Healthy Volunteer
Conditions
Brief summary
This two-group study will investigate the effect of food (Group 1) and esomeprazole (Group 2) on the single oral dose pharmacokinetics of alectinib in healthy volunteers. Participants in Group 1 will be randomly assigned to a two period treatment sequence (AB or BA) in which they will receive a single, oral dose of alectinib per period separated by at least 10 days. Each participant will receive single, oral doses alectinib given under fasted conditions (Treatment A) or following the ingestion of a high fat, high calorie meal (Treatment B) as determined by their assigned sequence. Participants in Group 2 will be given a single, oral dose of alectinib following a standard meal. After a washout period of at least 10 days, they will receive an oral dose of esomeprazole (40 mg) once daily for 6 days. On the 6th day of esomeprazole administration, a single, oral dose alectinib will be given after ingestion of a standard meal. In all groups, pharmacokinetics will be assessed in the 4 days following alectinib administration.
Interventions
DRUGAlectinib
A single 600-mg oral dose of alectinib will be administered in a fasted or fed condition.
DRUGEsomeprazole
Esomeprazole 40 mg will be administered orally once daily for 6 days prior to alectinib administration.
OTHERHigh Fat and Calorie Meal
High fat and calorie meal served prior to alectinib administration
OTHERStandard Meal
Standard meal served prior to alectinib administration
Sponsors
Hoffmann-La Roche
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
* Body mass index (BMI) between 18 to 32 kilogram per square meter (kg/m\^2) * Healthy male and female participants. Healthy status will be defined by absence of evidence of any active or chronic disease following a detailed medical and surgical history, a complete physical examination including vital signs, 12-lead electrocardiogram (ECG), hematology, blood chemistry, serology and urinalysis * Female participants must be surgically sterile or post-menopausal for the past year confirmed by a blood follicle stimulating hormone (FSH) test for females without hormone replacement therapy (HRT) * Male participants must be willing to use effective contraception, as defined by the protocol, throughout the study and for 3 months after last drug administration * Willing to abstain from xanthine-containing beverages or food (coffee, tea, cola, chocolate, and energy drinks) use from 72 hours prior to admission to the study clinic until discharge * Willing to abstain from consuming grapefruit, pomelo, star fruit, or Seville orange containing products from 7 days prior to first dose of study medication through discharge * Willing to avoid prolonged sun exposure while taking alectinib and through follow-up. Participants should also be advised to use a broad spectrum sun screen and lip balm of at least sun protection factor (SPF) \> 30 to help protect against potential sunburn * Group 2 participants should be H. Pylori negative via breath test
Exclusion criteria
* Pregnant or breastfeeding women, males with female partners who are pregnant or breastfeeding, or women of childbearing potential. * Positive test for drugs of abuse, alcohol or cotinine test at screening or prior to admission to the study unit * Suspicion of regular consumption of drug(s) of abuse including marijuana. * Current smokers or participants who have discontinued smoking less than six months prior to first dosing. Participants should avoid smoky environments for at least 1 weeks prior to each cotinine test * History (within 3 months of screening) of alcohol consumption exceeding 2 standard drinks per day on average (1 standard drink = 10 grams of alcohol). Alcohol consumption will be prohibited 72 hours prior to admission to the study clinic and throughout the entire study until discharge * Participants with any risk factors or family history for QT/QTcF prolongation or ECG abnormalities or any abnormality in the ECG that, in the opinion of the investigator, increases the risk of participating in the study * Confirmed systolic blood pressure (SBP) greater than 140 millimeter of mercury (mmHg) or less than 90 mmHg or diastolic blood pressure (DBP) greater than 90 mmHg or less than 45 mmHg at screening, admission to the study center or prior to dosing. * Notable resting bradycardia (mean pulse rate \< 45 beats per minute \[bpm\]) or tachycardia (mean pulse rate \> 90 bpm) * Use of any medications (prescription or over-the-counter) within 2 weeks or 5 half-lives (whichever is longer) before the first dose of the study medication with the exception of acetaminophen up to 2 g per day up to 48 hours prior to dosing, not to exceed 4 g total during the week prior to dosing * Use of any herbal supplements or any metabolic inducers within 4 weeks or 5 half-lives (whichever is longer) before the first dose of study medication, including but not limited to the following drugs: rifampin, rifabutin, glucocorticoids, carbamazepine, phenytoin and phenobarbital * Strenuous activity, sunbathing or contact sports are not allowed from 4 days prior to entry into the clinical site and for the duration of the study until follow-up * Participation in an investigational drug or device study within 45 days or 5 half-lives (whichever is longer) or 6 months for biologic therapies prior to first dosing * Donation of blood over 450 mL within 45 days prior to screening * Regular use of antacids, Histamine 2 (H2) receptor blockers, proton pump inhibitors (PPIs) or any medications which may alter the normal gastric environment and/or motility. No use of such medications within 2 weeks prior to first dose.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Observed Plasma Concentration (Cmax) of Alectinib: Group 1 | Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours after dosing in each treatment arm | — |
