Source: European Medicines Agency (EU) Revision Year: 2023 Publisher: Vertex Pharmaceuticals (Ireland) Limited, Unit 49, Block F2, Northwood Court, Santry, Dublin 9, D09 T665, Ireland
Pharmacotherapeutic group: Other respiratory system products
ATC code: R07AX02
Ivacaftor is a potentiator of the CFTR protein, i.e., in vitro ivacaftor increases CFTR channel gating to enhance chloride transport in specified gating mutations (as listed in section 4.1) with reduced channel-open probability compared to normal CFTR. Ivacaftor also potentiated the channel-open probability of R117H-CFTR, which has both low channel-open probability (gating) and reduced channel current amplitude (conductance). The G970R mutation causes a splicing defect resulting in little-to-no CFTR protein at the cell surface which may explain the results observed in subjects with this mutation in study 5 (see Pharmacodynamic effects and Clinical efficacy and safety).
In vitro responses seen in single channel patch clamp experiments using membrane patches from rodent cells expressing mutant CFTR forms do not necessarily correspond to in vivo pharmacodynamic response (e.g., sweat chloride) or clinical benefit. The exact mechanism leading ivacaftor to potentiate the gating activity of normal and some mutant CFTR forms in this system has not been completely elucidated.
In studies 1 and 2 in patients with the G551D mutation in one allele of the CFTR gene, ivacaftor led to rapid (15 days), substantial (the mean change in sweat chloride from baseline through week 24 was -48 mmol/L [95% CI -51, -45] and -54 mmol/L [95% CI -62, -47], respectively) and sustained (through 48 weeks) reductions in sweat chloride concentration.
In study 5, part 1 in patients who had a non-G551D gating mutation in the CFTR gene, treatment with ivacaftor led to a rapid (15 days) and substantial mean change from baseline in sweat chloride of -49 mmol/L (95% CI -57, 41) through 8 weeks of treatment. However, in patients with the G970RCFTR mutation, the mean (SD) absolute change in sweat chloride at week 8 was -6.25 (6.55) mmol/L. Similar results to part 1 were seen in part 2 of the study. At the 4-week follow-up visit (4 weeks after dosing with ivacaftor ended), mean sweat chloride values for each group were trending to pre-treatment levels.
In study 6 in patients aged 6 years or older with CF who had an R117H mutation in the CFTR gene, the treatment difference in mean change in sweat chloride from baseline through 24 weeks of treatment was -24 mmol/L (95% CI -28, -20). In subgroup analyses by age, the treatment difference was -21.87 mmol/L (95% CI: -26.46, -17.28) in patients aged 18 years or older, and -27.63 mmol/L (95% CI: -37.16, -18.10) in patients aged 6-11 years. Two patients 12 to 17 years of age were enrolled in this study.
In study 7 in patients aged 2 to less than 6 years with a gating mutation on at least 1 allele of the CFTR gene administered either 50 mg or 75 mg of ivacaftor twice daily, the mean absolute change from baseline in sweat chloride was -47 mmol/L (95% CI -58, -36) at week 24.
In study 8 in patients with CF aged less than 24 months, the mean absolute change from baseline in sweat chloride was -65.1 mmol/L (95% CI -74.1, -56.0) at week 24. Results were consistent in the 12 months to less than 24 months, 6 months to less than 12 months, and 4 months to less than 6 months age cohorts.
The efficacy of ivacaftor has been evaluated in two phase 3 randomised, double-blind, placebo-controlled, multi-centre studies of clinically stable patients with CF who had the G551D mutation in the CFTR gene on at least 1 allele and had FEV1 ≥40% predicted.
Patients in both studies were randomised 1:1 to receive either 150 mg of ivacaftor or placebo every 12 hours with food containing fat for 48 weeks in addition to their prescribed CF therapies (e.g., tobramycin, dornase alfa). The use of inhaled hypertonic sodium chloride was not permitted.
