12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The CFTR protein is a chloride channel present at the surface of epithelial cells in multiple organs. The F508del mutation results in protein misfolding, causing a defect in cellular processing and trafficking that targets the protein for degradation and therefore reduces the quantity of CFTR at the cell surface. The small amount of F508del-CFTR that reaches the cell surface is less stable and has low channel-open probability (defective gating activity) compared to wild-type CFTR protein.

Lumacaftor improves the conformational stability of F508del-CFTR, resulting in increased processing and trafficking of mature protein to 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. In vitro studies have demonstrated that both lumacaftor and ivacaftor act directly on the CFTR protein in primary human bronchial epithelial cultures and other cell lines harboring the F508del-CFTR mutation to increase the quantity, stability, and function of F508del-CFTR at the cell surface, resulting in increased chloride ion transport. In vitro responses do not necessarily correspond to in vivo pharmacodynamic response or clinical benefit.

12.2 Pharmacodynamics

Sweat Chloride Evaluation

Changes in sweat chloride in response to relevant doses of 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 either homozygous or heterozygous for the F508del mutation. In that trial, 10 patients (homozygous for F508del) 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 compared to placebo was -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 compared to placebo was -11 mmol/L (95% CI: -18, -4).

Changes in sweat chloride in response to lumacaftor/ivacaftor were also evaluated in a 24-week, open-label, clinical trial (Trial 3) in 58 patients with CF, aged 6 through 11 years (homozygous for F508del) who received lumacaftor 200 mg/ivacaftor 250 mg q12h for 24 weeks. Patients treated with lumacaftor/ivacaftor had a reduction in sweat chloride at Day 15 that was sustained through Week 24. The within-group LS mean absolute change from baseline in sweat chloride was -20.4 mmol/L at Day 15 and -24.8 mmol/L at Week 24. In addition, sweat chloride was also assessed after a 2-week washout period to evaluate the off-drug response. The within-group LS mean absolute change in sweat chloride from Week 24 at Week 26 following the 2-week washout period was 21.3 mmol/L.

Changes in sweat chloride in response to lumacaftor/ivacaftor were also evaluated in a 24-week, open-label, clinical trial (Trial 6) in 60 patients with CF, aged 2 through 5 years (homozygous for F508del) who received either lumacaftor 100 mg/ivacaftor 125 mg every 12 hours or lumacaftor 150 mg/ivacaftor 188 mg every 12 hours for 24 weeks. Treatment with lumacaftor/ivacaftor demonstrated a reduction in sweat chloride at Week 4 that was sustained through Week 24. The mean absolute change from baseline in sweat chloride was –31.7 mmol/L (95% CI: -35.7, -27.6) at Week 24. In addition, sweat chloride was also assessed after a 2-week washout period to evaluate the off-drug response. The mean absolute change in sweat chloride from Week 24 at Week 26 following the 2-week washout period was an increase of 33.0 mmol/L (95% CI: 28.9, 37.1; P<0.0001).

Changes in sweat chloride in response to lumacaftor/ivacaftor were evaluated in a 24-week, open-label, clinical trial (Trial 7) in 46 patients with CF, aged 1 through 2 years (homozygous for F508del) who received lumacaftor 75 mg/ivacaftor 94 mg (patient weighing 7 kg to <9 kg at screening), lumacaftor 100 mg/ivacaftor 125 mg (patient weighing 9 kg to <14 kg at screening), lumacaftor 150 mg/ivacaftor 188 mg (patient weighing ≥14 kg at screening), every 12 hours for 24 weeks. 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 mmol/L (95% CI: -34.8, -23.4). In addition, sweat chloride was also assessed after a 2-week washout period to evaluate the off-drug response. The mean absolute change in sweat chloride from Week 24 at Week 26 following the 2-week washout period was 27.3 mmol/L (95% CI: 22.3, 32.3).

There was no direct correlation between decrease in sweat chloride levels and improvement in lung function (ppFEV1).

Cardiac Electrophysiology

The effect of multiple doses of lumacaftor 600 mg once daily/ivacaftor 250 mg q12h and lumacaftor 1000 mg once daily/ivacaftor 450 mg q12h on QTc interval was evaluated in a randomized, placebo- and active-controlled (400 mg moxifloxacin), parallel, thorough QT study in 168 healthy subjects. No meaningful changes in QTc interval were observed with either lumacaftor 600 mg once daily/ivacaftor 250 mg q12h and lumacaftor 1000 mg once daily/ivacaftor 450 mg q12h dose groups. A maximum decrease in mean heart rate of up to 8 beats per minute (bpm) from baseline was observed with lumacaftor/ivacaftor treatment. In Trials 1 and 2, a similar decrease in heart rate was observed in patients during initiation of ORKAMBI (lumacaftor 400 mg/ivacaftor 250 mg q12h).

