Rationale: We previously reported that ivacaftor was safe and well tolerated in cohorts aged 12 to <24 months with cystic fibrosis and gating mutations in the ARRIVAL study; here, we report results for cohorts aged 4 to <12 months. Objectives: To evaluate the safety, pharmacokinetics, and pharmacodynamics of ivacaftor in infants aged 4 to <12 months with one or more gating mutations. Methods: ARRIVAL is a single-arm phase 3 study. Infants received 25 mg or 50 mg ivacaftor every 12 hours on the basis of age and weight for 4 days in part A and 24 weeks in part B. Measurements and Main Results: Primary endpoints were safety (parts A and B) and pharmacokinetics (part A). Secondary/tertiary endpoints (part B) included pharmacokinetics and changes in sweat chloride levels, growth, and markers of pancreatic function. Twenty-five infants received ivacaftor, 12 in part A and 17 in part B (four infants participated in both parts). Pharmacokinetics was consistent with that in older groups. Most adverse events were mild or moderate. In part B, cough was the most common adverse event ( n = 10 [58.8%]). Five infants (part A, n = 1 [8.3%]; part B, n = 4 [23.5%]) had serious adverse events, all of which were considered to be not or unlikely related to ivacaftor. No deaths or treatment discontinuations occurred. One infant (5.9%) experienced an alanine transaminase elevation >3 to ≤5× the upper limit of normal at Week 24. No other adverse trends in laboratory tests, vital signs, or ECG parameters were reported. Sweat chloride concentrations and measures of pancreatic obstruction improved. Conclusions: This study of ivacaftor in the first year of life supports treating the underlying cause of cystic fibrosis in children aged ≥4 months with one or more gating mutations. Clinical trial registered with clinicaltrials.gov (NCT02725567).

Background: The CFTR modulator tezacaftor/ivacaftor was efficacious and generally safe and well tolerated in Phase 3 studies in participants ≥12 years of age with cystic fibrosis (CF) homozygous for the F508del-CFTR mutation or heterozygous with a residual function-CFTR mutation (F/F or F /RF respectively). We evaluated tezacaftor/ivacaftor's efficacy and safety over 8 weeks in participants 6 through 11 years of age with these mutations. Methods: Participants were randomized 4:1 to tezacaftor/ivacaftor or a blinding group (placebo for F/F , ivacaftor for F /RF). The primary endpoint was within-group change from baseline in the lung clearance index 2 •5 (LCI 2 •5) through Week 8. Secondary endpoints were change from baseline in sweat chloride (SwCl), cystic fibrosis questionnaire-revised (CFQ-R) respiratory domain score, and safety. Results: Sixty-seven participants received at least one study drug dose. Of those, 54 received tezacaftor/ivacaftor (F/F , 42; F /RF, 12), 10 placebo, and 3 ivacaftor; 66 completed the study. The within-group change in LCI 2 •5 was significantly reduced (improved) by −0 •51 (95% CI: −0 •74, −0 •29). SwCl concentration decreased (improved) by −12 •3 mmol/L and CFQ-R respiratory domain score increased (improved, nonsignificantly) by 2 •3 points. There were no serious adverse events (AEs) or AEs leading to tezacaftor/ivacaftor discontinuation or interruption. The most common AEs (≥10%) in participants receiving tezacaftor/ivacaftor were cough, headache, and productive cough. Conclusions: Tezacaftor/ivacaftor improved lung function (assessed using LCI) and CFTR function (measured by SwCl concentration) in participants 6 through 11 years of age with F/F or F /RF genotypes. Tezacaftor/ivacaftor was safe and well tolerated; no new safety concerns were identified.

Ivacaftor, a CFTR potentiator that enhances chloride transport by acting directly on CFTR to increase its channel gating activity, has been evaluated in patients with different CFTR mutations. Several previous analyses have reported no statistical correlation between change from baseline in ppFEV and reduction in sweat chloride levels for individuals treated with ivacaftor. The objective of the post hoc analysis described here was to expand upon previous analyses and evaluate the correlation between sweat chloride levels and absolute ppFEV changes across multiple cohorts of patients with different CF-causing mutations who were treated with ivacaftor. The goal of the analysis was to help define the potential value of sweat chloride as a pharmacodynamic biomarker for use in CFTR modulator trials. For any given study, reductions in sweat chloride levels and improvements in absolute ppFEV were not correlated for individual patients. However, when the data from all studies were combined, a statistically significant correlation between sweat chloride levels and ppFEV changes was observed (p<0.0001). Thus, sweat chloride level changes in response to potentiation of the CFTR protein by ivacaftor appear to be a predictive pharmacodynamic biomarker of lung function changes on a population basis but are unsuitable for the prediction of treatment benefits for individuals.

