Renal Impairment
Conditions
Brief summary
This is a Phase 1, open-label, multi-center, single treatment study in subjects with normal renal function and varying degrees of renal impairment.
Detailed description
This is a Phase 1, open-label, multi-center, single treatment study in subjects with normal renal function and varying degrees of renal impairment. Each subject will receive a single oral dose of lorlatinib administered in the fasted state. Subjects with mild, moderate, and severe renal impairment will be enrolled and normal healthy subjects will be enrolled as matched controls.
Interventions
DRUGLorlatinib
Lorlatinib single oral dose
Sponsors
Pfizer
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
Yes
Inclusion criteria
* Female subjects of non-childbearing potential * Body mass index (BMI) of 17.5 to 30.5 kg/m2; and a total body weight \>50 kg (110 lb) * Evidence of a personally signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the study * Subjects who are willing and able to comply with all scheduled visits, treatment plan, laboratory tests, and other study procedures. * Demonstrate stable renal function
Exclusion criteria
* Renal allograft recipients * Any condition possibly affecting drug absorption (eg, gastrectomy) * A positive urine drug test * History of regular alcohol consumption exceeding 7 drinks/week for female subjects or 14 drinks/week for male subjects (1 drink = 5 ounces \[150 mL\] of wine or 12 ounces \[360 mL\] of beer or 1.5 ounces \[45 mL\] of hard liquor) within 6 months before screening. * Treatment with an investigational drug within 30 days (or as determined by the local requirement) or 5 half lives preceding the first dose of investigational product (whichever is longer). * Screening supine triplicate 12 lead ECG demonstrating a corrected QT (QTc) interval \>450 msec or a QRS interval \>120 msec * Second-degree or third-degree AV block (unless paced) or baseline PR interval \>180 msec at any time prior to dosing of study treatment. * Abnormalities in clinical laboratory tests at screening * Pregnant or breastfeeding female subjects * History of HIV, Hepatitis B, Hepatitis C, HIT, sensitivity to heparin * Other acute or chronic medical or psychiatric condition including recent (within the past year) or active suicidal ideation or behavior or laboratory abnormality that may increase the risk associated with study participation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Plasma Concentration-Time Profile From Time 0 Extrapolated to Infinite Time (AUCinf) of Lorlatinib | 0 (pre-dose), 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 48, 72, 96 and 120 hours postdose | AUCinf was calculated by AUClast + (Clast\*/kel), where AUClast was the area under the plasma concentration-time profile from time 0 to the time of the last quantifiable concentration; Clast\* was the predicted plasma concentration at the last quantifiable time point estimated from the log-linear regression analysis, and kel was the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve. |
| Maximum Observed Plasma Concentration (Cmax) of Lorlatinib | 0 (pre-dose), 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 48, 72, 96 and 120 hours postdose | Cmax was observed directly from data. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Baseline up to 28 days after last dose of study treatment (approximately 29 days) | An adverse event (AE) was any untoward medical occurrence in a study participant administered a product or medical device; the event did not need to have a causal relationship with the treatment or usage. A serious adverse event (SAE) was any untoward medical occurrence at any dose that resulted in death; was life threatening; required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; resulted in congenital anomaly/birth defect. AEs included both SAEs and AEs. TEAEs were AEs occurred following the start of treatment or AEs increasing in severity during treatment. Number of participants with both all-causality and treatment-related TEAEs are presented below. |
| Number of Participants With Laboratory Test Abnormalities Without Regard to Baseline Abnormalities | Screening, Day -1, Day 2 and Day 6 | The hematology, chemistry and urinalysis tests were included in the laboratory examination. Hematology evaluation included hemoglobin, hematocrit, red blood cell count, platelet count, white blood cell count, total neutrophils, eosinophils, monocytes, basophils, lymphocytes, erythrocyte mean corpuscular volume, erythrocyte mean corpuscular hemoglobin concentration and erythrocyte mean corpuscular hemoglobin. Chemistry evaluation included blood urea nitrogen, creatinine, glucose, calcium, sodium, potassium, chloride, total bicarbonate, aspartate aminotransferase, alanine aminotransferase, total bilirubin, alkaline phosphatase, uric acid albumin, total protein, lipase and amylase. Urinalysis evaluation included decimal logarithm of reciprocal of hydrogen ion activity \[pH\], glucose, protein, blood, ketones, microscopy, ketones, nitrite, leukocyte esterase, urobilinogen, urine bilirubin and bacteria. The lab abnormalities were reported in accordance with the sponsor reporting standards. |
| Number of Participants With Vital Signs Data Meeting Categorical Summarization Criteria | Baseline up to 28 days after last dose of study treatment (approximately 29 days) | Vital signs evaluations included supine diastolic blood pressure (DBP), and supine systolic blood pressure (SBP) were measured with the participant's arm supported at the level of the heart and recorded to the nearest mmHg after approximately 5 minutes of rest. Number of participants with vital signs data meeting the categorical summarization criteria is presented. The pre-specified criteria of vital signs data were categorized as follows: SBP (minimum) \<90 mmHg, maximum of decrease and increase from baseline for SBP \>=30 mmHg; DBP (minimum) \<50 mmHg, maximum of decrease and increase from baseline for DBP\>=20 mmHg. |