12.3 Pharmacokinetics

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.

Table 4: Mean (SD) Pharmacokinetic Parameters of Lumacaftor and Ivacaftor at Steady-State in Subjects with CF
	Drug	Cmax (μg/mL)	t½* (h)	AUC0-12h (μg∙h/mL)
* Based on lumacaftor 200 mg q12h/ivacaftor 250 mg q12h studied in healthy subjects.
Lumacaftor 400 mg q12h/ Ivacaftor 250 mg q12h	Lumacaftor	25.0 (7.96)	25.2 (9.94)	198 (64.8)
Lumacaftor 400 mg q12h/ Ivacaftor 250 mg q12h	Ivacaftor	0.602 (0.304)	9.34 (3.81)	3.66 (2.25)

Absorption

When a single dose of lumacaftor/ivacaftor was administered with fat-containing foods, lumacaftor exposure was approximately 2 times higher and ivacaftor exposure was approximately 3 times higher than when taken in a fasting state.

Following multiple oral dose administration of lumacaftor in combination with ivacaftor, the exposure of lumacaftor generally increased proportional to dose over the range of 200 mg every 24 hours to 400 mg every 12 hours. 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 median (range) tmax of ivacaftor is approximately 4.0 hours (2.0; 6.0) in the fed state.

Distribution

Lumacaftor is approximately 99% bound to plasma proteins, primarily to albumin. After oral administration of 200 mg every 24 hours for 28 days to patients with CF in a fed state, the mean (±SD) for apparent volumes of distribution was 86.0 (69.8) L.

Ivacaftor is approximately 99% bound to plasma proteins, primarily to alpha 1-acid glycoprotein and albumin.

Elimination

The half-life of lumacaftor is approximately 26 hours in patients with CF. The typical apparent clearance, CL/F (CV), of lumacaftor was estimated to be 2.38 L/hr (29.4%) for patients with CF. The half-life of ivacaftor when given with lumacaftor is approximately 9 hours in healthy subjects. The typical CL/F (CV), of ivacaftor when given in combination with lumacaftor was estimated to be 25.1 L/hr (40.5%) for patients with CF.

Metabolism

Lumacaftor is not extensively metabolized in humans with the majority of lumacaftor excreted unchanged in the feces. In vitro and in vivo data indicate that lumacaftor is mainly metabolized via oxidation and glucuronidation.

Ivacaftor is extensively metabolized in humans. In vitro and in vivo data indicate that ivacaftor is primarily metabolized by CYP3A. M1 and M6 are the two major metabolites of ivacaftor in humans.

Excretion

Following oral administration of lumacaftor, the majority of lumacaftor (51%) is excreted unchanged in the feces. 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).

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).

Specific Populations

Pediatric Patients

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

Table 5: Mean (SD) Lumacaftor and Ivacaftor Exposure by Age Group
Age Group	Weight	Dose	Mean Lumacaftor (SD)* AUCss (µg∙h/mL)	Mean Ivacaftor (SD)† AUCss (µg∙h/mL)
* The mean lumacaftor (SD) AUCss is comparable to the mean AUCss in patients aged 12 years and older administered ORKAMBI tablets. † The mean ivacaftor (SD) AUCss is comparable to the mean AUCss in patients aged 12 years and older administered ORKAMBI tablets.
Patients aged 1 to <2 years	7 kg to <9 kg	lumacaftor 75 mg/ivacaftor 94 mg every 12 hours.	234	7.98
	9 kg to <14 kg	lumacaftor 100 mg/ivacaftor 125 mg every 12 hours.	191 (40.6)	5.35 (1.61)
	≥14 kg	lumacaftor 150 mg/ivacaftor 188 mg every 12 hours.	116	5.82
Patients aged 2 through 5 years	<14 kg	lumacaftor 100 mg/ivacaftor 125 mg every 12 hours.	180 (45.5)	5.92 (4.61)
Patients aged 2 through 5 years	≥14 kg	lumacaftor 150 mg/ivacaftor 188 mg every 12 hours.	217 (48.6)	5.90 (1.93)
Patients aged 6 through 11 years	-	lumacaftor 200 mg/ivacaftor 250 mg every 12 hours.	203 (57.4)	5.26 (3.08)
Patients aged 12 to <18 years	-	lumacaftor 400 mg/ivacaftor 250 mg every 12 hours.	241 (61.4)	3.90 (1.56)

Male and Female Patients

The pharmacokinetics of ORKAMBI was evaluated using a population PK analyses of data from clinical studies of lumacaftor given in combination with ivacaftor. Results indicate no clinically relevant difference in pharmacokinetic parameters for lumacaftor and ivacaftor between males and females.

