Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

12.2 Pharmacodynamics
Pharmacotherapeutic group: anti-gonadotropin releasing hormones, H01CC03.
Effect on Ovulation and Estradiol
In a 3-menstrual cycle study in healthy women, ORILISSA 150 mg once daily and 200 mg twice daily resulted in an ovulation rate of approximately 50% and 32%, respectively. In the Phase 3 trials in women with endometriosis, ORILISSA caused a dose-dependent reduction in median estradiol concentrations to approximately 42 pg/mL for 150 mg once daily regimen and 12 pg/mL for the 200 mg twice daily regimen.
Cardiac Electrophysiology
The effect of elagolix on the QTc interval was evaluated in a randomized, placebo- and positive- controlled, open-label, single-dose, crossover thorough QTc study in 48 healthy adult premenopausal women. Elagolix concentrations in subjects given a single dose of 1200 mg was 17-times higher than the concentration in subjects given elagolix 200 mg twice daily. There was no clinically relevant prolongation of the QTc interval.

Pharmacokinetic Properties

12.3 Pharmacokinetics
The pharmacokinetic properties of ORILISSA in healthy subjects are summarized in Table 8.
The steady state pharmacokinetic parameters under fasting conditions are summarized in Table 9.


Table 8. Pharmacokinetic Properties of ORILISSA in Healthy Subjects
Absorption
Tmax (h)                                                          1.0 Effect of high-fat meal (relative to fasting)             AUC: ↓24%, Cmax: ↓36% Distribution
% Bound to human plasma proteins                                   80 Blood-to-plasma ratio                                             0.6 Metabolism
CYP3A (major)
Metabolism                                     Minor pathways include: CYP2D6, CYP2C8, and uridine glucuronosyl transferases (UGTs)
Elimination
Major route of elimination                                  Hepatic metabolism Terminal phase elimination
4-6 half-life (t1/2) (h)
% of dose excreted in urine                                           <3 % of dose excreted in feces                                           90 

Table 9. Mean (%CV) Steady State Pharmacokinetic Parameters of ORILISSA Pharmacokinetic Parameter               150 mg Once Daily      200 mg Twice Daily (Units)                               N=6                    N=7
Cmax (ng/mL)                            574 (29)               774 (68) AUCτ (ng●hr/mL)                          1292 (31)              1725 (57) CL/F (L/hr)                            123 (21)               144 (43) Vdss/F                            1674 (94)               881 (38)
Rac                               0.98 (7)               0.89 (19)
CV: Coefficient of variation
Cmax: peak concentration
AUCτ: area under the plasma concentration-time curve during the dosing interval (τ) i.e., 12 hours for twice daily regimen, 24 hours for once daily regimen.
CL/F: oral clearance
Vdss/F: apparent volume of distribution at steady state
Rac: drug accumulation ratio
Specific Populations
Patients with Renal Impairment
Elagolix exposures (Cmax and AUC) are not altered by renal impairment. The mean exposures are similar for women with moderate to severe or end stage renal disease (including women on dialysis) compared to women with normal renal function.
Patients with Hepatic Impairment
Elagolix exposures (Cmax and AUC) are similar between women with normal hepatic function and women with mild hepatic impairment. Elagolix exposures in women with moderate and severe hepatic impairment are approximately 3-fold and 7-fold, respectively, higher than exposures from women with normal hepatic function [see Use in Specific Populations (9.6)].
Racial or Ethnic Groups
No clinically meaningful difference in the pharmacokinetics of ORILISSA between White and Black subjects or between Hispanics and others was observed. There is no clinically meaningful difference in the pharmacokinetics of ORILISSA between Japanese and Han Chinese subjects.
Body weight/Body mass index

Body weight or body mass index does not affect the pharmacokinetics of ORILISSA.
Drug Interaction Studies
Drug interaction studies were performed with ORILISSA and other drugs that are likely to be co- administered and with drugs commonly used as probes for pharmacokinetic interactions. Tables 10 and 11 summarize the pharmacokinetic effects when elagolix was co-administered with these drugs.


