate CYP3A inducer) is predicted to decrease avapritinib Cmax by 55% and AUC by 62% at steady state [see Drug Interactions (7.1)].
Effect of Acid-Reducing Agents on Avapritinib: No clinically significant differences in the pharmacokinetics of avapritinib were identified when coadministered with gastric acid reducing agents in patients with GIST and AdvSM.
In Vitro Studies
Cytochrome P450 (CYP) Enzymes: In vitro studies indicate that avapritinib is a time-dependent inhibitor as well as an inducer of CYP3A at clinically relevant concentrations.
Avapritinib is an inhibitor of CYP2C9 at clinically relevant concentrations. Avapritinib is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C19, or CYP2D6 at clinically relevant concentrations.
Avapritinib is not an inducer of CYP1A2 or CYP2B6. Avapritinib is a substrate of CYP3A.
M499 is an inhibitor of CYP3A, CYP2C8, or CYP2C9 at clinically relevant concentrations. M499 is not an inhibitor of CYP1A2, CYP2B6, CYP2C19, or CYP2D6 at clinically relevant concentrations.
Transporter Systems: Avapritinib is an inhibitor of P-glycoprotein (P-gp), intestinal BCRP, MATE1, MATE2-K, and BSEP, but not an inhibitor of OATP1B1, OATP1B3, OAT1, OAT3, OCT1, or OCT2.
Avapritinib is not a substrate of P-gp or BCRP, OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, MATE1, MATE2-K and BSEP. The effect of M499 on transporter systems is unknown.