Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

12.2       Pharmacodynamics
Left Ventricular Ejection Fraction and Left Ventricular Outflow Tract Obstruction In the EXPLORER-HCM trial, patients achieved reductions in mean resting and provoked (Valsalva) LVOT gradient by Week 4 which were sustained throughout the 30-week trial. At Week 30, the mean (SD) changes from baseline in resting and Valsalva LVOT gradients were -39 (29) mmHg and -49 (34) mmHg, respectively, for the CAMZYOS group and -6 (28) mmHg and -12 (31) mmHg, respectively, for the placebo group. The reductions in Valsalva LVOT gradient were accompanied by decreases in LVEF, generally within the normal range. Eight weeks after discontinuation of CAMZYOS, mean LVEF and Valsalva LVOT gradients were similar to baseline.
Cardiac Structure
In EXPLORER-HCM, echocardiographic measurements of cardiac structure showed a mean (SD) reduction from baseline at Week 30 in left ventricular mass index (LVMI) in the mavacamten group (-7.4 [17.8] g/m2) versus an increase in LVMI in the placebo group (8.9 [15.3] g/m2). There was also a mean (SD) reduction from baseline in left atrial volume index (LAVI) in the mavacamten group (-7.5 [7.8] mL/m2) versus no change in the placebo group (-0.1 [8.7] mL/m2).
The clinical significance of these findings is unknown.
Cardiac Biomarkers
In the EXPLORER-HCM trial [see Clinical Studies (14)], reductions in a biomarker of cardiac wall stress, NT-proBNP, were observed by Week 4 and sustained through the end of treatment. At Week 30 compared with baseline, the reduction in NT-proBNP after mavacamten treatment was 80% greater than for placebo (proportion of geometric mean ratio between the two groups, 0.20 [95% CI: 0.17, 0.24]).
In the VALOR-HCM trial [see Clinical Studies (14)], a reduction in NT-proBNP was observed by Week 8 and sustained throughout treatment. At Week 16 compared with baseline, the reduction in NT-proBNP after mavacamten treatment was 67% greater than for placebo (proportion of geometric mean ratio between the two groups, 0.33 [95% CI: 0.27, 0.42]). At Week 16 compared with baseline, a reduction in cardiac troponin I after mavacamten treatment was 47% greater than for placebo (proportion of geometric mean ratio between the two groups, 0.53 [95% CI: 0.41, 0.70]).
The clinical significance of the NT-proBNP and troponin findings is unknown.
Cardiac Electrophysiology
In healthy volunteers receiving multiple doses of CAMZYOS, a concentration-dependent increase in the QTc interval was observed at doses up to 25 mg once daily. No acute QTc changes have been observed at similar exposures during single-dose studies. The mechanism of the QT prolongation effect is not known.
A meta-analysis across clinical studies in HCM patients does not suggest clinically relevant increases in the QTc interval in the therapeutic exposure range. In HCM, the QT interval may be intrinsically prolonged due to the underlying disease, in association with ventricular pacing, or in association with drugs with potential for QT prolongation commonly used in the HCM population.
The effect of coadministration of CAMZYOS with other QT-prolonging drugs or in patients with potassium channel variants resulting in a long QT interval have not been characterized.

