Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties
Pharmacotherapeutic group: Other respiratory system products, ATC code: R07AX02 
Mechanism of action
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. 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 data).

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.


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Pharmacodynamic effects
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 G970R-CFTR 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 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.

Clinical efficacy and safety
Studies 1 and 2: studies in patients with CF with G551D gating mutations The efficacy of Kalydeco 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 FEV 1 ≥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 medications 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 FEV 1 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 FEV 1 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 FEV 1 less than 70% predicted at baseline.

The primary efficacy endpoint in both studies was the mean absolute change from baseline in percent predicted FEV 1 through 24 weeks of treatment.

The treatment difference between ivacaftor and placebo for the mean absolute change (95% CI) in percent predicted FEV 1 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 FEV 1 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 FEV 1 (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 FEV 1 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 FEV 1 from baseline through week 24 in patients 12 to 17 years of age in study 1 was KALY_50_75_150-SPC-0921-V1                    Page 10 of 19
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 FEV 1 from baseline through week 24 in patients with baseline predicted FEV 1 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 6.

Table 6: Effect of ivacaftor on other efficacy endpoints in studies 1 and 2 Study 1                                 Study 2

Treatment                            Treatment differencea                          differencea

Endpoint                         (95% CI)               P value       (95% CI)                P value 
Mean absolute change from baseline in CFQ-Rb respiratory domain score (points)c 
Through week 24                      8.1               < 0.0001           6.1                 0.1092 
(4.7, 11.4)                          (-1.4, 13.5)

Through week 48                      8.6               < 0.0001           5.1                 0.1354 
(5.3, 11.9)                          (-1.6, 11.8)

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               < 0.0001           1.9                 0.0004 
(1.8, 3.7)                           (0.9, 2.9)

At week 48                           2.7                0.0001            2.8                 0.0002 
(1.3, 4.1)                           (1.3, 4.2)

Mean absolute change from baseline in BMI (kg/m2)
At week 24                          0.94               < 0.0001          0.81                 0.0008 
(0.62, 1.26)                         (0.34, 1.28)

At week 48                          0.93               < 0.0001          1.09                 0.0003 
(0.48, 1.38)                         (0.51, 1.67)

Mean change from baseline in z-scores
Weight-for-age z-score at           0.33                0.0260           0.39                 < 0.0001 week 48e
(0.04, 0.62)                         (0.24, 0.53)

BMI-for-age z-score at              0.33                0.0490           0.45                 < 0.0001 week 48e

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Study 1                                 Study 2

Treatment                             Treatment differencea                           differencea
Endpoint                          (95% CI)            P value           (95% CI)             P value 
(0.002, 0.65)                          (0.26, 0.65)

CI: confidence interval; NA: not analyzed 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 patients under 20 years of age (CDC growth charts)

Study 5: study in patients with CF with non-G551D gating mutations
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 the part 1 ivacaftor/placebo treatment sequence.

Thirty-nine patients (mean age 23 years) with baseline FEV 1 ≥ 40% predicted (mean FEV 1 78% predicted [range: 43% to 119%]) were enrolled. Fifty-nine percent (23/39) 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 FEV 1 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 FEV 1 (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 of 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 FEV 1 at week 8) is shown in Table 7. Based on clinical (percent predicted FEV 1 ) and pharmacodynamic (sweat chloride) responses to ivacaftor, efficacy in patients with the G970R mutation could not be established.


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Table 7: Effect of ivacaftor for efficacy variables in the overall population and for specific CFTR mutations

Absolute change in percent                  BMI                    CFQ-R respiratory domain predicted FEV 1                    (kg/m2)                         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          Absolute change in percent predicted (mmol/L)                            FEV 1 (percentage points)
At week 8                                     At week 8
G1244E (5)                     -55 (-75, -34)                                   8 (-1, 18) G1349D (2)                     -80 (-82, -79)                                  20 (3, 36) G178R (5)                     -53 (-65, -35)                                   8 (-1, 18) G551S (2)                            -68†                                          3 †

G970R (4)
#
-6 (-16, -2)                                    3 (-1, 5)
S1251N (8)                      -54 (-84, -7)                                  9 (-20, 21) S1255P (2)                    -78 (-82, -74)                                    3 (-1, 8) S549N (6)                     -74 (-93, -53)                                  11 (-2, 20) S549R (4)                        ††
-61 (-71, -54)                                    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 FEV 1 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 FEV 1 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 FEV 1 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 FEV 1 from Part 2 week 16 was -7.4% (5.5%).

Study 3: study in patients with CF with the F508del mutation in the CFTR gene 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 aged 12 years and older who were homozygous for the F508del mutation in the CFTR gene and who had FEV 1 ≥40% predicted.

The mean absolute change from baseline through week 16 in percent predicted FEV 1 (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).

Study 4: open-label extension study
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.

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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 8 shows the results of the mean (SD) absolute change in percent predicted FEV 1 for both groups of patients. For patients in the placebo/ivacaftor group, baseline percent predicted FEV 1 is that of study 4 while for patients in the ivacaftor/ivacaftor group, the baseline value is that of studies 1 and 2.

Table 8: Effect of ivacaftor on percent predicted FEV1 in study 4

Original study and          Duration of ivacaftor          Absolute change from baseline in percent treatment group              treatment (weeks)               predicted FEV 1 (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 FEV 1 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 FEV 1 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 FEV 1 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 7: study in paediatric patients with CF aged 2 to less than 6 years with G551D or another gating mutation
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.

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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 FEV 1 (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 FEV 1 from baseline at week 24 (exploratory endpoint) was 1.8 (17.81).

Pharmacokinetic Properties

5.2 Pharmacokinetic properties
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 C max 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
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 fat-containing food, the exposure of ivacaftor increased approximately 2.5- to 4-fold. Therefore, ivacaftor should be administered with fat-containing food. The median (range) t max is approximately 4.0 (3.0; 6.0) hours in the fed state.

Ivacaftor granules (2 x 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 AUC 0-∞ and 0.918 (0.750, 1.12) for C max . The effect of food on ivacaftor absorption is similar for both formulations, i.e., tablets and granules.

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 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).

Biotransformation
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 of CYP3A4*22 homozygous genotype patients is expected to be stronger. However, no data are available for such patients.
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Elimination
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 patients and patients with CF. The mean (±SD) CL/F for a single 150 mg dose was 17.3 (8.4) L/hr in healthy patients.

Linearity/non-linearity
The pharmacokinetics of ivacaftor are generally linear with respect to time or dose ranging from 50 mg to 250 mg.

Special populations
Hepatic impairment
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 C max (mean [±SD] of 735 [331] ng/mL) but an approximately two-fold increase in ivacaftor AUC 0-∞ (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 C min 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 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 has 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.

For guidance on appropriate use and dose modification see Table 3 in section 4.2.

Renal 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). Therefore, 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
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.

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

Elderly
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.

Paediatric population
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 9.


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Table 9: Mean (SD) ivacaftor exposure by age group
Age group                     Dose                            C min, ss (ng/mL)             AUC τ,ss (ng*h/mL)     2- to 5-year-olds             50 mg q12h                      577 (317)                     10500 (4260)
(<14 kg)
2- to 5-year-olds             75 mg q12h                      629 (296)                     11300 (3820)
(≥14 kg to <25 kg)
6- to 11-year-olds†           75 mg q12h                      641 (329)                     10760 (4470) (≥14 kg to <25 kg)
6- to 11-year-olds †          150 mg q12h                     958 (546)                     15300 (7340) (≥25 kg)
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.