SYMDEKO (Page 5 of 9)

12.2 Pharmacodynamics

Effects on Sweat Chloride

In Trial 1 (patients age 12 years and older who were homozygous for the F508del mutation), the treatment difference between SYMDEKO and placebo in mean absolute change from baseline in sweat chloride through Week 24 was -10.1 mmol/L (95% CI: -11.4, -8.8).

In Trial 2 (patients age 12 years and older who were heterozygous for the F508del mutation and a second mutation predicted to be responsive to tezacaftor/ivacaftor), the treatment difference in mean absolute change from baseline in sweat chloride through Week 8 was -9.5 mmol/L (95% CI: -11.7, -7.3) between SYMDEKO and placebo, and -4.5 mmol/L (95% CI: -6.7, -2.3) between ivacaftor and placebo.

In Trial 4 (patients age 6 to less than 12 years) a reduction in sweat chloride was observed from baseline through Week 4 and sustained throughout the 24-week treatment period. Mean absolute change in sweat chloride from baseline through Week 24 was -14.5 mmol/L (95% CI: -17.4, -11.6).

Cardiac Electrophysiology

At a dose 3 times the maximum approved recommended dose, tezacaftor does not prolong the QT interval to any clinically relevant extent.

In a separate study of ivacaftor evaluating doses up to 3 times the maximum approved recommended dose, ivacaftor does not prolong the QT interval to any clinically relevant extent.

12.3 Pharmacokinetics

The pharmacokinetics of tezacaftor and ivacaftor are similar between healthy adult volunteers and patients with CF. Following once-daily dosing of tezacaftor and twice-daily dosing of ivacaftor in patients with CF, plasma concentrations of tezacaftor and ivacaftor reach steady-state within 8 days and within 3 to 5 days, respectively, after starting treatment. At steady-state, the accumulation ratio is approximately 1.5 for tezacaftor and 2.2 for ivacaftor. Exposures of tezacaftor (administered alone or in combination with ivacaftor) increase in an approximately dose-proportional manner with increasing doses from 10 mg to 300 mg once daily.

Key pharmacokinetic parameters for tezacaftor and ivacaftor at steady state are shown in Table 7.

Table 7: Mean (SD) Pharmacokinetic Parameters of Tezacaftor and Ivacaftor at Steady State in Patients with CF
Drug Cmax (mcg/mL) Effective t½ (h) AUC0-24h or AUC0-12h (mcg∙h/mL)*
*
AUC0-24h for tezacaftor and AUC0-12h for ivacaftor
Tezacaftor 100 mg once daily/ivacaftor 150 mg every 12 hours Tezacaftor 5.95 (1.50) 15.0 (3.44) 84.5 (27.8)
Ivacaftor 1.17 (0.424) 13.7 (6.06) 11.3 (4.60)

Absorption

After a single dose in healthy subjects in the fed state, tezacaftor was absorbed with a median (range) time to maximum concentration (tmax ) of approximately 4 hours (2 to 6 hours). The median (range) tmax of ivacaftor was approximately 6 hours (3 to 10 hours) in the fed state.

When a single dose of tezacaftor/ivacaftor was administered with fat-containing foods, tezacaftor exposure was similar and ivacaftor exposure was approximately 3 times higher than when taken in a fasting state.

Distribution

Tezacaftor is approximately 99% bound to plasma proteins, primarily to albumin. Ivacaftor is approximately 99% bound to plasma proteins, primarily to alpha 1-acid glycoprotein and albumin. After oral administration of tezacaftor 100 mg once daily/ivacaftor 150 mg every 12 hours in patients with CF in the fed state, the mean (±SD) for apparent volume of distribution of tezacaftor and ivacaftor was 271 (157) L and 206 (82.9) L, respectively. Neither tezacaftor nor ivacaftor partition preferentially into human red blood cells.

