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Abstract

Advancements in Bioequivalence & Bioavailability

Comparative Bioavailability of a New Fixed Dose Combination Tablet Containing Lumacaftor/ Ivacaftor in Healthy Subjects: A Randomized, Single-Dose, 2-Way Crossover Study

Submission: August 23, 2019;Published: September 13, 2019

Volume2 Issue5
September, 2019

Abstract

Lumacaftor and ivacaftor, a CFTR modulator that comprises both a CFTR corrector and potentiator, is indicated as a fixed dose combination tablet for the treatment of cystic fibrosis in patients ≥12 years old with homozygous F508del-CFTR. The CFTR is a protein chloride channel responsible for the regulation of salt and water absorption and secretion. The purpose of this study was to compare rate and extent of absorption and to evaluate the bioequivalence between a new pharmaceutical equivalent film-coated tablet formulation containing a fixed-dose combination of lumacaftor/ivacaftor 200/125mg and the innovator product.

A single-center, open-label, randomized-sequence, single-dose, two-way, crossover bioequivalence study in 42 healthy adult subjects was performed. A wash-out period of 14 days separated dosing formulations. All subjects signed an informed consent form. Healthy male and female volunteers (non-pregnant and non-lactating) between 21-55 years with a Body Mass Index of 19-27kg/m2 were enrolled. Blood samples were collected in vacutainers containing EDTA over 72 hours.

Plasma levels of both lumacaftor and ivacaftor were measured by a validated HPLC/MS-MS method. No difference was found regarding rate and extend of absorption between products. The 90% confidence interval (CI) of the ratio of the geometric means for log-transformed Cmax, AUC0-last and AUC0-inf variables were used to determine bioequivalence between the two products using the equivalence range of 80 and 125%. Adverse events were recorded from the screening to the follow-up visit. Rate and extent of absorption were equitable between products. The point estimate and 90%CI of the ratios of Cmax, AUC0-last and AUC0-inf values for lumacaftor were 0.88(0.82-0.94), 0.92(0.86-0.99) and 0.90(0.82-0.97), respectively and for ivacaftor were 0.93(0.83-1.03), 0.96(0.87-1.05) and 0.95(0.87-1.03), respectively. Both treatments showed alike tolerability and safety. The new pharmaceutical formulation resulted bioequivalent to the innovators thus concluding that both products are therapeutically equivalent and interchangeable.

Keywords: Pharmacokinetics; Lumacaftor/ivacaftor; Fixed-dose combination; Bioequivalence; Healthy subjects

Abbreviations

AE: Adverse Event; ASD: Amorphous Solid Dispersion; AUC: Area Under the Curve; BCS: Biopharmaceutical Class System; BMI: Body Mass Index; CF: Cystic Fibrosis; CFTR: CF Transmembrane Conductance Regulator; CTAB: Hexadecyltrimethylamonium Bromide; CV: Coefficient of Variation; Cmax : Maximum Concentration; FDC: Fixed-Dose Combination; FEV: Forced Respiratory Volume; FDA: Food and Drug Administration; FSH: Follicle-Stimulating Hormone; HBE: Human Bronchial Epithelial; HPMCAS: Hydroxypropyl Methylcellulose Acetate Succinate; IFC: Informed Consent Form; IVA: Ivacaftor; LUM: Lumacaftor; MOH: Ministry Of Health; PK: Pharmacokinetics; Tmax: Time To Reach The Cmax.

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