| Cmax of Alectinib: Group 2 | Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours post alectinib dose in each treatment period | — |
| Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUC0-inf) of Alectinib: Group 1 | Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours after dosing in each treatment arm | AUC (0-inf) = Area under the plasma concentration versus time curve from time zero (pre-dose) to extrapolated infinite time (0-inf). It is obtained from AUC (0 - t) plus AUC (t - inf). |
| AUC0-inf of Alectinib: Group 2 | Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours post alectinib dose in each treatment period | AUC (0-inf) = Area under the plasma concentration versus time curve from time zero (pre-dose) to extrapolated infinite time (0-inf). It is obtained from AUC (0 - t) plus AUC (t - inf). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Metabolite/Parent Ratio for AUC0-inf: Group 1 | Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours after dosing in each treatment arm | AUC (0-inf) = Area under the plasma concentration versus time curve from time zero (pre-dose) to extrapolated infinite time (0-inf). It is obtained from AUC (0 - t) plus AUC (t - inf). RO5468924 is M4 metabolite of alectinib. The ratio is molecular weight adjusted. |
| Metabolite/Parent Ratio for AUC0-inf: Group 2 | Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours post alectinib dose in each treatment period | AUC (0-inf) = Area under the plasma concentration versus time curve from time zero (pre-dose) to extrapolated infinite time (0-inf). It is obtained from AUC (0 - t) plus AUC (t - inf). RO5468924 is M4 metabolite of alectinib. The ratio is molecular weight adjusted. |
| Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) of Alectinib: Group 1 | Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours after dosing in each treatment arm | Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast). |
| AUClast of Alectinib: Group 2 | Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours post alectinib dose in each treatment period | Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast). |
| AUClast of RO5468924: Group 1 | Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours after dosing in each treatment arm | Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast). RO5468924 is M4 metabolite of alectinib. |
| AUClast of RO5468924: Group 2 | Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours post alectinib dose in each treatment period | Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast). RO5468924 is M4 metabolite of alectinib. |
| Time to Reach Maximum Observed Plasma Concentration (Tmax) of Alectinib: Group 1 | Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours after dosing in each treatment arm | — |
| Tmax of Alectinib: Group 2 | Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours post alectinib dose in each treatment period | — |
| Tmax of RO5468924: Group 1 | Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours after dosing in each treatment arm | RO5468924 is M4 metabolite of alectinib. |
| AUC0-inf of RO5468924: Group 1 | Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours after dosing in each treatment arm | AUC (0-inf) = Area under the plasma concentration versus time curve from time zero (pre-dose) to extrapolated infinite time (0-inf). It is obtained from AUC (0 - t) plus AUC (t - inf). RO5468924 is M4 metabolite of alectinib. |
| Terminal Half-life (t1/2) of Alectinib: Group 1 | Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours after dosing in each treatment arm | Plasma decay half-life is the time measured for the plasma concentration to decrease by one half. |
| t1/2 of Alectinib: Group 2 | Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours post alectinib dose in each treatment period | Plasma decay half-life is the time measured for the plasma concentration to decrease by one half. |
| t1/2 of RO5468924: Group 1 | Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours after dosing in each treatment period | Plasma decay half-life is the time measured for the plasma concentration to decrease by one half. RO5468924 is M4 metabolite of alectinib. |
| t1/2 of RO5468924: Group 2 | Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours post alectinib dose in each treatment period | Plasma decay half-life is the time measured for the plasma concentration to decrease by one half. RO5468924 is M4 metabolite of alectinib. |
