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
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 12
- 试验地点
- 2
- 主要终点
- Maximum Observed Plasma Concentration (Cmax) after a single oral dose of pitavastatin administered without and with intravenous (IV) ceftobiprole
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Other
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •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
排除标准
- •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.
研究组 & 干预措施
Period 1; pitavastatin 2 mg
On Day 1, a single oral dose of pitavastatin was administered
干预措施: pitavastatin (Drug)
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.
干预措施: pitavastatin single dose combined with ceftobiprole (Drug)
结局指标
主要结局
Maximum Observed Plasma Concentration (Cmax) after a single oral dose of pitavastatin administered without and with intravenous (IV) ceftobiprole
时间窗: Up to Day 8
Area under the plasma concentration-time curve up to time (AUC0-t) after a single oral dose of pitavastatin administered without and with IV ceftobiprole
时间窗: Up to Day 8
Area under the plasma concentration-time curve from time 0 to infinity (AUC0-inf) after a single oral dose of pitavastatin administered without and with IV ceftobiprole
时间窗: Up to Day 8
Maximum Observed Plasma Concentration (Cmax) of Pitavastatin
时间窗: 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
时间窗: 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
时间窗: 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
次要结局
- Cmax of coproporphyrin I (CP-I) after IV ceftobiprole administration(Up to Day 8)
- Area under the plasma level-time curve up to time 25.5 hours (AUEC0-25.5h) of CP-I after IV ceftobiprole administration(Up to Day 8)
- Cmax of IV ceftobiprole without and with oral administration of pitavastatin(Up to Day 8)
- Area under the plasma concentration-time curve up to 8 hours (AUC0-8h) after IV ceftobiprole without and with oral administration of pitavastatin(Up to Day 8)
- Cmax of the pitavastatin metabolite pitavastatin lactone after a single oral dose of pitavastatin, administered without and with IV ceftobiprole(Up to Day 8)
- AUC0-t of the pitavastatin metabolite pitavastatin lactone after a single oral dose of pitavastatin, administered without and with IV ceftobiprole(Up to Day 8)
- AUC0-inf of the pitavastatin metabolite pitavastatin lactone after a single oral dose of pitavastatin, administered without and with IV ceftobiprole(Up to Day 8)
- Number of participants reporting Treatment-emergent adverse events (TEAEs) after administration of ceftobiprole without and with a single oral dose of pitavastatin(Up to Day 17)
- Number of participants with clinically significant change from baseline in laboratory parameters after administration of ceftobiprole without and with a single oral dose of pitavastatin(Up to Day 17)
- Number of participants with clinically significant change from baseline in vital signs after administration of ceftobiprole without and with a single oral dose of pitavastatin(Up to Day 17)
- Number of participants with clinically significant change from baseline in 12-lead electrocardiogram (ECG) parameters after administration of ceftobiprole without and with a single oral dose of pitavastatin(Up to Day 17)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)