A Study to Assess the Effect of Ceftobiprole on the PK of Pitavastatin and on Plasma Levels of Coproporphyrin

A Phase 1, Single-center, Open-label, Non-randomized, Fixed-sequence, Drug-drug Interaction Study to Assess the Effect of Repeated Doses of Intravenous Ceftobiprole on the Pharmacokinetics of Oral Pitavastatin (OATP1B Substrate) and on Plasma Levels of Coproporphyrin I (OATP1B Biomarker) in Healthy Subjects

The goal of this clinical study was to determine the effect of the test drug ceftobiprole (a drug approved for the treatment of bacterial infections) on the elimination of pitavastatin (a drug approved for the treatment of increased levels of cholesterol in blood) from the body. This interaction was investigated by pharmacokinetic (PK) assessments. The clinical study also investigated the safety of ceftobiprole and how well ceftobiprole was tolerated by healthy subjects when it was administered in combination with pitavastatin.

This study assessed whether there was an inhibitory effect of ceftobiprole on hepatic organic anion-transporting polypeptide 1B (OATP1B) activity. Pitavastatin was used as an OATP1B substrate in this study. The pharmacokinetics of oral pitavastatin were assessed when administered alone and when administered together with IV ceftobiprole in a study design including 2 treatment periods. In addition, the pharmacodynamic effect of repeated doses of IV ceftobiprole on the diurnal plasma levels of coproporphyrin I (CP-I) was assessed in this study as CP-I is an endogenous biomarker for hepatic OATPB1 activity.

The study duration was up to 38 days.

Main Inclusion Criteria:

• Body mass index: 18.0 to 30.0 kg/m2, inclusive
• Good physical and mental health
• Normal renal function (creatinine clearance ≥ 90 mL/min as determined by the Cockcroft-Gault equation)
• Female participants of childbearing potential were required not be pregnant or lactating and had to agree to use adequate contraception
• Male subjects, if not surgically sterilized, were required to agree to use adequate contraception
• All prescribed medication had to be stopped at least 30 days prior to admission to the clinical research center (an exception was made for hormonal contraceptives)
• All over-the-counter medication, vitamin preparations and other food supplements, or herbal medications (e.g., St. John's wort) had to be stopped at least 14 days prior to admission to the clinical research center
• Ability and willingness to abstain from alcohol from 48 hours (2 days) prior to Screening and admission to the clinical research center
• Ability and willingness to abstain from methylxanthine-containing beverages or food from 48 hours (2 days) prior to admission to the clinical research center

Main Exclusion Criteria:

• History of relevant drug and/or food allergies, particularly to antibiotics.
• Subject received a known potent inhibitor of OATP1B activity within 30 days prior to admission
• Subject received a potential inducer of OATP1B activity within 30 days prior to admission
• Subject had a history of seizures
• Subject had a history of frequent diarrhea
• Smoking more than 5 cigarettes, 1 cigar, or 1 pipe daily; the use of tobacco products in the 48 hours (2 days) prior to admission
• History of alcohol abuse or drug addiction within 12 months prior to Screening.
• Average intake of more than 24 units of alcohol per week
• Positive drug and/or alcohol screen
• Donation or loss of more than 450 mL of blood within 60 days prior to the first pitavastatin administration on Day 1 of the current study. Donation or loss of more than 1.5 liters of blood (for male subjects)/more than 1.0 liters of blood (for female subjects) in the 10 months prior to the first pitavastatin administration on Day 1 of the current study.