| Apparent Oral Clearance (CL/F) for Alectinib: Group 1 | Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours after dosing in each treatment arm | Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. |
| CL/F for Alectinib: Group 2 | Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours post alectinib dose in each treatment period | Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. |
| Apparent Volume of Distribution (Vz/F) for Alectinib: Group 1 | Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours after dosing in each treatment arm | Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Vz/F is influenced by the fraction absorbed. |
| Vz/F for Alectinib: Group 2 | Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours post alectinib dose in each treatment period | Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Vz/F is influenced by the fraction absorbed. |
| Tmax of RO5468924: Group 2 | Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours post alectinib dose in each treatment period | RO5468924 is M4 metabolite of alectinib. |
| Cmax of RO5468924: Group 1 | Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours after dosing in each treatment arm | RO5468924 is M4 metabolite of alectinib. |
| Cmax of RO5468924: Group 2 | Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours post alectinib dose in each treatment period | RO5468924 is M4 metabolite of alectinib. |
| AUC0-inf of RO5468924: Group 2 | Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours post alectinib dose in each treatment period | AUC (0-inf) = Area under the plasma concentration versus time curve from time zero (pre-dose) to extrapolated infinite time (0-inf). It is obtained from AUC (0 - t) plus AUC (t - inf). RO5468924 is M4 metabolite of alectinib. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Group 1 (Treatment Sequence AB or BA) Participants in Group 1 were randomly assigned to a two period treatment sequence (AB or BA) in which they received a single, oral dose of 600 mg of alectinib per period separated by at least 10 days. Each participant received single, oral doses alectinib given under fasted conditions (Treatment A) or following the ingestion of a high fat, high calorie meal (Treatment B) as determined by their assigned sequence. | 18 |
| Group 2: Alectinib Alone, Alectinib + Esomeprazole Period 1 (Days 1 to 10): Following an overnight fast of at least 10 hours, participants started a standardized meal and were to consume the meal in 30 minutes or less. The single 600-mg oral dose of alectinib was administered 30 minutes after the start of the meal on Day 1 of Period 1. Period 2 (Days 11 to 20): Participants received oral esomeprazole 40 mg once daily for 6 days (Days 11-16) in the morning after an overnight fast of at least 10 hours, and at least 1 hour before a regular breakfast; On Day 16, following an overnight fast of at least 10 hours, a single oral dose of 40 mg esomeprazole was administered 1.5 hours prior to the start of a standardized meal. Following a standardized meal, a single oral 600 mg dose of alectinib was then administered. | 24 |
| Total | 42 |
Baseline characteristics
| Characteristic | Group 1 (Treatment Sequence AB or BA) | Group 2: Alectinib Alone, Alectinib + Esomeprazole | Total |
|---|---|---|---|
| Age, Continuous | 35.3 years STANDARD_DEVIATION 8.5 | 35.4 years STANDARD_DEVIATION 8.3 | 35.4 years STANDARD_DEVIATION 8.3 |
| Sex: Female, Male Female | 1 Participants | 2 Participants | 3 Participants |
| Sex: Female, Male Male | 17 Participants | 22 Participants | 39 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 8 / 18 | 8 / 18 | 5 / 24 | 3 / 24 | 4 / 24 |
| serious Total, serious adverse events | 0 / 18 | 0 / 18 | 0 / 24 | 0 / 24 | 0 / 24 |
Outcome results
Primary
Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUC0-inf) of Alectinib: Group 1
AUC (0-inf) = Area under the plasma concentration versus time curve from time zero (pre-dose) to extrapolated infinite time (0-inf). It is obtained from AUC (0 - t) plus AUC (t - inf).
Time frame: Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours after dosing in each treatment arm
Population: PK Analysis Population \[Group 1\]
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group 1: Treatment A (Fasted Treatment) | Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUC0-inf) of Alectinib: Group 1 | 1900 hours*nanograms per milliliter (h*ng/mL) | Standard Deviation 665 |
| Group 1: Treatment B (Fed Treatment) | Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUC0-inf) of Alectinib: Group 1 | 5480 hours*nanograms per milliliter (h*ng/mL) | Standard Deviation 1800 |
Comparison: ANOVA was applied to the log-transformed PK parameter and then back transformed to provide geometric least square mean ratios (Treatment B/Treatment A) and CIs.90% CI: [258, 329]
Primary
AUC0-inf of Alectinib: Group 2
AUC (0-inf) = Area under the plasma concentration versus time curve from time zero (pre-dose) to extrapolated infinite time (0-inf). It is obtained from AUC (0 - t) plus AUC (t - inf).
