Open-Label Crossover Oral Bioequivalence Pharmacokinetics Comparison for a 3-Day Loading Dose Regimen and 15-Day Steady-State Administration of SUBA-Itraconazole and Conventional Itraconazole Capsules in Healthy Adults

Abstract

Super bioavailability (SUBA) itraconazole (S-ITZ), which releases drug in the duodenum, and conventional itraconazole (C-ITZ), which releases drug in the stomach, were compared in two pharmacokinetic (PK) studies: a 3-day loading dose study and a 15-day steady-state administration study. These were crossover oral bioequivalence studies performed under fed conditions in healthy adult volunteers. In the loading dose study, C-ITZ (two doses of 100 mg each) and S-ITZ (two doses of 65 mg each) were administered three times daily for 3 days and once on day 4 (n = 15). For the steady-state administration study, C-ITZ (two doses of 100 mg each) and S-ITZ (two doses of 65 mg each) were administered twice daily for 14 days and a last dose was administered 30 min after a meal on day 15 (n = 16). Blood samples collected throughout both studies were analyzed for ITZ and hydroxy-ITZ (OH-ITZ) levels. Least-squares geometric means were used to compare the maximum peak concentration of drug after administration at steady state prior to administration of the subsequent dose (Cmax_ss), the minimum drug level after administration prior to the subsequent dose (Ctrough), and the area under the curve over the dosing interval (AUCtau) of each formulation. The ratios of itraconazole (ITZ) and OH-ITZ for S-ITZ to C-ITZ were between 107% and 118% in both studies for Cmax_ss, Ctrough, and AUCtau, which were within the U.S. FDA-required bioequivalence range of 80% to 125%. At the end of the steady-state administration study, 13 of 16 volunteers obtained higher mean ITZ blood Ctrough levels of >1,000 ng/ml when they were administered S-ITZ (81%) than when they were administered C-ITZ (44%). The study drugs were well tolerated in both studies, with similar adverse events (AEs). All treatment-emergent AEs resolved after study completion. One volunteer receiving C-ITZ discontinued due to a treatment-unrelated AE in the steady-state administration study. No serious AEs were reported. Total, trough, and peak ITZ and OH-ITZ exposures were similar between the two formulations. Therefore, SUBA-ITZ, which has 35% less drug than C-ITZ, was bioequivalent to C-ITZ in healthy adult volunteers and exhibited a safety profile similar to that of C-ITZ.

Trial registration: ClinicalTrials.gov NCT03572049.

Keywords: absorption; antifungal agents; bioequivalence; itraconazole; pharmacokinetics.

Copyright © 2020 Thompson et al.

Figures

FIG 1

Day 1 to day 15 plasma levels of itraconazole (A) and hydroxyitraconazole (B) for the SUBA-itraconazole (solid line) and conventional itraconazole (dashed line) formulations.

FIG 2

Fifteen-day steady-state patient-level data for the geometric mean Ctrough values for conventional itraconazole (CI) and SUBA-itraconazole (SI). The dotted line represents the geometric mean of the conventional itraconazole plasma trough level (1,034 ng/ml).

FIG 3

Fifteen-day steady-state patient-level crossover PK data for the geometric mean plasma AUCtau (left), Ctrough (middle), and Cmax_ss (right) values for itraconazole achieved with the conventional itraconazole (C-ITZ) and SUBA-itraconazole (S-ITZ) formulations. Data are represented as whisker plots for both each group and the individual volunteer response (lines).

FIG 4

Three-day steady-state patient-level crossover PK data for the geometric mean plasma AUCtau (left), Ctrough (middle), and Cmax_ss (right) values for the conventional itraconazole (C-ITZ) and SUBA-itraconazole (S-ITZ) formulations. Data are represented as whisker plots for both each group and the individual volunteer response (lines).