Elimination

After oral administration of tezacaftor 100 mg once daily/ivacaftor 150 mg every 12 hours in patients with CF in the fed state, the mean (±SD) for apparent clearance values of tezacaftor and ivacaftor were 1.31 (0.41) and 15.7 (6.38) L/h, respectively. After steady-state dosing of tezacaftor in combination with ivacaftor in patients with CF, the effective half-lives of tezacaftor and ivacaftor were approximately 15 (3.44) and 13.7 (6.06) hours, respectively.

Metabolism

Tezacaftor is metabolized extensively in humans. In vitro data suggested that tezacaftor is metabolized mainly by CYP3A4 and CYP3A5. Following oral administration of a single dose of 100 mg 14 C-tezacaftor to healthy male subjects, M1, M2, and M5 were the three major circulating metabolites of tezacaftor in humans. M1 has the similar potency to that of tezacaftor and is considered pharmacologically active. M2 is much less pharmacologically active than tezacaftor or M1, and M5 is not considered pharmacologically active. Another minor circulating metabolite, M3, is formed by direct glucuronidation of tezacaftor.

Ivacaftor is also metabolized extensively in humans. In vitro and in vivo data indicate that ivacaftor is metabolized primarily by CYP3A4 and CYP3A5. M1 and M6 are the two major metabolites of ivacaftor in humans. M1 has approximately one-sixth the potency of ivacaftor and is considered pharmacologically active. M6 is not considered pharmacologically active.

Excretion

Following oral administration of 14 C-tezacaftor, the majority of the dose (72%) was excreted in the feces (unchanged or as the M2 metabolite) and about 14% was recovered in urine (mostly as M2 metabolite), resulting in a mean overall recovery of 86% up to 21 days after the dose. Less than 1% of the administrated dose was excreted in urine as unchanged tezacaftor, showing that renal excretion is not the major pathway of tezacaftor elimination in humans.

Following oral administration of ivacaftor alone, the majority of ivacaftor (87.8%) is eliminated in the feces after metabolic conversion. There was minimal elimination of ivacaftor and its metabolites in urine (only 6.6% of total radioactivity was recovered in the urine), and there was negligible urinary excretion of ivacaftor as unchanged drug.

Specific Populations

Based on population PK analyses, the PK exposure parameters of tezacaftor/ivacaftor in children and adolescents (ages 6 to <18 years) are similar to the AUCss range observed in adults when given in combination.

Pediatric patients age 6 to less than 12 years

Table 8: Tezacaftor/ivacaftor exposure by age group, mean (SD)
Age Group Dose tezacaftor AUCssmcg∙h/mL * ivacaftor AUCssmcg∙h/mL *
*
AUC 0-24h for tezacaftor and AUC 0-12h for ivacaftor
Exposures in 30 kg weight range are predictions derived from the population PK model
6 to <12 years 71.3 (28.3) 8.5 (3.34)
6 to <12 years (<30 kg) tezacaftor 50 mg/ ivacaftor 75 mg 56.7 (22.3) 6.92 (2.07)
6 to <12 years (≥30 kg) tezacaftor 100 mg/ ivacaftor 150 mg 92.7 (21.9) 10.8 (3.52)

Pediatric patients age 12 to less than 18 years

Following oral administration of SYMDEKO tablets, tezacaftor 100 mg once daily/ivacaftor 150 mg every 12 hours, the mean (±SD) AUCss for tezacaftor and ivacaftor was 97.1 (35.8) mcg∙h/mL and 11.4 (5.50) mcg∙h/mL, respectively, similar to the mean AUCss in adult patients administered SYMDEKO tablets, tezacaftor 100 mg once daily/ivacaftor 150 mg every 12 hours.

Patients with Hepatic Impairment

Following multiple doses of tezacaftor and ivacaftor for 10 days, patients with moderately impaired hepatic function (Child-Pugh Class B, score 7-9) had an approximately 36% increase in AUC and a 10% increase in Cmax for tezacaftor, and a 1.5-fold increase in ivacaftor AUC compared with healthy subjects matched for demographics. In a separate study, patients with moderately impaired hepatic function (Child-Pugh Class B, score 7-9) had similar ivacaftor Cmax , but an approximately 2.0-fold increase in ivacaftor AUC0-∞ compared with healthy subjects matched for demographics.