Time frame: Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours post alectinib dose in each treatment period
Population: PK Analysis Population \[Group 2\]
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group 1: Treatment A (Fasted Treatment) | AUC0-inf of Alectinib: Group 2 | 3180 h*ng/mL | Standard Deviation 876 |
| Group 1: Treatment B (Fed Treatment) | AUC0-inf of Alectinib: Group 2 | 3940 h*ng/mL | Standard Deviation 1310 |
Comparison: ANOVA was applied to the log-transformed PK parameter and then back transformed to provide geometric least square mean ratios (Alectinib + Esomeprazole/Alectinib Alone) and CIs.90% CI: [109, 136]
Primary
Cmax of Alectinib: Group 2
Time frame: Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours post alectinib dose in each treatment period
Population: PK Analysis Population \[Group 2\] consisted of all participants who received both scheduled doses of Alectinib, and provided adequate PK assessments.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group 1: Treatment A (Fasted Treatment) | Cmax of Alectinib: Group 2 | 169 ng/mL | Standard Deviation 47.3 |
| Group 1: Treatment B (Fed Treatment) | Cmax of Alectinib: Group 2 | 196 ng/mL | Standard Deviation 54.7 |
Comparison: ANOVA was applied to the log-transformed PK parameter and then back transformed to provide geometric least square mean ratios (Alectinib + Esomeprazole/Alectinib Alone) and CIs.90% CI: [103, 132]
Primary
Maximum Observed Plasma Concentration (Cmax) of Alectinib: Group 1
Time frame: Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours after dosing in each treatment arm
Population: Pharmacokinetic (PK) Analysis Population \[Group 1\] consisted of all participants who received both scheduled doses of Alectinib, and provided adequate PK assessments.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group 1: Treatment A (Fasted Treatment) | Maximum Observed Plasma Concentration (Cmax) of Alectinib: Group 1 | 103 nanograms per milliliter (ng/mL) | Standard Deviation 41.1 |
| Group 1: Treatment B (Fed Treatment) | Maximum Observed Plasma Concentration (Cmax) of Alectinib: Group 1 | 270 nanograms per milliliter (ng/mL) | Standard Deviation 86.4 |
Comparison: Analysis of variance (ANOVA) was applied to the log-transformed PK parameter and then back transformed to provide geometric least square mean ratios (Treatment B/Treatment A) and confidence intervals (CIs).90% CI: [228, 320]
Secondary
Apparent Oral Clearance (CL/F) for Alectinib: Group 1
Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood.
Time frame: Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours after dosing in each treatment arm
Population: PK Analysis Population \[Group 1\]
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group 1: Treatment A (Fasted Treatment) | Apparent Oral Clearance (CL/F) for Alectinib: Group 1 | 357 Liters per hour (L/h) | Standard Deviation 136 |
| Group 1: Treatment B (Fed Treatment) | Apparent Oral Clearance (CL/F) for Alectinib: Group 1 | 120 Liters per hour (L/h) | Standard Deviation 38.1 |
Secondary
Apparent Volume of Distribution (Vz/F) for Alectinib: Group 1
Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Vz/F is influenced by the fraction absorbed.
Time frame: Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours after dosing in each treatment arm
Population: PK Analysis Population \[Group 1\]
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group 1: Treatment A (Fasted Treatment) | Apparent Volume of Distribution (Vz/F) for Alectinib: Group 1 | 11800 Liters | Standard Deviation 7200 |
| Group 1: Treatment B (Fed Treatment) | Apparent Volume of Distribution (Vz/F) for Alectinib: Group 1 | 3060 Liters | Standard Deviation 1290 |
Secondary
Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) of Alectinib: Group 1
Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast).
