Ivacaftor and lumacaftor Drugs

IVACAFTOR AND LUMACAFTOR

Anatomic Therapeutic Chemical (ATC)Classification

R07AX02

Ranjit Saha (Pharm.D)

CHITKARA UNIVERSITY

DRUG DESCRIPTION

Lumacaftor and Ivacaftor

Brand name : orkambi

Cystic Fibrosis Transmembrane Conductance Regulator Potentiator

Ivacaftor approved by the FDA in the following formulation(s):

Ivacaftor And Lumacaftor - Granule;oral

• Manufacturer: VERTEX PHARMS INC

• Approval Date March 17, 2015

• Strength(s): 50mg/PACKET, 75mg/PACKET

Dosage form - Tablet;oral

Orkambi

It is a combination of two categories of

molecules, FDA-approved ivacaftor (known by

its brand-name Kalydeco) and experimental

therapy lumacaftor (known also as VX-809),

both of which help in correcting the mutated

genes in patients with cystic fibrosis – a novel

therapeutic approach designed to treat the root

cause of cystic fibrosis instead of treating the

severity of symptoms.

INDICATIONS

Cystic Fibrosis

Pharmacologic Category: Cystic fibrosis Transmembrane Conductance

Regulator Potentiator

Clinical Pharmacology Mechanism of Action

Lumacaftor

CFTR corrector

Corrects the processing and trafficking defect of the F508del-CFTR protein to enable it to reach the cell

surface where the CFTR potentiator, ivacaftor, can further enhance the ion channel function of the

CFTR protein

Ivacaftor

CFTR potentiator

The CFTR protein is a chloride channel present at the surface of epithelial cells in multiple organs;

ivacaftor facilitates increased chloride transport by potentiating the channel-open probability (or gating)

of mutated CFTR proteins mutations in the CFTR gene.

Pharmacodynamics/kinetics

Onset of action: FEV1 increased, sweat chloride decreased within ~2 weeks

Absorption: Variable; increased (by two- to fourfold) with fatty foods

Distribution: Vd: 353 L

Protein binding: ~99%; primarily to alpha1 acid glycoprotein, albumin

Pharmacodynamics/kinetics

Metabolism: Hepatic; extensive via CYP3A; forms 2 major metabolites (M1 [active; 1/6

potency] and M6 [inactive])

Half-life elimination: ~12 hours

Time to peak: ~4 hours

Excretion: Feces (88%, 65% of administered dose as metabolites); urine (minimal,

as unchanged drug)

Organs Affected

Lungs

Pancreas

Small intestine

Stomach

Pancreatic duct

DosesAdult

Cystic fibrosis: Oral: Tablet: 150 mg every 12 hours

Pediatric

Cystic fibrosis: Oral:Granules:

Children 2 to <6 years:

<14 kg: 50 mg packet every 12 hours

≥14 kg: 75 mg packet every 12 hours

Tablet: Children ≥6 years and Adolescents: Refer to adult dosing.

Missed dose: If dose is missed within 6 hours of the usual time it is taken, take the dose

as soon as possible; otherwise, skip the missed dose and resume the normal dosing schedule

Doses

Dosing Renal Impairment

Mild to moderate impairment (CrCl >30 mL/minute): No dosage adjustment

necessary (has not been studied).

Severe impairment CrCl ≤30 (mL/minute): There are no dosage adjustments

provided in the manufacturer's labeling (has not been studied); use with caution.

End-stage renal disease (ESRD): There are no dosage adjustments provided in

the manufacturer's labeling (has not been studied); use with caution.

Doses

Dosing Hepatic Impairment

Mild impairment (Child-Pugh class A): No dosage adjustment necessary.

Moderate impairment (Child-Pugh class B):

Children ≥6 years, Adolescents, and Adults: 150 mg once daily


<14 kg: 50 mg granule packet once daily

≥14 kg: 75 mg granule packet once daily

Contd….

Doses

Severe impairment (Child-Pugh class C): Has not been studied; use with caution

US labeling:

Children ≥6 years, Adolescents, and Adults: 150 mg once daily or less frequently.


<14 kg: 50 mg granule packet once daily or less frequently

≥14 kg: 75 mg granule packet once daily or less frequently

Storages

Store at controlled room temperature (20-25°C [68-

77°F]); excursions permitted to 15-30°C (59-86°F)

Patient Handout

A Patient Handout is not currently available for this

monograph.

Side EffectsMost common

Shortness of breath and/or chest tightness

Upper respiratory tract infection (common cold), including sore throat, stuffy or runny nose

Gastrointestinal symptoms, including nausea, diarrhea, or gas

Rash

Fatigue

Flu or flu-like symptoms

Increase in muscle enzyme levels

Irregular, missed, or abnormal periods (menses) and increase in the amount of menstrual

bleeding

Used In Cystic Fibrosis Diseases

Cystic Fibrosis

Cystic fibrosis is a disease that causes mucus in the body to become

thick, dry, and sticky. This glue-like mucus builds up and causes

problems in many of the body's organs, especially the lungs and

pancreas. Cystic fibrosis is also known as mucoviscidosis, pulmonary

fibrosis, and pancreatic cystic fibrosis. Approximately 30,000 people in

the United States have cystic fibrosis.

