The CFTR protein is a chloride channel present at the surface of epithelial cells in multiple organs. The F508del mutation impacts the CFTR protein in multiple ways, primarily by causing a defect in cellular processing and trafficking that reduces the quantity of CFTR at the cell surface. The small amount of F508del-CFTR that reaches the cell surface has low channel-open probability (defective channel gating).
Lumacaftor is a CFTR corrector that acts directly on F508del-CFTR to improve its cellular processing and trafficking, thereby increasing the quantity of functional CFTR at the cell surface.
Ivacaftor is a CFTR potentiator that facilitates increased chloride transport by potentiating the channel-open probability (or gating) of the CFTR protein at the cell surface.
The combined effect of lumacaftor and ivacaftor is increased quantity and function of F508delCFTR at the cell surface, resulting in increased chloride ion transport. The exact mechanisms by which lumacaftor improves cellular processing and trafficking of F508delCFTR and ivacaftor potentiates F508del-CFTR are not known.
Changes in sweat chloride in response to lumacaftor alone or in combination with ivacaftor were evaluated in a double-blind, placebo-controlled, Phase 2 clinical trial in patients with CF aged 18 years and older. In this trial, 10 patients (homozygous for F508del-CFTR mutation) completed dosing with lumacaftor alone 400 mg q12h for 28 days followed by the addition of ivacaftor 250 mg q12h for an additional 28 days, and 25 patients (homozygous or heterozygous for F508del) completed dosing with placebo. The treatment difference between lumacaftor 400 mg q12h alone and placebo evaluated as mean change in sweat chloride from baseline to day 28 was statistically significant at -8.2 mmol/L (95% CI: -14, -2). The treatment difference between the combination of lumacaftor 400 mg/ivacaftor 250 mg q12h and placebo evaluated as mean change in sweat chloride from baseline to day 56 was statistically significant at -11 mmol/L (95% CI: -18, -4).
In trial 809-109 in patients homozygous for the F508del-CFTR mutation aged 6 to less than 12 years, the treatment difference (LS mean) in sweat chloride for the absolute change at week 24 as compared to placebo was -24.9 mmol/L (nominal P<0.0001). The treatment difference (LS mean) in sweat chloride for the average absolute change at day 15 and at week 4 as compared to placebo was -20.8 mmol/L (95% CI: -23.4, -18.2; nominal P<0.0001).
In trial 809-115 in patients homozygous for F508del-CFTR mutation aged 2 to 5 years, the mean absolute within-group change in sweat chloride from baseline at week 24 was -31.7 mmol/L (95% CI: -35.7, -27.6). In addition, the mean absolute change in sweat chloride from week 24 at week 26 following the 2-week washout period (to evaluate off-drug response) was an increase of 33.0 mmol/L (95% CI: 28.9, 37.1; nominal P<0.0001), representing a return to baseline after treatment washout. At week 24, 16% of children had a reduction in sweat chloride below 60 mmol/L, and none below 30 mmol/L.
In trial 809-122 in patients homozygous for F508del-CFTR mutation aged 1 to less than 2 years, treatment with lumacaftor/ivacaftor demonstrated a reduction in sweat chloride at week 4 which was sustained through week 24. The mean absolute change from baseline in sweat chloride at week 24 was -29.1(13.5) mmol/L (95% CI: -34.8, -23.4). In addition, the mean (SD) absolute change in sweat chloride from week 24 at week 26 following the 2-week washout period was 27.3 (11.1) mmol/L (95% CI: 22.3, 32.3). This change represents a return towards baseline after treatment washout.
Changes in ppFEV1 in response to lumacaftor alone or in combination with ivacaftor were also evaluated in the double-blind, placebo-controlled, Phase 2 trial in patients with CF aged 18 years and older. The treatment difference between lumacaftor 400 mg q12h alone and placebo evaluated as mean absolute change in ppFEV1 was -4.6 percentage points (95% CI: -9.6, 0.4) from baseline to day 28, 4.2 percentage points (95% CI: –1.3, 9.7) from baseline to day 56, and 7.7 percentage points (95% CI: 2.6, 12.8; statistically significant) from day 28 to day 56 (following the addition of ivacaftor to lumacaftor monotherapy).
