Comparative Bioavailability Study of Elexacaftor/Tezacaftor/Ivacaftor Formulations in Children with Cystic Fibrosis

Abstract

Introduction: The cystic fibrosis transmembrane conductance regulator (CFTR) protein modulators Elexacaftor (Ele)/Tezacaftor (Tez)/Ivacaftor (Iva) - ETI - significantly improved treatment outcomes.

Objective: To evaluate the bioavailability of ETI Trixacar® (MA) compared to reference data from the original Trikafta® (MB), and assess systemic exposure of active metabolites M23-Ele and M1-Tez in pediatric CF patients.

Materials and Methods: Prospective-observational clinical study (Exploratory phase) in CF patients (12-18 years) at a tertiary pediatric hospital (approved by Institutional Review Board). Pharmacokinetic (PK) parameters evaluated: area under the curve (AUC), maximum plasma concentration (Cmax), and time to Cmax (Tmax). Blood samples collected at 0, 2, 4, 5, 6, 7, and 8h, with plasma concentrations quantified by ultra-high-performance liquid chromatography. Reference values: Ele AUC 162(±48) mcg·h/mL, Cmax 8.7±2.1 mcg/mL, Tmax 6(4-12) h; Tez AUC 95±24 mcg·h/mL, Cmax 6.8±1.5 mcg/mL, Tmax 3(2-4) h; Iva AUC 12±4 mcg·h/mL, Cmax 1.2±0.3 mcg/mL, Tmax 4 h.

Results: Ten patients enrolled; age: 15 (13-18) years; weight: 52 (35-61) kg; females n=6. 90%CI for MA AUC: 48-199 mcg·h/mL (Ele), 54-109 mcg·h/mL (Tez), 14-24 mcg·h/mL (Iva). Cmax (90%CI) and Tmax were: 3.4-10.3 mcg/mL and 5 (0-8) h (Ele); 5.29-8.16 mcg/mL and 2 (2-7) h (Tez); 1.74-2.77 mcg/mL and 2 (2-7) h (Iva). For Ele-M23 and Tez-M1, AUC values were 82±40 mcg·h/mL and 162±37 mcg·h/mL, respectively.

Conclusion: MA showed PK parameters comparable to MB, with potential pharmacological contributions from both metabolites. MB's mean AUC and Cmax values fell within MA's 90%CI; mean Cmax, Tmax and AUC values were within 80-125% range. MA's Iva showed higher AUC and Cmax. MA may be considered a bioequivalent to MB in pediatric CF.