Cystic Fibrosis

Cystic fibrosis is a disease

that causes mucus in the

body to become thick, dry,

and sticky.

Adverse Drug

Reaction

Adverse Reactions OrkambiN=369(%)

PlaceboN=360(%)

Dyspnea 48 (13) 29 (8)

Nasopharyngitis 48 (13) 40 (11)

Nausea 46 (13) 28 (8)

Dirrahea 45 (12) 31 (8)

Upper respiratory tract

infection

37 (10) 20 (5)

fatique 34 (9) 29 (8)

Respiration abnormal 32 (9) 22 (6)

Blood creatinine

phosphokinase

increased

27 (7) 20 (5)

Rash 25 (7) 7 (2)

Flatulence 24 (7) 11 (3)

rhinorrhea 21 (6) 15 (4)

influenja 19 (5) 8 (2)

(ADR)

overdose

If overdose is suspected, contact a poison control center or

emergency room immediately.

Clinical Trials

Purpose

The Purpose of the study is to examine drug drug interaction effects

ofcifroloxacin , itroconazole and rifampin on the pharmacokinetics of

lumacaftor in combination with ivacaftor on lung function.

Condition Intervention Phase

Cystic Fibrosis Drug: Lumacaftor

Drug: Ivacaftor

Drug: Ciprofloxacin

Drug: Itraconazole

Drug: Rifampin

Phase 1

https://clinicaltrials.gov/ct2/help/conditions_desc

https://clinicaltrials.gov/ct2/help/interventions_desc

https://clinicaltrials.gov/ct2/help/phase_desc

Study Type : Interventional

Study Design: Allocation : NOT RANDOMISED

End point classification : pharmacokinetics study

Intervention Model : Single Group Assignment

Masking : Open Label

Primary Purpose : Treatment

Official Site: To Examine Effects of Cifroloxacin , Itroconazole and Rifampin on the

Pharmacokinetics of Lumacaftor in combination with Ivacaftor in health adult subjects

Arms Assigned Interventions

Experimental: Treatment Group (Cohort 1)Subjects will

take lumacaftor in combination with ivacaftor for 14

days. Beginning on Day 15, subjects will

take lumacaftor in combination with ivacaftorand

ciprofloxacin through Day 21.

Drug: Lumacaftortablet, 200mg taken every 12 hours

Other Name: VX-809

Drug: Ivacaftortablet, 250mg taken every 12 hours

Other Name: VX-770

Drug: Ciprofloxacin750 mg taken every 12 hours

Experimental: Treatment Group (Cohort 2)Subjects will

take lumacaftor in combination with ivacaftor for 14

days. Beginning on Day 15, subjects will

take lumacaftor in combination with ivacaftorand

itraconazole through Day 21.

Drug: Lumacaftor tablet, 200mg taken every 12 hours

Other Name: VX-809

Drug: Ivacaftortablet, 250mg taken every 12 hours

Other Name: VX-770

Drug: Itraconazole200mg taken once daily

https://clinicaltrials.gov/ct2/help/arm_group_desc


Clinical Trials

Purpose

The purpose of this study is to evaluate of the

safety,efficacy,pharmacokinetics and pharmacodynamics effect of

lumacaftor (vx-809) alone and when coadministered with ivacaftor (vx-

770) in participants with cystic fibrosis,homozygous or heterozygous for

the F508Del-CFTR mutation.Condition Intervention Phase

Cystic Fibrosis Drug: Lumacaftor

Drug: Ivacaftor

Drug: Lumacaftor

Placebo

Drug: Ivacaftor Pla

cebo

Phase 2

https://clinicaltrials.gov/ct2/help/conditions_desc


https://clinicaltrials.gov/ct2/help/phase_desc

Study type : Interventional

Study Design : Allocation : Randomized

End Point Classification: Safety/Efficacy study

Intervention Model : factorial Assignment

Masking : Double Blind (subject,caregiver,Investigator)

Primary Purpose : Treatment

Official title : A phase 2, multicenter, Double-Binded, Placebo-controlled, Multiple Dose study

to evaluate safety, Tolerability,Efficacy, Pharmacokinetics and Pharmacodynamics of Lumacaftor

Monotherapy, and Lumacaftor and Ivacaftor combination therapy in subjects with cstic

Fibrosis Homozygous or heterozygous for the F508eely Heterozygous for the F508del-CFTR

Mutation

Clinical Trials

Arms Assigned Interventions

Placebo Comparator: Cohort 1: PlaceboParticipants homozygous (HO)

for the F508del-CF transmembrane conductance regulator gene (CFTR)

mutation received lumacaftor matched placebo once daily (qd) (Day 1

through Day 14), followed by lumacaftor matched placebo qd in

combination with ivacaftor matched placebo every 12 hours (q12h) (Day

15 through Day 21).

Drug:LumacaftorPlaceboMatching placebo tablet.