Study 1 evaluated 161 patients who were 12 years of age or older; 122 (75.8%) patients had the F508del mutation in the second allele. At the start of the study, patients in the placebo group used some medicinal products at a higher frequency than the ivacaftor group. These medicinal products included dornase alfa (73.1% versus 65.1%), salbutamol (53.8% versus 42.2%), tobramycin (44.9% versus 33.7%) and salmeterol/fluticasone (41.0% versus 27.7%). At baseline, mean predicted FEV1 was 63.6% (range: 31.6% to 98.2%) and mean age was 26 years (range: 12 to 53 years).
Study 2 evaluated 52 patients who were 6 to 11 years of age at screening; mean (SD) body weight was 30.9 (8.63) kg; 42 (80.8%) patients had the F508del mutation in the second allele. At baseline, mean predicted FEV1 was 84.2% (range: 44.0% to 133.8%) and mean age was 9 years (range: 6 to 12 years); 8 (30.8%) patients in the placebo group and 4 (15.4%) patients in the ivacaftor group had an FEV1 less than 70% predicted at baseline.
The primary efficacy endpoint in both studies was the mean absolute change from baseline in percent predicted FEV1 through 24 weeks of treatment.
The treatment difference between ivacaftor and placebo for the mean absolute change (95% CI) in percent predicted FEV1 from baseline through week 24 was 10.6 percentage points (8.6, 12.6) in study 1 and 12.5 percentage points (6.6, 18.3) in study 2. The treatment difference between ivacaftor and placebo for the mean relative change (95% CI) in percent predicted FEV1 from baseline through week 24 was 17.1% (13.9, 20.2) in study 1 and 15.8% (8.4, 23.2) in study 2. The mean change from baseline through week 24 in FEV1 (L) was 0.37 L in the ivacaftor group and 0.01 L in the placebo group in study 1 and 0.30 L in the ivacaftor group and 0.07 L in the placebo group in study 2. In both studies, improvements in FEV1 were rapid in onset (day 15) and durable through 48 weeks.
The treatment difference between ivacaftor and placebo for the mean absolute change (95% CI) in percent predicted FEV1 from baseline through week 24 in patients 12 to 17 years of age in study 1 was 11.9 percentage points (5.9, 17.9). The treatment difference between ivacaftor and placebo for the mean absolute change (95% CI) in percent predicted FEV1 from baseline through week 24 in patients with baseline predicted FEV1 greater than 90% in study 2 was 6.9 percentage points (-3.8, 17.6).
The results for clinically relevant secondary endpoints are shown in Table 4.
Table 4. Effect of ivacaftor on other efficacy endpoints in studies 1 and 2:
| Study 1 | Study 2 | |||
|---|---|---|---|---|
| Endpoint | Treatment differencea (95% CI) | P value | Treatment differencea (95% CI) | P value |
| Mean absolute change from baseline in CFQ-Rb respiratory domain score (points)c | ||||
| Through week 24 | 8.1 (4.7, 11.4) | <0.0001 | 6.1 (-1.4, 13.5) | 0.1092 |
| Through week 48 | 8.6 (5.3, 11.9) | <0.0001 | 5.1 (-1.6, 11.8) | 0.1354 |
| Relative risk of pulmonary exacerbation | ||||
| Through week 24 | 0.40d | 0.0016 | NA | NA |
| Through week 48 | 0.46d | 0.0012 | NA | NA |
| Mean absolute change from baseline in body weight (kg) | ||||
| At week 24 | 2.8 (1.8, 3.7) | <0.0001 | 1.9 (0.9, 2.9) | 0.0004 |
| At week 48 | 2.7 (1.3, 4.1) | 0.0001 | 2.8 (1.3, 4.2) | 0.0002 |
| Mean absolute change from baseline in BMI (kg/m²) | ||||
| At week 24 | 0.94 (0.62, 1.26) | <0.0001 | 0.81 (0.34, 1.28) | 0.0008 |
| At week 48 | 0.93 (0.48, 1.38) | <0.0001 | 1.09 (0.51, 1.67) | 0.0003 |
| Mean change from baseline in z-scores | ||||
| Weight-for-age z-score at week 48e | 0.33 (0.04, 0.62) | 0.0260 | 0.39 (0.24, 0.53) | <0.0001 |
| BMI-for-age z-score at week 48e | 0.33 (0.002, 0.65) | 0.0490 | 0.45 (0.26, 0.65) | <0.0001 |
CI: confidence interval; NA: not analysed due to low incidence of events
a Treatment difference = effect of ivacaftor – effect of placebo
b CFQ-R: Cystic Fibrosis Questionnaire-Revised is a disease-specific, health-related quality-of-life measure for
CF.
