Therapeutic challenges posed by critical drug–drug interactions in cystic fibrosis

Abstract

This review seeks to re-introduce cystic fibrosis (CF) clinicians to the pharmacology of drug-drug interactions among medications commonly used in CF and provide a framework for understanding these interactions among medications outside the scope of this discussion. We here focus on drugs impacted by the cytochrome P-450 (CYP450) enzyme system and on interactions involving antimicrobials, psychotropic medications, and cystic fibrosis transmembrane conductance regulator (CFTR) modulators. Particular attention is needed when prescribing rifampin, azole antifungals and the CFTR modulators, ivacaftor, and lumacaftor/ivacaftor, in combination with other medications. The complexities of these interactions provide a strong rationale for case management by pharmacists and pharmacologists as a routine part of CF care. Pediatr Pulmonol. 2016;51:S61-S70. © 2016 Wiley Periodicals, Inc.

Lumacaftor/ivacaftor initiation in two liver transplantation patients under tacrolimus and antifungal azoles

“…On one hand, antifungal azoles are inhibitors of CYP3A4, 2C9, and 2C19 and are responsible for an increase in TCS blood levels . On the other hand, LUM/IVA is a strong inducer of CYP3A4 and therefore decreases blood levels of other CYP3A4 substrates such as VCZ and PCZ . The LUM/IVA induction effect was much steeper on both VCZ and PCZ than on TCS.…”

“…Finally, the concomitant use of azoles in our cases can be seen as beneficial because it likely participated in maintaining adequate TCS levels. However, whenever possible, we would advise withdrawing azoles before LUM/IVA initiation, or using azoles not metabolized through CYP3A4 such as itraconazole …”

“…However, it is not recommended for patients receiving tacrolimus (TCS) for solid organ transplantation because of the drug‐drug interaction . As a cytochrome P450/3A4 (CYP3A4) inducer, LUM/IVA decreases blood levels of the molecules that are substrates of CYP3A4 such as TCS …”

Personalized or Precision Medicine? The Example of Cystic Fibrosis

“…It must be considered that various drugs interact with one another and with the body, and that we must seek the best way to achieve the balance between the individual and a good response to the treatment, maintaining and/or improving the quality and expectation of life (Jordan et al, 2016). …”

Impact of a cystic fibrosis transmembrane conductance regulator (CFTR) modulator on high‐dose ibuprofen therapy in pediatric cystic fibrosis patients

“…This interaction is also proposed in a recent article discussing therapeutic implications of drug-drug interactions in CF. 5 As mentioned in the prescribing information, data exist suggesting both induction and inhibition of enzymes; therefore, our study focused solely on the effect of lumacaftor/ivacaftor on the CYP450 substrate, ibuprofen. 4 However, to our knowledge, this is one of the first published case series reporting on clinical data of an interaction between ibuprofen and lumacaftor/ivacaftor.…”