Drug:IvacaftorPlaceboMatching placebo tablet.

Experimental: Cohort 1: LUM 200 mg qd/LUM 200 mg qd+IVA 150 mg

q12hParticipants homozygous for the F508del-CFTR mutation received

200 milligram (mg) of lumacaftor (LUM) qd (Day 1 through Day 14),

followed by 200 mg of lumacaftorqd in combination with 150 mg

of ivacaftor (IVA) q12h (Day 15 through Day 21).

Drug:LumacaftorTablet

Other Name: VX-809, LUM

Drug:IvacaftorTablet.

Other Name: VX-770, IVA

Experimental: Cohort 1: LUM 200 mg qd/LUM 200 mg qd+IVA 250 mg

q12hParticipants homozygous for the F508del-CFTR mutation received

200 mg of lumacaftor alone qd (Day 1 through Day 14), followed by

200 mg of lumacaftor qd in combination with 250 mg of ivacaftor q12h

(Day 15 through Day 21).





https://clinicaltrials.gov/ct2/help/arm_group_desc


Placebo Comparator: Cohort 2 and 3: Placebo (HO and

HE)Participants homozygous or heterozygous for the F508del-CFTR

mutation received lumacaftor matched placebo qd (Day 1 through

Day 28), followed by lumacaftormatched placebo in combination

with ivacaftor matched placebo q12h (Day 29 through Day 56).



Experimental: Cohort 2: LUM 200 mg qd/LUM 200 mg qd+IVA 250

mg q12h (HO)Participants homozygous for the F508del-CFTR

mutation received 200 mg of lumacaftor alone qd (Day 1 through Day

28), followed by 200 mg of lumacaftor qd in combination with 250

mg of ivacaftor q12h (Day 29 through Day 56).





Experimental: Cohort 2: LUM 400 mg qd/LUM 400 mg qd+IVA 250

mg q12h (HO)Participants homozygous for the F508del-CFTR

mutation received 400 mg of lumacaftor alone qd (Day 1 through Day

28), followed by 400 mg of lumacaftor qd in combination with 250

mg of ivacaftor q12h (Day 29 through Day 56).





Experimental: Cohort 2: LUM 600 mg qd/LUM 600 mg

qd+IVA 250 mg q12h (HO&HE)Participants homozygous or

heterozygous for the F508del-CFTR mutation received 600 mg

of lumacaftor alone qd (Day 1 through Day 28), followed by 600 mg

oflumacaftor qd in combination with 250 mg of ivacaftor q12h (Day

29 through Day 56).





Experimental: Cohort 3: LUM 400 mg q12h/LUM 400 mg

q12h+IVA 250 mg q12h (HO)Participants homozygous for the

F508del-CFTR mutation received 400 mg of lumacaftor alone q12h

(Day 1 through Day 28), followed by 400 mg of lumacaftor q12h in

combination with 250 mg of ivacaftor q12h (Day 29 through Day

56).





Placebo Comparator: Cohort 4: PlaceboParticipants

heterozygous for the F508del-CFTR mutation

received lumacaftor matched placebo in combination

with ivacaftor matched placebo q12h (Day 1 through Day

56).



Experimental: Cohort 4: LUM 400 mg q12h+IVA 250 mg

q12hParticipants heterozygous for the F508del-CFTR

mutation received 400 mg of lumacaftor q12h in

combination with 250 mg of ivacaftor q12h (Day 1 through

Day 56).





Worsening liver function, including hepatic encephalopathy, in patients with advanced liver

disease reported

Elevated transaminases have been reported and may require therapy interruption (see

Dosage Modifications)

Respiratory events (eg, chest discomfort, dyspnea, abnormal respiration) were observed

more commonly in patients during initiation compared with placebo

Cases of noncongenital lens opacities have been reported in pediatric patients treated with

ivacaftor

Lumacaftor is a strong inducer of CYP3A; coadministration with sensitive CYP3A

substrates or those with a narrow therapeutic index is not recommended

Ivacaftor is a substrate of CYP3A4 and CYP3A5; coadministration with strong inducers is

not recommended because of significantly reduced systemic exposure of ivacaftor

Cautions

References

https://clinicaltrials.gov/ct2/results?term=ivacaftor+and+lumacaftor&Search=Sear

ch

https://clinicaltrials.gov/ct2/show/NCT01768663?term=ivacaftor+and+lumacaftor

&rank=2

https://clinicaltrials.gov/ct2/show/NCT01225211?term=ivacaftor+and+lumacaftor

&rank=9

http://reference.medscape.com/drug/orkambi-lumacaftor-ivacaftor-1000000#5



https://clinicaltrials.gov/ct2/results?term=ivacaftor+and+lumacaftor&Search=Search

https://clinicaltrials.gov/ct2/show/NCT01768663?term=ivacaftor+and+lumacaftor&rank=2

https://clinicaltrials.gov/ct2/show/NCT01225211?term=ivacaftor+and+lumacaftor&rank=9




Education

Ivacaftor and lumacaftor Drugs