Single Centre in Vivo Cocktail Phenotyping Study on OATP1B1, OCT1/2, MATE1/2K, OAT1/3, and P-gp Drug Transporters in Healthy Volunteers
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 入组人数
- 24
- 试验地点
- 1
- 主要终点
- organic anionic transporter polypeptide 1B1 (OATP1B1): Clearance over bioavailability (CL/F) of pitavastatin
研究概览
简要总结
The objective of the present study is to contribute to establishing in vivo phenotyping procedures for organic anionic transporter polypeptide 1B1 (OATP1B1), organic cation transporters 1 and 2 (OCT1/2), multidrug and toxic compound extrusion transporters 1 and 2,kidney splice variant (MATE1/2K), organic anion transporters 1 and 3 (OAT1/3), and p-glycoprotein (P-gp) transporters via a cocktail approach. To this end, marker substrates for each of the respective transporters are administered as single doses in one period each and as a cocktail in one period to 24 healthy volunteers, and phenotyping metrics are derived from plasma and urine concentrations.
详细描述
Blood sampling: - 0:15 h pre-dose, 0:15, 0:30, 0:45, 1:00, 1:20, 1:40, 2:00, 2:20, 2:40, 3:00, 3:30, 4:00, 5:00, 6:00, 8:00, 12:00, 16:00, 24:00 hours post-dose
Urine Sampling: Pre-dose, 0-4 hours, 4-8 hours, 8-12 hours, 12-16 hours, 16-24 hours
Drug analysis: by liquid chromatography - tandem mass spectrometry (LC-MS/MS)
Pharmacokinetic Characteristics: Evaluation is carried out using standard noncompartmental characteristics including: area under the plasma concentration vs. time curve truncated at time t (AUC0-t), area under the plasma concentration vs. time curve extrapolated to infinity (AUC0-∞), peak plasma concentration (Cmax), time of occurrence of Cmax (tmax), apparent elimination half-life (t½), clearance over bioavailability (CL/F), renal clearance (CLr) and renal secretion. The evaluation may be completed by compartmental population pharmacokinetic approaches.
Statistical evaluation: Pharmacokinetic characteristics are compared for cocktail administration vs. individual administration by standard average bioequivalence assessment.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Basic Science
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 85 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Caucasian
- •Body mass index (BMI) between and inclusive 18.5 and 30 kg/m2
- •Willing and capable to confirm written consent prior to enrolment after ample information has been provided
- •Normal findings in the medical history unless the principal investigator considers an abnormality to be clinically relevant.
- •Considered to be healthy by the principal investigator on the basis of extensive pre-study screening-
排除标准
- •Standard for healthy volunteers, including:
- •Female subjects only: positive results in pregnancy test
- •Female subjects only: lactating women
- •Female subjects only: subjects who do not use or do not agree to use appropriate contraceptive methods during the study as defined in Note for Guidance on Non-Clinical Safety Studies for the Conduct of Human Clinical Trials for Pharmaceuticals (CHMP/ICH/286/95 modification)
研究组 & 干预措施
pitavastatin (OATP1B1)
2 mg pitavastatin single dose
干预措施: pitavastatin (Drug)
metformin (MATE1, MATE2K, OCT1, OCT2)
500 mg metformin single dose
干预措施: Metformin (Drug)
digoxin (intestinal & renal P-glycoprotein)
0.5 mg digoxin single dose
干预措施: digoxin (Drug)
adefovir dipivoxil (OAT1)
10 mg adefovir dipivoxil single dose
干预措施: Adefovir (Drug)
sitagliptin (OAT3)
100 mg sitagliptin single dose
干预措施: sitagliptin (Drug)
cocktail (all substances)
combination of all individual drugs at respective single doses
干预措施: pitavastatin (Drug)
cocktail (all substances)
combination of all individual drugs at respective single doses
干预措施: Metformin (Drug)
cocktail (all substances)
combination of all individual drugs at respective single doses
干预措施: digoxin (Drug)
cocktail (all substances)
combination of all individual drugs at respective single doses
干预措施: Adefovir (Drug)
cocktail (all substances)
combination of all individual drugs at respective single doses
干预措施: sitagliptin (Drug)
结局指标
主要结局
organic anionic transporter polypeptide 1B1 (OATP1B1): Clearance over bioavailability (CL/F) of pitavastatin
时间窗: 24 hours
PK parameter
organic cation transporters 1 and 2 (OCT1/2), multidrug and toxic compound extrusion transporters 1 and 2,kidney splice variant (MATE1/2K): Renal clearance (CLr) of metformin
时间窗: 24 hours
PK parameter
intestinal p-glycoprotein (P-gp): Peak Plasma Concentration (Cmax) of digoxin
时间窗: 24 hours
PK parameter
renal p-glycoprotein (P-gp): Renal clearance (CLr) of digoxin:
时间窗: 24 hours
PK parameter
organic anion transporter 1 (OAT1): Renal clearance (CLr) of adefovir
时间窗: 24 hours
PK parameter
organic anion transporter 3 (OAT3): Renal clearance (CLr) of sitagliptin
时间窗: 24 hours
PK parameter
次要结局
未报告次要终点
研究者
Prof. Dr. Uwe Fuhr
Acting Director, Department of Pharmacology I
University of Cologne