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.

Study Overview

• Status: Completed
• Conditions: Drug-drug Interaction Study
• Intervention / Treatment: Drug: pitavastatin; Drug: pitavastatin single dose combined with ceftobiprole

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Phase 1

Contacts and Locations

Study Locations

• Netherlands
  • Groningen, Netherlands, 9728
    • ICON Early Clinical & Bioanalytical Solutions

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Period 1; pitavastatin 2 mg; On Day 1, a single oral dose of pitavastatin was administered	Drug: pitavastatin; Single oral administration
Experimental: Period 2; pitavastatin 2 mg combined with ceftobiprole 500 mg; From Day 4 to Day 7, ceftobiprole (as the prodrug ceftobiprole medocaril sodium) will be administered intravenously (IV) every 8 hours (q8h) for four days. On Day 6, a single oral dose of pitavastatin will be co-administered with ceftobiprole From Day 4 to Day 7, 500 mg ceftobiprole (as the prodrug ceftobiprole medocaril sodium) was administered as a 2-hour IV dose every 8 hours (q8h) under fasted conditions in the morning, and irrespective of timing of food intake further on the day. On Day 6, a single oral dose of 2 mg pitavastatin was co-administered with ceftobiprole 30 minutes prior to the end of the first IV dose of 500 mg ceftobiprole under fasted conditions.	Drug: pitavastatin single dose combined with ceftobiprole; Single oral pitavastatin co-administered with IV ceftobiprole

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Observed Plasma Concentration (Cmax) of Pitavastatin	To assess the pharmacokinetic parameter Cmax in plasma after a single oral dose of pitavastatin administered without and with intravenous (IV) ceftobiprole	Sampling on Day 1 and Day 6; before dosing, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12 hours (h) post-dose. Day 2 and Day 7; 24 and 36 h post-dose. Day 3 and Day 8; 48 h post-dose
Area Under the Plasma Concentration-time Curve up to Time (AUC0-t) After Pitavastatin Administration	To assess the pharmacokinetic parameter AUC0-t after a single oral dose of pitavastatin administered without and with IV ceftobiprole	Sampling on Day 1 and Day 6; before dosing, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12 hours (h) post-dose. Day 2 and Day 7; 24 and 36 h post-dose. Day 3 and Day 8; 48 h post-dose
Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-inf) After Pitavastatin Administration	To assess the pharmacokinetic parameter AUC0-inf after a single oral dose of pitavastatin administered without and with IV ceftobiprole	Sampling on Day 1 and Day 6; before dosing, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12 hours (h) post-dose. Day 2 and Day 7; 24 and 36 h post-dose. Day 3 and Day 8; 48 h post-dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cmax of Coproporphyrin I (CP-I)	The pharmacokinetic parameter Cmax for CP-I in plasma was assessed with and without administration of IV ceftobiprole	Sampling on Day 5; pre-dose, 2, 4, 6, 8 h, 16, and 25.5 (Day 6) hours post-dose and corresponding samples on Day -1
Area Under the Plasma Level-time Curve up to Time 25.5 Hours (AUEC0-25.5h) of CP-I in Plasma	The pharmacokinetic parameter AUEC0-25.5h for CP-I was assessed with and without administration of IV ceftobiprole	Sampling on Day 5; pre-dose, 2, 4, 6, 8 h, 16, and 25.5 (Day 6) hours post-dose and corresponding samples on Day -1
Cmax of Ceftobiprole in Plasma	To assess the pharmacokinetic parameter Cmax of IV ceftobiprole without and with oral administration of pitavastatin	Sampling on Day 5: pre-dose ,1, 2, 4, 6, 8 h post-dose, on Day 6; pre-dose,1, 2, 4, 6, 8 h post-dose
Area Under the Plasma Concentration-time Curve up to 8 Hours (AUC0-8h) After IV Ceftobiprole	To assess the pharmacokinetic parameter AUC0-8h after IV ceftobiprole without and with oral administration of pitavastatin	Sampling on Day 5: pre-dose ,1, 2, 4, 6, 8 h post-dose, on Day 6; pre-dose,1, 2, 4, 6, 8 h post-dose
Cmax of the Pitavastatin Metabolite Pitavastatin Lactone in Plasma After Pitavastatin Administration	To assess the pharmacokinetic parameter Cmax of pitavastatin lactone after a single oral dose of pitavastatin administered without and with IV ceftobiprole	Sampling on Day 1 and Day 6; before dosing, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12 hours (h) post-dose. Day 2 and Day 7; 24 and 36 h post-dose. Day 3 and Day 8; 48 h post-dose
AUC0-t of the Pitavastatin Metabolite Pitavastatin Lactone in Plasma After Pitavastatin Administration	To assess the pharmacokinetic parameter AUC0-t of pitavastatin lactone after a single oral dose of pitavastatin administered without and with IV ceftobiprole	Sampling on Day 1 and Day 6; before dosing, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12 hours (h) post-dose. Day 2 and Day 7; 24 and 36 h post-dose. Day 3 and Day 8; 48 h post-dose
AUC0-inf of of the Pitavastatin Metabolite Pitavastatin Lactone in Plasma After Pitavastatin Administration	To assess the pharmacokinetic parameter AUC0-inf of pitavastatin lactone after a single oral dose of pitavastatin administered without and with IV ceftobiprole	Sampling on Day 1 and Day 6; before dosing, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12 hours (h) post-dose. Day 2 and Day 7; 24 and 36 h post-dose. Day 3 and Day 8; 48 h post-dose
Number of Participants Reporting Treatment-emergent Adverse Events (TEAEs) After Administration of Ceftobiprole Without and With a Single Oral Dose of Pitavastatin	A treatment-emergent AE (TEAE) was defined as any event not present prior to the first administration of the study drug, or any event already present that worsens in either severity or frequency following exposure to the study drug	Up to 17 days after first dosing; Pitavastatin Period 1 between first dose on Day1 and before first dose on Day4; ceftobiprole Period 2 between first dose on Day4 and before first dose on Day6; pitavastatin + ceftopibrole Period 2 after first dose on Day6

Collaborators and Investigators

• Sponsor: Basilea Pharmaceutica
• Collaborators: Biomedical Advanced Research and Development Authority
• Investigators: Study Director: Thomas Kaindl, MD, Basilea Pharmaceutica International Ltd, Allschwil

Study record dates

Study Major Dates

• Study Start (Actual): January 17, 2025
• Primary Completion (Actual): February 25, 2025
• Study Completion (Actual): February 25, 2025

Study Registration Dates

• First Submitted: January 9, 2025
• First Submitted That Met QC Criteria: January 29, 2025
• First Posted (Actual): February 5, 2025

Study Record Updates

• Last Update Posted (Actual): April 21, 2026
• Last Update Submitted That Met QC Criteria: March 31, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: DDI; Pitavastatin; Ceftobiprole; OATP1B; Coproporphyrin
• Additional Relevant MeSH Terms: Anti-Bacterial Agents; Anti-Infective Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; pitavastatin; ceftobiprole
• Other Study ID Numbers: BPR-CP-101; HHSO100201600002C (Other Grant/Funding Number: BARDA); 2024-518592-60-00 (Ctis)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No