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Page 1 BI Trial No.: 1314.7 2012-002538 36 1 of 5 Title of trial: Relative bioavailability of single oral dose of when administered alone or in combination with multiple oral doses of ketoconazole or voriconazole in healthy male subjects (an open-label, randomised, three-period cross-over trial) Principal Investigator: Trial site: Publication (reference): Clinical phase: Objectives: Methodology: Data of this trial have not been published. I The trial investigated the effects of multiple oral doses of ketoconazole or voriconazole on the single oral dose pharmacokinetics (PK) of ; the primary objective was to assess the relative bioavailability of. Randomised, open-label, 3-way crossover intra-individual comparison in healthy male volunteers, single-centre, Phase I No. of subjects: planned: entered: 18 actual: BI (reference): : entered: 20 treated: 18 analysed (for primary PK endpoint): 18 BI + K (test): plus ketoconazole: entered: 20 treated: 19 analysed (for primary PK endpoint): 18 BI + V (test): plus voriconazole: entered: 20 treated: 20 analysed (for primary PK endpoint): 18 Diagnosis and main criteria for inclusion: Healthy male volunteers in the age range of 18 years and 50 years and with a Body Mass Index (BMI) of 18.5 kg/m 2 and 29.9 kg/m 2 were included.
Page 2 BI Trial No.: 1314.7 2 of 5 Test products: doses: mode of admin.: batch nos.: Reference therapy: doses: mode of admin.: batch no.: BI + K: ketoconazole 200 mg tablets; film-coated tablet 25 mg BI + V: voriconazole 200 mg tablets; film-coated tablet 25 mg BI + K: ketoconazole 200 mg bid for 4 days: 25 mg single dose BI + V: voriconazole 400 mg bid loading dose for 1 day, then 200 mg bid for 3 days; 25 mg single dose Oral with 240 ml of water after an overnight fast of at least 10 hours Ketoconazole: 010412; voriconazole: not applicable; BI: B121001955 film-coated tablet 25 mg 25 mg Oral with 240 ml of water BI: B121001955 Duration of treatment: BI: (25 mg single dose) for 1 day (Day 1) BI + K: Ketoconazole (200 mg bid) for 4 days (Days -2, -1, 1, and 2) plus (25 mg single dose) for 1 day (Day 1) BI + V: Voriconazole (400 mg bid) for 1 day on Day -2 (loading dose) followed by voriconazole (200 mg bid) for 3 days (Days -1, 1, and 2) plus (25 mg single dose) for 1 day (Day 1) A wash-out period of at least 6 days was respected between the administrations of. Criteria for evaluation: Clinical pharmacology: Primary PK endpoints: AUC 0-tz and C max of Secondary PK endpoints: AUC 0-, t max, and t 1/2 of Other PK endpoints: %AUC tz-, λ z, AUC t1-t2, MRT po, CL/F, Vz/F, further PK parameters as appropriate Safety: All safety endpoints were defined as other endpoints. Safety measures primarily involved the monitoring of adverse events (AEs). Further safety assessments included safety laboratory tests, vital signs (blood pressure [BP], pulse rate [PR]), and 12-lead electrocardiograms (ECGs), as well as physical examinations.
Page 3 BI Trial No.: 1314.7 3 of 5 Statistical methods: SUMMARY CONCLUSIONS: Clinical pharmacology results: To estimate the relative bioavailability, the ratios of geometric means (gmeans) and their two-sided 90% confidence intervals (CIs) were calculated for primary and secondary PK endpoints regarding alone compared with ketoconazole plus and voriconazole plus. The statistical model was an ANOVA on the logarithmic scale including effects for sequence, subjects within sequences, period, and treatment. CIs were calculated based on the residual errors from ANOVA. Moreover, descriptive statistics were calculated for all endpoints. All 20 subjects enrolled were male and of White racial origin. Their mean age was 36.3 years (range: 23 to 50 years) and they had a mean BMI of 25.87 kg/m 2 (range: 20.9 to 29.0 kg/m 2 ). A total of 18 subjects completed the trial according to protocol, while 2 subjects were withdrawn due to major protocol violations (positive drug screens). Pharmacokinetics The plasma concentration-time profiles of were similarly shaped, whether given alone (BI) or in combination with ketoconazole (BI + K) or voriconazole (BI + V). The table below summarises the most relevant PK parameters of. PK parameters BI N=18 BI + K N=18 BI + V N=18 gmean (gcv%) gmean (gcv%) gmean (gcv%) AUC 0-tz [nmol h/l] 494 (36.7) 1840 (36.9) 1320 (51.4) C max [nmol/l] 102 (55.5) 267 (41.9) 218 (54.0) AUC 0- [nmol h/l] 496 (36.7) 1850 (36.9) 1320 (51.4) 1 t max [h] 1.0 (0.50 4.07) 1.25 (0.50 4.00) 1.5 (0.48 4.00) t 1/2 [h] 11.0 (28.0) 9.20 (18.3) 10.6 (18.8) 1 For t max the median and range (min - max) are given The time to maximum plasma concentration and the terminal half-life of were not relevantly affected by coadministration of ketoconazole or voriconazole.