Pharmacokinetic Properties

12.3          Pharmacokinetics
Mavacamten exposure increases dose proportionally following multiple once-daily doses of 1 mg to 15 mg. At the same dose level of CAMZYOS, 170% higher exposures of mavacamten are observed in patients with HCM compared to healthy subjects. Mavacamten accumulation is approximately 100% for Cmax and approximately 600% for AUC in CYP2C19 normal metabolizers (NMs). The accumulation is dependent upon the CYP2C19 metabolism status with the largest accumulation occurring in CYP2C19 poor metabolizers (PMs). At steady-state, the peak-to-trough mavacamten plasma concentration ratio with once daily dosing is approximately 1.5.
Absorption
Mavacamten has an estimated oral bioavailability of at least 85% and median time to maximum concentration (Tmax) of 1 to 2 hours.
Effect of Food
No clinically significant differences in mavacamten AUC were observed following its administration with a high fat meal.
Distribution
Plasma protein binding of mavacamten is between 97 and 98%.
Elimination
Mavacamten has a variable terminal t1/2 that depends on CYP2C19 metabolic status. Mavacamten terminal half-life is 6 to 9 days in CYP2C19 normal metabolizers (NMs), which is prolonged in CYP2C19 poor metabolizers (PMs) to 23 days.
Metabolism
Mavacamten is extensively metabolized, primarily through CYP2C19 (74%), CYP3A4 (18%), and CYP2C9 (8%).
Excretion
Following a single 25 mg dose of radiolabeled mavacamten, 7% of the dose was recovered in feces (1% unchanged) and 85% in urine (3% unchanged).
Specific Populations
No clinically significant differences in the pharmacokinetics of mavacamten were observed based on age (range: 18-82 years), sex, race, ethnicity, or mild (eGFR: 60 to 89 mL/min/1.73 m2) to moderate (eGFR: 30 to 59 mL/min/1.73 m2) renal impairment. The effects of severe (eGFR: 15 to 30 mL/min/1.73 m2) renal impairment and kidney failure (eGFR: <15 mL/min/1.73 m2; including patients on dialysis) are unknown.
Hepatic Impairment
Mavacamten exposures (AUC) increased up to 220% in patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment. The effect of severe (Child-Pugh C) hepatic impairment is unknown.
Drug Interactions
Clinical Studies and Model-Informed Approaches
Weak CYP2C19 Inhibitors: Concomitant use of mavacamten (15 mg) with omeprazole (20 mg) once daily increased mavacamten AUCinf by 48% with no effect on Cmax in healthy CYP2C19 NMs and rapid metabolizers (RMs; e.g., *1/*17).
Moderate CYP3A4 Inhibitors: Concomitant use of mavacamten (25 mg) with verapamil sustained release (240 mg) increased mavacamten AUCinf by 16% and Cmax by 52% in intermediate metabolizers (IMs; e.g., *1/*2, *1/*3, *2/*17, *3/*17) and NMs of CYP2C19. Concomitant use of mavacamten with diltiazem in CYP2C19 PMs is predicted to increase mavacamten AUC0-24h and Cmax up to 55% and 42%, respectively.
Strong CYP3A4 Inhibitors: Concomitant use of mavacamten (15 mg) with ketoconazole 400 mg once daily is predicted to increase mavacamten AUC0-24 and Cmax up to 130% and 90%, respectively.
Strong CYP2C19 and CYP3A4 Inducers: Concomitant use of mavacamten (a single 15 mg dose) with a strong CYP2C19 and CYP3A4 inducer (rifampin 600 mg daily dose) is predicted to decrease mavacamten AUC0-inf and Cmax by 87% and 22%, respectively, in CYP2C19 NMs, and by 69% and 4%, respectively, in CYP2C19 PMs.
CYP3A4 Substrates: Concomitant use of a 16-day course of mavacamten (25 mg on days 1 and 2, followed by 15 mg for 14 days) decreased AUCinf and Cmax of midazolam by 13% and 7%, respectively, in healthy subjects. Following coadministration of mavacamten once daily in HCM patients at the upper end of the therapeutic range, midazolam AUCinf and Cmax are predicted to decrease up to 45% and 24%, respectively.
Certain combined oral contraceptives: No clinically significant differences in ethinyl estradiol and norethindrone exposure were observed in healthy female subjects with CYP2C19 NM phenotype following concomitant use of a combined oral contraceptive containing ethinyl estradiol and norethindrone with a 17-day course of mavacamten (25 mg on days 1 and 2, followed by 15 mg for 15 days). The impact of mavacamten on oral contraceptives containing other progestins is unknown.
CYP2C8 Substrates: Concomitant use of mavacamten once daily in HCM patients is predicted to decrease AUC and Cmax of repaglinide, a CYP2C8 and CYP3A substrate, by up to 27% and 19%, respectively, depending on the dose of mavacamten and CYP2C19 phenotype.

CYP2C9 Substrates: Concomitant use of mavacamten once daily in HCM patients is predicted to decrease AUC and Cmax of tolbutamide, a CYP2C9 substrate, by up to 54% and 23%, respectively, depending on the dose of mavacamten and CYP2C19 phenotype.
CYP2C19 Substrates: Concomitant use of mavacamten once daily in HCM patients is predicted to decrease AUC and Cmax of omeprazole, a CYP2C19 substrate, by up to 48% and 17%, respectively, depending on the dose of mavacamten and CYP2C19 phenotype.Activated Charcoal: Mavacamten AUC0-72h and AUC0-infinity was reduced by 14% and 34%, respectively, following administration of 50 g activated charcoal with sorbitol 2 hours after ingestion of a single mavacamten 15 mg dose. Administration of activated charcoal 6 hours after the mavacamten dose had minimal effect on mavacamten exposure.
In Vitro Studies
CYP Enzymes: Mavacamten does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2D6, CYP2C9, CYP2C19, or CYP3A4. Mavacamten is a CYP2B6 inducer.
Transporter Systems: Mavacamten does not inhibit P-gp, BCRP, BSEP, MATE1, MATE2-K, organic anion transporting polypeptides (OATPs), organic cation transporters (OCTs), or organic anion transporters (OATs).
12.5        Pharmacogenomics
Mavacamten AUCinf increased by 241% and Cmax increased by 47% in CYP2C19 poor metabolizers (PMs) compared to normal metabolizers (NMs) following a single dose of 15 mg mavacamten. Mean half-life is prolonged in CYP2C19 PMs compared to NMs (23 days vs. 6 to 9 days, respectively).
Polymorphic CYP2C19 is the main enzyme involved in the metabolism of CAMZYOS. An individual carrying two normal function alleles is a NM (e.g., *1/*1). An individual carrying two no function alleles is a PM (e.g., *2/*2, *2/*3, *3/*3).
The prevalence of CYP2C19 poor metabolizers differs depending on ancestry. Approximately 2% of individuals of European ancestry and 4% of individuals of African ancestry are PMs; the prevalence of PMs is higher in Asian populations (e.g., approximately 13% of East Asians).