Cystic Fibrosis Pharmacology

Which medications are CFTR modulators?

ivacaftor, lumacaftor, tezacaftor, elexacaftor, deutivacaftor, vanzacaftor

What medications are mucociliary clearance agents/bronchodilators used in CF?

dornase alfa, hypertonic saline, mannitol (inhaled), and albuterol

What medications are used as anti-inflammatory agents in CF?

azithromycin, ibuprofen (high-dose)

What antibiotics are used in CF management?

inhaled antibiotics, systemic antibiotics

What are the pros of inhaled medications in cystic fibrosis?

direct delivery of medication to target site provides for high concentrations in the lung and rapid onset of effect with minimal systemic exposure

What are the cons of using inhaled medications in cystic fibrosis?

variable lung deposition due to airway obstruction

What is the brand name of ivacaftor?

Kalydeco

What is the indication for ivacaftor?

age ≥ 1 month with ≥ 1 ivacaftor- responsive mutation (typically classes III and IV)

What is the brand name of lumacaftor/ivacaftor?

Orkambi

What is the indication of lumacaftor/ivacaftor?

age ≥1 year with 2 copies of the F508del mutation (homozygous)

What is the brand name of tezacaftor/ivacaftor?

Symdeko

What is the indication of tezacaftor/ivacaftor

age ≥ 6 years with 2 copies of the F508del mutation or ≥ 1 TEZ/IVA responsive mutation

What is the brand name of elexacaftor/tezacaftor/ ivacaftor?

Trikafta

What is the indication of elexacaftor/ tezacafotr/ ivacaftor?

age ≥ 2 years with ≥1 copy of F508del mutation or ≥ ELE/TEZ/IVA responsive mutation

What is the brand name of vanzacaftor/ tezacaftor/ deutivacaftor?

Alyftrek

What is the indication of vanzacaftor/ tezacaftor/ deutivactor?

age ≥6 years with ≥1 copy of F508del mutation or ≥1 VAN/TEZ/DIVA responsive mutation

What is the MOA of ivacaftor and deutivacaftor?

potentiators; potentiates channel opening probability (gating) of the CFTR protein at the cell surface; decrease in sweat chloride

Which CFTR modulators are potentiators?

ivacaftor and deutivacaftor

Which CFTR modulators are correctors?

lumacaftor, tezacaftor, elexacaftor, and vanzacaftor

What is the MOA of corrector CFTR modulators?

facilitates processing and trafficking of select mutant forms of CFTR, increasing amount of CFTR protein delivered to the cell surface; decrease in sweat chloride

What effect does a potentiator + corrector cause?

synergistic effect

What effect does a corrector + corrector cause?

additive effect

What is the MOA of a corrector + potentiator drug?

increases amount of CFTR protein delivered to the cell surface, AND increases channel opening, increasing chloride transfer

True or False: all CFTR modulators are oral medications

true

What is the distribution of CFTR modulators?

99% protein bound

Which CFTR modulator is the only one that AUC is similar irrespective of fed state?

tezacaftor

How are CFTR modulators primarily eliminated?

via feces

Which CFTR modulator has the longest half-life?

vamzacaftor

How are CFTR modulators metabolized?

extensively via CYP3A4/5 (except lumacaftor)

What metabolism does lumacaftor go through?

oxidation and gluronidation

Which medication requires dose adjustment for mild hepatic impairment?

Kalydeco

Which CFTR modulators should be avoided in severe hepatic impairment?

Trikafta and Alyftrek

What CFTR modulator is a strong CYP3A4 inducer?

lumacaftor

What CFTR modulator is an inhibitor of CYP3A4, CYP2C8/9, and p-glycoprotein?

ivacaftor

What DDIs does vanzacaftor and tezacaftor have?

inhibits p-glycoprotein

What medications are examples of moderate CYP3A4 inhibitors?

fluconazole, erythromycin, and grapefruit juice

What medications are examples of strong CYP3A4 inhibitors?

ketoconazole, itraconazole, posaconazole, voriconazole, telithromycin, clarithromycin

What medications are examples of CYP3A4 inducers?

rifampin, rifabutin, phenobarbital, carbamazepine, phenytoin, st. john’s wort

What other drugs does ivacaftor and deutivacaftor interact with?

warfarin, midazolam, digoxin, tacrolimus, cyclosporin

What other drugs does tezacaftor and vanzacaftor interact with?

digoxin, tacrolimus, cyclosporine

What other drugs does elexacaftor interact with?

statins, glyburide, meglitinides

What other drugs does lumacaftor interact with?

hormonal contraceptives, tacrolimus, cyclosporine, some macrolides and azoles

What precautions do CFTR modulators have?

moderate- severe liver disease

What contraindication does Alyftrek have?

moderate-severe liver disease

What contraindication does Trikafta have?

severe liver disease

What are serious ADRs of CFTR modulators?

elevated transaminases (AST/A:T) and bilirubin; possible risk for cataracts; hypersensitivity reactions; rash (female>males)

What should be monitored when on a CFTR modulator?