c Study 1 data were pooled from CFQ-R for adults/adolescents and CFQ-R for children 12 to 13 years of age; Study 2 data were obtained from CFQ-R for children 6 to 11 years of age.
d Hazard ratio for time to first pulmonary exacerbation e In subjects under 20 years of age (CDC growth charts)
Study 5 was a phase 3, two-part, randomised, double-blind, placebo-controlled, crossover study (part 1) followed by a 16-week open-label extension period (part 2) to evaluate the efficacy and safety of ivacaftor in patients with CF aged 6 years and older who have a G970R or non-G551D gating mutation in the CFTR gene (G178R, S549N, S549R, G551S, G1244E, S1251N, S1255P or G1349D).
In part 1, patients were randomised 1:1 to receive either 150 mg of ivacaftor or placebo every 12 hours with fat-containing food for 8 weeks in addition to their prescribed CF therapies and crossed over to the other treatment for the second 8 weeks after a 4- to 8-week washout period. The use of inhaled hypertonic saline was not permitted. In part 2, all patients received ivacaftor as indicated in part 1 for 16 additional weeks. The duration of continuous ivacaftor treatment was 24 weeks for patients randomised to part 1 placebo/ivacaftor treatment sequence and 16 weeks for patients randomised to part 1 ivacaftor/placebo treatment sequence.
Thirty-nine patients (mean age 23 years) with baseline FEV1 ≥40% predicted (mean FEV1 78% predicted [range: 43% to 119%]) were enrolled. Sixty-two percent (24/39) of them carried the F508del-CFTR mutation in the second allele. A total of 36 patients continued into part 2 (18 per treatment sequence).
In part 1 of study 5, the mean FEV1 percent predicted at baseline in placebo-treated patients was 79.3% while in ivacaftor-treated patients this value was 76.4%. The mean overall post-baseline value was 76.0% and 83.7%, respectively. The mean absolute change from baseline through week 8 in percent predicted FEV1 (primary efficacy endpoint) was 7.5% in the ivacaftor period and -3.2% in the placebo period. The observed treatment difference (95% CI) between ivacaftor and placebo was 10.7% (7.3, 14.1) (P<0.0001).
The effect of ivacaftor in the overall population of study 5 (including the secondary endpoints absolute change in BMI at 8 weeks of treatment and absolute change in the respiratory domain score of the CFQ-R through 8 weeks of treatment) and by individual mutation (absolute change in sweat chloride and in percent predicted FEV1 at week 8) is shown in Table 5. Based on clinical (percent predicted FEV1) and pharmacodynamic (sweat chloride) responses to ivacaftor, efficacy in patients with the G970R mutation could not be established.
Table 5. Effect of ivacaftor for efficacy variables in the overall population and for specific CFTR mutations:
| Absolute change in percent predicted FEV | BMI (kg/m²) | CFQ-R respiratory domain score (points) |
|---|---|---|
| Through week 8 | At week 8 | Through week 8 |
| All patients (N=39) Results shown as mean (95% CI) change from baseline ivacaftor vs placebo-treated patients: | ||
| 10.7 (7.3, 14.1) | 0.66 (0.34, 0.99) | 9.6 (4.5, 14.7) |
Patients grouped under mutation types (n)
Results shown as mean (minimum, maximum) change from baseline for ivacaftor-treated patients at week 8*:
| Mutation (n) | Absolute change in sweat chloride (mmol/L) | Absolute change in percent predicted FEV1 (percentage points) |
|---|---|---|
| G1244E (5) G1349D (2) G178R (5) G551S (2) G970R# (4) S1251N (8) S1255P (2) S549N (6) S549R (4) | ‑55 (-75, -34) -80 (-82, -79) -53 (-65, -35) -68† -6 (-16, -2) -54 (-84, -7) -78 (-82, -74) -74 (-93, -53) -61†† (-71, -54) | 8 (-1, 18) 20 (3, 36) 8 (-1, 18) 3† 3 (-1, 5) 9 (-20, 21) 3 (-1, 8) 11 (-2, 20) 5 (-3, 13) |
* Statistical testing was not performed due to small numbers for individual mutations.
