A PHASE 1, RANDOMIZED, OPEN-LABEL STUDY IN HEALTHY PARTICIPANTS TO ESTIMATE THE BIOAVAILABILITY OF TWO NEW ENCORAFENIB FORMULATIONS RELATIVE TO THE CURRENT FORMULATION AND TO EVALUATE THE EFFECT OF A PROTON-PUMP INHIBITOR ON ENCORAFENIB PLASMA PHARMACOKINETICS
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- Pfizer
- 入组人数
- 18
- 试验地点
- 1
- 主要终点
- Area Under the Plasma Concentration-Time Profile From Time Zero to Extrapolated Infinite Time (AUCinf) Following Single Oral Doses of Encorafenib 75 mg Alone and With Rabeprazole
研究概览
简要总结
Relative bioavailability study to evaluate the pharmacokinetics of two new encorafenib formulations
详细描述
In order to decrease the size of the current formulated encorafenib capsule and improve the physical stability, 2 new encorafenib tablet formulations have been developed.
This study is intended to select the optimal tablet formulation for commercialization based on the tablet pharmacokinetics.
A preliminary assessment of the effect of a proton-pump inhibitor on the pharmacokinetics of the 2 encorafenib tablet formulations will also be conducted to assist in the formulation selection.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Other
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Participants must be male or female of non-childbearing potential of 18 years of age or older, inclusive, at the time of signing the informed consent document.
- •Male and female participants who are overtly healthy as determined by medical evaluation including medical history, physical examination, laboratory tests, and cardiac monitoring.
- •Participants who are willing and able to comply with all scheduled visits, treatment plan, laboratory tests, lifestyle considerations, and other study procedures.
- •Body Mass Index of 17.5 to 30.5 kg/meters squared; and a body weight >50 kg (110 lb).
- •Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent document and the protocol.
排除标准
- •Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurological, or allergic disease. Evidence of any active and uncontrolled bacterial or viral infection.
- •Any condition possibly affecting drug absorption (eg, gastrectomy, cholecystectomy).
- •History of human immunodeficiency virus infection, hepatitis B, or hepatitis C; positive testing for human immunodeficiency virus, Hepatitis B surface antigen, Hepatitis B core antibody or hepatitis C virus antibody. Hepatitis B vaccination is allowed.
- •Positive COVID-19 test at first admission.
- •Other medical or psychiatric conditions, laboratory test abnormalities, other conditions or situations related to COVID-19 pandemic or, in the investigator's judgment, make the participant inappropriate for the study.
- •Use of prescription or non-prescription medications within 7 days prior to the first dose of encorafenib with the exception of moderate/potent CYP3A inducers which are prohibited within 14 days plus 5 half-lives prior to the first dose.
- •History of known sensitivity to rabeprazole, substituted benzimidazoles or to any component of the rabeprazole formulation.
- •Previous administration with an investigational product (drug or vaccine) within 30 days.
- •Known hypersensitivity to encorafenib or its excipients.
- •A positive urine drug or cotinine test.
- •Screening supine blood pressure ≥140 mm Hg (systolic) or ≥90 mm Hg (diastolic), following at least 5 minutes of supine rest.
- •Baseline standard 12 lead electrocardiogram that demonstrates clinically relevant abnormalities that may affect participant safety or interpretation of study results.
- •Aspartate transaminase or alanine aminotransferase level ≥ 1.5 × upper limit of normal.
- •Total bilirubin level ≥1.5 × upper limit of normal.
- •Estimated glomerular filtration rate <60 ml/min/1.73 m2
研究组 & 干预措施
Four Period Treatment Sequence: PPI Effect
Participants will receive a single encorafenib dose formulation, a single encorafenib dose of the formulated capsule (CAP), and a single encorafenib dose of the formulation after administration of 20 mg rabeprazole every evening for 5 days.
干预措施: Encorafenib capsule formulation (CAP) (Drug)
Four Period Treatment Sequence: PPI Effect
Participants will receive a single encorafenib dose formulation, a single encorafenib dose of the formulated capsule (CAP), and a single encorafenib dose of the formulation after administration of 20 mg rabeprazole every evening for 5 days.
干预措施: Encorafenib first formulation (Drug)
Four Period Treatment Sequence: PPI Effect
Participants will receive a single encorafenib dose formulation, a single encorafenib dose of the formulated capsule (CAP), and a single encorafenib dose of the formulation after administration of 20 mg rabeprazole every evening for 5 days.
干预措施: Encorafenib second formulation (Drug)
Four Period Treatment Sequence: PPI Effect
Participants will receive a single encorafenib dose formulation, a single encorafenib dose of the formulated capsule (CAP), and a single encorafenib dose of the formulation after administration of 20 mg rabeprazole every evening for 5 days.
