Drugs for CF

Question 1

What does CFTR do?

Answer 1

CFTR functions as an anion channel (which is regulated by PKA-dependent phosphorylation of its regulatory domain and binding of ATP to
the nucleotide binding domains) and conducts Cl- and HCO3- into airways

CFTR also functions as a negative-regulator of the amiloride-sensitive epithelial Na+ channel (ENaC) that is responsible for moving Na+ out of airways.

Question 2

Drugs for CF?

Answer 2

• Ivacaftor

- Orkambi

Question 3

Ivacaftor is approved to treat which CF patients?

Answer 3

G551D patients only

Question 4

How does Ivacaftor work?

Answer 4

Improving chloride transport through the

mutated channels.

Question 5

How is Ivacaftor metabolized?

Answer 5

In the liver by CYP3A4/5 and is itself an inhibitor of CYP3A and P-gp (drug-drug interactions).

Question 6

AEs of Ivacaftor?

Answer 6

• URT symptomatology (infections)
• GI pain and rash
• oropharyngeal pain

Question 7

How does Orkambi work?

Answer 7

This combination product adds a conformation stabilizer drug to the action of ivacaftor. Thus,
the combined agent both improves delivery of more fully functional protein to the apical surface of the cell and also potentiates the effect of the protein produced.

Question 8

How is Lumacaftor metabolized?

Answer 8

Minimally metabolized but does function as a strong inducer of CYP3A4.

Question 9

Other drugs for CF?

Answer 9

-mucolytics (Dornase Alfa)

Question 10

How does Dornase Alfa work?

Answer 10

A recombinant human (rh)DNAase taken
by nebulizer, this drug cleaves and depolymerizes extracellular DNA, separating DNA from
proteins and thus facilitating proteolytic enzyme activity.

Question 11

Net effect of Dornase Alfa?

Answer 11

The net result is a substantial

reduction in the viscoelasticity and surface tension of the purulent sputum.