† Reflects results from the one patient with the G551S mutation with data at the 8-week time point.
†† n=3 for the analysis of absolute change in sweat chloride.
# Causes a splicing defect resulting in little-to-no CFTR protein at the cell surface.
In part 2 of study 5, the mean (SD) absolute change in percent predicted FEV1 following 16 weeks (patients randomised to the ivacaftor/placebo treatment sequence in part 1) of continuous ivacaftor treatment was 10.4% (13.2%). At the follow-up visit, 4 weeks after ivacaftor dosing had ended, the mean (SD) absolute change in percent predicted FEV1 from part 2 week 16 was -5.9% (9.4%). For patients randomised to the placebo/ivacaftor treatment sequence in part 1 there was a further mean (SD) change of 3.3% (9.3%) in percent predicted FEV1 after the additional 16 weeks of treatment with ivacaftor. At the follow up visit, 4 weeks after ivacaftor dosing had ended, the mean (SD) absolute change in percent predicted FEV1 from part 2 week 16 was -7.4% (5.5%).
Study 3 (part A) was a 16-week, 4:1 randomised, double-blind, placebo-controlled, parallel-group phase 2 study of ivacaftor (150 mg every 12 hours) in 140 patients with CF age 12 years and older who were homozygous for the F508del mutation in the CFTR gene and who had FEV1 ≥ 40% predicted.
The mean absolute change from baseline through week 16 in percent predicted FEV1 (primary efficacy endpoint) was 1.5 percentage points in the ivacaftor group and -0.2 percentage points in the placebo group. The estimated treatment difference for ivacaftor versus placebo was 1.7 percentage points (95% CI -0.6, 4.1); this difference was not statistically significant (P=0.15).
In study 4, patients who completed treatment in studies 1 and 2 with placebo were switched to ivacaftor while patients on ivacaftor continued to receive it for a minimum of 96 weeks, i.e., the length of treatment with ivacaftor was at least 96 weeks for patients in the placebo/ivacaftor group and at least 144 weeks for patients in the ivacaftor/ivacaftor group.
One hundred and forty-four (144) patients from study 1 were rolled over in study 4, 67 in the placebo/ivacaftor group and 77 in the ivacaftor/ivacaftor group. Forty-eight (48) patients from study 2 were rolled over in study 4, 22 in the placebo/ivacaftor group and 26 in the ivacaftor/ivacaftor group.
Table 6 shows the results of the mean (SD) absolute change in percent predicted FEV1 for both groups of patients. For patients in the placebo/ivacaftor group baseline percent predicted FEV1 is that of study 4 while for patients in the ivacaftor/ivacaftor group the baseline value is that of studies 1 and 2.
Table 6. Effect of ivacaftor on percent predicted FEV1 in study 4:
| Original study and treatment group | Duration of ivacaftor treatment (weeks) | Absolute change from baseline in percent predicted FEV1 (percentage points) | |
|---|---|---|---|
| N | Mean (SD) | ||
| Study 1 | |||
| Ivacaftor | 48* | 77 | 9.4 (8.3) |
| 144 | 72 | 9.4 (10.8) | |
| Placebo | 0* | 67 | -1.2 (7.8)† |
| 96 | 55 | 9.5 (11.2) | |
| Study 2 | |||
| Ivacaftor | 48* | 26 | 10.2 (15.7) |
| 144 | 25 | 10.3 (12.4) | |
| Placebo | 0* | 22 | -0.6 (10.1)† |
| 96 | 21 | 10.5 (11.5) | |
* Treatment occurred during blinded, controlled, 48-week phase 3 study.