| Number of Participants With Electrocardiogram (ECG) Data Meeting Categorical Summarization Criteria | Screening, Day -1, 0 hours (pre-dose), 1 hour, 2 hours, 4 hours, 24 hours and 120 hours postdose. | ECG evaluation included: PR interval, time from ECG Q wave to the end of the S wave corresponding to ventricle depolarization (QRS interval), time between the start of the Q wave and the end of the T wave in the heart's electrical cycle (QT interval), and QT interval corrected for heart rate using Fridericia's formula (QTcF interval). The pre-specified criteria of ESG data were categorized as below. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Plasma Concentration-time Profile From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) of Lorlatinib | 0 (pre-dose), 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 48, 72, 96 and 120 hours postdose | AUClast was calculated by linear/Log trapezoidal method. |
| Time for Cmax (Tmax) of Lorlatinib | 0 (pre-dose), 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 48, 72, 96 and 120 hours postdose | Tmax was observed directly from data as time of first occurrence. |
| Terminal Elimination Plasma Half-life (t½) of Lorlatinib | 0 (pre-dose), 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 48, 72, 96 and 120 hours postdose | t1/2 was calculated by ln(2)/kel. |
| Apparent Clearance After Oral Dose (CL/F) of Lorlatinib | 0 (pre-dose), 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 48, 72, 96 and 120 hours postdose | CL/F was calculated by Dose/AUCinf. |
| Apparent Volume of Distribution Following Oral Dose (Vz/F) of Lorlatinib | 0 (pre-dose), 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 48, 72, 96 and 120 hours postdose | Vz/F was calculated by Dose/(AUCinf\*kel). kel was the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve. |
| Renal Clearance (CLR) of Lorlatinib | 0 (pre-dose), 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 48, 72, 96 and 120 hours postdose | CLR was calculated by Ae/AUClast. Ae was cumulative amount of drug recovered unchanged in urine, which was calculated by sum of (urine concentration × sample volume) for each collection interval from 0 to time 120 hours postdose. Sample volume = (urine weight in g/1.020), where 1.020 g/mL is the approximate specific gravity of urine. |
Countries
United States
Participant flow
Recruitment details
The mild renal impairment participants were recruited first. After lorlatinib was tolerated in at least 3 mild impairment participants, moderate impairment participants were enrolled. After dosing of 3 moderate impairment participants for at least 1 week, the remaining moderate impairment participants and the severe impairment participants were enrolled. The enrollment of normal renal function participants began after all renal impairment participants completed the PK collection.
Participants by arm
| Arm | Count |
|---|---|
| Normal Function Participants with normal renal function received a 100 mg dose of lorlatinib tablets with approximately 240 mL of ambient temperature water at approximately 0800 hours (±3 hours) following an overnight fast of at least 10 hours. | 8 |
| Mild Impairment Participants with mild renal impairment received a 100 mg single oral dose of lorlatinib tablet on day 1 with approximately 240 mL of ambient temperature water at approximately 0800 hours (±3 hours) following an overnight fast of at least 10 hours. | 8 |
| Moderate Impairment Participants with moderate renal function received a 100 mg single oral dose of lorlatinib tablet on day 1 with approximately 240 mL of ambient temperature water at approximately 0800 hours (±3 hours) following an overnight fast of at least 10 hours. | 8 |
| Severe Impairment Participants with severe renal function received a 100 mg single oral dose of lorlatinib tablet on day 1 with approximately 240 mL of ambient temperature water at approximately 0800 hours (±3 hours) following an overnight fast of at least 10 hours. | 5 |
| Total | 29 |
Baseline characteristics
| Characteristic | Normal Function | Mild Impairment | Moderate Impairment | Severe Impairment | Total |
|---|---|---|---|---|---|
| Age, Continuous | 56.6 Years STANDARD_DEVIATION 3.66 | 59.0 Years STANDARD_DEVIATION 7.27 | 63.1 Years STANDARD_DEVIATION 4.88 | 60.4 Years STANDARD_DEVIATION 11.08 | 59.7 Years STANDARD_DEVIATION 6.81 |
| Race/Ethnicity, Customized Asian | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Black or African American | 3 Participants | 0 Participants | 0 Participants | 2 Participants | 5 Participants |
| Race/Ethnicity, Customized white | 5 Participants | 7 Participants | 8 Participants | 3 Participants | 23 Participants |
| Sex: Female, Male Female | 3 Participants | 3 Participants | 5 Participants | 1 Participants | 12 Participants |
| Sex: Female, Male Male | 5 Participants | 5 Participants | 3 Participants | 4 Participants | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 5 |
| other Total, other adverse events | 5 / 8 | 2 / 8 | 4 / 8 | 1 / 5 |
| serious Total, serious adverse events | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 5 |
Outcome results
Primary
Area Under the Plasma Concentration-Time Profile From Time 0 Extrapolated to Infinite Time (AUCinf) of Lorlatinib
AUCinf was calculated by AUClast + (Clast\*/kel), where AUClast was the area under the plasma concentration-time profile from time 0 to the time of the last quantifiable concentration; Clast\* was the predicted plasma concentration at the last quantifiable time point estimated from the log-linear regression analysis, and kel was the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve.