During the 24-week, placebo-controlled, Phase 3 studies, a maximum decrease in mean heart rate of 6 beats per minute (bpm) from baseline was observed on day 1 and day 15 around 4 to 6 hours after dosing. After day 15, heart rate was not monitored in the period after dosing in these studies. From week 4, the change in mean heart rate at pre-dose ranged from 1 to 2 bpm below baseline among patients treated with lumacaftor/ivacaftor. The percentage of patients with heart rate values <50 bpm on treatment was 11% for patients who received lumacaftor/ivacaftor, compared to 4.9% for patients who received placebo.
No meaningful changes in QTc interval or blood pressure were observed in a thorough QT clinical study evaluating lumacaftor 600 mg once daily/ivacaftor 250 mg q12h and lumacaftor 1000 mg once daily/ivacaftor 450 mg q12h.
The exposure (AUC) of lumacaftor is approximately 2-fold higher in healthy adult volunteers compared to exposure in patients with CF. The exposure of ivacaftor is similar between healthy adult volunteers and patients with CF. After twice-daily dosing, steady-state plasma concentrations of lumacaftor and ivacaftor in healthy subjects were generally reached after approximately 7 days of treatment, with an accumulation ratio of approximately 1.9 for lumacaftor. The steady-state exposure of ivacaftor is lower than that of day 1 due to the CYP3A induction effect of lumacaftor.
After oral administration of lumacaftor 400 mg q12h/ivacaftor 250 mg q12h in a fed state, the steady-state mean (± SD) for AUC0-12h and Cmax were 198 (64.8) µg∙h/mL and 25.0 (7.96) µg/mL for lumacaftor, respectively, and 3.66 (2.25) µg∙h/mL and 0.602 (0.304) µg/mL for ivacaftor, respectively. After oral administration of ivacaftor alone as 150 mg q12h in a fed state, the steady-state mean (± SD) for AUC0-12h and Cmax were 9.08 (3.20) µg∙h/mL and 1.12 (0.319) µg/mL, respectively.
Following multiple oral doses of lumacaftor, the exposure of lumacaftor generally increased proportional to dose over the range of 50 mg to 1000 mg every 24 hours. The exposure of lumacaftor increased approximately 2.0-fold when given with fat-containing food relative to fasted conditions. The median (range) Tmax of lumacaftor is approximately 4.0 hours (2.0; 9.0) in the fed state. Following multiple oral dose administration of ivacaftor in combination with lumacaftor, the exposure of ivacaftor generally increased with dose from 150 mg every 12 hours to 250 mg every 12 hours. The exposure of ivacaftor when given in combination with lumacaftor increased approximately 3-fold when given with fat-containing food in healthy volunteers. Therefore, lumacaftor/ivacaftor should be administered with fat-containing food. The median (range) Tmax of ivacaftor is approximately 4.0 hours (2.0; 6.0) in the fed state.
Lumacaftor is approximately 99% bound to plasma proteins, primarily to albumin. After oral administration of 400 mg every 12 hours in patients with CF in a fed state, the typical apparent volumes of distribution for the central and peripheral compartments [coefficient of variation as a percentage (CV)] were estimated to be 23.5 L (48.7%) and 33.3 L (30.5%), respectively. Ivacaftor is approximately 99% bound to plasma proteins, primarily to alpha 1-acid glycoprotein and albumin. After oral administration of ivacaftor 250 mg every 12 hours in combination with lumacaftor, the typical apparent volumes of distribution for the central and peripheral compartments (CV) were estimated to be 95.0 L (53.9%) and 201 L (26.6%), respectively.
In vitro studies indicate that lumacaftor is a substrate of Breast Cancer Resistance Protein (BCRP).
Lumacaftor is not extensively metabolised in humans, with the majority of lumacaftor excreted unchanged in the faeces. In vitro and in vivo data indicate that lumacaftor is mainly metabolised via oxidation and glucuronidation.
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.