† Change from prior study baseline after 48 weeks of placebo treatment.
When the mean (SD) absolute change in percent predicted FEV1 is compared from study 4 baseline for patients in the ivacaftor/ivacaftor group (n=72) who rolled over from study 1, the mean (SD) absolute change in percent predicted FEV1 was 0.0% (9.05), while for patients in the ivacaftor/ivacaftor group (n=25) who rolled over from study 2 this figure was 0.6% (9.1). This shows that patients in the ivacaftor/ivacaftor group maintained the improvement seen at week 48 of the initial study (day 0 through week 48) in percent predicted FEV1 through week 144. There were no additional improvements in study 4 (week 48 through week 144).
For patients in the placebo/ivacaftor group from study 1, the annualised rate of pulmonary exacerbations was higher in the initial study when patients were on placebo (1.34 events/year) than during the subsequent study 4 when patients rolled over to ivacaftor (0.48 events/year across day 1 to week 48, and 0.67 events/year across weeks 48 to 96). For patients in the ivacaftor/ivacaftor group from study 1, the annualised rate of pulmonary exacerbations was 0.57 events/year across day 1 to week 48 when patients were on ivacaftor. When they rolled over into study 4, the rate of annualised pulmonary exacerbations was 0.91 events/year across day 1 to week 48 and 0.77 events/year across weeks 48 to 96.
For patients who rolled over from study 2 the number of events was, overall, low.
Study 6 evaluated 69 patients who were 6 years of age or older; 53 (76.8%) patients had the F508del mutation in the second allele. The confirmed R117H poly-T variant was 5T in 38 patients and 7T in 16 patients. At baseline, mean predicted FEV1 was 73% (range: 32.5% to 105.5%) and mean age was 31 years (range: 6 to 68 years). The mean absolute change from baseline through week 24 in percent predicted FEV1 (primary efficacy endpoint) was 2.57 percentage points in the ivacaftor group and 0.46 percentage points in the placebo group. The estimated treatment difference for ivacaftor versus placebo was 2.1 percentage points (95% CI -1.1, 5.4).
A pre-planned subgroup analysis was conducted in patients 18 years and older (26 patients on placebo and 24 on ivacaftor). Treatment with ivacaftor resulted in a mean absolute change in percent predicted FEV1 through week 24 of 4.5 percentage points in the ivacaftor group versus -0.46 percentage points in the placebo group. The estimated treatment difference for ivacaftor versus placebo was 5.0 percentage points (95% CI 1.1, 8.8).
In a subgroup analysis in patients with a confirmed R117H-5T genetic variant, the difference in the mean absolute change from baseline through week 24 in percent predicted FEV1 between ivacaftor and placebo was 5.3% (95% CI 1.3, 9.3). In patients with a confirmed R117H-7T genetic variant, the treatment difference between ivacaftor and placebo was 0.2% (95% CI -8.1, 8.5).
For secondary efficacy variables, no treatment differences were observed for ivacaftor versus placebo in absolute change from baseline in BMI at week 24 or time to first pulmonary exacerbation. Treatment differences were observed in absolute change in CFQ-R respiratory domain score through week 24 (treatment difference of ivacaftor versus placebo was 8.4 [95% CI 2.2, 14.6] points) and for the mean change from baseline in sweat chloride (see Pharmacodynamic effects).
The pharmacokinetic profile, safety and efficacy of ivacaftor in 34 patients aged 2 to less than 6 years with CF who had a G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N or S549R mutation in the CFTR gene were assessed in a 24-week uncontrolled study with ivacaftor (patients weighing less than 14 kg received ivacaftor 50 mg and patients weighing 14 kg or more received ivacaftor 75 mg). Ivacaftor was administered orally every 12 hours with fat-containing food in addition to their prescribed CF therapies.
