Healthy Volunteer
Conditions
Brief summary
This 2-part, single center, open-label, randomized, single-dose, 4-sequence, 4-period cross-over study will compare the bioequivalence of three test RO5424802 capsule formulations with the reference capsule formulation in healthy adult volunteers. All participants in both fasted (Part 1) and fed (Part 2) conditions of the study will receive each of 4 treatments (Ro542-4802/F03 \[RO5424802 with 50 percentage (%) sodium lauryl sulfate (SLS) (reference)\], Ro542-4802/F07 \[RO5424802 with 25% SLS (test)\], Ro542-4802/F14 \[RO5424802 with 12.5% SLS (test)\] and Ro542-4802/F08 \[RO5424802 with 3% SLS (test)\] in a randomized sequence. Each treatment will be given as a single 600 milligrams (mg) oral administration in an upright position on Day 1 after an overnight fast, followed by a 10-day washout period. Total time on study is expected to last up to 75 days, for each enrolled participant.
Interventions
DRUGRo542-4802/F03 (Reference)
Participants will receive Ro542-4802/F03 (containing 50% SLS) 600 mg capsules orally on Day 1.
DRUGRo542-4802/F07 (Test)
Participants will receive Ro542-4802/F07 (containing 25% SLS) 600 mg capsules orally on Day 1.
DRUGRo542-4802/F08 (Test)
Participants will receive Ro542-4802/F08 (containing 3% SLS) 600 mg capsules orally on Day 1.
DRUGRo542-4802/F14 (Test)
Participants will receive Ro542-4802/F14 (containing 12.5% SLS) 600 mg capsules orally on Day 1.
Sponsors
Hoffmann-La Roche
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy male and surgically sterile or post-menopausal female participants 18-55 years of age * Body mass index (BMI) between 18 to 32 kilograms per meter-squared (kg/m\^2) * Non-smoking participants and former smoking participants (who have not smoked for the past six months before first dosing) * Male participants and their partners of child-bearing potential must be willing to use two effective contraceptive methods as defined by protocol * Willing to abstain from xanthine-containing beverages and food (coffee, tea, cola, chocolate, and energy drinks) from 72 hours prior to Day -1 through the study * Willing to abstain from grapefruit, pomelo, star fruit or Seville orange containing products from day 7 prior study start until study end * Willing to avoid prolonged sun exposure while taking RO5424802 and through follow-up
Exclusion criteria
* Pregnant or lactating women, men with female partners who are pregnant or lactating, or women of child bearing potential * Clinically significant abnormalities on physical examination, vital signs, or laboratory test results during screening or prior to admission to the study unit * Positive test for drugs of abuse, alcohol or cotinine test at screening or prior to admission to the study unit or suspicion of regular consumption of drug(s) of abuse * History of recent alcohol consumption exceeding 2 standard drinks per day on average. Alcohol consuming is prohibited from 72 hours prior to study start until the end of the study * Participants with any risk factors or family history for QT/QTcF and electrocardiogram (ECG) abnormalities * A history of any concurrent clinically significant hematologic, renal, hepatic, pulmonary, neurological, psychiatric, allergies, gastrointestinal, metabolic or endocrine disorder, or cardiovascular disease or infections * Positive screening test for hepatitis B, C, or human immunodeficiency virus (HIV) * Use of any medications (prescriptions or over-the-counter), within 2 weeks or 5 half-lives (whichever is longer) before the first dose of study medication with exception of acetaminophen up to 2 grams (g) per day up to 48 hours prior to dosing, not to exceed 4 g total during the week prior to dosing * Routine or chronic use of more than 2 g of acetaminophen daily * Use of any herbal supplements (for example, St. John's Wort) 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 study start until the end of the study * Participation in an investigational drug or device study within 45 days or 5 half-lives (whichever time period is longer), or 6 months for biologic therapies, prior to first dosing * Donation of blood over 450 milliliters (mL) within 45 days prior to screening
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Plasma Concentration-Time Curve From Time Zero to Extrapolated Infinite Time (AUC[0-inf]) of Alectinib | Predose (0 hour), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, 24, 36, 48, 60, 72, and 96 hours postdose | AUC(0-inf) is the area under the alectinib plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0-inf). AUC is a measure of the plasma concentration of a drug over time. AUC(0-inf) is presented in nanogram times (\*) hour per milliliter (ng\*hour/mL). |
| Area Under the Plasma Concentration-Time Curve From Time Zero to Last Measurable Concentration (AUC[0-last]) of Alectinib | Predose (0 hour), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, 24, 36, 48, 60, 72, and 96 hours postdose | AUC(0-last) is the area under the alectinib plasma concentration versus time curve from time zero to the time of last measured concentration of alectinib. AUC is a measure of the plasma concentration of a drug over time. AUC(0-last) is presented in ng\*hour/mL. |
| Maximum Observed Plasma Concentration (Cmax) of Alectinib | Predose (0 hour), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, 24, 36, 48, 60, 72, and 96 hours postdose | Cmax is the maximum observed plasma alectinib concentration, presented in nanogram per milliliter (ng/mL). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| AUC(0-inf) of RO5468924 | Predose (0 hour), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, 24, 36, 48, 60, 72, and 96 hours postdose | AUC(0-inf) is the area under the RO5468924 plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0-inf). RO5468924 is the major pharmacologically active metabolite of alectinib. AUC is a measure of the plasma concentration of a drug over time. AUC(0-inf) is presented in ng\*hour/mL. |
| AUC(0-last) of RO5468924 | Predose (0 hour), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, 24, 36, 48, 60, 72, and 96 hours postdose | AUC(0-last) is the area under the RO5468924 plasma concentration versus time curve from time zero to the time of last measured concentration of RO5468924. RO5468924 is the major pharmacologically active metabolite of alectinib. AUC is a measure of the plasma concentration of a drug over time. AUC(0-last) is presented in ng\*hour/mL. |
| Plasma Terminal Half-Life (t1/2) of Alectinib and RO5468924 | Predose (0 hour), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, 24, 36, 48, 60, 72, and 96 hours postdose | Plasma terminal half-life is the time measured during drug elimination phase for the plasma drug concentration to decrease by one half. RO5468924 is the major pharmacologically active metabolite of alectinib. |
| Elimination Rate Constant (Kel) of Alectinib and RO5468924 | Predose (0 hour), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, 24, 36, 48, 60, 72, and 96 hours postdose | First-order terminal elimination rate constant (Kel) was calculated as the negative slope of the linear regression of the terminal phase in plasma alectinib and RO5468924 concentration versus time profile using appropriate time points. RO5468924 is the major pharmacologically active metabolite of alectinib. |
| Total Molar Concentration of Alectinib and RO5468924 as Derived by AUC(0-inf) | Predose (0 hour), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, 24, 36, 48, 60, 72, and 96 hours postdose | AUC(0-inf) is the area under the alectinib + RO5468924 (major pharmacologically active metabolite of alectinib) molar plasma concentration versus time curve from time zero (pre-dose) to extrapolated infinite time (0-inf). AUC is a measure of the plasma concentration of the alectinib + RO5468924 over time. AUC(0-inf) is presented in nanomoles times (\*) hour per liter (nmol\*hour/L). |
| Total Molar Concentration of Alectinib and RO5468924 as Derived by Cmax | Predose (0 hour), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, 24, 36, 48, 60, 72, and 96 hours postdose | Cmax is the maximum observed molar plasma concentration for alectinib + RO5468924 (major pharmacologically active metabolite of alectinib). Cmax is presented in nanomoles per liter (nmol/L). |
| Total Molar Concentration of Alectinib and RO5468924 as Derived by AUC(0-last) | Predose (0 hour), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, 24, 36, 48, 60, 72, and 96 hours postdose | AUC(0-last) is the area under the alectinib + RO5468924 (major pharmacologically active metabolite of alectinib) molar plasma concentration versus time curve from time zero to the time of last measured concentration of alectinib + RO5468924. AUC(0-last) is presented in nmol\*hour/L. |
| Time to Reach Maximum Observed Plasma Concentration (Tmax) of Alectinib | Predose (0 hour), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, 24, 36, 48, 60, 72, and 96 hours postdose | Tmax is the time from alectinib administration to reach Cmax for alectinib. |
| Apparent Volume of Distribution (Vz/F) of Alectinib | Predose (0 hour), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, 24, 36, 48, 60, 72, and 96 hours postdose | 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. Apparent volume of distribution after oral dose (Vz/F) is influenced by the fraction of drug absorbed. |
| Percent Extrapolated AUC(0-inf) (AUC%Extrap[0-inf]) for Alectinib and RO5468924 | Predose (0 hour), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, 24, 36, 48, 60, 72, and 96 hours postdose | The AUC%extrap(0-inf), that is, area obtained after extrapolation (extrap) from time to last quantifiable plasma concentration (Tlast) to infinity is calculated by using the formula AUC%extrap(0-inf) = 100\*(AUC\[0-inf\] minus AUC\[0-last\])/AUC(0-inf); where AUC(0-inf) = Area under the plasma concentration versus time curve from time zero (pre-dose) to extrapolated infinite time and AUC(0-last) is area under the plasma concentration time-curve from zero (pre-dose) to the time of last measured concentration. The function of this parameter is to provide information about what percentage of the theoretical curve AUC(0-inf) was possible to determine experimentally (AUC0-last). |
