Kalydeco (Page 5 of 11)

12.2 Pharmacodynamics

Sweat Chloride Evaluation

Changes in sweat chloride (a biomarker) response to KALYDECO were evaluated in seven clinical trials [see Clinical Studies (14)]. In a two-part, randomized, double-blind, placebo-controlled, crossover clinical trial in patients with CF who had a G1244E , G1349D , G178R , G551S , G970R , S1251N , S1255P , S549N , or S549R mutation in the CFTR gene (Trial 4), the treatment difference in mean change in sweat chloride from baseline through 8 weeks of treatment was -49 mmol/L (95% CI -57, -41). The mean changes in sweat chloride for the mutations for which KALYDECO is indicated ranged from -51 to -8, whereas the range for individual subjects with the G970R mutation was -1 to -11 mmol/L. In an open-label clinical trial in 34 patients ages 2 to less than 6 years administered either 50 mg or 75 mg of ivacaftor twice daily (Trial 6), the mean absolute change from baseline in sweat chloride through 24 weeks of treatment was -45 mmol/L (95% CI -53, -38) [see Use in Specific Populations (8.4) ]. In a randomized, double-blind, placebo-controlled, 2-period, 3-treatment, 8-week crossover study in patients with CF age 12 years and older who were heterozygous for the F508del mutation and with a second CFTR mutation predicted to be responsive to ivacaftor (Trial 7), the treatment difference in mean change in sweat chloride from study baseline to the average of Week 4 and Week 8 of treatment for KALYDECO treated patients was -4.5 mmol/L (95% CI -6.7, -2.3). In a 24-week, open-label clinical trial in patients with CF aged less than 24 months administered 5.8 mg, 11.4 mg, 17.1 mg, 22.8 mg, 25 mg, 50 mg, or 75 mg (11.4 mg, 17.1 mg, and 22.8 mg are not recommended dosages) of ivacaftor twice daily (Trial 8), the mean absolute change from baseline in sweat chloride for patients aged 12 months to less than 24 months (n=10) was -73.5 mmol/L (95% CI -86.0, -61.0) at Week 24, the mean absolute change from baseline in sweat chloride for patients aged 6 months to less than 12 months (n=6) was -58.6 mmol/L (95% CI -75.9, -41.3) at Week 24, and the mean absolute change from baseline in sweat chloride for patients aged 4 months to less than 6 months (n=3) was -50 mmol/L (95% CI -93.1, -6.9) at Week 24. The mean absolute change from baseline in sweat chloride through 24 weeks for patients aged 1 month to less than 4 months (n=5) was -40.3 mmol/L (95% CI -76.6, -4.1) [see Use in Specific Populations (8.4)].

There was no direct correlation between decrease in sweat chloride levels and improvement in lung function (FEV1 ).

Cardiac Electrophysiology

The effect of multiple doses of ivacaftor 150 mg and 450 mg twice daily on QTc interval was evaluated in a randomized, placebo- and active-controlled (moxifloxacin 400 mg) four-period crossover thorough QT study in 72 healthy subjects. In a study with demonstrated ability to detect small effects, the upper bound of the one-sided 95% confidence interval for the largest placebo adjusted, baseline-corrected QTc based on Fridericia’s correction method (QTcF) was below 10 ms, the threshold for regulatory concern.

12.3 Pharmacokinetics

The pharmacokinetics of ivacaftor is similar between healthy adult volunteers and patients with CF.

After oral administration of a single 150 mg dose to healthy volunteers in a fed state, peak plasma concentrations (Tmax ) occurred at approximately 4 hours, and the mean (±SD) for AUC and Cmax were 10600 (5260) ng*hr/mL and 768 (233) ng/mL, respectively.

After every 12-hour dosing, steady-state plasma concentrations of ivacaftor were reached by days 3 to 5, with an accumulation ratio ranging from 2.2 to 2.9.

Absorption

The exposure of ivacaftor increased approximately 2.5- to 4-fold when given with food that contains fat. Therefore, KALYDECO should be administered with fat-containing food. Examples of fat-containing foods include eggs, butter, peanut butter, cheese pizza, whole-milk dairy products (such as whole milk, cheese, yogurt, breast milk, and infant formula), etc. The median (range) Tmax is approximately 4.0 (3.0; 6.0) hours in the fed state.

KALYDECO granules (2 × 75 mg) had similar bioavailability as the 150 mg tablet when given with fat-containing food in adult subjects. The effect of food on ivacaftor absorption is similar for KALYDECO granules and the 150 mg tablet formulation.

Distribution

Ivacaftor is approximately 99% bound to plasma proteins, primarily to alpha 1-acid glycoprotein and albumin. Ivacaftor does not bind to human red blood cells.

After oral administration of 150 mg every 12 hours for 7 days to healthy volunteers in a fed state, the mean (±SD) for apparent volume of distribution was 353 (122) L.

Elimination

The apparent terminal half-life was approximately 12 hours following a single dose. The mean apparent clearance (CL/F) of ivacaftor was similar for healthy subjects and patients with CF. The CL/F (SD) for the 150 mg dose was 17.3 (8.4) L/hr in healthy subjects.

Metabolism

Ivacaftor is extensively metabolized in humans. In vitro and clinical studies indicate that ivacaftor is primarily metabolized by CYP3A. 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 has less than one-fiftieth the potency of ivacaftor and is not considered pharmacologically active.

