Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

13.2 Pharmacodynamics
Sweat Chloride Evaluation
In Trial 1 (patients with an F508del mutation on one allele and a mutation on the second allele that results in either no CFTR protein or a CFTR protein that is not responsive ivacaftor and tezacaftor/ivacaftor), a reduction in sweat chloride was observed from baseline at Week 4 and sustained through the 24-week treatment period [see Clinical Studies (15.1)]. In Trial 2 (patients homozygous for the F508del mutation), a reduction in sweat chloride was observed from baseline at Week 4 [see Clinical Studies (15.2)].

Cardiac Electrophysiology
At doses up to 2 times the maximum recommended dose of elexacaftor and 3 times the maximum recommended dose of tezacaftor and ivacaftor, the QT/QTc interval in healthy subjects was not prolonged to any clinically relevant extent.

Pharmacokinetic Properties

13.3 Pharmacokinetics
The pharmacokinetics of elexacaftor, tezacaftor and ivacaftor are similar between healthy adult subjects and patients with CF. The pharmacokinetic parameters for elexacaftor, tezacaftor and ivacaftor in patients with CF aged 12 years and older are shown in Table 5.

Table 5: Pharmacokinetic Parameters of Trikafta Components
Elexacaftor                                      Tezacaftor                                 Ivacaftor General Information
AUCss (SD), mcg∙h/mLa                          162 (47.5)b                                      89.3 (23.2)b                              11.7 (4.01)c a
Cmax (SD), mcg/mL                               9.2 (2.1)                                        7.7 (1.7)                                 1.2 (0.3) 
TRIK-SPC-0923-V1                                             Page 8 of 14 Table 5: Pharmacokinetic Parameters of Trikafta Components
Elexacaftor                               Tezacaftor                               Ivacaftor Time to Steady State, days                           Within 7 days                             Within 8 days                          Within 3-5 days Accumulation Ratio                                         2.2                                       2.07                                    2.4 Absorption
Absolute Bioavailability                                  80%                                 Not determined                           Not determined Median Tmax (range), hours                            6 (4 to 12)                                3 (2 to 4)                             4 (3 to 6) AUC increases 1.9- to 2.5-fold
Effect of Food                                                                         No clinically significant effect       Exposure increases 2.5- to 4-fold (moderate-fat meal)
Distribution
Mean (SD) Apparent Volume of
53.7 (17.7)                               82.0 (22.3)                             293 (89.8) Distribution, Ld e
Protein Binding                                          > 99%                              approximately 99%                       approximately 99% Elimination
Mean (SD) Effective Half-Life,
27.4 (9.31)                               25.1 (4.93)                            15.0 (3.92) hoursf
Mean (SD) Apparent Clearance,
1.18 (0.29)                               0.79 (0.10)                            10.2 (3.13) L/hours
Metabolism
Primary Pathway                                        CYP3A4/5                                  CYP3A4/5                               CYP3A4/5 Active Metabolites                                     M23-ELX                                    M1-TEZ                                  M1-IVA Metabolite Potency Relative to
Similar                                   Similar                     approximately 1/6th of parent Parent
Excretiong
• Feces: 87.3% (primarily as              • Feces: 72% (unchanged or as           • Feces: 87.8% Primary Pathway                            metabolites)                              M2-TEZ)                               • Urine: 6.6% • Urine: 0.23%                            • Urine: 14% (0.79% unchanged) a
Based on elexacaftor 200 mg and tezacaftor 100 mg once daily/ivacaftor 150 mg every 12 hours at steady state in patients with CF aged 12 years and older.
b
AUC0-24h.
c
AUC0-12h.
d
Elexacaftor, tezacaftor and ivacaftor do not partition preferentially into human red blood cells.
e
Elexacaftor and tezacaftor bind primarily to albumin. Ivacaftor primarily bind to albumin, alpha 1-acid glycoprotein and human gamma-globulin.
f
Mean (SD) terminal half-lives of elexacaftor, tezacaftor and ivacaftor are approximately 24.7 (4.87) hours, 60.3 (15.7) hours and 13.1 (2.98) hours, respectively.
g
Following radiolabeled doses.
AUCss: area under the concentration versus time curve at steady state; SD: Standard Deviation; Cmax: maximum observed concentration; Tmax: time of maximum concentration; AUC: area under the concentration versus time curve.

Specific Populations
Pediatric patients 12 to less than 18 years of age
The following conclusions about exposures between adults and the pediatric population are based on population pharmacokinetic (PK) analyses.
Following oral administration of Trikafta to patients 12 to less than 18 years of age (elexacaftor 200 mg qd/tezacaftor 100 mg qd/ivacaftor 150 mg q12h), the mean (±SD) AUCss was 147 (36.8) mcg∙h/mL, 88.8 (21.8) mcg∙h/mL and 10.6 (3.35) mcg∙h/mL, respectively for elexacaftor, tezacaftor and ivacaftor, similar to the AUCss in adult patients.

