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.