| Adjusted r^2 Value (Rsq) for Regression Estimation of Kel for Alectinib and RO5468924 | Predose (0 hour), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, 24, 36, 48, 60, 72, and 96 hours postdose | — |
| Molecular Weight Adjusted Metabolite to Parent (M/P) Ratio for AUC(0-inf) | Predose (0 hour), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, 24, 36, 48, 60, 72, and 96 hours postdose | AUC(0-inf) is the area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0-inf). AUC is a measure of the plasma concentration of the alectinib and RO5468924 (major pharmacologically active metabolite of alectinib) over time. The molecular weight adjusted M/P ratio (RO5468924/alectinib) for AUC(0-inf) is presented. |
| Molecular Weight Adjusted M/P Ratio for AUC(0-last) | Predose (0 hour), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, 24, 36, 48, 60, 72, and 96 hours postdose | AUC(0-last) is the area under the plasma concentration versus time curve from time zero to the time of last measured concentration. AUC is a measure of the plasma concentration of the alectinib and RO5468924 (major pharmacologically active metabolite of alectinib) over time. The molecular weight adjusted M/P ratio (RO5468924/alectinib) for AUC(0-last) is presented. |
| Molecular Weight Adjusted M/P Ratio for Cmax | Predose (0 hour), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, 24, 36, 48, 60, 72, and 96 hours postdose | Cmax is the maximum observed plasma concentration of the alectinib and RO5468924 (major pharmacologically active metabolite of alectinib). The molecular weight adjusted M/P ratio (RO5468924/alectinib) for Cmax is presented. |
| Time to Reach Last Quantifiable Plasma Concentration (Tlast) of Alectinib and RO5468924 | Predose (0 hour), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, 24, 36, 48, 60, 72, and 96 hours postdose | Tlast is the time from alectinib administration to reach last quantifiable concentration of alectinib and its major pharmacologically active metabolite RO5468924. |
| Apparent Oral Clearance (CL/F) of Alectinib | Predose (0 hour), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, 24, 36, 48, 60, 72, and 96 hours postdose | 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. |
| Cmax of RO5468924 | Predose (0 hour), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, 24, 36, 48, 60, 72, and 96 hours postdose | Cmax is the maximum observed plasma RO5468924 concentration, presented in ng/mL. RO5468924 is the major pharmacologically active metabolite of alectinib. |
| Tmax of RO5468924 | Predose (0 hour), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, 24, 36, 48, 60, 72, and 96 hours postdose | Tmax is the time from alectinib administration to reach Cmax for RO5468924 (the major pharmacologically active metabolite of alectinib). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Part 1 (Fasted): Study Population Participants following an overnight fast of at least 10 hours received alectinib 600 mg capsules orally as Treatment A, B, C, and D according to any of the four treatment sequences in Part 1 of the study. | 49 |
| Part 2 (Fed): Study Population Participants following an overnight fast of at least 10 hours ate the high-fat, high-calorie meal in 30 minutes or less and 30 minutes after the start of the meal received alectinib 600 mg capsules orally as Treatment A, B, C, and D according to any of the four treatment sequences in Part 2 of the study. | 48 |
| Total | 97 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 |
|---|---|---|---|---|---|---|---|---|---|
| Intervention Period 1 | Family Emergency | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 |
| Washout Period 1 | Adverse Event | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Washout Period 1 | Other | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 |
| Washout Period 1 | Physician Decision | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 |
| Washout Period 2 | Adverse Event | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
| Washout Period 2 | Lost to Follow-up | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 |
| Washout Period 2 | Physician Decision | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 |
| Washout Period 3 | Physician Decision | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Part 1 (Fasted): Study Population | Part 2 (Fed): Study Population | Total |
|---|---|---|---|
| Age, Continuous | 37.6 years STANDARD_DEVIATION 10.01 | 36.1 years STANDARD_DEVIATION 10.49 | 36.9 years STANDARD_DEVIATION 10.2 |
| Sex: Female, Male Female | 8 Participants | 6 Participants | 14 Participants |
| Sex: Female, Male Male | 41 Participants | 42 Participants | 83 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 | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 47 | 3 / 45 | 3 / 46 | 3 / 47 | 6 / 45 | 6 / 47 | 4 / 46 | 7 / 46 |
| serious Total, serious adverse events | 0 / 47 | 0 / 45 | 0 / 46 | 0 / 47 | 0 / 45 | 0 / 47 | 0 / 46 | 0 / 46 |
Outcome results
Primary
Area Under the Plasma Concentration-Time Curve From Time Zero to Extrapolated Infinite Time (AUC[0-inf]) of Alectinib
AUC(0-inf) is the area under the alectinib plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0-inf). AUC is a measure of the plasma concentration of a drug over time. AUC(0-inf) is presented in nanogram times (\*) hour per milliliter (ng\*hour/mL).
Time frame: Predose (0 hour), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, 24, 36, 48, 60, 72, and 96 hours postdose
Population: The Pharmacokinetic (PK) analysis set included all participants who received the reference formulation 50% SLS alectinib (Treatment A) and at least 1 test formulation (Treatments B, C, or D) and provided adequate PK assessments.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1 (Fasted): Treatment A | Area Under the Plasma Concentration-Time Curve From Time Zero to Extrapolated Infinite Time (AUC[0-inf]) of Alectinib | 1920 ng*hour/mL | Standard Deviation 1000 |
| Part 1 (Fasted): Treatment B | Area Under the Plasma Concentration-Time Curve From Time Zero to Extrapolated Infinite Time (AUC[0-inf]) of Alectinib | 1840 ng*hour/mL | Standard Deviation 754 |
| Part 1 (Fasted): Treatment C | Area Under the Plasma Concentration-Time Curve From Time Zero to Extrapolated Infinite Time (AUC[0-inf]) of Alectinib | 1850 ng*hour/mL | Standard Deviation 841 |
| Part 1 (Fasted): Treatment D | Area Under the Plasma Concentration-Time Curve From Time Zero to Extrapolated Infinite Time (AUC[0-inf]) of Alectinib | 1630 ng*hour/mL | Standard Deviation 792 |
| Part 2 (Fed): Treatment A | Area Under the Plasma Concentration-Time Curve From Time Zero to Extrapolated Infinite Time (AUC[0-inf]) of Alectinib | 5720 ng*hour/mL | Standard Deviation 1530 |
| Part 2 (Fed): Treatment B | Area Under the Plasma Concentration-Time Curve From Time Zero to Extrapolated Infinite Time (AUC[0-inf]) of Alectinib | 5050 ng*hour/mL | Standard Deviation 1200 |
| Part 2 (Fed): Treatment C | Area Under the Plasma Concentration-Time Curve From Time Zero to Extrapolated Infinite Time (AUC[0-inf]) of Alectinib | 4600 ng*hour/mL | Standard Deviation 1260 |
| Part 2 (Fed): Treatment D | Area Under the Plasma Concentration-Time Curve From Time Zero to Extrapolated Infinite Time (AUC[0-inf]) of Alectinib | 4580 ng*hour/mL | Standard Deviation 1240 |
Comparison: Analysis of variance (ANOVA) (fixed factors: treatment, period, and treatment sequence; and random factor: participant) was applied to the log-transformed PK parameter, and then back transformed to provide geometric least square mean ratio (Test/Reference) and 90% confidence interval (CI).90% CI: [93.14, 108.44]
Comparison: ANOVA (fixed factors: treatment, period, and treatment sequence; and random factor: participant) was applied to the log-transformed PK parameter, and then back transformed to provide geometric least square mean ratio (Test/Reference) and 90% CI.90% CI: [90.71, 105.48]
Comparison: ANOVA (fixed factors: treatment, period, and treatment sequence; and random factor: participant) was applied to the log-transformed PK parameter, and then back transformed to provide geometric least square mean ratio (Test/Reference) and 90% CI.90% CI: [80.32, 93.5]
Comparison: ANOVA (fixed factors: treatment, period, and treatment sequence; and random factor: participant) was applied to the log-transformed PK parameter, and then back transformed to provide geometric least square mean ratio (Test/Reference) and 90% CI.90% CI: [85.15, 92.24]
Comparison: ANOVA (fixed factors: treatment, period, and treatment sequence; and random factor: participant) was applied to the log-transformed PK parameter, and then back transformed to provide geometric least square mean ratio (Test/Reference) and 90% CI.90% CI: [77.08, 83.39]
Comparison: ANOVA (fixed factors: treatment, period, and treatment sequence; and random factor: participant) was applied to the log-transformed PK parameter, and then back transformed to provide geometric least square mean ratio (Test/Reference) and 90% CI.90% CI: [76.84, 83.19]
Primary
Area Under the Plasma Concentration-Time Curve From Time Zero to Last Measurable Concentration (AUC[0-last]) of Alectinib
AUC(0-last) is the area under the alectinib plasma concentration versus time curve from time zero to the time of last measured concentration of alectinib. AUC is a measure of the plasma concentration of a drug over time. AUC(0-last) is presented in ng\*hour/mL.