Time frame: Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours after dosing in each treatment arm
Population: PK Analysis Population \[Group 1\]
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group 1: Treatment A (Fasted Treatment) | Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) of Alectinib: Group 1 | 1780 h*ng/mL | Standard Deviation 648 |
| Group 1: Treatment B (Fed Treatment) | Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) of Alectinib: Group 1 | 5360 h*ng/mL | Standard Deviation 1750 |
Comparison: ANOVA was applied to the log-transformed PK parameter and then back transformed to provide geometric least square mean ratios (Treatment B/Treatment A) and CIs.90% CI: [269, 348]
Secondary
AUC0-inf of RO5468924: Group 1
AUC (0-inf) = Area under the plasma concentration versus time curve from time zero (pre-dose) to extrapolated infinite time (0-inf). It is obtained from AUC (0 - t) plus AUC (t - inf). RO5468924 is M4 metabolite of alectinib.
Time frame: Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours after dosing in each treatment arm
Population: PK Analysis Population \[Group 1\]
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group 1: Treatment A (Fasted Treatment) | AUC0-inf of RO5468924: Group 1 | 1140 h*ng/mL | Standard Deviation 497 |
| Group 1: Treatment B (Fed Treatment) | AUC0-inf of RO5468924: Group 1 | 3480 h*ng/mL | Standard Deviation 758 |
Comparison: ANOVA was applied to the log-transformed PK parameter and then back transformed to provide geometric least square mean ratios (Treatment B/Treatment A) and CIs.90% CI: [276, 389]
Secondary
AUC0-inf of RO5468924: Group 2
AUC (0-inf) = Area under the plasma concentration versus time curve from time zero (pre-dose) to extrapolated infinite time (0-inf). It is obtained from AUC (0 - t) plus AUC (t - inf). RO5468924 is M4 metabolite of alectinib.
Time frame: Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours post alectinib dose in each treatment period
Population: PK Analysis Population \[Group 2\]
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group 1: Treatment A (Fasted Treatment) | AUC0-inf of RO5468924: Group 2 | 1860 h*ng/mL | Standard Deviation 639 |
| Group 1: Treatment B (Fed Treatment) | AUC0-inf of RO5468924: Group 2 | 2050 h*ng/mL | Standard Deviation 713 |
Comparison: ANOVA was applied to the log-transformed PK parameter and then back transformed to provide geometric least square mean ratios (Alectinib + Esomeprazole/Alectinib Alone) and CIs.90% CI: [96.3, 126]
Secondary
AUClast of Alectinib: Group 2
Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast).
Time frame: Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours post alectinib dose in each treatment period
Population: PK Analysis Population \[Group 2\]
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group 1: Treatment A (Fasted Treatment) | AUClast of Alectinib: Group 2 | 3050 h*ng/mL | Standard Deviation 867 |
| Group 1: Treatment B (Fed Treatment) | AUClast of Alectinib: Group 2 | 3790 h*ng/mL | Standard Deviation 1280 |
Comparison: ANOVA was applied to the log-transformed PK parameter and then back transformed to provide geometric least square mean ratios (Alectinib + Esomeprazole/Alectinib Alone) and CIs.90% CI: [110, 136]
Secondary
AUClast of RO5468924: Group 1
Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast). RO5468924 is M4 metabolite of alectinib.
Time frame: Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours after dosing in each treatment arm
Population: PK Analysis Population \[Group 1\]
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group 1: Treatment A (Fasted Treatment) | AUClast of RO5468924: Group 1 | 1030 h*ng/mL | Standard Deviation 491 |
| Group 1: Treatment B (Fed Treatment) | AUClast of RO5468924: Group 1 | 3290 h*ng/mL | Standard Deviation 715 |
Comparison: ANOVA was applied to the log-transformed PK parameter and then back transformed to provide geometric least square mean ratios (Treatment B/Treatment A) and CIs.90% CI: [288, 422]
Secondary
AUClast of RO5468924: Group 2
Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast). RO5468924 is M4 metabolite of alectinib.
Time frame: Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours post alectinib dose in each treatment period
Population: PK Analysis Population \[Group 2\]
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group 1: Treatment A (Fasted Treatment) | AUClast of RO5468924: Group 2 | 1750 h*ng/mL | Standard Deviation 617 |
| Group 1: Treatment B (Fed Treatment) | AUClast of RO5468924: Group 2 | 1920 h*ng/mL | Standard Deviation 685 |
Comparison: ANOVA was applied to the log-transformed PK parameter and then back transformed to provide geometric least square mean ratios (Alectinib + Esomeprazole/Alectinib Alone) and CIs.90% CI: [95.3, 126]
Secondary
CL/F for Alectinib: Group 2
Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood.
