The primary goal of this phase 1 study is to evaluate the effect of food and cobicistat on the pharmacokinetics of plixorafenib in healthy participants. Healthy male and female participants between the ages of 18 and 55 will be enrolled into this study. This study is looking to examine the following in two parts: Part A * The effect of food on the single dose PK of plixorafenib administered with cobicistat. * The effect of cobicistat administration on the single dose PK of plixorafenib. * The safety of plixorafenib administered alone and with cobicistat in a single dose regimen in healthy participants. Part B * To examine the effect of a high-fat and a low-fat meal versus fasted state on the single dose PK of plixorafenib administered alone. * To examine the effect of a low-fat meal versus fasted state on the single dose PK of plixorafenib administered with cobicistat. * To determine the safety of plixorafenib administered alone or with cobicistat (low-fat meal only) in a single dose regimen.
Part A is an open-label, randomized, single dose, 3-treatment, 3-period, crossover design. On Day 1 of each period (Days 1, 8, and 15 of the confinement), participants will receive a single oral dose of plixorafenib administered either with or without cobicistat, under fasting conditions or following a standardized high-fat/high-calorie meal. PK blood and urine samples will be collected at pre-dose and at several post-dose time points. There will be a washout period between doses. Participants will be confined for total of 19 days. Part B is an open-label, randomized, single dose, 4-treatment, 3-period, crossover design. On Day 1 of each period (Days 1, 8, and 15 of the confinement), participants will receive a single oral dose of plixorafenib administered without cobicistat, under fasting conditions, following a standardized high-fat/high-calorie meal without cobicistat, or following a low-fat meal with or without cobicistat. PK blood and urine samples will be collected at pre-dose and at several post-dose time points. There will be a washout period between doses. participants will be confined for total of 19 days.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
BASIC_SCIENCE
Masking
NONE
Enrollment
28
Oral Tablet
Oral Tablet
PPD - Austin Research Unit
Austin, Texas, United States
Number of Participants With Treatment Emergent Adverse Events (TEAEs).
Number of Participants with at least one reported Treatment Emergent Adverse Events (TEAEs).
Time frame: First dose of Plixorafenib to day 19 (Treatment Period 3).
Area Under the Plasma Concentration Versus Time Curve (AUC) From Time 0 to the Last Quantifiable Concentration (AUC0-t).
Area under the concentration versus time curve from time 0 to the last quantifiable concentration within the dosing interval.
Time frame: Predose (0 hours) and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 32, 48, 72, and 96 hours after dosing in each treatment period.
AUC From Time 0 Extrapolated to Infinity (AUC0-inf).
Area under the concentration versus time curve from time 0 extrapolated to infinity calculated as AUC0-t + Clast/λz, where Clast is the last quantifiable concentration and lambda z is the terminal rate constant.
Time frame: Predose (0 hours) and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 32, 48, 72, and 96 hours after dosing in each treatment period.
Maximum Observed Plasma Concentration (Cmax).
Maximum observed concentration, obtained by inspection.
Time frame: Predose (0 hours) and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 32, 48, 72, and 96 hours after dosing in each treatment period.
Time to Maximum Observed Plasma Concentration (Tmax).
Time at which the maximum concentration was observed, obtained by inspection.
Time frame: Predose (0 hours) and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 32, 48, 72, and 96 hours after dosing in each treatment period.
Terminal Elimination Rate Constant (λz).
Terminal rate constant calculated from the terminal slope of the natural log-linear regression of concentration with time.
Time frame: Predose (0 hours) and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 32, 48, 72, and 96 hours after dosing in each treatment period.
Terminal Phase Half-life (t1/2).
Terminal half-life, calculated as ln (2)/λz.
Time frame: Predose (0 hours) and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 32, 48, 72, and 96 hours after dosing in each treatment period.
Apparent Oral Clearance (CL/F).
Oral clearance, calculated as Dose/AUC0 inf.
Time frame: Predose (0 hours) and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 32, 48, 72, and 96 hours after dosing in each treatment period.
Apparent Volume of Distribution (Vz/F).
Time frame: Predose (0 hours) and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 32, 48, 72, and 96 hours after dosing in each treatment period.
Lag Time of Absorption or the Time Delay Between Time 0 and the First Observed Quantifiable Concentration, Obtained by Inspection.
Time frame: Predose (0 hours) and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 32, 48, 72, and 96 hours after dosing in each treatment period.
Cumulative Amount of Plixorafenib Excreted in Urine(Ae)
The cumulative amount of plixorafenib in urine from 0 to 48 hours, Ae,48, was calculated for the Part A participants only as the sum between 0 and 48 hours of the product of the urine concentration and the urine volume for each collection interval by participant for each treatment.
Time frame: Predose (0 hours) and at intervals 0-4, 4-8, 8-12, 12-24 and 24-48 hours after dosing in each treatment period.
Percent of Dose Excreted in Urine in 48 Hours.
The percent of the dose excreted in urine in 48 hours (fe,48%) was calculated as Ae,48\*100/Dose.
Time frame: Predose (0 hours) and at intervals 0-4, 4-8, 8-12, 12-24 and 24-48 hours after dosing in each treatment period.
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