A-008. No Relevant Food Effect in Man on Isavuconazole Oral Pharmacokinetics Preliminary Data
Session: Poster Session: Antifungal Pharmacokinetics/Dynamics
Saturday, October 25, 2008: 12:00 AM
Room: Hall C
Background: Isavuconazole is an extended-spectrum azole administered orally or intravenously as a water-soluble pro-drug (WSA). Isavuconazole is currently under investigation in phase 3. The PK/PD drivers are AUC/MIC and trough/MIC for candida spp and aspergillus spp, respectively. Preclinical evidence suggested a negative food effect on the PK of isavuconazole when administered as WSA, therefore, we investigated the effect of food on the oral pharmacokinetics of isavuconazole in man. Methods: In an open-label, randomized, cross-over study, 26 healthy male subjects received orally 400 mg isavuconazole as WSA in the fed or fasted state. Serial blood samples for PK were collected up to 480 hours and analyzed by a specific LC-MS/MS method. PK parameters were derived using WinNonLin 5.0. The 90% confidence intervals of the geometric mean ratios were estimated. Results: Although a delayed Tmax and decreased Cmax of isavuconazole were observed in presence of food, there was no effect on the AUCs, T1/2 nor on the C24h-values. This indicates that in presence of food the rate of absorption was delayed but its extent was unaffected.
Tmax (h)Cmax (g/mL)AUClast (g.h/mL)T1/2 (h)AUC0-24h
(g.h/mL)
C24h (g/mL)
1Fasted n=253.0 (1.5-4.0)3.77 (0.889)183 (57.0)117 (48.6)37.8 (9.47)1.07 (0.309)
1Fed n=255.0 (4.0-12.0)3.46 (0.680)201 (58.0)115 (45.8)38.1 (8.37)1.18 (0.293)

2Geometric mean ratio

-1.090.911.001.000.92
90% CI-1.02-1.160.85-0.980.96-1.040.94-1.060.86-0.98

Arithmetic mean (± SD), except for Tmax presented as median and range 1One drop-out ,2fasted vs fed
Conclusions: The PK/PD drivers: trough levels and daily AUC, are unaffected by fasted or fed state. Therefore, the slightly delayed absorption in presence of food is considered not clinically relevant. By contrast to, other azoles exhibit a clinically relevant food effect.
Andy Schoetzau1, Anne-Hortense Schmitt-Hoffmann, PhD, PharmD2, Brigitte Roos3, Jochen Spickermann3, Markus Heep, MD, PhD4, Michael Roehrle5, Urs Simmens1 and  A. Schmitt-Hoffmann, None., (1)Schoetzau & Simmen, Statistical Consulting,, (2)Basilea Pharmaceutica, Basel, Switzerland, (3)Basilea Pharmaceutica, (4)Basilea AG, Basel, Switzerland, (5)AAIPharma Deutschland GmbH & Co. KG