Pharmacokinetic studies have not been conducted in patients with mild (Child-Pugh Class A, score 5-6) or severe hepatic impairment (Child-Pugh Class C, score 10-15) receiving SYMDEKO. The magnitude of increase in exposure in patients with severe hepatic impairment is unknown but is expected to be higher than that observed in patients with moderate hepatic impairment [see Dosage and Administration (2.3), Use in Specific Populations (8.6), and Patient Counseling Information (17)].

Patients with Renal Impairment

SYMDEKO has not been studied in patients with moderate or severe renal impairment (creatinine clearance ≤30 mL/min) or in patients with end-stage renal disease. In a human pharmacokinetic study with tezacaftor alone, there was minimal elimination of tezacaftor and its metabolites in urine (only 13.7% of total radioactivity was recovered in the urine with 0.79% as unchanged drug).

In a human pharmacokinetic study with ivacaftor alone, there was minimal elimination of ivacaftor and its metabolites in urine (only 6.6% of total radioactivity was recovered in the urine).

In population pharmacokinetic analysis, data from 665 patients on tezacaftor or tezacaftor in combination with ivacaftor in clinical trials indicated that mild renal impairment (N=147; eGFR 60 to less than 90 mL/min/1.73 m2) and moderate renal impairment (N=7; eGFR 30 to less than 60 mL/min/1.73 m2) did not affect the clearance of tezacaftor significantly [see Use in Specific Populations (8.7)].

Male and Female Patients

The pharmacokinetic parameters of tezacaftor and ivacaftor are similar in males and females.

Drug Interactions Studies

Drug interaction studies were performed with SYMDEKO and other drugs likely to be co-administered or drugs commonly used as probes for pharmacokinetic interaction studies [see Drug Interactions (7)].

Potential for Tezacaftor/Ivacaftor to Affect Other Drugs

Clinical studies (with rosiglitazone and desipramine – see Table 9) showed that ivacaftor is not an inhibitor of CYP2C8 or CYP2D6. Based on in vitro results, ivacaftor has the potential to inhibit CYP3A and P-gp, and may also inhibit CYP2C9. In vitro , ivacaftor was not an inducer of CYP isozymes. Ivacaftor is not an inhibitor of transporters OATP1B1, OATP1B3, OCT1, OCT2, OAT1, or OAT3.

Based on in vitro results, tezacaftor has a low potential to inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Tezacaftor has a low potential to induce CYP3A, but it is not an inducer of CYP1A2 and CYP2B6. Tezacaftor has a low potential to inhibit transporters P-gp, BCRP, OATP1B3, OCT2, OAT1, or OAT3.

Clinical studies with midazolam showed that SYMDEKO is not an inhibitor of CYP3A. Co-administration of SYMDEKO with digoxin, a sensitive P-gp substrate, increased digoxin exposure by 1.3-fold. Co-administration of SYMDEKO with an ethinyl estradiol/ norethindrone oral contraceptive had no significant effect on the exposures of the hormonal contraceptives. Co-administration of SYMDEKO with pitavastatin, an OATP1B1 substrate, had no clinically relevant effect on the exposure of pitavastatin.

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

Potential for Other Drugs to Affect Tezacaftor/Ivacaftor

In vitro studies showed that ivacaftor and tezacaftor were substrates of CYP3A enzymes (i.e. , CYP3A4 and CYP3A5). Exposure to ivacaftor and tezacaftor will be reduced by concomitant CYP3A inducers and increased by concomitant CYP3A inhibitors.

In vitro studies showed that tezacaftor is a substrate for the uptake transporter OATP1B1, and efflux transporters P-gp and BCRP. Tezacaftor is not a substrate for OATP1B3. In vitro studies showed that ivacaftor is not a substrate for OATP1B1, OATP1B3, or P-gp.