AS, ALT, bilirubin at baseline, every month for the first 6 months, every 3 months for the next 12 months, and annually thereafter; ophthalmological exams at baseline and during treatment

What is the MOA of dornase alfa?

cleaves neutrophil-derived DNA, which reduces sputum viscoelasticity, aiding its clearance

What is the MOA of hypertonic saline?

provides for high concentrations of sodium chloride in the airway which encourages osmosis of water into the ASL, which rehydrates the mucus and reduces its viscosity, aiding its clearance

What is the MOA of inhaled mannitol?

the sugar alcohol is thought to act as an osmotic agent; this facilitates movement of water into the lumen of the airways which rehydrates the mucus and reduces its viscosity, aiding its clearance

What is the brand name of dornase alfa?

Pulmozyme

What is the brand name of inhaled mannitol?

Bronchitol

Which of the mucociliary clearance agents are a dry powder?

inhaled mannitol

What precautions does inhaled mannitol have?

failure to pass the Bronchitol Tolerance Test

What is an ADR of dornase alfa?

voice alteration

What is an ADR of hypertonic saline?

bronchospasm

What are the ADRs of inhaled mannitol?

bronchospasm, hemoptysis

What is the MOA of azithromycin in CF?

precise mechanism unknown; likely involves multiple pathways, including inhibition of pseudomonas aeruginosa virulence

What is the MOA of high dose ibuprofen in CF?

inhibition of the lipoxygenase pathway, leukotriene B4 production is mitigates and neutrophil migration and function are impaired; anti-inflammatory effect occurs when peak plasma concentration is >50 mcg/mL

True or False: concentrations of ibuprofen <50 results in a paradoxical increase in inflammation, possibly due to shunting form the cyclooxygenase to the lipoxygenase pathway

true

What is the indication for azithromycin in CF?

age ≥ 6 month with pseudomonas aeruginosa

What is the indication for ibuprofen high dose in CF?

age ≥ 6 years old

What are the precautions related to azithromycin in CF?

colonization with NTM

What are the ADRs of azithromycin?

nausea, diarrhea, wheezing

What are the precautions of ibuprofen?

history of gastric ulcers, renal impairment

What are the ADRs related to ibuprofen?

gastric ulceration, nephrotoxicity

What is the brand name of tobramycin DPI?

TOBI Podhaler

What is the brand name of tobramycin solution?

TOBI

What is the brand name of amikacin solution?

Arikayce

What is the brand name of aztreonam solution?

Cayston

What is the indication of tobramycin in CF?

age ≥ 6 years with pseudomonas

What is the indication for amikacin in CF?

age ≥18 years w/ MAC

What is the indication for aztreonam in CF?

age ≥ 7 years with pseudomonas

What are the ADRs for tobramycin and amikacin?

bronchospasm, cough, dysphonia

What is the ADR associated with aztreonam?

bronchospasm

What systemic ADRs does tobramycin and amikacin have?

ototoxicity (tinnitus and hearing loss)

Do you remember your antibiotic coverages?

hellllllll (no) yeah

What clinically important systemic ADRs do pencillins, cephalosporins, aztreonam, and carbapenems have?

hypersensitivity, GI ADRs

What clinically important systemic ADRs do vancomycin and aminoglycosides have?

nephrotoxicity, ototoxicity

What clinically important systemic ADRs does FQs have?

tendonitis

What clinically important systemic ADRs does SMX-TMP have?

rash

What clinically important systemic ADRs does linezolid have?

leukopenia

What PD parameter should be optimized for penicillins, cephalosporins, and carbapenems?

Time > MIC

What PD parameter should be optimized for vancomycin and FQs?

AUC:MIC

What PD parameter should be optimized for aminoglycosides?

Peak: MIC, AUC:MIC

What is the goal peak of tobramycin in traditional dosing?

10-12

What is the goal peak of tobramycin in extended interval dosing?

20-30

What is the goal trough of tobramycin in traditional dsoing?

<1

What is the goal trough of tobramycin in extended interval dosing?

0

What is the goal 18-hour level of tobramycin in extended interval dosing?

<1

What is the goal through of vancomycin?

10-15

What is the goal AUC:MIC ratio of vancomcyin?

400