Time frame: Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours post alectinib dose in each treatment period
Population: PK Analysis Population \[Group 2\]
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group 1: Treatment A (Fasted Treatment) | CL/F for Alectinib: Group 2 | 206 L/h | Standard Deviation 72.5 |
| Group 1: Treatment B (Fed Treatment) | CL/F for Alectinib: Group 2 | 170 L/h | Standard Deviation 61 |
Secondary
Cmax of RO5468924: Group 1
RO5468924 is M4 metabolite of alectinib.
Time frame: Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours after dosing in each treatment arm
Population: PK Analysis Population \[Group 1\]
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group 1: Treatment A (Fasted Treatment) | Cmax of RO5468924: Group 1 | 37.5 ng/mL | Standard Deviation 20.7 |
| Group 1: Treatment B (Fed Treatment) | Cmax of RO5468924: Group 1 | 126 ng/mL | Standard Deviation 31.9 |
Comparison: ANOVA was applied to the log-transformed PK parameter and then back transformed to provide geometric least square mean ratios (Treatment B/Treatment A) and CIs.90% CI: [303, 468]
Secondary
Cmax of RO5468924: Group 2
RO5468924 is M4 metabolite of alectinib.
Time frame: Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours post alectinib dose in each treatment period
Population: PK Analysis Population \[Group 2\]
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group 1: Treatment A (Fasted Treatment) | Cmax of RO5468924: Group 2 | 72.1 ng/mL | Standard Deviation 28.8 |
| Group 1: Treatment B (Fed Treatment) | Cmax of RO5468924: Group 2 | 72.1 ng/mL | Standard Deviation 26.4 |
Comparison: ANOVA was applied to the log-transformed PK parameter and then back transformed to provide geometric least square mean ratios (Alectinib + Esomeprazole/Alectinib Alone) and CIs.90% CI: [87, 119]
Secondary
Metabolite/Parent Ratio for AUC0-inf: Group 1
AUC (0-inf) = Area under the plasma concentration versus time curve from time zero (pre-dose) to extrapolated infinite time (0-inf). It is obtained from AUC (0 - t) plus AUC (t - inf). RO5468924 is M4 metabolite of alectinib. The ratio is molecular weight adjusted.
Time frame: Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours after dosing in each treatment arm
Population: PK Analysis Population \[Group 1\]
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Group 1: Treatment A (Fasted Treatment) | Metabolite/Parent Ratio for AUC0-inf: Group 1 | 0.610 ratio | Standard Deviation 0.07 |
| Group 1: Treatment B (Fed Treatment) | Metabolite/Parent Ratio for AUC0-inf: Group 1 | 0.686 ratio | Standard Deviation 0.08 |
Secondary
Metabolite/Parent Ratio for AUC0-inf: Group 2
AUC (0-inf) = Area under the plasma concentration versus time curve from time zero (pre-dose) to extrapolated infinite time (0-inf). It is obtained from AUC (0 - t) plus AUC (t - inf). RO5468924 is M4 metabolite of alectinib. The ratio is molecular weight adjusted.
Time frame: Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours post alectinib dose in each treatment period
Population: PK Analysis Population \[Group 2\]
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Group 1: Treatment A (Fasted Treatment) | Metabolite/Parent Ratio for AUC0-inf: Group 2 | 0.548 ratio | Standard Deviation 0.05 |
| Group 1: Treatment B (Fed Treatment) | Metabolite/Parent Ratio for AUC0-inf: Group 2 | 0.607 ratio | Standard Deviation 0.08 |
Secondary
t1/2 of Alectinib: Group 2
Plasma decay half-life is the time measured for the plasma concentration to decrease by one half.
Time frame: Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours post alectinib dose in each treatment period
Population: PK Analysis Population \[Group 2\]
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group 1: Treatment A (Fasted Treatment) | t1/2 of Alectinib: Group 2 | 20.4 hours | Standard Deviation 9.33 |
| Group 1: Treatment B (Fed Treatment) | t1/2 of Alectinib: Group 2 | 20.4 hours | Standard Deviation 7.56 |
Secondary
t1/2 of RO5468924: Group 1
Plasma decay half-life is the time measured for the plasma concentration to decrease by one half. RO5468924 is M4 metabolite of alectinib.