Following oral administration of lumacaftor, the majority of lumacaftor (51%) is excreted unchanged in the faeces. There was negligible urinary excretion of lumacaftor as unchanged drug. The apparent terminal half-life is approximately 26 hours. The typical apparent clearance, CL/F (CV), of lumacaftor was estimated to be 2.38 L/h (29.4%) for patients with CF.
Following oral administration of ivacaftor alone, the majority of ivacaftor (87.8%) is eliminated in the faeces after metabolic conversion. There was negligible urinary excretion of ivacaftor as unchanged drug. In healthy subjects, the half-life of ivacaftor when given with lumacaftor is approximately 9 hours. The typical CL/F (CV) of ivacaftor when given in combination with lumacaftor was estimated to be 25.1 L/h (40.5%) for patients with CF.
Following multiple doses of lumacaftor/ivacaftor for 10 days, subjects with moderately impaired hepatic function (Child-Pugh Class B, score 7 to 9) had higher exposures (AUC0-12h by approximately 50% and Cmax by approximately 30%) compared with healthy subjects matched for demographics. The impact of mild hepatic impairment (Child-Pugh Class A, score 5 to 6) on pharmacokinetics of lumacaftor given in combination with ivacaftor has not been studied, but the increase in exposure is expected to be less than 50%.
Studies have not been conducted in patients with severe hepatic impairment (Child-Pugh Class C, score 10 to 15), but exposure is expected to be higher than in patients with moderate hepatic impairment.
Pharmacokinetic studies have not been performed with lumacaftor/ivacaftor in patients with renal impairment. In a human pharmacokinetic study with lumacaftor alone, there was minimal elimination of lumacaftor and its metabolites in urine (only 8.6% of total radioactivity was recovered in the urine with 0.18% as unchanged parent). 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). A population pharmacokinetic analysis of clearance versus creatinine clearance shows no trend for subjects with mild and moderate renal impairment.
The safety and efficacy of lumacaftor/ivacaftor in patients aged 65 years or older have not been evaluated.
The effect of gender on lumacaftor pharmacokinetics was evaluated using a population pharmacokinetics analysis of data from clinical studies of lumacaftor given in combination with ivacaftor. Results indicate no clinically relevant difference in pharmacokinetic parameters for lumacaftor or ivacaftor between males and females. No dose adjustments are necessary based on gender.
The exposures are similar between adults and the paediatric populations based on population PK analysis as presented in the following table.
Mean (SD) lumacaftor and ivacaftor exposure by age group:
| Age group | Weight | Dose | Mean lumacaftor (SD) AUCss (μgꞏh/mL) | Mean ivacaftor (SD) AUCss (μgꞏh/mL) |
|---|---|---|---|---|
| Patients aged 1 to <2 years | 7 kg to <9 kg N=1 | lumacaftor 75 mg/ivacaftor 94 mg sachet every 12 hours | 234 | 7.98 |
| 9 kg to <14 kg N=44 | lumacaftor 100 mg/ivacaftor 125 mg sachet every 12 hours | 191 (40.6) | 5.35 (1.61) | |
| ≥14 kg N=1 | lumacaftor 150 mg/ivacaftor 188 mg sachet every 12 hours | 116 | 5.82 | |
| Patients aged 2 to 5 years | <14 kg N=20 | lumacaftor 100 mg/ivacaftor 125 mg sachet every 12 hours | 180 (45.5) | 5.92 (4.61) |
| ≥14 kg N=42 | lumacaftor 150 mg/ivacaftor 188 mg sachet every 12 hours | 217 (48.6) | 5.90 (1.93) | |
| Patients aged 6 to <12 years | - N=62 | lumacaftor 200 mg/ivacaftor 250 mg every 12 hours | 203 (57.4) | 5.26 (3.08) |
| Patients aged 12 <18 years | - N=98 | lumacaftor 400 mg/ivacaftor 250 mg every 12 hours | 241 (61.4) | 3.90 (1.56) |
| Patients aged 18 years and older | - N=55 | Lumacaftor 400 mg/ivacaftor 250 mg every 12 hours | 198 (64.8) | 3.66 (2.25) |
Notes: Exposures for patients <18 years of age are from population PK analyses. Exposures for adult patients are from noncompartmental analyses.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, and toxicity to reproduction and development. Specific studies to evaluate the phototoxic potential of lumacaftor were not conducted; however, evaluation of the available non-clinical and clinical data suggests no phototoxic liability.