Page 4 BI Trial No.: 1314.7 4 of 5 Clinical pharmacology results (continued): Safety results: Pharmacokinetics (continued) Coadministration of ketoconazole increased the relative bioavailability of by 374% (90% CI: 346.03, 403.51) based on AUC 0-tz, by 373% (90% CI: 345.46, 402.48) based on AUC 0-, and by 261% (90% CI: 211.69, 322.63) based on C max. Coadministration of voriconazole increased the relative bioavailability of by 267% based on AUC 0-tz (90% CI: 243.27, 292.91) and AUC 0- (90% CI: 242.96, 292.46) as well as by 213% (90% CI: 175.78, 259.05) based on C max. Adverse events The majority of all subjects (80.0%) developed at least one AE. All AEs were of mild to moderate intensity and had resolved at the end of the observation period. Following monotherapy, 16.7% of subjects developed at least one AE and 11.1% of subjects developed at least one drug-related AE. Coadministration with ketoconazole did not increase the incidences of AEs (16.7%) / drug-related AEs (5.6%) compared with given alone, while the combination with voriconazole led to a higher incidence of AEs (26.3%) / drug-related AEs (26.3%). Across all treatments, the incidences of AEs / drug-related AEs were highest during the ketoconazole and voriconazole induction periods prior to the dosing of (ketoconazole: 47.4% / 26.3%; voriconazole: 60.0% / 60.0%). The most frequent SOCs were eye disorders (total incidence 60.0%) followed by nervous system disorders (total incidence 45.0%). On the PT level, photopsia and headache were the most frequently reported AEs. Photopsia occurred only in subjects exposed to voriconazole (incidence 55.0% on voriconazole alone; 5.3% on plus voriconazole). Headache was most frequent during the ketoconazole (26.3%) and voriconazole (15.0%) induction periods compared with alone (5.6%) or in combination with ketoconazole (11.1%) or voriconazole (5.3%). Following monotherapy with, drug-related AEs were abdominal pain and headache in 1 subject each (5.6%). Taking all administration days of together (i.e., given either alone or in combination with ketoconazole or voriconazole), drug-related AEs comprised rhinitis (5.3%), headache (15.8%), photopsia (5.3%), blurred vision (10.5%), and abdominal pain (5.3%).
Page 5 BI Trial No.: 1314.7 5 of 5 Safety results (cont.): Conclusions: Safety laboratory Across all treatments, relevant abnormalities in safety laboratory values were not observed, including clinical chemistry, haematology, coagulation parameters, and urinalysis. Vital signs and 12-lead ECG No clinically relevant changes from baseline were observed in vital signs (BP, PR) or 12-lead ECG. In this randomised, 3-way crossover trial in 20 healthy male subjects, the potent CYP 3A4 and P-gp inhibitor ketoconazole significantly increased the exposure to 25 mg by 3.7 fold (AUC) and by 2.6-fold (C max ). The potent CYP 3A4 inhibitor voriconazole significantly increased the exposure to 25 mg by 2.7-fold (AUC) and by 2.1-fold (C max ). was well tolerated. The increased exposure to following coadministration with ketoconazole or voriconazole did not translate into a higher incidence of AEs associated with the administration of. Photopsia, blurred vision, and insomnia can be reasonably attributed to voriconazole, given its established safety profile. New safety signals precluding the further clinical development of were not identified.