Time frame: Predose (0 hour), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, 24, 36, 48, 60, 72, and 96 hours postdose
Population: PK analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1 (Fasted): Treatment A | Area Under the Plasma Concentration-Time Curve From Time Zero to Last Measurable Concentration (AUC[0-last]) of Alectinib | 1790 ng*hour/mL | Standard Deviation 925 |
| Part 1 (Fasted): Treatment B | Area Under the Plasma Concentration-Time Curve From Time Zero to Last Measurable Concentration (AUC[0-last]) of Alectinib | 1680 ng*hour/mL | Standard Deviation 620 |
| Part 1 (Fasted): Treatment C | Area Under the Plasma Concentration-Time Curve From Time Zero to Last Measurable Concentration (AUC[0-last]) of Alectinib | 1620 ng*hour/mL | Standard Deviation 637 |
| Part 1 (Fasted): Treatment D | Area Under the Plasma Concentration-Time Curve From Time Zero to Last Measurable Concentration (AUC[0-last]) of Alectinib | 1380 ng*hour/mL | Standard Deviation 573 |
| Part 2 (Fed): Treatment A | Area Under the Plasma Concentration-Time Curve From Time Zero to Last Measurable Concentration (AUC[0-last]) of Alectinib | 5540 ng*hour/mL | Standard Deviation 1460 |
| Part 2 (Fed): Treatment B | Area Under the Plasma Concentration-Time Curve From Time Zero to Last Measurable Concentration (AUC[0-last]) of Alectinib | 4820 ng*hour/mL | Standard Deviation 1130 |
| Part 2 (Fed): Treatment C | Area Under the Plasma Concentration-Time Curve From Time Zero to Last Measurable Concentration (AUC[0-last]) of Alectinib | 4370 ng*hour/mL | Standard Deviation 1170 |
| Part 2 (Fed): Treatment D | Area Under the Plasma Concentration-Time Curve From Time Zero to Last Measurable Concentration (AUC[0-last]) of Alectinib | 4360 ng*hour/mL | Standard Deviation 1160 |
Comparison: ANOVA (fixed factors: treatment, period, and treatment sequence; and random factor: participant) was applied to the log-transformed PK parameter, and then back transformed to provide geometric least square mean ratio (Test/Reference) and 90% CI.90% CI: [91.83, 106.99]
Comparison: ANOVA (fixed factors: treatment, period, and treatment sequence; and random factor: participant) was applied to the log-transformed PK parameter, and then back transformed to provide geometric least square mean ratio (Test/Reference) and 90% CI.90% CI: [86.94, 101.17]
Comparison: ANOVA (fixed factors: treatment, period, and treatment sequence; and random factor: participant) was applied to the log-transformed PK parameter, and then back transformed to provide geometric least square mean ratio (Test/Reference) and 90% CI.90% CI: [74.41, 86.7]
Comparison: ANOVA (fixed factors: treatment, period, and treatment sequence; and random factor: participant) was applied to the log-transformed PK parameter, and then back transformed to provide geometric least square mean ratio (Test/Reference) and 90% CI.90% CI: [83.92, 91.07]
Comparison: ANOVA (fixed factors: treatment, period, and treatment sequence; and random factor: participant) was applied to the log-transformed PK parameter, and then back transformed to provide geometric least square mean ratio (Test/Reference) and 90% CI.90% CI: [75.76, 82.11]
Comparison: ANOVA (fixed factors: treatment, period, and treatment sequence; and random factor: participant) was applied to the log-transformed PK parameter, and then back transformed to provide geometric least square mean ratio (Test/Reference) and 90% CI.90% CI: [75.53, 81.92]
Primary
Maximum Observed Plasma Concentration (Cmax) of Alectinib
Cmax is the maximum observed plasma alectinib concentration, presented in nanogram per milliliter (ng/mL).
Time frame: Predose (0 hour), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, 24, 36, 48, 60, 72, and 96 hours postdose
Population: PK analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1 (Fasted): Treatment A | Maximum Observed Plasma Concentration (Cmax) of Alectinib | 106 ng/mL | Standard Deviation 53.3 |
| Part 1 (Fasted): Treatment B | Maximum Observed Plasma Concentration (Cmax) of Alectinib | 91.7 ng/mL | Standard Deviation 34.5 |
| Part 1 (Fasted): Treatment C | Maximum Observed Plasma Concentration (Cmax) of Alectinib | 67.0 ng/mL | Standard Deviation 23.6 |
| Part 1 (Fasted): Treatment D | Maximum Observed Plasma Concentration (Cmax) of Alectinib | 42.2 ng/mL | Standard Deviation 19.2 |
| Part 2 (Fed): Treatment A | Maximum Observed Plasma Concentration (Cmax) of Alectinib | 271 ng/mL | Standard Deviation 81.8 |
| Part 2 (Fed): Treatment B | Maximum Observed Plasma Concentration (Cmax) of Alectinib | 232 ng/mL | Standard Deviation 59.3 |
| Part 2 (Fed): Treatment C | Maximum Observed Plasma Concentration (Cmax) of Alectinib | 206 ng/mL | Standard Deviation 50.4 |
| Part 2 (Fed): Treatment D | Maximum Observed Plasma Concentration (Cmax) of Alectinib | 204 ng/mL | Standard Deviation 57.1 |
Comparison: ANOVA (fixed factors: treatment, period, and treatment sequence; and random factor: participant) was applied to the log-transformed PK parameter, and then back transformed to provide geometric least square mean ratio (Test/Reference) and 90% CI.90% CI: [82.33, 99.12]
Comparison: ANOVA (fixed factors: treatment, period, and treatment sequence; and random factor: participant) was applied to the log-transformed PK parameter, and then back transformed to provide geometric least square mean ratio (Test/Reference) and 90% CI.90% CI: [60.45, 72.68]
Comparison: ANOVA (fixed factors: treatment, period, and treatment sequence; and random factor: participant) was applied to the log-transformed PK parameter, and then back transformed to provide geometric least square mean ratio (Test/Reference) and 90% CI.90% CI: [37.4, 45.03]
Comparison: ANOVA (fixed factors: treatment, period, and treatment sequence; and random factor: participant) was applied to the log-transformed PK parameter, and then back transformed to provide geometric least square mean ratio (Test/Reference) and 90% CI.90% CI: [81.77, 91.09]
Comparison: ANOVA (fixed factors: treatment, period, and treatment sequence; and random factor: participant) was applied to the log-transformed PK parameter, and then back transformed to provide geometric least square mean ratio (Test/Reference) and 90% CI.90% CI: [73.01, 81.2]
Comparison: ANOVA (fixed factors: treatment, period, and treatment sequence; and random factor: participant) was applied to the log-transformed PK parameter, and then back transformed to provide geometric least square mean ratio (Test/Reference) and 90% CI.90% CI: [71.71, 79.82]
Secondary
Adjusted r^2 Value (Rsq) for Regression Estimation of Kel for Alectinib and RO5468924
Time frame: Predose (0 hour), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, 24, 36, 48, 60, 72, and 96 hours postdose
Population: PK analysis set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1 (Fasted): Treatment A | Adjusted r^2 Value (Rsq) for Regression Estimation of Kel for Alectinib and RO5468924 | Alectinib | 0.987 no units | Standard Deviation 0.0252 |
| Part 1 (Fasted): Treatment A | Adjusted r^2 Value (Rsq) for Regression Estimation of Kel for Alectinib and RO5468924 | RO5468924 | 0.977 no units | Standard Deviation 0.0233 |
| Part 1 (Fasted): Treatment B | Adjusted r^2 Value (Rsq) for Regression Estimation of Kel for Alectinib and RO5468924 | Alectinib | 0.983 no units | Standard Deviation 0.0277 |
| Part 1 (Fasted): Treatment B | Adjusted r^2 Value (Rsq) for Regression Estimation of Kel for Alectinib and RO5468924 | RO5468924 | 0.970 no units | Standard Deviation 0.0293 |
| Part 1 (Fasted): Treatment C | Adjusted r^2 Value (Rsq) for Regression Estimation of Kel for Alectinib and RO5468924 | Alectinib | 0.973 no units | Standard Deviation 0.0622 |
| Part 1 (Fasted): Treatment C | Adjusted r^2 Value (Rsq) for Regression Estimation of Kel for Alectinib and RO5468924 | RO5468924 | 0.963 no units | Standard Deviation 0.0591 |
| Part 1 (Fasted): Treatment D | Adjusted r^2 Value (Rsq) for Regression Estimation of Kel for Alectinib and RO5468924 | Alectinib | 0.976 no units | Standard Deviation 0.0337 |
| Part 1 (Fasted): Treatment D | Adjusted r^2 Value (Rsq) for Regression Estimation of Kel for Alectinib and RO5468924 | RO5468924 | 0.958 no units | Standard Deviation 0.0687 |
| Part 2 (Fed): Treatment A | Adjusted r^2 Value (Rsq) for Regression Estimation of Kel for Alectinib and RO5468924 | Alectinib | 0.994 no units | Standard Deviation 0.00812 |
| Part 2 (Fed): Treatment A | Adjusted r^2 Value (Rsq) for Regression Estimation of Kel for Alectinib and RO5468924 | RO5468924 | 0.986 no units | Standard Deviation 0.0124 |
| Part 2 (Fed): Treatment B | Adjusted r^2 Value (Rsq) for Regression Estimation of Kel for Alectinib and RO5468924 | Alectinib | 0.991 no units | Standard Deviation 0.0189 |
| Part 2 (Fed): Treatment B | Adjusted r^2 Value (Rsq) for Regression Estimation of Kel for Alectinib and RO5468924 | RO5468924 | 0.980 no units | Standard Deviation 0.0186 |
| Part 2 (Fed): Treatment C | Adjusted r^2 Value (Rsq) for Regression Estimation of Kel for Alectinib and RO5468924 | RO5468924 | 0.977 no units | Standard Deviation 0.0178 |
| Part 2 (Fed): Treatment C | Adjusted r^2 Value (Rsq) for Regression Estimation of Kel for Alectinib and RO5468924 | Alectinib | 0.990 no units | Standard Deviation 0.0206 |
| Part 2 (Fed): Treatment D | Adjusted r^2 Value (Rsq) for Regression Estimation of Kel for Alectinib and RO5468924 | Alectinib | 0.991 no units | Standard Deviation 0.0153 |
| Part 2 (Fed): Treatment D | Adjusted r^2 Value (Rsq) for Regression Estimation of Kel for Alectinib and RO5468924 | RO5468924 | 0.982 no units | Standard Deviation 0.0195 |
Secondary
Apparent Oral Clearance (CL/F) of Alectinib
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 hour), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, 24, 36, 48, 60, 72, and 96 hours postdose
Population: PK analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1 (Fasted): Treatment A | Apparent Oral Clearance (CL/F) of Alectinib | 377 liters/hour | Standard Deviation 149 |
| Part 1 (Fasted): Treatment B | Apparent Oral Clearance (CL/F) of Alectinib | 380 liters/hour | Standard Deviation 152 |
| Part 1 (Fasted): Treatment C | Apparent Oral Clearance (CL/F) of Alectinib | 383 liters/hour | Standard Deviation 151 |
| Part 1 (Fasted): Treatment D | Apparent Oral Clearance (CL/F) of Alectinib | 449 liters/hour | Standard Deviation 199 |
| Part 2 (Fed): Treatment A | Apparent Oral Clearance (CL/F) of Alectinib | 113 liters/hour | Standard Deviation 30.9 |
| Part 2 (Fed): Treatment B | Apparent Oral Clearance (CL/F) of Alectinib | 126 liters/hour | Standard Deviation 31.5 |
| Part 2 (Fed): Treatment C | Apparent Oral Clearance (CL/F) of Alectinib | 141 liters/hour | Standard Deviation 39.3 |
| Part 2 (Fed): Treatment D | Apparent Oral Clearance (CL/F) of Alectinib | 141 liters/hour | Standard Deviation 40.2 |
Secondary
Apparent Volume of Distribution (Vz/F) of Alectinib
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. Apparent volume of distribution after oral dose (Vz/F) is influenced by the fraction of drug absorbed.