Excretion

Following oral administration, the majority of ivacaftor (87.8%) is eliminated in the feces after metabolic conversion. The major metabolites M1 and M6 accounted for approximately 65% of the total dose eliminated with 22% as M1 and 43% as M6. There was negligible urinary excretion of ivacaftor as unchanged parent.

Specific Populations

Pediatric Patients

The following conclusions about exposures between adults and the pediatric population are based on population PK analyses:

Table 4: Ivacaftor Exposure by Age Group, Mean (SD)
Age Group Dose AUCss (ng∙h/mL)
*
Patients 1 to less than 6 months of age were of ≥37 weeks gestational age.
Exposures for 2 to less than 4 months of age are predictions based on simulations from the population PK model incorporating data for this age group.
Values based on population PK modeling incorporating data from patients 4 to <6 months of age from Trial 8.
§
Value based on data from a single patient; standard deviation not reported.
1 to less than 2 months (≥3 kg) * 5.8 mg q12h 5490 (1310)
2 to less than 4 months (≥3 kg) * 13.4 mg q12h 6730 (3650)
4 to less than 6 months (≥5 kg) * 25 mg q12h 6480 (2520)
6 to less than 12 months (5 kg to <7 kg) § 25 mg q12h 5360
6 to less than 12 months (7 kg to <14 kg) 50 mg q12h 9390 (3120)
12 to less than 24 months (7 kg to <14 kg) 50 mg q12h 9050 (3050)
12 to less than 24 months (≥14 kg to <25 kg) 75 mg q12h 9600 (1800)
2 to less than 6 years (<14 kg) 50 mg q12h 10500 (4260)
2 to less than 6 years (≥14 kg to <25 kg) 75 mg q12h 11300 (3820)
6 to less than 12 years 150 mg q12h 20000 (8330)
12 to less than 18 years 150 mg q12h 9240 (3420)
Adults (≥18 years) 150 mg q12h 10700 (4100)

Patients with Hepatic Impairment

Adult subjects with moderately impaired hepatic function (Child-Pugh Class B, score 7 -9) had similar ivacaftor Cmax , but an approximately two-fold increase in ivacaftor AUC0-∞ compared with healthy subjects matched for demographics. Based on simulations of these results, a reduced KALYDECO dose to one tablet or packet of granules once daily is recommended for patients with moderate hepatic impairment aged 6 months and older. The impact of mild hepatic impairment (Child-Pugh Class A) on the pharmacokinetics of ivacaftor has not been studied, but the increase in ivacaftor AUC0-∞ is expected to be less than two-fold. Therefore, no dose adjustment is necessary for patients with mild hepatic impairment aged 6 months and older. The impact of severe hepatic impairment (Child-Pugh Class C, score 10-15) on the pharmacokinetics of ivacaftor has not been studied. The magnitude of increase in exposure in these patients is unknown but is expected to be substantially higher than that observed in patients with moderate hepatic impairment. When benefits are expected to outweigh the risks, KALYDECO should be used with caution in patients with severe hepatic impairment aged 6 months and older at a dose of one tablet or one packet of granules given once daily or less frequently [see Dosage and Administration (2.3) and Use in Specific Populations (8.6)]. KALYDECO is not recommended in patients aged 1 month to less than 6 months with any level of hepatic impairment.

Patients with Renal Impairment

KALYDECO has not been studied in patients with mild, moderate, or severe renal impairment (creatinine clearance less than or equal to 30 mL/min) or in patients with end-stage renal disease. No dose adjustments are recommended for mild and moderate renal impairment patients because of minimal elimination of ivacaftor and its metabolites in urine (only 6.6% of total radioactivity was recovered in the urine in a human PK study); however, caution is recommended when administering KALYDECO to patients with severe renal impairment or end-stage renal disease.

Male and Female Patients

The effect of gender on KALYDECO pharmacokinetics was evaluated using population pharmacokinetics of data from clinical studies of KALYDECO. No dose adjustments are necessary based on gender.

Drug Interaction Studies

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

Dosing recommendations based on clinical studies or potential drug interactions with KALYDECO are presented below.

Potential for Ivacaftor to Affect Other Drugs

Based on in vitro results, ivacaftor and metabolite M1 have the potential to inhibit CYP3A and P-gp. Clinical studies showed that KALYDECO is a weak inhibitor of CYP3A and P-gp, but not an inhibitor of CYP2C8. In vitro studies suggest that ivacaftor and M1 may inhibit CYP2C9. In vitro , ivacaftor, M1, and M6 were not inducers of CYP isozymes. Dosing recommendations for co-administered drugs with KALYDECO are shown in Figure 2.

Figure 2: Impact of KALYDECO on Other Drugs
Note: The data obtained with substrates but without co-administration of KALYDECO are used as reference.* NE: Norethindrone; ** EE: Ethinyl EstradiolThe vertical lines are at 0.8, 1.0, and 1.25, respectively.

Figure 2
(click image for full-size original)

Potential for Other Drugs to Affect Ivacaftor

In vitro studies showed that ivacaftor and metabolite M1 were substrates of CYP3A enzymes (i.e., CYP3A4 and CYP3A5). Exposure to ivacaftor is reduced by concomitant CYP3A inducers and increased by concomitant CYP3A inhibitors [see Dosage and Administration (2.4) and Drug Interactions (7)]. KALYDECO dosing recommendations for co-administration with other drugs are shown in Figure 3.

Figure 3: Impact of Other Drugs on KALYDECO
Note: The data obtained for KALYDECO without co-administration of inducers or inhibitors are used as reference.The vertical lines are at 0.8, 1.0, and 1.25, respectively.

Figure 3
(click image for full-size original)

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