Patients with Renal Impairment
Renal excretion of elexacaftor, tezacaftor and ivacaftor is minimal. Elexacaftor alone or in combination with tezacaftor and ivacaftor has not been studied in subjects with severe (eGFR <30 mL/min/1.73 m2) renal impairment or end-stage renal disease. Based on population PK analyses, the clearance of elexacaftor and tezacaftor was similar in subjects with mild (eGFR 60 to <90 mL/min/1.73 m2) or moderate (eGFR 30 to <60 mL/min/1.73 m2) renal impairment relative to patients with normal renal function [see Use in Specific Populations (10.5)].

Patients with Hepatic Impairment
Elexacaftor alone or in combination with tezacaftor and ivacaftor has not been studied in subjects with severe hepatic impairment (Child-Pugh Class C, score 10-15).
In a clinical study, following multiple doses of elexacaftor, tezacaftor and ivacaftor for 10 days, subjects with moderately impaired hepatic function (Child-Pugh Class B, score 7 to 9) had 25% higher AUC and 12% higher Cmax for elexacaftor, 73% higher AUC and 70% higher Cmax for M23-ELX, 36% higher AUC and 24% higher Cmax for combined elexacaftor and M23-ELX, 20% higher AUC but similar Cmax for tezacaftor and 1.5-fold higher AUC and 10% higher Cmax for ivacaftor compared with healthy subjects matched for demographics [see Dosage and Administration (5.3) ,Warnings and Precautions (7.1), Adverse Reactions (8) and Use in Specific Populations (10.6)].

Tezacaftor and Ivacaftor
Following multiple doses of tezacaftor and ivacaftor for 10 days, subjects with moderately impaired hepatic function had an approximately 36% higher AUC and a 10% higher in Cmax for tezacaftor and a 1.5-fold higher AUC but similar Cmax for ivacaftor compared with healthy subjects matched for demographics.

Ivacaftor
In a study with ivacaftor alone, subjects with moderately impaired hepatic function had similar ivacaftor Cmax, but an approximately 2.0-fold higher ivacaftor AUC0-∞ compared with healthy subjects matched for demographics.

Male and Female Patients
Based on population PK analysis, the exposures of elexacaftor, tezacaftor and ivacaftor are similar in males and females.

TRIK-SPC-0923-V1                                             Page 9 of 14 Drug Interaction Studies
Drug interaction studies were performed with elexacaftor, tezacaftor and/or ivacaftor and other drugs likely to be co-administered or drugs commonly used as probes for pharmacokinetic interaction studies [see Drug Interactions (9)].

Potential for Elexacaftor, Tezacaftor and/or Ivacaftor to Affect Other Drugs Based on in vitro results, elexacaftor and tezacaftor have a low potential to inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4, whereas ivacaftor has the potential to inhibit CYP2C8, CYP2C9 and CYP3A. However, clinical studies showed that the combination regimen of tezacaftor/ivacaftor is not an inhibitor of CYP3A and ivacaftor is not an inhibitor of CYP2C8 or CYP2D6.

Based on in vitro results, elexacaftor, tezacaftor and ivacaftor are not likely to induce CYP3A, CYP1A2 and CYP2B6.

Based on in vitro results, elexacaftor and tezacaftor have a low potential to inhibit the transporter P-gp, while ivacaftor has the potential to inhibit P-gp. Co- administration of tezacaftor/ivacaftor with digoxin, a sensitive P-gp substrate, increased digoxin exposure by 1.3-fold in a clinical study. Based on in vitro results, elexacaftor and M23-ELX may inhibit OATP1B1 and OATP1B3 uptake. Tezacaftor has a low potential to inhibit BCRP, OCT2, OAT1, or OAT3. Ivacaftor is not an inhibitor of the transporters OCT1, OCT2, OAT1, or OAT3.

The effects of elexacaftor, tezacaftor and/or ivacaftor on the exposure of co-administered drugs are shown in Table 6 [see Drug Interactions (9)].