Patients in study 7 were aged 2 to less than 6 years (mean age 3 years). Twenty-six patients out of the 34 enrolled (76.5%) had a CFTR genotype G551D/F508del with only 2 patients with a non-G551D mutation (S549N). The mean (SD) sweat chloride at baseline (n=25) was 97.88 mmol/L (14.00). The mean (SD) faecal elastase-1 value at baseline (n=27) was 28 µg/g (95).
The primary endpoint of safety was evaluated through week 24 (see section 4.8). Secondary and exploratory efficacy endpoints evaluated were absolute change from baseline in sweat chloride through 24 weeks of treatment, absolute change from baseline in weight, body mass index (BMI) and stature (supported by weight, BMI and stature z-scores) at 24 weeks of treatment, and measures of pancreatic function such as faecal elastase-1. Data on percent predicted FEV1 (exploratory endpoint) were available for 3 patients in the ivacaftor 50 mg group and 17 patients in the 75 mg dosing group.
The mean (SD) overall (both ivacaftor dosing groups combined) absolute change from baseline in BMI at week 24 was 0.32 kg/m² (0.54) and the mean (SD) overall change in BMI-for-age z-score was 0.37 (0.42). The mean (SD) overall change in stature-for-age z-score was -0.01 (0.33). The mean (SD) overall change from baseline in faecal elastase-1 (n=27) was 99.8 µg/g (138.4). Six patients with initial levels below 200 µg/g achieved, at week 24, a level of ≥200 µg/g. The mean (SD) overall change in percent predicted FEV1 from baseline at week 24 (exploratory endpoint) was 1.8 (17.81).
The pharmacokinetic profile, safety, and efficacy of ivacaftor in patients with CF aged 4 months to less than 24 months were assessed in a completed cohort of patients in an on-going 24-week, open-label, phase 3 clinical study in patients aged less than 24 months (study 8).
Part B of study 8 enrolled 19 patients aged 12 months to less than 24 months (mean age 15.2 months at baseline), with 18 patients completing the 24-week treatment period, 11 patients aged 6 months to less than 12 months (mean age 9.0 months at baseline) with all 11 patients completing the 24-week treatment period, and 6 patients aged 4 months to less than 6 months (mean age 4.5 months at baseline) with all 6 patients completing the 24-week treatment period. Patients received ivacaftor 25 mg, 50 mg or 75 mg according to their age and weight at each study visit (see section 4.2). Ivacaftor was administered orally every 12 hours with fat-containing food. Patients continued on their prescribed standard-of-care CF therapies.
In part B of study 8 the primary endpoint of safety was evaluated through 24 weeks (see section 4.8). Secondary endpoints were evaluation of pharmacokinetics and the absolute change from baseline in sweat chloride through 24 weeks of treatment (see Pharmacodynamic effects). Tertiary endpoints included efficacy measures such as faecal elastase-1 and growth parameters.
For patients aged 4 months to less than 24 months, with both baseline and week 24 values available, mean (SD) weight-for-age, length-for-age, and weight-for-length z-scores are provided in Table 7.
Table 7. Effect of ivacaftor on growth parameters in patients aged 4 months to less than 24 months with baseline and week 24 values:
| <_.Parameter | Number of patients | Baseline | Absolute change at week 24 | ||
|---|---|---|---|---|---|
| Mean (SD) | Median (min, max) | Mean (SD) | Median (min, max) | ||
| Weight–for-age z-score | 35 | 0.17 (0.85) | 0.20 [-1.92, 1.79] | 0.33 (0.53) | 0.26 [-0.54, 1.63] |
| Length-for-age z-score | 34 | 0.06 (1.03) | 0.12 [-1.99, 2.79] | 0.32 (0.92) | 0.47 [-1.81, 3.38] |
| Weight-for-length z-score | 34 | 0.24 (1.01) | 0.26 [-1.72, 2.16] | 0.24 (0.98) | 0.29 [-2.04, 2.22] |
In patients aged 4 months to less than 24 months, with both baseline and week 24 values available, 18 patients were pancreatic insufficient at baseline (defined as faecal elastase-1 <200 µg/g) with mean (SD) faecal elastase-1 values at baseline and week 24 of 25.5 µg/g (27.6) and 253.6 µg/g (128.3), respectively (mean [SD] absolute change 228.41 µg/g [128.3]). Results were consistent in the 12 months to less than 24 months, 6 months to less than 12 months, and 4 months to less than 6
months age cohorts.