Time frame: Predose (0 hour), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, 24, 36, 48, 60, 72, and 96 hours postdose
Population: PK analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1 (Fasted): Treatment A | Apparent Volume of Distribution (Vz/F) of Alectinib | 12200 liters | Standard Deviation 6240 |
| Part 1 (Fasted): Treatment B | Apparent Volume of Distribution (Vz/F) of Alectinib | 12200 liters | Standard Deviation 5120 |
| Part 1 (Fasted): Treatment C | Apparent Volume of Distribution (Vz/F) of Alectinib | 12900 liters | Standard Deviation 4430 |
| Part 1 (Fasted): Treatment D | Apparent Volume of Distribution (Vz/F) of Alectinib | 16500 liters | Standard Deviation 7300 |
| Part 2 (Fed): Treatment A | Apparent Volume of Distribution (Vz/F) of Alectinib | 3180 liters | Standard Deviation 1260 |
| Part 2 (Fed): Treatment B | Apparent Volume of Distribution (Vz/F) of Alectinib | 3730 liters | Standard Deviation 1530 |
| Part 2 (Fed): Treatment C | Apparent Volume of Distribution (Vz/F) of Alectinib | 4180 liters | Standard Deviation 1920 |
| Part 2 (Fed): Treatment D | Apparent Volume of Distribution (Vz/F) of Alectinib | 4290 liters | Standard Deviation 2240 |
Secondary
AUC(0-inf) of RO5468924
AUC(0-inf) is the area under the RO5468924 plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0-inf). RO5468924 is the major pharmacologically active metabolite of alectinib. AUC is a measure of the plasma concentration of a drug over time. AUC(0-inf) is presented in ng\*hour/mL.
Time frame: Predose (0 hour), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, 24, 36, 48, 60, 72, and 96 hours postdose
Population: PK analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1 (Fasted): Treatment A | AUC(0-inf) of RO5468924 | 968 ng*hour/mL | Standard Deviation 397 |
| Part 1 (Fasted): Treatment B | AUC(0-inf) of RO5468924 | 936 ng*hour/mL | Standard Deviation 419 |
| Part 1 (Fasted): Treatment C | AUC(0-inf) of RO5468924 | 754 ng*hour/mL | Standard Deviation 298 |
| Part 1 (Fasted): Treatment D | AUC(0-inf) of RO5468924 | 534 ng*hour/mL | Standard Deviation 279 |
| Part 2 (Fed): Treatment A | AUC(0-inf) of RO5468924 | 3010 ng*hour/mL | Standard Deviation 819 |
| Part 2 (Fed): Treatment B | AUC(0-inf) of RO5468924 | 2660 ng*hour/mL | Standard Deviation 687 |
| Part 2 (Fed): Treatment C | AUC(0-inf) of RO5468924 | 2200 ng*hour/mL | Standard Deviation 578 |
| Part 2 (Fed): Treatment D | AUC(0-inf) of RO5468924 | 2100 ng*hour/mL | Standard Deviation 543 |
Comparison: ANOVA (fixed factors: treatment, period, and treatment sequence; and random factor: participant) was applied to the log-transformed PK parameter, and then back transformed to provide geometric least square mean ratio (Test/Reference) and 90% CI.90% CI: [87.54, 104.79]
Comparison: ANOVA (fixed factors: treatment, period, and treatment sequence; and random factor: participant) was applied to the log-transformed PK parameter, and then back transformed to provide geometric least square mean ratio (Test/Reference) and 90% CI.90% CI: [71.97, 86.04]
Comparison: ANOVA (fixed factors: treatment, period, and treatment sequence; and random factor: participant) was applied to the log-transformed PK parameter, and then back transformed to provide geometric least square mean ratio (Test/Reference) and 90% CI.90% CI: [49.27, 58.98]
Comparison: ANOVA (fixed factors: treatment, period, and treatment sequence; and random factor: participant) was applied to the log-transformed PK parameter, and then back transformed to provide geometric least square mean ratio (Test/Reference) and 90% CI.90% CI: [86.14, 94.37]
Comparison: ANOVA (fixed factors: treatment, period, and treatment sequence; and random factor: participant) was applied to the log-transformed PK parameter, and then back transformed to provide geometric least square mean ratio (Test/Reference) and 90% CI.90% CI: [70.52, 77.15]
Comparison: ANOVA (fixed factors: treatment, period, and treatment sequence; and random factor: participant) was applied to the log-transformed PK parameter, and then back transformed to provide geometric least square mean ratio (Test/Reference) and 90% CI.90% CI: [67.8, 74.22]
Secondary
AUC(0-last) of RO5468924
AUC(0-last) is the area under the RO5468924 plasma concentration versus time curve from time zero to the time of last measured concentration of RO5468924. RO5468924 is the major pharmacologically active metabolite of alectinib. AUC is a measure of the plasma concentration of a drug over time. AUC(0-last) is presented in ng\*hour/mL.
Time frame: Predose (0 hour), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, 24, 36, 48, 60, 72, and 96 hours postdose
Population: PK analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1 (Fasted): Treatment A | AUC(0-last) of RO5468924 | 876 ng*hour/mL | Standard Deviation 375 |
| Part 1 (Fasted): Treatment B | AUC(0-last) of RO5468924 | 826 ng*hour/mL | Standard Deviation 376 |
| Part 1 (Fasted): Treatment C | AUC(0-last) of RO5468924 | 641 ng*hour/mL | Standard Deviation 248 |
| Part 1 (Fasted): Treatment D | AUC(0-last) of RO5468924 | 392 ng*hour/mL | Standard Deviation 199 |
| Part 2 (Fed): Treatment A | AUC(0-last) of RO5468924 | 2780 ng*hour/mL | Standard Deviation 773 |
| Part 2 (Fed): Treatment B | AUC(0-last) of RO5468924 | 2460 ng*hour/mL | Standard Deviation 669 |
| Part 2 (Fed): Treatment C | AUC(0-last) of RO5468924 | 2000 ng*hour/mL | Standard Deviation 531 |
| Part 2 (Fed): Treatment D | AUC(0-last) of RO5468924 | 1890 ng*hour/mL | Standard Deviation 477 |
Comparison: ANOVA (fixed factors: treatment, period, and treatment sequence; and random factor: participant) was applied to the log-transformed PK parameter, and then back transformed to provide geometric least square mean ratio (Test/Reference) and 90% CI.90% CI: [84.24, 102.78]
Comparison: ANOVA (fixed factors: treatment, period, and treatment sequence; and random factor: participant) was applied to the log-transformed PK parameter, and then back transformed to provide geometric least square mean ratio (Test/Reference) and 90% CI.90% CI: [67.37, 82.06]
Comparison: ANOVA (fixed factors: treatment, period, and treatment sequence; and random factor: participant) was applied to the log-transformed PK parameter, and then back transformed to provide geometric least square mean ratio (Test/Reference) and 90% CI.90% CI: [39.78, 48.53]
Comparison: ANOVA (fixed factors: treatment, period, and treatment sequence; and random factor: participant) was applied to the log-transformed PK parameter, and then back transformed to provide geometric least square mean ratio (Test/Reference) and 90% CI.90% CI: [86.12, 94.49]
Comparison: ANOVA (fixed factors: treatment, period, and treatment sequence; and random factor: participant) was applied to the log-transformed PK parameter, and then back transformed to provide geometric least square mean ratio (Test/Reference) and 90% CI.90% CI: [69.48, 76.12]
Comparison: ANOVA (fixed factors: treatment, period, and treatment sequence; and random factor: participant) was applied to the log-transformed PK parameter, and then back transformed to provide geometric least square mean ratio (Test/Reference) and 90% CI.90% CI: [66.23, 72.61]
Secondary
Cmax of RO5468924
Cmax is the maximum observed plasma RO5468924 concentration, presented in ng/mL. RO5468924 is the major pharmacologically active metabolite of alectinib.
