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sample was withdrawn from the catheter to determine the baseline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.