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

Basilea Pharmaceutica12 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

OTHER

Masking

NONE

Enrollment

Conditions

Drug-drug Interaction Study

Interventions

pitavastatinDRUG

Single oral administration

pitavastatin single dose combined with ceftobiproleDRUG

Single oral pitavastatin co-administered with IV ceftobiprole

Eligibility

Sex: ALLMin age: 18 YearsMax age: 65 YearsHealthy volunteers:

Medical Language ↔ Plain English

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.

Locations (1)

ICON Early Clinical & Bioanalytical Solutions

Groningen, Netherlands

Outcomes

Primary Outcomes

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

Time frame: 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

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

Secondary Outcomes

Cmax of Coproporphyrin I (CP-I)

The pharmacokinetic parameter Cmax for CP-I in plasma was assessed with and without administration of IV ceftobiprole

Time frame: 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

Data from ClinicalTrials.gov

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