Time frame: Predose (0 hour), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, 24, 36, 48, 60, 72, and 96 hours postdose
Population: PK analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1 (Fasted): Treatment A | Cmax of RO5468924 | 33.0 ng/mL | Standard Deviation 15.4 |
| Part 1 (Fasted): Treatment B | Cmax of RO5468924 | 30.7 ng/mL | Standard Deviation 14.9 |
| Part 1 (Fasted): Treatment C | Cmax of RO5468924 | 21.9 ng/mL | Standard Deviation 8.94 |
| Part 1 (Fasted): Treatment D | Cmax of RO5468924 | 11.3 ng/mL | Standard Deviation 5.71 |
| Part 2 (Fed): Treatment A | Cmax of RO5468924 | 98.8 ng/mL | Standard Deviation 28.6 |
| Part 2 (Fed): Treatment B | Cmax of RO5468924 | 92.2 ng/mL | Standard Deviation 28.7 |
| Part 2 (Fed): Treatment C | Cmax of RO5468924 | 71.4 ng/mL | Standard Deviation 20.6 |
| Part 2 (Fed): Treatment D | Cmax of RO5468924 | 65.2 ng/mL | Standard Deviation 16.8 |
Comparison: ANOVA (fixed factors: treatment, period, and treatment sequence; and random factor: participant) was applied to the log-transformed PK parameter, and then back transformed to provide geometric least square mean ratio (Test/Reference) and 90% CI.90% CI: [82.34, 102.05]
Comparison: ANOVA (fixed factors: treatment, period, and treatment sequence; and random factor: participant) was applied to the log-transformed PK parameter, and then back transformed to provide geometric least square mean ratio (Test/Reference) and 90% CI.90% CI: [60.44, 74.79]
Comparison: ANOVA (fixed factors: treatment, period, and treatment sequence; and random factor: participant) was applied to the log-transformed PK parameter, and then back transformed to provide geometric least square mean ratio (Test/Reference) and 90% CI.90% CI: [30.83, 38.21]
Comparison: ANOVA (fixed factors: treatment, period, and treatment sequence; and random factor: participant) was applied to the log-transformed PK parameter, and then back transformed to provide geometric least square mean ratio (Test/Reference) and 90% CI.90% CI: [89.1, 101.62]
Comparison: ANOVA (fixed factors: treatment, period, and treatment sequence; and random factor: participant) was applied to the log-transformed PK parameter, and then back transformed to provide geometric least square mean ratio (Test/Reference) and 90% CI.90% CI: [68.67, 78.16]
Comparison: ANOVA (fixed factors: treatment, period, and treatment sequence; and random factor: participant) was applied to the log-transformed PK parameter, and then back transformed to provide geometric least square mean ratio (Test/Reference) and 90% CI.90% CI: [63.48, 72.33]
Secondary
Elimination Rate Constant (Kel) of Alectinib and RO5468924
First-order terminal elimination rate constant (Kel) was calculated as the negative slope of the linear regression of the terminal phase in plasma alectinib and RO5468924 concentration versus time profile using appropriate time points. RO5468924 is the major pharmacologically active metabolite of alectinib.
Time frame: Predose (0 hour), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, 24, 36, 48, 60, 72, and 96 hours postdose
Population: PK analysis set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1 (Fasted): Treatment A | Elimination Rate Constant (Kel) of Alectinib and RO5468924 | Alectinib | 0.0340 1/hour | Standard Deviation 0.0113 |
| Part 1 (Fasted): Treatment A | Elimination Rate Constant (Kel) of Alectinib and RO5468924 | RO5468924 | 0.0267 1/hour | Standard Deviation 0.0075 |
| Part 1 (Fasted): Treatment B | Elimination Rate Constant (Kel) of Alectinib and RO5468924 | Alectinib | 0.0333 1/hour | Standard Deviation 0.0119 |
| Part 1 (Fasted): Treatment B | Elimination Rate Constant (Kel) of Alectinib and RO5468924 | RO5468924 | 0.0248 1/hour | Standard Deviation 0.00767 |
| Part 1 (Fasted): Treatment C | Elimination Rate Constant (Kel) of Alectinib and RO5468924 | Alectinib | 0.0312 1/hour | Standard Deviation 0.0108 |
| Part 1 (Fasted): Treatment C | Elimination Rate Constant (Kel) of Alectinib and RO5468924 | RO5468924 | 0.0240 1/hour | Standard Deviation 0.00654 |
| Part 1 (Fasted): Treatment D | Elimination Rate Constant (Kel) of Alectinib and RO5468924 | Alectinib | 0.0303 1/hour | Standard Deviation 0.0123 |
| Part 1 (Fasted): Treatment D | Elimination Rate Constant (Kel) of Alectinib and RO5468924 | RO5468924 | 0.0199 1/hour | Standard Deviation 0.00753 |
| Part 2 (Fed): Treatment A | Elimination Rate Constant (Kel) of Alectinib and RO5468924 | Alectinib | 0.0371 1/hour | Standard Deviation 0.00732 |
| Part 2 (Fed): Treatment A | Elimination Rate Constant (Kel) of Alectinib and RO5468924 | RO5468924 | 0.0256 1/hour | Standard Deviation 0.00493 |
| Part 2 (Fed): Treatment B | Elimination Rate Constant (Kel) of Alectinib and RO5468924 | Alectinib | 0.0369 1/hour | Standard Deviation 0.0117 |
| Part 2 (Fed): Treatment B | Elimination Rate Constant (Kel) of Alectinib and RO5468924 | RO5468924 | 0.0263 1/hour | Standard Deviation 0.0054 |
| Part 2 (Fed): Treatment C | Elimination Rate Constant (Kel) of Alectinib and RO5468924 | RO5468924 | 0.0252 1/hour | Standard Deviation 0.00618 |
| Part 2 (Fed): Treatment C | Elimination Rate Constant (Kel) of Alectinib and RO5468924 | Alectinib | 0.0371 1/hour | Standard Deviation 0.0117 |
| Part 2 (Fed): Treatment D | Elimination Rate Constant (Kel) of Alectinib and RO5468924 | Alectinib | 0.0367 1/hour | Standard Deviation 0.011 |
| Part 2 (Fed): Treatment D | Elimination Rate Constant (Kel) of Alectinib and RO5468924 | RO5468924 | 0.0236 1/hour | Standard Deviation 0.00538 |
Secondary
Molecular Weight Adjusted Metabolite to Parent (M/P) Ratio for AUC(0-inf)
AUC(0-inf) is the area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0-inf). AUC is a measure of the plasma concentration of the alectinib and RO5468924 (major pharmacologically active metabolite of alectinib) over time. The molecular weight adjusted M/P ratio (RO5468924/alectinib) for AUC(0-inf) is presented.
Time frame: Predose (0 hour), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, 24, 36, 48, 60, 72, and 96 hours postdose
Population: PK analysis set
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1 (Fasted): Treatment A | Molecular Weight Adjusted Metabolite to Parent (M/P) Ratio for AUC(0-inf) | 0.54 ratio | Standard Deviation 0.0705 |
| Part 1 (Fasted): Treatment B | Molecular Weight Adjusted Metabolite to Parent (M/P) Ratio for AUC(0-inf) | 0.52 ratio | Standard Deviation 0.072 |
| Part 1 (Fasted): Treatment C | Molecular Weight Adjusted Metabolite to Parent (M/P) Ratio for AUC(0-inf) | 0.43 ratio | Standard Deviation 0.0512 |
| Part 1 (Fasted): Treatment D | Molecular Weight Adjusted Metabolite to Parent (M/P) Ratio for AUC(0-inf) | 0.34 ratio | Standard Deviation 0.0233 |
| Part 2 (Fed): Treatment A | Molecular Weight Adjusted Metabolite to Parent (M/P) Ratio for AUC(0-inf) | 0.55 ratio | Standard Deviation 0.0468 |
| Part 2 (Fed): Treatment B | Molecular Weight Adjusted Metabolite to Parent (M/P) Ratio for AUC(0-inf) | 0.56 ratio | Standard Deviation 0.0393 |
| Part 2 (Fed): Treatment C | Molecular Weight Adjusted Metabolite to Parent (M/P) Ratio for AUC(0-inf) | 0.51 ratio | Standard Deviation 0.029 |
| Part 2 (Fed): Treatment D | Molecular Weight Adjusted Metabolite to Parent (M/P) Ratio for AUC(0-inf) | 0.49 ratio | Standard Deviation 0.03 |
Secondary
Molecular Weight Adjusted M/P Ratio for AUC(0-last)
AUC(0-last) is the area under the plasma concentration versus time curve from time zero to the time of last measured concentration. AUC is a measure of the plasma concentration of the alectinib and RO5468924 (major pharmacologically active metabolite of alectinib) over time. The molecular weight adjusted M/P ratio (RO5468924/alectinib) for AUC(0-last) is presented.
