Drug-drug Interaction Study
Conditions
Keywords
Ceftobiprole, Pitavastatin, OATP1B, Coproporphyrin, DDI
Brief summary
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.
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.
Interventions
DRUGpitavastatin
Single oral administration
DRUGpitavastatin single dose combined with ceftobiprole
Single oral pitavastatin co-administered with IV ceftobiprole
Sponsors
Basilea Pharmaceutica
Biomedical Advanced Research and Development Authority
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Observed Plasma Concentration (Cmax) of Pitavastatin | 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 | To assess the pharmacokinetic parameter Cmax in plasma after a single oral dose of pitavastatin administered without and with intravenous (IV) ceftobiprole |
| Area Under the Plasma Concentration-time Curve up to Time (AUC0-t) After Pitavastatin Administration | 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 | 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 | 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 | To assess the pharmacokinetic parameter AUC0-inf after a single oral dose of pitavastatin administered without and with IV ceftobiprole |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cmax of Coproporphyrin I (CP-I) | 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 | The pharmacokinetic parameter Cmax for CP-I in plasma was assessed with and without administration of IV ceftobiprole |
| Area Under the Plasma Level-time Curve up to Time 25.5 Hours (AUEC0-25.5h) of CP-I in Plasma | 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 | The pharmacokinetic parameter AUEC0-25.5h for CP-I was assessed with and without administration of IV ceftobiprole |
| Cmax of Ceftobiprole in Plasma | 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 | To assess the pharmacokinetic parameter Cmax of IV ceftobiprole without and with oral administration of pitavastatin |
| Area Under the Plasma Concentration-time Curve up to 8 Hours (AUC0-8h) After IV Ceftobiprole | 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 | To assess the pharmacokinetic parameter AUC0-8h after IV ceftobiprole without and with oral administration of pitavastatin |
| Cmax of the Pitavastatin Metabolite Pitavastatin Lactone in Plasma After Pitavastatin Administration | 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 | To assess the pharmacokinetic parameter Cmax of pitavastatin lactone after a single oral dose of pitavastatin administered without and with IV ceftobiprole |
| AUC0-t of the Pitavastatin Metabolite Pitavastatin Lactone in Plasma After Pitavastatin Administration | 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 | To assess the pharmacokinetic parameter AUC0-t of pitavastatin lactone after a single oral dose of pitavastatin administered without and with IV ceftobiprole |
| AUC0-inf of of the Pitavastatin Metabolite Pitavastatin Lactone in Plasma After Pitavastatin Administration | 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 | To assess the pharmacokinetic parameter AUC0-inf of pitavastatin lactone after a single oral dose of pitavastatin administered without and with IV ceftobiprole |
| Number of Participants Reporting Treatment-emergent Adverse Events (TEAEs) After Administration of Ceftobiprole Without and With a Single Oral Dose of Pitavastatin | 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 | 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 |
Countries
Netherlands
Contacts
STUDY_DIRECTORThomas Kaindl, MD
Basilea Pharmaceutica International Ltd, Allschwil
Participant flow
Recruitment details
Twelve (12) subjects were enrolled in the study and completed the study as per protocol. The study was conducted in one research center in the Netherlands.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 40.4 years STANDARD_DEVIATION 15.36 |
| BMI | 25.00 kg/m2 STANDARD_DEVIATION 3.06 |
| Height (cm) | 174.8 cm STANDARD_DEVIATION 7.5 |
| Race/Ethnicity, Customized Other | 1 Participants |
| Race/Ethnicity, Customized White | 11 Participants |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 6 Participants |
| Weight (kg) | 76.67 kg STANDARD_DEVIATION 12.51 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 12 | 0 / 12 | 0 / 12 |
| other Total, other adverse events | 5 / 12 | 7 / 12 | 5 / 12 |
| serious Total, serious adverse events | 0 / 12 | 0 / 12 | 0 / 12 |
Outcome results
None listed