Table 10. Drug Interactions: Change in Pharmacokinetics of Elagolix in the Presence of Co-administered Drugs
Regimen
Co-                 of Co-           Regimen administered          administered            of
Drug                 Drug             Elagolix     N          Ratio (90% CI)* Cmax            AUC
400 mg once       150 mg single
Ketoconazole                                               11       1.77            2.20 daily             dose
(1.48 – 2.12) (1.98 – 2.44)
600 mg single                              4.37            5.58 dose          150 mg single       (3.62 – 5.28) (4.88 – 6.37)
Rifampin#                                                  12
600 mg once           dose                2.00            1.65 daily                             (1.66 – 2.41) (1.45 – 1.89)
CI: Confidence interval
*ratios for Cmax and AUC compare co-administration of the medication with elagolix vs.
administration of elagolix alone.
#
A single dose of 600 mg rifampin inhibits OATP1B1; 600 mg once daily dose of rifampin inhibits OATP1B1 and induces CYP3A.
No clinically significant changes in elagolix exposures were observed when co-administered with rosuvastatin (20 mg once daily), sertraline (25 mg once daily) or fluconazole (200 mg single dose).

Table 11. Drug Interactions: Change in Pharmacokinetics of Co-administered Drug in the Presence of Elagolix
Regimen
Co-                of Co-           Regimen administered        administered             of
Drug                Drug             Elagolix      N         Ratio (90% CI)* 200 mg              Cmax          AUC
0.5 mg single
Digoxin                                  twice daily   11      1.71           1.26 dose x 10 days        (1.53 – 1.91) (1.17 – 1.35)
300 mg
20 mg once                               0.99           0.60
Rosuvastatin                             twice daily   10 daily                            (0.73 – 1.35) (0.50 – 0.71) x 7 days


300 mg
0.56            0.46 twice daily     20
(0.51 – 0.62)   (0.41 – 0.50)
2 mg single             x 11 days
Midazolam dose                  150 mg
0.81            0.65 once daily     11
(0.74 – 0.89)   (0.58 – 0.72) x 13 days
150 mg
0.35 mg once                                      0.95            0.88 Norethindrone                                  once daily     32 daily x 112 days                               (0.86 – 1.05)   (0.79 – 0.99) x 56 days
Ethinyl             Ethinyl estradiol                                1.15              1.30 Estradiol             35 mcg and                                 (1.07 – 1.25)     (1.19 – 1.42) triphasic              150 mg                0.87              0.85
Norelgestromina                                               21 norgestimate             once daily         (0.78 – 0.97)     (0.78 – 0.92) 0.18/0.215/0.25                                  0.89              0.92 Norgestrela          mg once daily                               (0.78 – 1.00)     (0.84 – 1.01) Ethinyl                                                              1.36              2.18 Estradiol         Ethinyl estradiol             200 mg           (1.27 – 1.45)     (1.99 – 2.39) 20 mcg/Levonorgestrel          twice daily     20     0.97
0.73
Levonorgestrel   0.1 mg single dose            x 15 days         (0.88 – 1.07) (0.64 – 0.82)
300 mg
40 mg single                                     1.95            1.78 Omeprazole                                    twice daily     20 dose                                     (1.50 – 2.53)   (1.39 – 2.27) x 9 days
CI: Confidence interval
*ratios for Cmax and AUC compare co-administration of the medication with elagolix vs.
administration of the medication alone.
a metabolite of norgestimate

No clinically significant changes were observed in exposures of sertraline, fluconazole, or bupropion when co-administered with elagolix 300 mg twice daily.

12.4 Pharmacogenomics
Hepatic uptake of elagolix involves the OATP 1B1 transporter protein. Higher plasma concentrations of elagolix have been observed in patients who have two reduced function alleles of the gene that encodes OATP 1B1 (SLCO1B1 521T>C) (these patients are likely to have reduced hepatic uptake of elagolix and thus, higher plasma elagolix concentrations). The frequency of this SLCO1B1 521 C/C genotype is generally less than 5% in most racial/ethnic groups. Subjects with this genotype are expected to have a 78% mean increase in elagolix concentrations compared to subjects with normal transporter function (i.e., SLCO1B1 521T/T genotype). Adverse effects of elagolix have not been fully evaluated in subjects who have two reduced function alleles of the gene that encodes OATP1B1 (SLCO1B1 521T>C).