MK-7246, an antagonist of the chemoattractant receptor on T helper type 2 (Th2) cells, is being developed for the treatment of respiratory diseases. In a first-in-human study, we investigated whether genetic polymorphisms contributed to the marked intersubject variability in the pharmacokinetics of MK-7246 and its glucuronide metabolite M3. Results from in vitro enzyme kinetic studies suggested that UGT2B17 is probably the major enzyme responsible for MK-7246 metabolism in both the liver and the intestine. As compared with those with the UGT2B17*1/*1 wild-type genotype, UGT2B17*2/*2 carriers, who possess no UGT2B17 protein, had 25- and 82-fold greater mean dose-normalized values of area under the plasma concentration–time curve (AUC) and peak concentration of MK-7246, respectively, and a 24-fold lower M3-to-MK-7246 AUC ratio. The apparent half-life of MK-7246 was not as variable between these two genotypes. Therefore, the highly variable pharmacokinetics of MK-7246 is attributable primarily to the impact of UGT2B17 genetic polymorphisms and extensive first-pass metabolism of MK-7246.

Introduction: The triple-combination (TC) cystic fibrosis transmembrane conductance regulator (CFTR) modulator regimen elexacaftor, tezacaftor, and ivacaftor was shown to be safe and efficacious in phase 3 trials of people with cystic fibrosis (pwCF) C 12 years of age with C 1 F508del-CFTR allele. Here, a simulation study predicted ivacaftor, tezacaftor, and elexacaftor exposures and impacts on CFTR modulation following transition from ivacaftor [a cytochrome P450 3A (CYP3A) substrate], lumacaftor (a CYP3A inducer)/ivacaftor, or tezacaftor/ivacaftor to TC. Methods: Physiologically based pharmacokinetic (PBPK) modeling was used to evaluate plasma exposures during transition from monoor dual-combination CFTR modulator regimens to TC. PBPK models were parameterized using data from human hepatocytes to account for CYP3A induction by lumacaftor and validated to match clinical data from healthy volunteers and pwCF. Using dosing regimens for pwCF C 12 years of age, simulations were performed for ivacaftor, lumacaftor/ivacaftor, and tezacaftor/ivacaftor dosing for 14 days followed by immediate transition to elexacaftor/tezacaftor/ivacaftor dosing for 14 days. Drug exposures during transitions were compared with respective half-maximal effective concentrations (EC 50) estimated from efficacy endpoint data from clinical studies. Results: In simulations of immediate transition from ivacaftor or tezacaftor/ivacaftor to TC, the preceding treatment had no impact on ivacaftor, tezacaftor, or elexacaftor exposures. In simulations of immediate transition from lumacaftor/ivacaftor to TC, ivacaftor exposure decreased to 64% of maximum effective concentration (EC), due to reduction in ivacaftor dose and residual CYP3A4 induction, then returned to 90-95% of maximum EC. Lumacaftor-mediated CYP3A induction resolved within approximately 2 weeks. In all simulations, ivacaftor, tezacaftor, and elexacaftor exposures approached steady state within 2 weeks following transition and, at all times, ivacaftor and C 1 CFTR corrector remained above EC 50. Conclusion: PBPK modeling indicates that immediate transition to the elexacaftor/tezacaftor/ivacaftor regimen from an ivacaftor, lumacaftor/ivacaftor, or tezacaftor/ivacaftor Digital Features To view digital features for this article go to

No abstract

Background Some drugs that are actively taken up into the liver exhibit greater than dose proportional increases in plasma exposure, although human liver-to-plasma concentration ratios have rarely been evaluated. Understanding these relationships has implications for drug concentrations at the target site for certain classes of compounds, such as direct-acting antivirals, targeted towards HCV. Methods Treatment-experienced, chronic HCV non-cirrhotic patients (n=3) received vaniprevir (600 mg or 300 mg twice daily) on days 1–3 and (600 mg or 300 mg single dose) on day 4. Core needle biopsy was performed at 6 or 12 h post-dose on day 4. Blood samples were collected pre-dose on days 1 and 4, and for 24 h post-dose on day 4. The primary study objective was the hepatic concentration of vaniprevir at 6 and 12 h post-dose. Results Vaniprevir plasma pharmacokinetic parameters increased in a greater than dose-proportional manner between the 300 mg and 600 mg doses, with approximately fivefold increases in AUC0–12 and Cmax associated with a twofold increase in dose (AUC0–12, 10.6 µM/h to 59.5 µM/h; Cmax, 2.60 µM to 13.5 µM). In the 300 mg and 600 mg dose groups, mean liver concentrations of vaniprevir were 84.6 µM and 169 µM at 6 h post-dose, and 29.4 µM and 53.7 µM at 12 h post-dose. Liver concentrations were higher than plasma with liver-to-plasma concentration ratios of approximately 20–280. Conclusions These data confirm higher vaniprevir concentrations in human liver compared with plasma and demonstrate that measurement of human liver drug concentration using needle biopsy is feasible.

No abstract