Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

12.2 Pharmacodynamics
Exposure-Response Relationship
Selpercatinib exposure-response relationships and the time course of pharmacodynamic response have not been fully characterized.
Cardiac Electrophysiology
The effect of RETEVMO on the QTc interval was evaluated in a thorough QT study in healthy subjects. The largest mean increase in QTc is predicted to be 10.6 msec (upper 90% confidence interval: 12.1 msec) at the 

mean steady-state maximum concentration (Cmax) observed in patients after administration of 160 mg twice daily. The increase in QTc was concentration-dependent.

Pharmacokinetic Properties

12.3 Pharmacokinetics
The pharmacokinetics of selpercatinib were evaluated in patients with locally advanced or metastatic solid tumors administered 160 mg twice daily unless otherwise specified. Steady state selpercatinib AUC and Cmax increased in a slightly greater than dose proportional manner over the dose range of 20 mg once daily to 240 mg twice daily [0.06 to 1.5 times the maximum recommended total daily dosage].
Steady-state was reached by approximately 7 days and the median accumulation ratio after administration of 160 mg twice daily was 3.4-fold. Mean steady-state selpercatinib [coefficient of variation (CV%)] Cmax was 2,980 (53%) ng/mL and AUC0-24h was 51,600 (58%) ng*h/mL.
Absorption
The median tmax of selpercatinib is 2 hours. The mean absolute bioavailability of RETEVMO capsules is 73% (60% to 82%) in healthy subjects.
Effect of Food
No clinically significant differences in selpercatinib AUC or Cmax were observed following administration of a high-fat meal (approximately 900 calories, 58 grams carbohydrate, 56 grams fat and 43 grams protein) in healthy subjects.
Distribution
The apparent volume of distribution (Vss/F) of selpercatinib is 203 L.
Protein binding of selpercatinib is 96% in vitro and is independent of concentration. The blood-to-plasma concentration ratio is 0.7.
Elimination
The apparent clearance (CL/F) of selpercatinib is 6 L/h in patients and the half-life is 32 hours following oral administration of RETEVMO in healthy subjects.
Metabolism
Selpercatinib is metabolized predominantly by CYP3A4. Following oral administration of a single radiolabeled 160 mg dose of selpercatinib to healthy subjects, unchanged selpercatinib constituted 86% of the radioactive drug components in plasma.
Excretion
Following oral administration of a single radiolabeled 160 mg dose of selpercatinib to healthy subjects, 69% of the administered dose was recovered in feces (14% unchanged) and 24% in urine (12% unchanged).
Specific Populations
The apparent volume of distribution and clearance of selpercatinib increase with increasing body weight (27 kg to 179 kg).
No clinically significant differences in the pharmacokinetics of selpercatinib were observed based on age (15 years to 92 years), sex, or mild, moderate, or severe renal impairment (eGFR ≥15 to 89 mL/min). The effect of ESRD on selpercatinib pharmacokinetics has not been studied.
Patients with Hepatic Impairment
The selpercatinib AUC0-INF increased 1.07-fold, 1.32-fold, and 1.77-fold in subjects with mild (total bilirubin less than or equal to ULN with AST greater than ULN or total bilirubin greater than 1 to 1.5 times ULN with any AST), moderate (total bilirubin greater than 1.5 to 3 times ULN and any AST), and severe (total bilirubin greater than 3 to 10 times ULN and any AST) hepatic impairment, respectively, compared to subjects with normal hepatic function.


Drug Interaction Studies
Clinical Studies and Model-Informed Approaches
Proton-Pump Inhibitors (PPI): Coadministration with multiple daily doses of omeprazole (PPI) decreased selpercatinib AUC0-INF and Cmax when RETEVMO was administered fasting. Coadministration with multiple daily doses of omeprazole did not significantly change the selpercatinib AUC0-INF and Cmax when RETEVMO was administered with food (Table 13).

Table 13: Change in Selpercatinib Exposure After Coadministration with PPI Selpercatinib                         Selpercatinib
AUC0-INF                                Cmax
RETEVMO fasting                                          Reference                             Reference RETEVMO fasting + PPI                                      ↓ 69%                                 ↓ 88% RETEVMO with a high-fat     meal1   + PPI                   ↑ 2%                                 ↓ 49% RETEVMO with a low-fat     meal2   + PPI                No change                                ↓ 22% 1
High-fat meal: approximately 150, 250, and 500-600 calories from protein, carbohydrate, and fat, respectively; approximately 800 to 1,000 calories total.
2
Low-fat meal: approximately 390 calories and 10 g of fat.


H2 Receptor Antagonists: No clinically significant differences in selpercatinib pharmacokinetics were observed when coadministered with multiple daily doses of ranitidine (H2 receptor antagonist) given 10 hours prior to and 2 hours after the RETEVMO dose (administered fasting).
Strong CYP3A Inhibitors: Coadministration of multiple doses of itraconazole (strong CYP3A inhibitor) increased the selpercatinib AUC0-INF 2.33-fold and Cmax 1.3-fold.
Moderate CYP3A Inhibitors: Coadministration of multiple doses of diltiazem, fluconazole, or verapamil (moderate CYP3A inhibitors) is predicted to increase the selpercatinib AUC 1.6 to 1.99-fold and Cmax 1.46 to 1.76-fold.
Strong CYP3A Inducers: Coadministration of multiple doses of rifampin (strong CYP3A inducer) decreased the selpercatinib AUC0-INF by 87% and Cmax by 70%.
Moderate CYP3A Inducers: Coadministration of multiple doses of bosentan or efavirenz (moderate CYP3A inducers) is predicted to decrease the selpercatinib AUC by 40-70% and Cmax by 34-57%.
Weak CYP3A Inducers: Coadministration of multiple doses of modafinil (weak CYP3A inducer) is predicted to decrease the selpercatinib AUC by 33% and Cmax by 26%.
CYP2C8 Substrates: Coadministration of RETEVMO with repaglinide (sensitive CYP2C8 substrate) increased the repaglinide AUC0-INF 2.88-fold and Cmax 1.91-fold.
CYP3A Substrates: Coadministration of RETEVMO with midazolam (sensitive CYP3A substrate) increased the midazolam AUC0-INF 1.54-fold and Cmax 1.39-fold.
P-glycoprotein (P-gp) Substrates: Coadministration of RETEVMO with dabigatran (P-gp substrate) increased the dabigatran AUC0-INF 1.38-fold and Cmax 1.43-fold.
P-gp Inhibitors: No clinically significant differences in selpercatinib pharmacokinetics were observed when coadministered with a single dose of rifampin (P-gp inhibitor).
MATE1 Substrates: No clinically significant differences in glucose levels were observed when metformin (MATE1 substrate) was coadministered with selpercatinib.


In Vitro Studies
CYP Enzymes: Selpercatinib does not inhibit or induce CYP1A2, CYP2B6, CYP2C9, CYP2C19, or CYP2D6 at clinically relevant concentrations.
Transporter Systems: Selpercatinib inhibits MATE1 and BCRP, but does not inhibit OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, BSEP, and MATE2-K at clinically relevant concentrations. Selpercatinib may increase serum creatinine by decreasing renal tubular secretion of creatinine via inhibition of MATE1 [see Adverse Effects (6.1)]. Selpercatinib is a substrate for P-gp and BCRP, but not for OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, MATE1, or MATE2-K.