Time frame: Predose (0 hour), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, 24, 36, 48, 60, 72, and 96 hours postdose
Population: PK analysis set
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1 (Fasted): Treatment A | Molecular Weight Adjusted M/P Ratio for AUC(0-last) | 0.52 ratio | Standard Deviation 0.0708 |
| Part 1 (Fasted): Treatment B | Molecular Weight Adjusted M/P Ratio for AUC(0-last) | 0.49 ratio | Standard Deviation 0.0838 |
| Part 1 (Fasted): Treatment C | Molecular Weight Adjusted M/P Ratio for AUC(0-last) | 0.41 ratio | Standard Deviation 0.0458 |
| Part 1 (Fasted): Treatment D | Molecular Weight Adjusted M/P Ratio for AUC(0-last) | 0.29 ratio | Standard Deviation 0.0347 |
| Part 2 (Fed): Treatment A | Molecular Weight Adjusted M/P Ratio for AUC(0-last) | 0.52 ratio | Standard Deviation 0.0474 |
| Part 2 (Fed): Treatment B | Molecular Weight Adjusted M/P Ratio for AUC(0-last) | 0.54 ratio | Standard Deviation 0.0384 |
| Part 2 (Fed): Treatment C | Molecular Weight Adjusted M/P Ratio for AUC(0-last) | 0.48 ratio | Standard Deviation 0.0264 |
| Part 2 (Fed): Treatment D | Molecular Weight Adjusted M/P Ratio for AUC(0-last) | 0.46 ratio | Standard Deviation 0.0237 |
Secondary
Molecular Weight Adjusted M/P Ratio for Cmax
Cmax is the maximum observed plasma concentration of the alectinib and RO5468924 (major pharmacologically active metabolite of alectinib). The molecular weight adjusted M/P ratio (RO5468924/alectinib) for Cmax is presented.
Time frame: Predose (0 hour), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, 24, 36, 48, 60, 72, and 96 hours postdose
Population: PK analysis set
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1 (Fasted): Treatment A | Molecular Weight Adjusted M/P Ratio for Cmax | 0.33 ratio | Standard Deviation 0.0376 |
| Part 1 (Fasted): Treatment B | Molecular Weight Adjusted M/P Ratio for Cmax | 0.34 ratio | Standard Deviation 0.0446 |
| Part 1 (Fasted): Treatment C | Molecular Weight Adjusted M/P Ratio for Cmax | 0.33 ratio | Standard Deviation 0.0438 |
| Part 1 (Fasted): Treatment D | Molecular Weight Adjusted M/P Ratio for Cmax | 0.28 ratio | Standard Deviation 0.0206 |
| Part 2 (Fed): Treatment A | Molecular Weight Adjusted M/P Ratio for Cmax | 0.38 ratio | Standard Deviation 0.0445 |
| Part 2 (Fed): Treatment B | Molecular Weight Adjusted M/P Ratio for Cmax | 0.42 ratio | Standard Deviation 0.0304 |
| Part 2 (Fed): Treatment C | Molecular Weight Adjusted M/P Ratio for Cmax | 0.36 ratio | Standard Deviation 0.0223 |
| Part 2 (Fed): Treatment D | Molecular Weight Adjusted M/P Ratio for Cmax | 0.34 ratio | Standard Deviation 0.0207 |
Secondary
Percent Extrapolated AUC(0-inf) (AUC%Extrap[0-inf]) for Alectinib and RO5468924
The AUC%extrap(0-inf), that is, area obtained after extrapolation (extrap) from time to last quantifiable plasma concentration (Tlast) to infinity is calculated by using the formula AUC%extrap(0-inf) = 100\*(AUC\[0-inf\] minus AUC\[0-last\])/AUC(0-inf); where AUC(0-inf) = Area under the plasma concentration versus time curve from time zero (pre-dose) to extrapolated infinite time and AUC(0-last) is area under the plasma concentration time-curve from zero (pre-dose) to the time of last measured concentration. The function of this parameter is to provide information about what percentage of the theoretical curve AUC(0-inf) was possible to determine experimentally (AUC0-last).
Time frame: Predose (0 hour), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, 24, 36, 48, 60, 72, and 96 hours postdose
Population: PK analysis set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1 (Fasted): Treatment A | Percent Extrapolated AUC(0-inf) (AUC%Extrap[0-inf]) for Alectinib and RO5468924 | Alectinib | 6.43 percent AUC | Standard Deviation 4.06 |
| Part 1 (Fasted): Treatment A | Percent Extrapolated AUC(0-inf) (AUC%Extrap[0-inf]) for Alectinib and RO5468924 | RO5468924 | 10.2 percent AUC | Standard Deviation 3.67 |
| Part 1 (Fasted): Treatment B | Percent Extrapolated AUC(0-inf) (AUC%Extrap[0-inf]) for Alectinib and RO5468924 | Alectinib | 7.45 percent AUC | Standard Deviation 6.25 |
| Part 1 (Fasted): Treatment B | Percent Extrapolated AUC(0-inf) (AUC%Extrap[0-inf]) for Alectinib and RO5468924 | RO5468924 | 12.6 percent AUC | Standard Deviation 6.14 |
| Part 1 (Fasted): Treatment C | Percent Extrapolated AUC(0-inf) (AUC%Extrap[0-inf]) for Alectinib and RO5468924 | Alectinib | 9.91 percent AUC | Standard Deviation 8.08 |
| Part 1 (Fasted): Treatment C | Percent Extrapolated AUC(0-inf) (AUC%Extrap[0-inf]) for Alectinib and RO5468924 | RO5468924 | 14.9 percent AUC | Standard Deviation 6.89 |
| Part 1 (Fasted): Treatment D | Percent Extrapolated AUC(0-inf) (AUC%Extrap[0-inf]) for Alectinib and RO5468924 | Alectinib | 12.5 percent AUC | Standard Deviation 10.9 |
| Part 1 (Fasted): Treatment D | Percent Extrapolated AUC(0-inf) (AUC%Extrap[0-inf]) for Alectinib and RO5468924 | RO5468924 | 26.0 percent AUC | Standard Deviation 11.2 |
| Part 2 (Fed): Treatment A | Percent Extrapolated AUC(0-inf) (AUC%Extrap[0-inf]) for Alectinib and RO5468924 | Alectinib | 3.04 percent AUC | Standard Deviation 2.57 |
| Part 2 (Fed): Treatment A | Percent Extrapolated AUC(0-inf) (AUC%Extrap[0-inf]) for Alectinib and RO5468924 | RO5468924 | 7.84 percent AUC | Standard Deviation 2.57 |
| Part 2 (Fed): Treatment B | Percent Extrapolated AUC(0-inf) (AUC%Extrap[0-inf]) for Alectinib and RO5468924 | Alectinib | 4.24 percent AUC | Standard Deviation 5.01 |
| Part 2 (Fed): Treatment B | Percent Extrapolated AUC(0-inf) (AUC%Extrap[0-inf]) for Alectinib and RO5468924 | RO5468924 | 7.84 percent AUC | Standard Deviation 2.52 |
| Part 2 (Fed): Treatment C | Percent Extrapolated AUC(0-inf) (AUC%Extrap[0-inf]) for Alectinib and RO5468924 | RO5468924 | 9.12 percent AUC | Standard Deviation 3.39 |
| Part 2 (Fed): Treatment C | Percent Extrapolated AUC(0-inf) (AUC%Extrap[0-inf]) for Alectinib and RO5468924 | Alectinib | 4.49 percent AUC | Standard Deviation 4.86 |
| Part 2 (Fed): Treatment D | Percent Extrapolated AUC(0-inf) (AUC%Extrap[0-inf]) for Alectinib and RO5468924 | Alectinib | 4.52 percent AUC | Standard Deviation 5.54 |
| Part 2 (Fed): Treatment D | Percent Extrapolated AUC(0-inf) (AUC%Extrap[0-inf]) for Alectinib and RO5468924 | RO5468924 | 9.94 percent AUC | Standard Deviation 3.93 |
Secondary
Plasma Terminal Half-Life (t1/2) of Alectinib and RO5468924
Plasma terminal half-life is the time measured during drug elimination phase for the plasma drug concentration to decrease by one half. RO5468924 is the major pharmacologically active metabolite of alectinib.