干预措施: Rabeprazole tablet (Drug)
Four Period Treatment Sequence: PPI Effect Second Formulation
Participants will receive a single encorafenib dose of the second formulation, a single encorafenib dose of the second formulation, a single encorafenib dose of the formulated capsule (CAP), and a single encorafenib dose of the second formulation after administration of 20 mg rabeprazole every evening for 5 days.
干预措施: Encorafenib capsule formulation (CAP) (Drug)
Four Period Treatment Sequence: PPI Effect Second Formulation
Participants will receive a single encorafenib dose of the second formulation, a single encorafenib dose of the second formulation, a single encorafenib dose of the formulated capsule (CAP), and a single encorafenib dose of the second formulation after administration of 20 mg rabeprazole every evening for 5 days.
干预措施: Encorafenib first formulation (Drug)
Four Period Treatment Sequence: PPI Effect Second Formulation
Participants will receive a single encorafenib dose of the second formulation, a single encorafenib dose of the second formulation, a single encorafenib dose of the formulated capsule (CAP), and a single encorafenib dose of the second formulation after administration of 20 mg rabeprazole every evening for 5 days.
干预措施: Encorafenib second formulation (Drug)
Four Period Treatment Sequence: PPI Effect Second Formulation
Participants will receive a single encorafenib dose of the second formulation, a single encorafenib dose of the second formulation, a single encorafenib dose of the formulated capsule (CAP), and a single encorafenib dose of the second formulation after administration of 20 mg rabeprazole every evening for 5 days.
干预措施: Rabeprazole tablet (Drug)
结局指标
主要结局
Area Under the Plasma Concentration-Time Profile From Time Zero to Extrapolated Infinite Time (AUCinf) Following Single Oral Doses of Encorafenib 75 mg Alone and With Rabeprazole
时间窗: Day 1 predose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 hours postdose
AUCinf for encorafenib eMCC, eMCCL and CAP formulations (75 mg, single dose administration), and for encorafenib eMCC and eMCCL formulations (75 mg, single dose administration) following 5 days of rabeprazole 20 mg daily were calculated by AUClast + (Clast/kel), where AUClast was the area under the plasma concentration-time profile from time zero to last quantifiable concentration, Clast was the predicted plasma concentration at the last quantifiable time point estimated from the log-linear regression analysis, and kel was first-order elimination rate constant.
Area Under the Plasma Concentration-Time Profile From Time Zero to Last Quantifiable Concentration (AUClast) Following Single Oral Doses of Encorafenib 75 mg Alone and With Rabeprazole
时间窗: Day 1 predose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 hours postdose
AUClast for encorafenib eMCC, eMCCL and CAP formulations (75 mg, single dose administration), and for encorafenib eMCC and eMCCL formulations (75 mg, single dose administration) following 5 days of rabeprazole 20 mg daily were calculated using Linear/Log trapezoidal method.
Maximum Observed Plasma Concentration (Cmax) Following Single Oral Doses of Encorafenib 75 mg Alone and With Rabeprazole
时间窗: Day 1 predose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 hours postdose
Cmax for encorafenib eMCC, eMCCL and CAP formulations (75 mg, single dose administration), and for encorafenib eMCC and eMCCL formulations (75 mg, single dose administration) following 5 days of rabeprazole 20 mg daily were observed directly from data.
次要结局
- Terminal Half-Life (t½) Following Single Oral Doses of Encorafenib 75 mg Alone and With Rabeprazole(Day 1 predose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 hours postdose)
- Apparent Clearance (CL/F) Following Single Oral Doses of Encorafenib 75 mg Alone and With Rabeprazole(0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 hours postdose)
- Number of Participants With Laboratory Test Abnormalities Without Regard to Baseline Abnormality(Baseline, and at early discontinuation or at the discretion of the investigator (the total duration of the study was approximately 60 days from baseline))
- Apparent Volume of Distribution (Vz/F) Following Single Oral Doses of Encorafenib 75 mg Alone and With Rabeprazole(0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 hours postdose)
- Number of Participants Meeting Vital Signs Categorical Criteria(Baseline, 0 and 2 hours postdose in each period, and at early discontinuation (the total duration of the study was approximately 60 days from baseline))
- Time for Cmax (Tmax) Following Single Oral Doses of Encorafenib 75 mg Alone and With Rabeprazole(Day 1 predose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 48 hours postdose)
- Number of Participants With Treatment-Emergent Adverse Events (TEAEs)(Baseline up to Day 28 after the last encorafenib dose (the total duration of the study was approximately 60 days from baseline))
- Number of Participnts With Clinically Significant Electrocardiogram (ECG) Abnormalities(Baseline, 0 and 2 hours postdose in each period, and at early discontinuation (the total duration of the study was approximately 60 days from baseline))