Effects in repeated dose studies were observed only at exposures considered sufficiently in excess (>25-, >45-, and >35-fold for mice, rats, and dogs, respectively) of the maximum human exposure of ivacaftor when administered as lumacaftor/ivacaftor fixed-dose combination, indicating little relevance to clinical use. Non-clinical data reveal no special hazard for humans based on conventional studies of genotoxicity and carcinogenic potential.
Ivacaftor produced concentration-dependent inhibitory effect on hERG (human ether-à-go-go related gene) tail currents, with an IC15 of 5.5 µM, compared to the Cmax (1.5 µM) for ivacaftor at the therapeutic dose for lumacaftor/ivacaftor. However, no ivacaftor-induced QT prolongation was observed in a dog telemetry study at single doses up to 60 mg/kg or in ECG measurements from repeat-dose studies of up to 1 year duration at the 60 mg/kg/day dose level in dogs (Cmax after 365 days = 36.2 to 47.6 μM). Ivacaftor produced a dose-related but transient increase in the blood pressure parameters in dogs at single oral doses up to 60 mg/kg.
Ivacaftor was not teratogenic when dosed orally to pregnant rats and rabbits during the organogenesis stage of foetal development at doses approximately 7 times (ivacaftor and metabolite exposure) and 46 times the ivacaftor exposure in humans at the therapeutic lumacaftor/ivacaftor dose, respectively. At maternally toxic doses in rats, ivacaftor produced reductions in foetal body weight; an increase in the incidence of variations in cervical ribs, hypoplastic ribs, and wavy ribs; and sternal irregularities, including fusions. The significance of these findings for humans is unknown.
Ivacaftor impaired fertility and reproductive performance indices in male and female rats at 200 mg/kg/day (yielding exposures approximately 11 and 7 times, respectively, those obtained with the maximum recommended human dose of the ivacaftor component of lumacaftor/ivacaftor fixed-dose combination based on summed AUCs of ivacaftor and its metabolites extrapolated from day 90 exposures at 150 mg/kg/day in the 6-month repeat-dose toxicity study and gestation day 17 exposures in the pilot embryofoetal development study in this species) when dams were dosed prior to and during early pregnancy. No effects on male or female fertility and reproductive performance indices were observed at ≤100 mg/kg/day (yielding exposures approximately 8 and 5 times, respectively, those obtained with the maximum recommended human dose of the ivacaftor component of lumacaftor/ivacaftor fixed-dose combination based on summed AUCs of ivacaftor and its metabolites extrapolated from day 90 exposures at 100 mg/kg/day in the 6-month repeat-dose toxicity study and gestation day 17 exposures in the embryofoetal development study in this species). Placental transfer of ivacaftor was observed in pregnant rats and rabbits.
Ivacaftor did not cause developmental defects in the offspring of pregnant rats dosed orally from pregnancy through parturition and weaning at 100 mg/kg/day (yielding exposures that were approximately 4 times those obtained with the maximum recommended human dose of the ivacaftor component of lumacaftor/ivacaftor fixed-dose combination based on summed AUCs of ivacaftor and its metabolites). Doses above 100 mg/kg/day resulted in survival and lactation indices that were 92% and 98% of control values, respectively, as well as reductions in pup body weights.
Findings of cataracts were observed in juvenile rats dosed with ivacaftor at 0.32 times the maximum recommended human dose based on systemic exposure of ivacaftor and its metabolites when co-administered with lumacaftor as lumacaftor/ivacaftor fixed-dose combination. Cataracts were not observed in foetuses derived from rat dams treated during the organogenesis stage of foetal development, in rat pups exposed to a certain extent through milk ingestion prior to weaning, or in repeated dose toxicity studies with ivacaftor. The potential relevance of these findings in humans is unknown.
Repeat-dose toxicity studies involving the co-administration of lumacaftor and ivacaftor revealed no special hazard for humans in terms of potential for additive and/or synergistic toxicities.
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