The effects of co-administered drugs on the exposure of tezacaftor and ivacaftor (or ivacaftor alone) are shown in Table 10 [see Dosage and Administration (2.4) and Drug Interactions (7)].

Table 9: Impact of Tezacaftor/Ivacaftor or Ivacaftor on Other Drugs
Dose and Schedule Mean Ratio (90% CI) of Other DrugsNo Effect=1.0
Drug Dose TEZ/IVA or IVA Effect on Drug PK AUC Cmax
↑ = increase, ↓ = decrease, ↔ = no change. CI = Confidence interval; TEZ = tezacaftor; IVA = ivacaftor; PK = Pharmacokinetics
*
Effect is not clinically significant – no dose adjustment is necessary
Midazolam 2 mg single oral dose TEZ 100 mg/IVA 150 mg every morning + IVA 150 mg every evening ↔ Midazolam 1.12(1.01, 1.25) 1.13(1.01, 1.25)
Digoxin 0.5 mg single dose TEZ 100 mg/IVA 150 mg every morning + IVA 150 mg every evening ↑ Digoxin 1.30(1.17, 1.45) 1.32(1.07, 1.64)
Oral Contraceptive Ethinyl estradiol/ Norethindrone0.035 mg/1.0 mg once daily TEZ 100 mg/IVA 150 mg every morning + IVA 150 mg every evening ↔ Ethinyl estradiol 1.12(1.03, 1.22) 1.15(0.99, 1.33)
↔ Norethindrone 1.05(0.98, 1.12) 1.01(0.87, 1.19)
Pitavastatin 2 mg single dose TEZ 100 mg/IVA 150 mg every morning + IVA 150 mg every evening ↑ Pitavastatin * 1.24(1.17, 1.31) 0.977(0.841, 1.14)
Rosiglitazone 4 mg single oral dose IVA 150 mg twice daily ↔ Rosiglitazone 0.975(0.897, 1.06) 0.928(0.858, 1.00)
Desipramine 50 mg single dose IVA 150 mg twice daily ↔ Desipramine 1.04(0.985, 1.10) 1.00(0.939; 1.07)
Table 10: Impact of Other Drugs on Tezacaftor/Ivacaftor or Ivacaftor
Dose and Schedule Mean Ratio (90% CI) of Tezacaftor and IvacaftorNo Effect = 1.0
Drug Dose TEZ/IVA or IVA Effect on TEZ/IVA PK AUC Cmax
↑ = increase, ↓ = decrease, ↔ = no change. CI = Confidence interval; TEZ = tezacaftor; IVA = ivacaftor; PK = Pharmacokinetics
*
Effect is not clinically significant – no dose adjustment is necessary
Itraconazole 200 mg twice a day on Day 1, followed by 200 mg once daily TEZ 25 mg + IVA 50 mg once daily ↑ Tezacaftor 4.02(3.71, 4.63) 2.83(2.62, 3.07)
↑ Ivacaftor 15.6(13.4, 18.1) 8.60(7.41, 9.98)
Ciprofloxacin 750 mg twice daily TEZ 50 mg + IVA 150 mg twice daily ↔ Tezacaftor 1.08(1.03, 1.13) 1.05(0.99, 1.11)
↑ Ivacaftor * 1.17(1.06, 1.30) 1.18(1.06, 1.31)
Oral Contraceptive Norethindrone/ethinyl estradiol 1.0 mg/0.035 mg once daily TEZ 100 mg/IVA 150 mg every morning + IVA 150 mg every evening ↔ Tezacaftor 1.01(0.963, 1.05) 1.01(0.933, 1.09)
↔ Ivacaftor 1.03(0.960, 1.11) 1.03(0.941, 1.14)
Rifampin 600 mg once daily IVA 150 mg single dose ↓ Ivacaftor 0.114(0.097, 0.136) 0.200(0.168, 0.239)
Fluconazole 400 mg single dose on Day 1, followed by 200 mg once daily IVA 150 mg twice daily ↑ Ivacaftor 2.95(2.27, 3.82) 2.47(1.93, 3.17)

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