Time frame: Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours after dosing in each treatment period
Population: PK Analysis Population \[Group 1\]
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group 1: Treatment A (Fasted Treatment) | t1/2 of RO5468924: Group 1 | 29.4 hours | Standard Deviation 7.05 |
| Group 1: Treatment B (Fed Treatment) | t1/2 of RO5468924: Group 1 | 22.7 hours | Standard Deviation 3.27 |
Secondary
t1/2 of RO5468924: Group 2
Plasma decay half-life is the time measured for the plasma concentration to decrease by one half. RO5468924 is M4 metabolite of alectinib.
Time frame: Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours post alectinib dose in each treatment period
Population: PK Analysis Population \[Group 2\]
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group 1: Treatment A (Fasted Treatment) | t1/2 of RO5468924: Group 2 | 25.0 hours | Standard Deviation 4.56 |
| Group 1: Treatment B (Fed Treatment) | t1/2 of RO5468924: Group 2 | 25.4 hours | Standard Deviation 5.06 |
Secondary
Terminal Half-life (t1/2) of Alectinib: Group 1
Plasma decay half-life is the time measured for the plasma concentration to decrease by one half.
Time frame: Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours after dosing in each treatment arm
Population: PK Analysis Population \[Group 1\]
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group 1: Treatment A (Fasted Treatment) | Terminal Half-life (t1/2) of Alectinib: Group 1 | 23.4 hours | Standard Deviation 13.7 |
| Group 1: Treatment B (Fed Treatment) | Terminal Half-life (t1/2) of Alectinib: Group 1 | 17.7 hours | Standard Deviation 5.12 |
Secondary
Time to Reach Maximum Observed Plasma Concentration (Tmax) of Alectinib: Group 1
Time frame: Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours after dosing in each treatment arm
Population: PK Analysis Population \[Group 1\]
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group 1: Treatment A (Fasted Treatment) | Time to Reach Maximum Observed Plasma Concentration (Tmax) of Alectinib: Group 1 | 4.00 hours |
| Group 1: Treatment B (Fed Treatment) | Time to Reach Maximum Observed Plasma Concentration (Tmax) of Alectinib: Group 1 | 8.00 hours |
Secondary
Tmax of Alectinib: Group 2
Time frame: Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours post alectinib dose in each treatment period
Population: PK Analysis Population \[Group 2\]
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group 1: Treatment A (Fasted Treatment) | Tmax of Alectinib: Group 2 | 6.00 hours |
| Group 1: Treatment B (Fed Treatment) | Tmax of Alectinib: Group 2 | 6.00 hours |
Secondary
Tmax of RO5468924: Group 1
RO5468924 is M4 metabolite of alectinib.
Time frame: Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours after dosing in each treatment arm
Population: PK Analysis Population \[Group 1\]
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group 1: Treatment A (Fasted Treatment) | Tmax of RO5468924: Group 1 | 8.00 hours |
| Group 1: Treatment B (Fed Treatment) | Tmax of RO5468924: Group 1 | 10.0 hours |
Secondary
Tmax of RO5468924: Group 2
RO5468924 is M4 metabolite of alectinib.
Time frame: Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours post alectinib dose in each treatment period
Population: PK Analysis Population \[Group 2\]
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group 1: Treatment A (Fasted Treatment) | Tmax of RO5468924: Group 2 | 6.02 hours |
| Group 1: Treatment B (Fed Treatment) | Tmax of RO5468924: Group 2 | 8.00 hours |
Secondary
Vz/F for Alectinib: Group 2
Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Vz/F is influenced by the fraction absorbed.
Time frame: Predose (0 hours) and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, and 96 hours post alectinib dose in each treatment period
Population: PK Analysis Population \[Group 2\]
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group 1: Treatment A (Fasted Treatment) | Vz/F for Alectinib: Group 2 | 5930 Liters | Standard Deviation 2950 |
| Group 1: Treatment B (Fed Treatment) | Vz/F for Alectinib: Group 2 | 4890 Liters | Standard Deviation 2070 |