The European Medicines Agency has deferred the obligation to submit the results of studies with Kalydeco in one or more subsets of the paediatric population in cystic fibrosis (see section 4.2 for information on paediatric use).
The pharmacokinetics of ivacaftor are 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, 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.
Following multiple oral dose administrations of ivacaftor, the exposure of ivacaftor generally increased with dose from 25 mg every 12 hours to 450 mg every 12 hours. When given with fatcontaining food the exposure of ivacaftor increased approximately 2.5- to 4-fold. Therefore, ivacaftor should be administered with fat-containing food. The median (range) tmax is approximately 4.0 (3.0; 6.0) hours in the fed state.
Ivacaftor granules (2 × 75 mg sachets) had similar bioavailability as the 150 mg tablet when given with fat-containing food to healthy adult subjects. The geometric least squares mean ratio (90% CI) for the granules relative to tablets was 0.951 (0.839, 1.08) for AUC0-∞ and 0.918 (0.750, 1.12) for Cmax. The effect of food on ivacaftor absorption is similar for both formulations, i.e., tablets and granules.
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 ivacaftor 150 mg every 12 hours for 7 days in healthy volunteers in a fed state, the mean (± SD) apparent volume of distribution was 353 L (122).
Ivacaftor is extensively metabolised in humans. In vitro and in vivo data indicate that ivacaftor is primarily metabolised 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.
The effect of the CYP3A4*22 heterozygous genotype on ivacaftor exposure is consistent with the effect of co-administration of a weak CYP3A4 inhibitor, which is not clinically relevant. No dose adjustment of ivacaftor is considered necessary. The effect in CYP3A4*22 homozygous genotype patients is expected to be stronger. However, no data are available for such patients.
Following oral administration in healthy volunteers, the majority of ivacaftor (87.8%) was eliminated in the faeces 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. The apparent terminal half-life was approximately 12 hours following a single dose in the fed state. The apparent clearance (CL/F) of ivacaftor was similar for healthy subjects and patients with CF. The mean (±SD) CL/F for a single 150 mg dose was 17.3 (8.4) L/hr in healthy subjects.
The pharmacokinetics of ivacaftor are generally linear with respect to time or dose ranging from 25 mg to 250 mg.
Following a single dose of 150 mg of ivacaftor, adult subjects with moderately impaired hepatic function (Child-Pugh Class B, score 7 to 9) had similar ivacaftor Cmax (mean [± SD] of 735 331 ng/mL) but an approximately two-fold increase in ivacaftor AUC0-∞ (mean [± SD] of 16800 6140 ng*hr/mL) compared with healthy subjects matched for demographics. Simulations for predicting the steady-state exposure of ivacaftor showed that by reducing the dosage from 150 mg q12h to 150 mg once daily, adults with moderate hepatic impairment would have comparable steady-state Cmin values as those obtained with a dose of 150 mg q12h in adults without hepatic impairment. Based on these results, a modified regimen of Kalydeco as monotherapy is recommended for patients with moderate hepatic impairment (see section 4.2)
The impact of severe hepatic impairment (Child Pugh Class C, score 10 to 15) on the pharmacokinetics of ivacaftor have not been studied. The magnitude of increase in exposure in these patients is unknown but is expected to be higher than that observed in patients with moderate hepatic impairment. The use of Kalydeco in patients with severe hepatic impairment is therefore not recommended unless the benefits outweigh the risks (see section 4.2 and section 4.4).
No dose adjustment is considered necessary for patients with mild hepatic impairment.
Pharmacokinetic studies have not been performed with ivacaftor in patients with renal impairment. In a human pharmacokinetic study, there was minimal elimination of ivacaftor and its metabolites in urine (only 6.6% of total radioactivity was recovered in the urine). There was negligible urinary excretion of ivacaftor as unchanged parent (less than 0.01% following a single oral dose of 500 mg).