Time frame: Predose (0 hour), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, 24, 36, 48, 60, 72, and 96 hours postdose
Population: PK analysis set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1 (Fasted): Treatment A | Plasma Terminal Half-Life (t1/2) of Alectinib and RO5468924 | Alectinib | 23.6 hours | Standard Deviation 11.1 |
| Part 1 (Fasted): Treatment A | Plasma Terminal Half-Life (t1/2) of Alectinib and RO5468924 | RO5468924 | 28.1 hours | Standard Deviation 8.29 |
| Part 1 (Fasted): Treatment B | Plasma Terminal Half-Life (t1/2) of Alectinib and RO5468924 | Alectinib | 24.3 hours | Standard Deviation 11.1 |
| Part 1 (Fasted): Treatment B | Plasma Terminal Half-Life (t1/2) of Alectinib and RO5468924 | RO5468924 | 30.7 hours | Standard Deviation 9.63 |
| Part 1 (Fasted): Treatment C | Plasma Terminal Half-Life (t1/2) of Alectinib and RO5468924 | Alectinib | 25.6 hours | Standard Deviation 11.2 |
| Part 1 (Fasted): Treatment C | Plasma Terminal Half-Life (t1/2) of Alectinib and RO5468924 | RO5468924 | 31.8 hours | Standard Deviation 12.7 |
| Part 1 (Fasted): Treatment D | Plasma Terminal Half-Life (t1/2) of Alectinib and RO5468924 | Alectinib | 28.8 hours | Standard Deviation 17.4 |
| Part 1 (Fasted): Treatment D | Plasma Terminal Half-Life (t1/2) of Alectinib and RO5468924 | RO5468924 | 41.7 hours | Standard Deviation 19.8 |
| Part 2 (Fed): Treatment A | Plasma Terminal Half-Life (t1/2) of Alectinib and RO5468924 | Alectinib | 19.8 hours | Standard Deviation 6.56 |
| Part 2 (Fed): Treatment A | Plasma Terminal Half-Life (t1/2) of Alectinib and RO5468924 | RO5468924 | 28.3 hours | Standard Deviation 6.79 |
| Part 2 (Fed): Treatment B | Plasma Terminal Half-Life (t1/2) of Alectinib and RO5468924 | Alectinib | 21.3 hours | Standard Deviation 10.6 |
| Part 2 (Fed): Treatment B | Plasma Terminal Half-Life (t1/2) of Alectinib and RO5468924 | RO5468924 | 27.4 hours | Standard Deviation 5.27 |
| Part 2 (Fed): Treatment C | Plasma Terminal Half-Life (t1/2) of Alectinib and RO5468924 | RO5468924 | 29.1 hours | Standard Deviation 7.13 |
| Part 2 (Fed): Treatment C | Plasma Terminal Half-Life (t1/2) of Alectinib and RO5468924 | Alectinib | 21.4 hours | Standard Deviation 10.3 |
| Part 2 (Fed): Treatment D | Plasma Terminal Half-Life (t1/2) of Alectinib and RO5468924 | Alectinib | 21.9 hours | Standard Deviation 12 |
| Part 2 (Fed): Treatment D | Plasma Terminal Half-Life (t1/2) of Alectinib and RO5468924 | RO5468924 | 31.0 hours | Standard Deviation 7.74 |
Secondary
Time to Reach Last Quantifiable Plasma Concentration (Tlast) of Alectinib and RO5468924
Tlast is the time from alectinib administration to reach last quantifiable concentration of alectinib and its major pharmacologically active metabolite RO5468924.
Time frame: Predose (0 hour), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, 24, 36, 48, 60, 72, and 96 hours postdose
Population: PK analysis set
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Part 1 (Fasted): Treatment A | Time to Reach Last Quantifiable Plasma Concentration (Tlast) of Alectinib and RO5468924 | RO5468924 | 96.0 hours |
| Part 1 (Fasted): Treatment A | Time to Reach Last Quantifiable Plasma Concentration (Tlast) of Alectinib and RO5468924 | Alectinib | 96.0 hours |
| Part 1 (Fasted): Treatment B | Time to Reach Last Quantifiable Plasma Concentration (Tlast) of Alectinib and RO5468924 | Alectinib | 96.0 hours |
| Part 1 (Fasted): Treatment B | Time to Reach Last Quantifiable Plasma Concentration (Tlast) of Alectinib and RO5468924 | RO5468924 | 96.0 hours |
| Part 1 (Fasted): Treatment C | Time to Reach Last Quantifiable Plasma Concentration (Tlast) of Alectinib and RO5468924 | Alectinib | 96.0 hours |
| Part 1 (Fasted): Treatment C | Time to Reach Last Quantifiable Plasma Concentration (Tlast) of Alectinib and RO5468924 | RO5468924 | 96.0 hours |
| Part 1 (Fasted): Treatment D | Time to Reach Last Quantifiable Plasma Concentration (Tlast) of Alectinib and RO5468924 | Alectinib | 96.0 hours |
| Part 1 (Fasted): Treatment D | Time to Reach Last Quantifiable Plasma Concentration (Tlast) of Alectinib and RO5468924 | RO5468924 | 72.0 hours |
| Part 2 (Fed): Treatment A | Time to Reach Last Quantifiable Plasma Concentration (Tlast) of Alectinib and RO5468924 | RO5468924 | 96.0 hours |
| Part 2 (Fed): Treatment A | Time to Reach Last Quantifiable Plasma Concentration (Tlast) of Alectinib and RO5468924 | Alectinib | 96.0 hours |
| Part 2 (Fed): Treatment B | Time to Reach Last Quantifiable Plasma Concentration (Tlast) of Alectinib and RO5468924 | RO5468924 | 96.0 hours |
| Part 2 (Fed): Treatment B | Time to Reach Last Quantifiable Plasma Concentration (Tlast) of Alectinib and RO5468924 | Alectinib | 96.0 hours |
| Part 2 (Fed): Treatment C | Time to Reach Last Quantifiable Plasma Concentration (Tlast) of Alectinib and RO5468924 | Alectinib | 96.0 hours |
| Part 2 (Fed): Treatment C | Time to Reach Last Quantifiable Plasma Concentration (Tlast) of Alectinib and RO5468924 | RO5468924 | 96.0 hours |
| Part 2 (Fed): Treatment D | Time to Reach Last Quantifiable Plasma Concentration (Tlast) of Alectinib and RO5468924 | Alectinib | 96.0 hours |
| Part 2 (Fed): Treatment D | Time to Reach Last Quantifiable Plasma Concentration (Tlast) of Alectinib and RO5468924 | RO5468924 | 96.0 hours |
Secondary
Time to Reach Maximum Observed Plasma Concentration (Tmax) of Alectinib
Tmax is the time from alectinib administration to reach Cmax for alectinib.
Time frame: Predose (0 hour), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, 24, 36, 48, 60, 72, and 96 hours postdose
Population: PK analysis set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1 (Fasted): Treatment A | Time to Reach Maximum Observed Plasma Concentration (Tmax) of Alectinib | 3.25 hours |
| Part 1 (Fasted): Treatment B | Time to Reach Maximum Observed Plasma Concentration (Tmax) of Alectinib | 3.00 hours |
| Part 1 (Fasted): Treatment C | Time to Reach Maximum Observed Plasma Concentration (Tmax) of Alectinib | 3.00 hours |
| Part 1 (Fasted): Treatment D | Time to Reach Maximum Observed Plasma Concentration (Tmax) of Alectinib | 4.00 hours |
| Part 2 (Fed): Treatment A | Time to Reach Maximum Observed Plasma Concentration (Tmax) of Alectinib | 8.00 hours |
| Part 2 (Fed): Treatment B | Time to Reach Maximum Observed Plasma Concentration (Tmax) of Alectinib | 8.00 hours |
| Part 2 (Fed): Treatment C | Time to Reach Maximum Observed Plasma Concentration (Tmax) of Alectinib | 6.00 hours |
| Part 2 (Fed): Treatment D | Time to Reach Maximum Observed Plasma Concentration (Tmax) of Alectinib | 6.00 hours |
Secondary
Tmax of RO5468924
Tmax is the time from alectinib administration to reach Cmax for RO5468924 (the major pharmacologically active metabolite of alectinib).
Time frame: Predose (0 hour), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, 24, 36, 48, 60, 72, and 96 hours postdose
Population: PK analysis set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1 (Fasted): Treatment A | Tmax of RO5468924 | 8.00 hours |
| Part 1 (Fasted): Treatment B | Tmax of RO5468924 | 8.02 hours |
| Part 1 (Fasted): Treatment C | Tmax of RO5468924 | 8.00 hours |
| Part 1 (Fasted): Treatment D | Tmax of RO5468924 | 8.07 hours |
| Part 2 (Fed): Treatment A | Tmax of RO5468924 | 12.0 hours |
| Part 2 (Fed): Treatment B | Tmax of RO5468924 | 10.0 hours |
| Part 2 (Fed): Treatment C | Tmax of RO5468924 | 8.02 hours |
| Part 2 (Fed): Treatment D | Tmax of RO5468924 | 9.00 hours |
Secondary
Total Molar Concentration of Alectinib and RO5468924 as Derived by AUC(0-inf)
AUC(0-inf) is the area under the alectinib + RO5468924 (major pharmacologically active metabolite of alectinib) molar plasma concentration versus time curve from time zero (pre-dose) to extrapolated infinite time (0-inf). AUC is a measure of the plasma concentration of the alectinib + RO5468924 over time. AUC(0-inf) is presented in nanomoles times (\*) hour per liter (nmol\*hour/L).
