CFTR Modulator Interactions
The interaction of CFTR modulators on the metabolism of other drugs such
as tobramycin is a salient point to consider, given the progressive
nature of CF pulmonary disease and the likely need for IV antibiotic
treatment for PEx despite having access to a CFTR modulator.Albricht JC et al reported a retrospective evaluation of 34
patients on modulator therapy (iva, lum/iva, tez/iva) to evaluate for
alterations in tobramycin pharmacokinetics and
nephrotoxicity50. Data obtained during inpatient
admission both prior to modulator use and at least 2 weeks post
modulator use, was assessed for patients 2-18 years of age. The median
values did not differ for pre/post CFTR modulator elimination rate (Ke)
(0.41hr-1 versus 0.39hr-1, p=0.5),
volume of distribution (Vd) (0.33L/kg versus 0.34L/kg, p=0.99), or peak
tobramycin concentration (Cmax) (28.9mcg/mL versus 27.2mcg/mL, p=0.22).
Nephrotoxicity (measured by the pRIFLE criteria, an increase in serum
creatinine by ≥50% from baseline) was present in 9 (26.5%) of patients
pre CFTR modulator and 6 (17.6%) of patients post modulator (p=0.25,
NS). Thus, CFTR modulators did not seem to affect the elimination rate
for IV administered tobramycin, and no increased nephrotoxicity was
seen.
Tobacco smoke exposure has negative effects on pulmonary function, and
tobacco smoke avoidance is advised in all patients with CF. The effect
of tobacco smoke on lung function improvement seen with CFTR modulators
is unknown. In a retrospective analysis of the CFF Registry from
2016-2018, a comparison between pediatric patients who were exposed to
tobacco smoke compared to unexposed individuals evaluated difference in
FEV1pp after initiation of tez/iva51. At baseline,
smoke exposed tez/iva treated patients had a 7.6% lower mean FEV1pp
compared to smoke unexposed tez/iva treated patients. At 2 years of
tez/iva treatment, the FEV1pp of smoke exposed patients was 8.8% lower
than smoke unexposed patients. In those not exposed to tobacco smoke,
with tez/iva FEV1pp increased by 1.2% (87%, 95%CI 86.3%-87.7%
versus 85.8%, 95%CI 85.2%-86.3% at baseline). This was definitely a
minimal increase, which is slightly lower compared to other studies with
tez/iva. However, among patients exposed to tobacco smoke, those treated
with tez/iva did not have improved FEV1pp compared to those who did not
receive tez/iva (82.9%, 95%CI 81.8%-83.9% versus 82.5%, CI
81%-83.2%). Therefore, tobacco smoke eliminated the small improvement
in FEV1pp seen with tez/iva treatment. The effect of tobacco smoke on
the improvements in lung function seen with the highly effective
modulator, ETI has not yet been studied, but would be interesting to
explore to see if smoke exposure attenuates the significant benefits
seen in FEV1pp with ETI.