No dose adjustments are recommended for mild and moderate renal impairment. However, caution is recommended when administering ivacaftor to patients with severe renal impairment (creatinine clearance less than or equal to 30 mL/min) or end-stage renal disease (see sections 4.2 and 4.4).
Race had no clinically meaningful effect on the PK of ivacaftor in white (n=379) and non-white (n=29) patients based on a population PK analysis.
The pharmacokinetic parameters of ivacaftor are similar in males and females.
Clinical studies of ivacaftor as monotherapy did not include sufficient numbers of patients aged 65 years and older to determine whether pharmacokinetic parameters are similar or not to those in younger adults.
Predicted ivacaftor exposure based on observed ivacaftor concentrations in phase 2 and 3 studies as determined using population PK analysis is presented by age group in Table 8.
Table 8. Mean (SD) ivacaftor exposure by age group:
| Age group | Dose | Cmin,ss (ng/mL) | AUCτ,ss (ng*h/mL) |
|---|---|---|---|
| 4 months to less than 6 months (≥5 kg) | 25 mg q12h | 371 (183) | 6480 (2520) |
| 6 months to less than 12 months (5 kg to <7 kg)* | 25 mg q12h | 336 | 5410 |
| 6 months to less than 12 months (7 kg to <14 kg) | 50 mg q12h | 508 (252) | 9140 (4200) |
| 12 months to less than 24 months (7 kg to <14 kg) | 50 mg q12h | 440 (212) | 9050 (3050) |
| 12 months to less than 24 months (≥14 kg to <25 kg) | 75 mg q12h | 451 (125) | 9600 (1800) |
| 2- to 5-year-olds (<14 kg) | 50 mg q12h | 577 (317) | 10500 (4260) |
| 2- to 5-year-olds (≥14 kg to <25 kg) | 75 mg q12h | 629 (296) | 11300 (3820) |
| 6- to 11-year-olds† (≥14 kg to <25 kg) | 75 mg q12h | 641 (329) | 10760 (4470) |
| 6- to 11-year-olds† (≥25 kg) | 150 mg q12h | 958 (546) | 15300 (7340) |
| 12- to 17-year-olds | 150 mg q12h | 564 (242) | 9240 (3420) |
| Adults (≥18 years old) | 150 mg q12h | 701 (317) | 10700 (4100) |
* Values based on data from a single patient; standard deviation not reported.
† Exposures in 6- to 11-year-olds are predictions based on simulations from the population PK model using data obtained for this age group.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, and carcinogenic potential.
Ivacaftor was associated with slight decreases of the seminal vesicle weights, a decrease of overall fertility index and number of pregnancies in females mated with treated males and significant reductions in number of corpora lutea and implantation sites with subsequent reductions in the average litter size and average number of viable embryos per litter in treated females. The No-Observed-Adverse-Effect-Level (NOAEL) for fertility findings provides an exposure level of approximately 4 times the systemic exposure of ivacaftor and its metabolites when administered as ivacaftor monotherapy in adult humans at the maximum recommended human dose (MRHD). Placental transfer of ivacaftor was observed in pregnant rats and rabbits.
Ivacaftor decreased survival and lactation indices and caused a reduction in pup body weights. The NOAEL for viability and growth in the offspring provides an exposure level of approximately 3 times the systemic exposure of ivacaftor and its metabolites when administered as ivacaftor monotherapy in adult humans at the MRHD.
Findings of cataracts were observed in juvenile rats dosed from postnatal day 7 through 35 at ivacaftor exposure levels of 0.22 times the MRHD based on systemic exposure of ivacaftor and its metabolites when administered as ivacaftor monotherapy. This finding has not been observed in foetuses derived from rat dams treated with ivacaftor on gestation days 7 to 17, in rat pups exposed to ivacaftor through milk ingestion up to postnatal day 20, in 7-week old rats, nor in 3.5 to 5-month old dogs treated with ivacaftor. The potential relevance of these findings in humans is unknown.
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