Clinical Study
We conducted a single center, phase I study (clinicaltrials.gov, ID: NCT04621253) in two successive periods in healthy male Caucasian volunteers. The study was approved by the ethics committee EKNZ (EthikkommissionNordwestschweiz/Zentalschweiz) and Swissmedic and conducted in accordance with good clinical practice guidelines and the current version of the Declaration of Helsinki. The participants were screened for any underlying diseases (physical examination, routine laboratory, and electrocardiogram). The use of known CYP inducers (e.g., St. John’s Wort) or inhibitors (e.g., grapefruit juice) within 2 weeks before study start was an exclusion criterion as well as excessive caffeine consumption, smoking (> 5 cigarettes per day) and use of over-the-counter medication. After signing the informed consent, 12 healthy male subjects were included (mean age: 28.3 years, range 22-39 years, mean body weight: 79.0 kg, range 63-117 kg, mean body mass index: 24.7 kg/m2, range 21.2-37.3 kg/m2) into the study. A venous blood sample was drawn to determine routine laboratory parameters and the subjects’ CYP1A2, CYP2B6, CYP2C9, CYP2C19, and CYP2D6 genotype. The first phase of the study was designed as a randomized, double-blind, 3-arm crossover study. The arms were placebo, ciprofloxacin or fluconazole treatment in a random order. Prior to the study day, the subjects were treated for 3 days with either placebo, ciprofloxacin (750 mg twice daily for 3 days) or fluconazole (400 mg loading dose on day -3, followed by 200 mg for day -2 and -1). Subjects arrived at the study facility in fasted state with 12 h abstinence of caffeine. The last dose of inhibitor or placebo was taken on the study day (750 mg ciprofloxacin, 200 mg fluconazole or placebo) 1h prior to arrival. After arrival in the study facility, a venous catheter was placed in the non-dominant forearm and a blood sample was withdrawn from the catheter to determine the baseline concentrations of the CYP inhibitors. At the same time, participants were treated orally with 1000 mg metamizole (Novalgin®tablets 500 mg, Sanofi) and 250 mL of water. After administration of metamizole, blood samples were drawn after 0.25, 0.5, 0.75, 1, 2, 3, 4h, 6, 8, 12 and 24 hours into EDTA coated tubes. The blood samples were centrifuged at 1500 g for 10 minutes and the plasma was stored at -20°C until analysis. In the second, open period of the study, 6 randomly chosen participants out of the 12 participants of the first part of the study gave their consent to participate in the study continuation. These 6 participants were treated with the combination of ciprofloxacin and fluconazole with the same schedule as in the first part of the study. The treatment at the study day was the same as described for the first part of study.
To review compliance of the placebo/inhibitor treatment, pill-counting journals were handed out to the subjects. They had to be filled out and returned at the study day for review as well as the empty blisters.