Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

12.2       Pharmacodynamics
Pralsetinib exposure-response relationships and the time course of pharmacodynamics response have not been fully characterized.
Cardiac Electrophysiology
The QT interval prolongation potential of pralsetinib was assessed in 34 patients with RET - altered solid tumors administered GAVRETO at the recommended dosage. No large mean increase in QTc (> 20 ms) was detected in the study.

Pharmacokinetic Properties

12.3       Pharmacokinetics
At 400 mg GAVRETO once daily under fasting conditions, the steady state geometric mean [% coefficient of variation (CV%)] of maximum observed plasma concentration (C max) and area under the concentration-time curve (AUC0-24h) of pralsetinib was 2470 (55.1%) ng/mL and 36700 (66.3%) h•ng/mL, respectively. Pralsetinib Cmax and AUC increased inconsistently over the dose range of 60 mg to 600 mg once daily (0.15 to 1.5 times the recommended dose).

Pralsetinib plasma concentrations reached steady state by 3 to 5 days. The mean accumulation ratio was approximately 2-fold after once-daily repeated oral administration.
Absorption
The median time to peak concentration (Tmax) ranged from 2 to 4 hours following single doses of pralsetinib 60 mg to 600 mg.
Food Effect
Following administration of a single dose of 200 mg GAVRETO with a high-fat meal, (approximately 800 to 1000 calories with 50 to 60% of calories from fat), the mean (90% CI) Cmax of pralsetinib was increased by 104% (65%, 153%), the mean (90% CI) AUC 0-INF was increased by 122% (96%,152%), and the median T max was delayed from 4 to 8.5 hours, compared to the fasted state.
Distribution
The mean (CV%) apparent volume of distribution (Vd/F) of pralsetinib is 303 L (68%). Protein binding of pralsetinib is 97.1% and is independent of concentration. The blood-to-plasma ratio is 0.6 to 0.7.
Elimination
The mean (±standard deviation) plasma elimination half-life (T ½) of pralsetinib is 15.7 hours (9.8) following single doses and 20 hours (11.7) following multiple doses of pralsetinib. The mean (CV%) apparent oral clearance (CL/F) of pralsetinib is 10.9 L/h (66%) at steady state.
Metabolism
Pralsetinib is primarily metabolized by CYP3A4 and to a lesser extent by CYP2D6 and CYP1A2, in vitro. Following a single oral dose of 310 mg of radiolabeled pralsetinib to healthy subjects, pralsetinib metabolites from oxidation and glucuronidation were detected as 5% or less.
Excretion
Approximately 73% (66% as unchanged) of the total administered radioactive dose [ 14C] pralsetinib was recovered in feces and 6% (4.8% as unchanged) was recovered in urine.
Specific Populations
No clinically significant differences in the PK of pralsetinib were observed based on age (19 to 87 years), sex, race (370 White, 22 Black, or 61 Asian), and body weight (32.1 to 128 kg). Mild and moderate renal impairment (CLcr 30 - 89 mL/min) had no effect on the exposure of pralsetinib. Pralsetinib has not been studied in patients with severe renal impairment (CLcr < 15 mL/min).
Patients with Hepatic Impairment
Mild hepatic impairment (total bilirubin ≤ 1.0 × ULN and AST > ULN, or total bilirubin > 1.0 to 1.5 × ULN and any AST) had no effect on the PK of pralsetinib. Pralsetinib has not been studied in patients with moderate (total bilirubin > 1.5 to 3.0 × ULN and any AST) or severe (total bilirubin > 3.0 ULN and any AST) hepatic impairment.

Drug Interaction Studies
Clinical Studies and Model-Informed Approaches
Combined P-gp and Strong CYP3A Inhibitors: Coadministration of itraconazole 200 mg with a single GAVRETO 200 mg dose increased pralsetinib Cmax by 84% and AUC0-INF by 251%.
Strong CYP3A Inducers: Coadministration of rifampin 600 mg once daily with a single GAVRETO 400 mg dose decreased pralsetinib Cmax by 30% and AUC0-inf by 68%.
Mild CYP3A Inducers: No clinically significant differences in the PK of pralsetinib were identified when GAVRETO was coadministered with mild CYP3A inducers.
Acid-Reducing Agents: No clinically significant differences in the PK of pralsetinib were observed when GAVRETO was coadministered with gastric acid reducing agents.
In Vitro Studies
Cytochrome P450 (CYP) Enzymes: Pralsetinib is a time-dependent inhibitor of CYP3A4/5 and an inhibitor of CYP2C8, CYP2C9, and CYP3A4/5, but not an inhibitor of CYP1A2, CYP2B6, CYP2C19 or CYP2D6 at clinically relevant concentrations.
Pralsetinib is an inducer of CYP2C8, CYP2C9, and CYP3A4/5, but not an inducer of CYP1A2, CYP2B6, or CYP2C19 at clinically relevant concentrations.
Transporter Systems: Pralsetinib is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), but not a substrate of bile salt efflux pump (BSEP), organic cation transporter [OCT]1, OCT2, organic anion transporting polypeptide [OATP]1B1, OATP1B3, multidrug and toxin extrusion [MATE]1, MATE2-K, organic anion transporter [OAT]1, or OAT3.
Pralsetinib is an inhibitor of P-gp, BCRP, OATP1B1, OATP1B3, OAT1, MATE1, MATE2-K, and BSEP, but not an inhibitor of OCT1, OCT2, and OAT1A3 at clinically relevant concentrations.