Patients with Renal Impairment

Pharmacokinetic studies have not been performed with ORKAMBI in patients with renal impairment [see Use in Specific Populations (8.7)].

Patients with Hepatic Impairment

Following multiple doses of lumacaftor/ivacaftor for 10 days, subjects with moderately impaired hepatic function (Child-Pugh Class B, score 7 to 9) had approximately 50% higher exposures (AUC0-12h) and approximately 30% higher Cmax for both lumacaftor and ivacaftor compared with healthy subjects matched for demographics.

Pharmacokinetic studies have not been conducted in patients with mild (Child-Pugh Class A, score 5 to 6) or severe hepatic impairment (Child-Pugh Class C, score 10 to 15) receiving ORKAMBI [see Dosage and Administration (2.2), Warnings and Precautions (5.1), Adverse Reactions (6), and Use in Specific Populations (8.6)].

Drug Interaction Studies

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

Potential for Lumacaftor/Ivacaftor to Affect Other Drugs

Lumacaftor is a strong inducer of CYP3A. Co-administration of lumacaftor with ivacaftor, a sensitive CYP3A substrate, decreased ivacaftor exposure by 80%. Ivacaftor is a weak inhibitor of CYP3A when given as monotherapy. The net effect of lumacaftor/ivacaftor therapy is strong CYP3A induction [see Drug Interactions (7.3)].

Based on in vitro results which showed P-gp inhibition and PXR activation, lumacaftor has the potential to both inhibit and induce P-gp. A clinical study with ivacaftor monotherapy showed that ivacaftor is a weak inhibitor of P-gp. Therefore, concomitant use of ORKAMBI with P-gp substrates may alter the exposure of these substrates [see Drug Interactions (7.5)].

In vitro studies suggest that lumacaftor has the potential to induce CYP2B6, CYP2C8, CYP2C9, and CYP2C19; inhibition of CYP2C8 and CYP2C9 has also been observed in vitro. In vitro studies suggest that ivacaftor may inhibit CYP2C9. Therefore, concomitant use of ORKAMBI with CYP2B6, CYP2C8, CYP2C9, and CYP2C19 substrates may alter the exposure of these substrates [see Drug Interactions (7.4)].

Potential for Other Drugs to Affect Lumacaftor/Ivacaftor

Lumacaftor exposure is not affected by concomitant CYP3A inducers or inhibitors. Exposure of ivacaftor when given in combination with lumacaftor is reduced by concomitant CYP3A inducers and increased by concomitant CYP3A inhibitors [see Dosage and Administration (2.3), Warnings and Precautions (5.6), and Drug Interactions (7)].

The effects of co-administered drugs on the exposure of lumacaftor and ivacaftor are shown in Table 6 [see Dosage and Administration (2.3), Warnings and Precautions (5.6), and Drug Interactions (7)].

Table 6: Impact of Other Drugs on Lumacaftor 200 mg q12h/Ivacaftor 250 mg q12h
Co-administered Drug	Dose of Co-administered Drug	Effect on PK*	Mean Ratio (90% CI) of Lumacaftor and Ivacaftor No Effect=1.0
Co-administered Drug	Dose of Co-administered Drug	Effect on PK*	AUC	Cmax
CI = Confidence Interval; PK = Pharmacokinetics.
* ↑ = increase, ↓ = decrease, ↔ = no change. † The net exposure of ivacaftor is not expected to exceed that when given in the absence of lumacaftor at a dose of 150 mg every 12 hours, the approved dose of ivacaftor monotherapy.
CYP3A inhibitor: itraconazole	200 mg once daily	↔ Lumacaftor	0.97 (0.91, 1.02)	0.99 (0.92, 1.05)
CYP3A inhibitor: itraconazole	200 mg once daily	↑ Ivacaftor	4.30† (3.78, 4.88)	3.64† (3.19, 4.17)
CYP3A inducer: rifampin	600 mg once daily	↔ Lumacaftor	0.87 (0.81, 0.93)	0.96 (0.87, 1.05)
CYP3A inducer: rifampin	600 mg once daily	↓ Ivacaftor	0.43 (0.38, 0.49)	0.50 (0.43, 0.58)
Other: ciprofloxacin	750 mg q12h	↔ Lumacaftor	0.86 (0.79, 0.95)	0.88 (0.80, 0.97)
Other: ciprofloxacin	750 mg q12h	↔ Ivacaftor	1.29 (1.12, 1.48)	1.29 (1.11, 1.49)