PMID- 32457106 OWN - NLM STAT- MEDLINE DCOM- 20210617 LR - 20210617 IS - 1098-6596 (Electronic) IS - 0066-4804 (Print) IS - 0066-4804 (Linking) VI - 64 IP - 8 DP - 2020 Jul 22 TI - 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. LID - 10.1128/AAC.00400-20 [doi] LID - e00400-20 AB - 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 (C(max_ss)), the minimum drug level after administration prior to the subsequent dose (C(trough)), and the area under the curve over the dosing interval (AUC(tau)) 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 C(max_ss), C(trough), and AUC(tau), 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 C(trough) 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. CI - Copyright (c) 2020 Thompson et al. FAU - Thompson, George R 3rd AU - Thompson GR 3rd AD - UC Davis School of Medicine, Department of Internal Medicine, Division of Infectious Diseases, Sacramento, California, USA. AD - UC Davis School of Medicine, Department of Medical Microbiology and Immunology, Sacramento, California, USA. FAU - Lewis, Phoebe AU - Lewis P AD - Department of Medical Affairs, Mayne Pharma, Inc., Raleigh, North Carolina, USA. FAU - Mudge, Stuart AU - Mudge S AD - Department of Medical Affairs, Mayne Pharma, LLC, Melbourne, Australia. FAU - Patterson, Thomas F AU - Patterson TF AD - University of Texas Health Science Center, Division of Infectious Diseases, San Antonio, Texas, USA. AD - South Texas Veterans Health Care System, San Antonio, Texas, USA. FAU - Burnett, Bruce P AU - Burnett BP AD - Department of Medical Affairs, Mayne Pharma, Inc., Raleigh, North Carolina, USA bruce.burnett@maynepharma.com. LA - eng SI - ClinicalTrials.gov/NCT03572049 PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20200722 PL - United States TA - Antimicrob Agents Chemother JT - Antimicrobial agents and chemotherapy JID - 0315061 RN - 0 (Capsules) RN - 304NUG5GF4 (Itraconazole) SB - IM MH - Administration, Oral MH - Adult MH - Area Under Curve MH - Biological Availability MH - Capsules MH - Cross-Over Studies MH - Humans MH - *Itraconazole MH - Therapeutic Equivalency PMC - PMC7526808 OTO - NOTNLM OT - absorption OT - antifungal agents OT - bioequivalence OT - itraconazole OT - pharmacokinetics EDAT- 2020/05/28 06:00 MHDA- 2021/06/22 06:00 PMCR- 2020/07/22 CRDT- 2020/05/28 06:00 PHST- 2020/03/02 00:00 [received] PHST- 2020/05/14 00:00 [accepted] PHST- 2020/05/28 06:00 [pubmed] PHST- 2021/06/22 06:00 [medline] PHST- 2020/05/28 06:00 [entrez] PHST- 2020/07/22 00:00 [pmc-release] AID - AAC.00400-20 [pii] AID - 00400-20 [pii] AID - 10.1128/AAC.00400-20 [doi] PST - epublish SO - Antimicrob Agents Chemother. 2020 Jul 22;64(8):e00400-20. doi: 10.1128/AAC.00400-20. Print 2020 Jul 22.