Time frame: Predose (0 hour), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, 24, 36, 48, 60, 72, and 96 hours postdose
Population: PK analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1 (Fasted): Treatment A | Total Molar Concentration of Alectinib and RO5468924 as Derived by AUC(0-inf) | 6040 nmol*hour/L | Standard Deviation 2870 |
| Part 1 (Fasted): Treatment B | Total Molar Concentration of Alectinib and RO5468924 as Derived by AUC(0-inf) | 5780 nmol*hour/L | Standard Deviation 2290 |
| Part 1 (Fasted): Treatment C | Total Molar Concentration of Alectinib and RO5468924 as Derived by AUC(0-inf) | 5450 nmol*hour/L | Standard Deviation 2310 |
| Part 1 (Fasted): Treatment D | Total Molar Concentration of Alectinib and RO5468924 as Derived by AUC(0-inf) | 4470 nmol*hour/L | Standard Deviation 2370 |
| Part 2 (Fed): Treatment A | Total Molar Concentration of Alectinib and RO5468924 as Derived by AUC(0-inf) | 18400 nmol*hour/L | Standard Deviation 4600 |
| Part 2 (Fed): Treatment B | Total Molar Concentration of Alectinib and RO5468924 as Derived by AUC(0-inf) | 16200 nmol*hour/L | Standard Deviation 3650 |
| Part 2 (Fed): Treatment C | Total Molar Concentration of Alectinib and RO5468924 as Derived by AUC(0-inf) | 14300 nmol*hour/L | Standard Deviation 3570 |
| Part 2 (Fed): Treatment D | Total Molar Concentration of Alectinib and RO5468924 as Derived by AUC(0-inf) | 14100 nmol*hour/L | Standard Deviation 3490 |
Comparison: ANOVA (fixed factors: treatment, period, and treatment sequence; and random factor: participant) was applied to the log-transformed PK parameter, and then back transformed to provide geometric least square mean ratio (Test/Reference) and 90% CI.90% CI: [91.25, 106.95]
Comparison: ANOVA (fixed factors: treatment, period, and treatment sequence; and random factor: participant) was applied to the log-transformed PK parameter, and then back transformed to provide geometric least square mean ratio (Test/Reference) and 90% CI.90% CI: [84.65, 99.08]
Comparison: ANOVA (fixed factors: treatment, period, and treatment sequence; and random factor: participant) was applied to the log-transformed PK parameter, and then back transformed to provide geometric least square mean ratio (Test/Reference) and 90% CI.90% CI: [67.81, 79.47]
Comparison: ANOVA (fixed factors: treatment, period, and treatment sequence; and random factor: participant) was applied to the log-transformed PK parameter, and then back transformed to provide geometric least square mean ratio (Test/Reference) and 90% CI.90% CI: [85.62, 92.13]
Comparison: ANOVA (fixed factors: treatment, period, and treatment sequence; and random factor: participant) was applied to the log-transformed PK parameter, and then back transformed to provide geometric least square mean ratio (Test/Reference) and 90% CI.90% CI: [74.99, 80.6]
Comparison: ANOVA (fixed factors: treatment, period, and treatment sequence; and random factor: participant) was applied to the log-transformed PK parameter, and then back transformed to provide geometric least square mean ratio (Test/Reference) and 90% CI.90% CI: [73.92, 79.49]
Secondary
Total Molar Concentration of Alectinib and RO5468924 as Derived by AUC(0-last)
AUC(0-last) is the area under the alectinib + RO5468924 (major pharmacologically active metabolite of alectinib) molar plasma concentration versus time curve from time zero to the time of last measured concentration of alectinib + RO5468924. AUC(0-last) is presented in nmol\*hour/L.
Time frame: Predose (0 hour), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, 24, 36, 48, 60, 72, and 96 hours postdose
Population: PK analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1 (Fasted): Treatment A | Total Molar Concentration of Alectinib and RO5468924 as Derived by AUC(0-last) | 5660 nmol*hour/L | Standard Deviation 2620 |
| Part 1 (Fasted): Treatment B | Total Molar Concentration of Alectinib and RO5468924 as Derived by AUC(0-last) | 5310 nmol*hour/L | Standard Deviation 1980 |
| Part 1 (Fasted): Treatment C | Total Molar Concentration of Alectinib and RO5468924 as Derived by AUC(0-last) | 4780 nmol*hour/L | Standard Deviation 1710 |
| Part 1 (Fasted): Treatment D | Total Molar Concentration of Alectinib and RO5468924 as Derived by AUC(0-last) | 3740 nmol*hour/L | Standard Deviation 1560 |
| Part 2 (Fed): Treatment A | Total Molar Concentration of Alectinib and RO5468924 as Derived by AUC(0-last) | 17600 nmol*hour/L | Standard Deviation 4370 |
| Part 2 (Fed): Treatment B | Total Molar Concentration of Alectinib and RO5468924 as Derived by AUC(0-last) | 15400 nmol*hour/L | Standard Deviation 3500 |
| Part 2 (Fed): Treatment C | Total Molar Concentration of Alectinib and RO5468924 as Derived by AUC(0-last) | 13400 nmol*hour/L | Standard Deviation 3260 |
| Part 2 (Fed): Treatment D | Total Molar Concentration of Alectinib and RO5468924 as Derived by AUC(0-last) | 13200 nmol*hour/L | Standard Deviation 3200 |
Comparison: ANOVA (fixed factors: treatment, period, and treatment sequence; and random factor: participant) was applied to the log-transformed PK parameter, and then back transformed to provide geometric least square mean ratio (Test/Reference) and 90% CI.90% CI: [89.85, 105.21]
Comparison: ANOVA (fixed factors: treatment, period, and treatment sequence; and random factor: participant) was applied to the log-transformed PK parameter, and then back transformed to provide geometric least square mean ratio (Test/Reference) and 90% CI.90% CI: [80.59, 94.26]
Comparison: ANOVA (fixed factors: treatment, period, and treatment sequence; and random factor: participant) was applied to the log-transformed PK parameter, and then back transformed to provide geometric least square mean ratio (Test/Reference) and 90% CI.90% CI: [62.71, 73.43]
Comparison: ANOVA (fixed factors: treatment, period, and treatment sequence; and random factor: participant) was applied to the log-transformed PK parameter, and then back transformed to provide geometric least square mean ratio (Test/Reference) and 90% CI.90% CI: [85.06, 91.63]
Comparison: ANOVA (fixed factors: treatment, period, and treatment sequence; and random factor: participant) was applied to the log-transformed PK parameter, and then back transformed to provide geometric least square mean ratio (Test/Reference) and 90% CI.90% CI: [74.03, 79.65]
Comparison: ANOVA (fixed factors: treatment, period, and treatment sequence; and random factor: participant) was applied to the log-transformed PK parameter, and then back transformed to provide geometric least square mean ratio (Test/Reference) and 90% CI.90% CI: [72.7, 78.27]
Secondary
Total Molar Concentration of Alectinib and RO5468924 as Derived by Cmax
Cmax is the maximum observed molar plasma concentration for alectinib + RO5468924 (major pharmacologically active metabolite of alectinib). Cmax is presented in nanomoles per liter (nmol/L).
Time frame: Predose (0 hour), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, 24, 36, 48, 60, 72, and 96 hours postdose
Population: PK analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1 (Fasted): Treatment A | Total Molar Concentration of Alectinib and RO5468924 as Derived by Cmax | 257 nmol/L | Standard Deviation 123 |
| Part 1 (Fasted): Treatment B | Total Molar Concentration of Alectinib and RO5468924 as Derived by Cmax | 221 nmol/L | Standard Deviation 79.6 |
| Part 1 (Fasted): Treatment C | Total Molar Concentration of Alectinib and RO5468924 as Derived by Cmax | 164 nmol/L | Standard Deviation 52.6 |
| Part 1 (Fasted): Treatment D | Total Molar Concentration of Alectinib and RO5468924 as Derived by Cmax | 106 nmol/L | Standard Deviation 48.6 |
| Part 2 (Fed): Treatment A | Total Molar Concentration of Alectinib and RO5468924 as Derived by Cmax | 754 nmol/L | Standard Deviation 209 |
| Part 2 (Fed): Treatment B | Total Molar Concentration of Alectinib and RO5468924 as Derived by Cmax | 662 nmol/L | Standard Deviation 162 |
| Part 2 (Fed): Treatment C | Total Molar Concentration of Alectinib and RO5468924 as Derived by Cmax | 566 nmol/L | Standard Deviation 138 |
| Part 2 (Fed): Treatment D | Total Molar Concentration of Alectinib and RO5468924 as Derived by Cmax | 548 nmol/L | Standard Deviation 141 |
Comparison: ANOVA (fixed factors: treatment, period, and treatment sequence; and random factor: participant) was applied to the log-transformed PK parameter, and then back transformed to provide geometric least square mean ratio (Test/Reference) and 90% CI.90% CI: [81.7, 97.84]
Comparison: ANOVA (fixed factors: treatment, period, and treatment sequence; and random factor: participant) was applied to the log-transformed PK parameter, and then back transformed to provide geometric least square mean ratio (Test/Reference) and 90% CI.90% CI: [61.12, 73.1]
Comparison: ANOVA (fixed factors: treatment, period, and treatment sequence; and random factor: participant) was applied to the log-transformed PK parameter, and then back transformed to provide geometric least square mean ratio (Test/Reference) and 90% CI.90% CI: [38.68, 46.32]
Comparison: ANOVA (fixed factors: treatment, period, and treatment sequence; and random factor: participant) was applied to the log-transformed PK parameter, and then back transformed to provide geometric least square mean ratio (Test/Reference) and 90% CI.90% CI: [84.21, 93.56]
Comparison: ANOVA (fixed factors: treatment, period, and treatment sequence; and random factor: participant) was applied to the log-transformed PK parameter, and then back transformed to provide geometric least square mean ratio (Test/Reference) and 90% CI.90% CI: [71.99, 79.86]
Comparison: ANOVA (fixed factors: treatment, period, and treatment sequence; and random factor: participant) was applied to the log-transformed PK parameter, and then back transformed to provide geometric least square mean ratio (Test/Reference) and 90% CI.90% CI: [69.53, 77.19]