Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

12.2    Pharmacodynamics
Exposure-Response Relationships
Ripretinib exposure-response relationships and the time course of pharmacodynamics have not been fully characterized.
Cardiac Electrophysiology
No large mean increase in QTc interval (i.e. >20 ms) was detected following treatment with QINLOCK at the recommended dose of 150 mg taken orally once daily.

Pharmacokinetic Properties

12.3    Pharmacokinetics
The pharmacokinetics of ripretinib and its equally active metabolite (DP-5439) were characterized in clinical studies. In patients with advanced malignancies, ripretinib AUC0-24h increased proportionally over a dose range of 20-250 mg (0.13 to 1.67 times the recommended dose), but Cmax was less than dose proportional; DP-5439 Cmax and AUC0-24h were less than dose proportional within the dose range of 50-250 mg (0.33 to 1.67 times the recommended dose).
No clinically significant differences in the Cmax and AUC0-24h were observed between administration of QINLOCK with a high-fat meal (150, 250, and 500-600 calories from protein, carbohydrate, and fat, respectively) and under fasted conditions. The pharmacokinetic parameters of ripretinib and DP-5439 are summarized in Table 5.
Table 5:              Pharmacokinetic Parameters of Ripretinib and DP-5439 Parameter                                      Ripretinib                            DP-5439 General Information
Steady state exposure               Cmax (ng/mL)             761 (32)                             804 (46) following
QINLOCK
150 mg once            AUC0-12h daily                                           5678 (32)                            7138 (44) (ng•h/mL)
[Mean (CV%)]
Time to steady state [Days]                        14                                   14 Accumulation ratio (AUC0-12h)
1.7 (55)                             5.29 (49)
[Mean (CV%)]a
Absorption
Tmax [Median in hours]b                            4                                   15.6 Distribution
Plasma protein         Human serum binding (in vitro)                               99.8%                                99.7% albumin
α-1 acid
99.4%                               >99.8% glycoprotein
Steady state apparent volume of distribution, L                                 307 (39)                             507 (51) [Mean (CV%)]b
Elimination
Apparent clearance, L/hr
15.3 (45)                            17.5 (63)
[Mean (CV%)]b


Half-life, hours
14.8 (30)                                    17.8 (23)
[Mean (CV%)]b
Metabolism
Metabolic           Major                             CYP3A4                                       CYP3A4 pathways
Minor                      CYP2C8 and CYP2D6                       CYP2C8, CYP2E1 and CYP2D6 Excretion
Excretion           Feces                                34%                                           6% pathways
Urine                               0.02%                                         0.1% a.
Estimated based on cycle 1, day 15 b.
After a single oral dose of 150 mg
CV=coefficient of variation; Cmax=maximum plasma concentration; AUC0-12h=area under the plasma concentration-time curve from time zero to 12 hours; AUC0-24h=area under the plasma concentration-time curve from time zero to 24 hours; Tmax=time to maximum concentration
Specific Populations
No clinically significant differences in the pharmacokinetics of ripretinib were observed based on age (19 to 87 years), sex, race (White, Black, and Asian), body weight (39 to 138 kg), tumor (GIST or other solid tumors), prior gastrectomy, mild to moderate renal impairment (CLcr 30 to <90 mL/min estimated by Cockcroft-Gault), and mild hepatic impairment (total bilirubin ≤ULN and AST >ULN or total bilirubin 1 to 1.5 × ULN and AST any). The effects of severe renal impairment (CLcr 15 to 29 mL/min) or moderate to severe hepatic impairment (total bilirubin >1.5 × ULN, AST any) on the pharmacokinetics of ripretinib have not been studied.
Drug Interaction Studies
Clinical Studies and Model-Informed Approaches
Strong CYP3A Inhibitors: Coadministration of QINLOCK with itraconazole (a strong CYP3A inhibitor and also a P-gp inhibitor) increased ripretinib Cmax by 36% and AUC0-inf by 99% and also increased DP-5439 AUC0- inf by 99% with no change in its Cmax.

Strong CYP3A Inducers: Coadministration of QINLOCK with rifampin (a strong CYP3A inducer) decreased ripretinib Cmax by 18% and AUC0-inf by 61% and also decreased DP-5439 AUC0-inf by 57% with increased Cmax by 37%.
Moderate CYP3A Inducers: Coadministration of QINLOCK with efavirenz (a moderate CYP3A inducer) was predicted to decrease ripretinib Cmax by 24% and decrease AUC0-inf by 56%.
Proton Pump Inhibitors: No clinically significant differences in the plasma exposure to ripretinib and DP-5439 were observed when QINLOCK was coadministered with pantoprazole (a proton pump inhibitor).
In Vitro Studies
CYP Enzymes: Ripretinib and DP-5439 are inhibitors of CYP2C8. Ripretinib and DP-5439 are not inducers of CYP1A2, CYP2B6, or CYP3A4.
Transporter Systems: Ripretinib and DP-5439 are substrates for P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP). Ripretinib is an inhibitor of P-gp and BCRP. DP-5439 is an inhibitor of BCRP and Multidrug And Toxin Extrusion Protein 1 (MATE1).