Table 6: Impact of Elexacaftor, Tezacaftor and/or Ivacaftor on Other Drugs Geometric Mean Ratio (90% CI)
Dose and Schedule                                           Effect on Other            of Other Drug Drug PK                  No Effect=1.0
AUC                  Cmax
Midazolam                         TEZ 100 mg qd/IVA 150 mg q12h                                       1.12                1.13 Midazolam
2 mg single oral dose                                                                                  (1.01, 1.25)        (1.01, 1.25)
Digoxin                                                                                             1.30                1.32 TEZ 100 mg qd/IVA 150 mg q12h               ↑ Digoxin
0.5 mg single dose                                                                                    (1.17, 1.45)        (1.07, 1.64) ↑ Ethinyl estradiol*         1.33                1.26
Oral Contraceptive
ELX 200 mg qd/TEZ 100 mg qd/IVA                                   (1.20, 1.49)        (1.14, 1.39) Ethinyl estradiol 30 µg/Levonorgestrel
150 mg q12h                  ↑ Levonorgestrel*           1.23                1.10 150 µg qd
(1.10, 1.37)       (0.985, 1.23)
Rosiglitazone                                                                                         0.975               0.928 IVA 150 mg q12h                    Rosiglitazone
4 mg single oral dose                                                                                 (0.897, 1.06)       (0.858, 1.00)
Desipramine                                                                                            1.04                1.00 IVA 150 mg q12h                     Desipramine
50 mg single dose                                                                                   (0.985, 1.10)       (0.939; 1.07) ↑ = increase, = decrease,       = no change. CI = Confidence Interval; ELX= elexacaftor; TEZ = tezacaftor; IVA = ivacaftor; PK = Pharmacokinetics * Effect not clinically significant [see Drug Interactions (9.6)].

Potential for Other Drugs to Affect Elexacaftor, Tezacaftor and/or Ivacaftor In vitro studies showed that elexacaftor, tezacaftor and ivacaftor are all metabolized by CYP3A. Exposure to elexacaftor, tezacaftor and ivacaftor may be reduced by concomitant CYP3A inducers and increased by concomitant CYP3A inhibitors.

In vitro studies showed that elexacaftor and tezacaftor are substrates for the efflux transporter P-gp, but ivacaftor is not. Elexacaftor and ivacaftor are not substrates for OATP1B1 or OATP1B3; tezacaftor is a substrate for OATP1B1, but not OATP1B3. Tezacaftor is a substrate for BCRP.

The effects of co-administered drugs on the exposure of elexacaftor, tezacaftor and/or ivacaftor are shown in Table 7 [see Dosage and Administration (5.4) and Drug Interactions (9)].

Table 7: Impact of Other Drugs on Elexacaftor, Tezacaftor and/or Ivacaftor Geometric Mean Ratio (90% CI) of
Effect on ELX,           Elexacaftor, Tezacaftor and
Dose and Schedule                                                                               Ivacaftor TEZ and/or IVA
PK                        No Effect = 1.0
AUC                    Cmax
4.02                  2.83
↑ Tezacaftor
Itraconazole                                   TEZ 25 mg qd +                                     (3.71, 4.63)          (2.62, 3.07)              200 mg q12h on Day 1, followed by 200 mg qd                    IVA 50 mg qd                                          15.6                  8.60
↑ Ivacaftor
(13.4, 18.1)          (7.41, 9.98)
2.83                  1.05
↑ Elexacaftor
Itraconazole                           ELX 20 mg + TEZ 50 mg                                   (2.59, 3.10)         (0.977, 1.13) 200 mg qd                                   single dose                                           4.51                  1.48 ↑ Tezacaftor
(3.85, 5.29)          (1.33, 1.65)
Ketoconazole                                                                                        8.45                  2.65 IVA 150 mg single dose             ↑ Ivacaftor
400 mg qd                                                                                      (7.14, 10.0)          (2.21, 3.18) 1.08                  1.05
Tezacaftor
Ciprofloxacin                               TEZ 50 mg q12h +                                    (1.03, 1.13)          (0.99, 1.11) 750 mg q12h                                 IVA 150 mg q12h                                         1.17                  1.18 ↑ Ivacaftor*
(1.06, 1.30)          (1.06, 1.31)
TRIK-SPC-0923-V1                                              Page 10 of 14 Table 7: Impact of Other Drugs on Elexacaftor, Tezacaftor and/or Ivacaftor Geometric Mean Ratio (90% CI) of
Effect on ELX,           Elexacaftor, Tezacaftor and
Dose and Schedule                                                                            Ivacaftor TEZ and/or IVA
PK                        No Effect = 1.0
AUC                  Cmax
Rifampin                                                                                        0.114               0.200 IVA 150 mg single dose              Ivacaftor
600 mg qd                                                                                   (0.097, 0.136)      (0.168, 0.239) Fluconazole                                                                                        2.95                2.47 IVA 150 mg q12h                ↑ Ivacaftor
400 mg single dose on Day 1, followed by 200 mg qd                                                                 (2.27, 3.82)        (1.93, 3.17)
↑ = increase, = decrease,        = no change. CI = Confidence Interval; ELX= elexacaftor; TEZ = tezacaftor; IVA = ivacaftor; PK = Pharmacokinetics * Effect is not clinically significant [see Drug Interactions (9.3)].