Effects of the P‐Glycoprotein Inhibitor Clarithromycin on the Pharmacokinetics of Intravenous and Oral Trospium Chloride: A 4‐Way Crossover Drug‐Drug Interaction Study in Healthy Subjects

Abstract

The quaternary ammonium compound trospium chloride is poorly absorbed from 2 “absorption windows” in the jejunum and cecum/ascending colon, respectively. To confirm whether intestinal P‐glycoprotein (P‐gp) is involved, a 4‐period, crossover drug interaction study with trospium chloride after intravenous (2 mg) and oral administration (30 mg) without and after comedication of clarithromycin (500 mg), an inhibitor for P‐gp, was initiated in 12 healthy subjects. Pharmacokinetics of trospium was evaluated using gas chromatography–mass spectrometry, noncompartmental evaluation, and pharmacokinetic modeling. Trospium chloride was poorly absorbed after oral administration (absolute bioavailability, ∼8%–10%). About 30% of the bioavailable dose fraction was absorbed from the “narrow window”. Comedication with clarithromycin increased steady‐state distribution volumes by ∼27% (P < .01). Bioavailability was not increased as hypothesized. The geometric mean ratios (90% confidence interval) for area under the plasma concentration–time curve, maximum concentration, and renal clearance accounted for 0.75 (0.56–1.01), 0.64 (0.45–0.89), and 1.00 (0.90–1.13), respectively. The amount of trospium absorbed from the “narrow window” was reduced in all subjects but from the “wider window” in only 9 of them. Bioavailability was strongly predicted by the maximum absorption rate of trospium in the distal “window” (rs2 = 0.910, P < .0001). In conclusion, the P‐gp inhibitor clarithromycin significantly increases distribution volumes but not oral absorption of trospium. The amount absorbed from the “narrow window” was lowered in all subjects. However, the extent of all influences seems not to be of clinical relevance.

Pharmacokinetic Drug‐Drug Interactions Between Trospium Chloride and Ranitidine Substrates of Organic Cation Transporters in Healthy Human Subjects

“…The pharmacokinetic DDI study in 24 healthy subjects was performed according to the International Council for Harmonisation guideline for Good Clinical Practice and the regulations of the German Medicines Act after being approved by the Independent Ethics Committee of the University of Greifswald and by the German Federal Department of Drugs and Medicinal Products, and after registration by eudract.emea.eu.int (identifier: EudraCT 2016‐002882‐69) and ClinicalTrials.gov (identifier: NCT03011463). The study was designed for 2 parallel subgroups, each with 12 healthy subjects, who were used to study the interactions of trospium chloride with clarithromycin and with ranitidine, the results of which are reported here.…”

“…Pharmacokinetics of trospium chloride and ranitidine, and the anticholinergic effects of trospium on salivation and accommodation of the eyes, were evaluated in a controlled, 4‐period, crossover study (7‐day washout) after block‐randomized administration of the following study medications in fasting subjects: (1) intravenous infusion of 2.0‐mg trospium chloride (Spasmex IV 2.0 mg Injektionslösung, Pfleger, Bamberg, Germany) in 20 mL of saline within 60 minutes and consumption of 240 mL of tap water; (2) oral administration of a 30‐mg immediate release tablet of trospium chloride (Spasmex 30‐mg coated tablets, Pfleger, Bamberg, Germany) with 240 mL of tap water; (3) intravenous infusion of 2.0‐mg trospium chloride in 20 mL of saline within 60 minutes together with 300 mg ranitidine (Ranitidin‐ratiopharm, ratiopharm, Ulm, Germany) swallowed with 240 mL of tap water; (4) 30 mg of immediate release trospium chloride together with 300 mg of ranitidine swallowed with 240 mL of tap water. Further details on administration, fasting periods, standard diet, and time points and intervals, respectively, of sampling and storage of plasma, urine, and feces are described in a recent publication …”

“…All quantitative assays for the study were performed under the conditions of Good Laboratory Practice. Trospium was quantified in plasma, urine, and feces using gas chromatography–mass spectrometry with selected ion monitoring mode (Agilent, Waldbronn, Germany) as described in previous papers . Accuracy ranged from 98.9% to 101.9% of the respective nominal values for plasma, 98.0% to 104.0% for feces, and 99.5% to 102.7% for urine.…”