Time frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 48, 72, 96 and 120 hours postdose
Population: The analysis population included all participants dosed who had at least 1 of the PK parameters of primary interest.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Normal Function | Area Under the Plasma Concentration-Time Profile From Time 0 Extrapolated to Infinite Time (AUCinf) of Lorlatinib | 8329 ng*hr/mL | Geometric Coefficient of Variation 33 |
| Mild Impairment | Area Under the Plasma Concentration-Time Profile From Time 0 Extrapolated to Infinite Time (AUCinf) of Lorlatinib | 8683 ng*hr/mL | Geometric Coefficient of Variation 29 |
| Moderate Impairment | Area Under the Plasma Concentration-Time Profile From Time 0 Extrapolated to Infinite Time (AUCinf) of Lorlatinib | 9890 ng*hr/mL | Geometric Coefficient of Variation 27 |
| Severe Impairment | Area Under the Plasma Concentration-Time Profile From Time 0 Extrapolated to Infinite Time (AUCinf) of Lorlatinib | 11760 ng*hr/mL | Geometric Coefficient of Variation 37 |
90% CI: [79.73, 136.31]ANOVA
90% CI: [91.43, 154.24]ANOVA
90% CI: [97.82, 203.66]ANOVA
Primary
Maximum Observed Plasma Concentration (Cmax) of Lorlatinib
Cmax was observed directly from data.
Time frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 48, 72, 96 and 120 hours postdose
Population: The analysis population included all participants dosed who had at least 1 of the PK parameters of primary interest.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Normal Function | Maximum Observed Plasma Concentration (Cmax) of Lorlatinib | 546.8 ng/mL | Geometric Coefficient of Variation 48 |
| Mild Impairment | Maximum Observed Plasma Concentration (Cmax) of Lorlatinib | 549.7 ng/mL | Geometric Coefficient of Variation 52 |
| Moderate Impairment | Maximum Observed Plasma Concentration (Cmax) of Lorlatinib | 485.9 ng/mL | Geometric Coefficient of Variation 24 |
| Severe Impairment | Maximum Observed Plasma Concentration (Cmax) of Lorlatinib | 504.8 ng/mL | Geometric Coefficient of Variation 50 |
90% CI: [66.48, 152.02]ANOVA
90% CI: [64.18, 123.06]ANOVA
90% CI: [56.58, 150.63]ANOVA
Secondary
Number of Participants With Electrocardiogram (ECG) Data Meeting Categorical Summarization Criteria
ECG evaluation included: PR interval, time from ECG Q wave to the end of the S wave corresponding to ventricle depolarization (QRS interval), time between the start of the Q wave and the end of the T wave in the heart's electrical cycle (QT interval), and QT interval corrected for heart rate using Fridericia's formula (QTcF interval). The pre-specified criteria of ESG data were categorized as below.
Time frame: Screening, Day -1, 0 hours (pre-dose), 1 hour, 2 hours, 4 hours, 24 hours and 120 hours postdose.
Population: The analysis population included all participants who received at least 1 dose of study medication.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Normal Function | Number of Participants With Electrocardiogram (ECG) Data Meeting Categorical Summarization Criteria | PR interval ≥ 260msec | 0 Participants |
| Normal Function | Number of Participants With Electrocardiogram (ECG) Data Meeting Categorical Summarization Criteria | QTcF interval change from baseline ≥ 60 msec | 0 Participants |
| Normal Function | Number of Participants With Electrocardiogram (ECG) Data Meeting Categorical Summarization Criteria | PR interval change from baseline ≥ 60 to <80 msec | 0 Participants |
| Normal Function | Number of Participants With Electrocardiogram (ECG) Data Meeting Categorical Summarization Criteria | PR interval change from baseline ≥ 40 to <60 msec | 0 Participants |
| Normal Function | Number of Participants With Electrocardiogram (ECG) Data Meeting Categorical Summarization Criteria | QTcF interval change from baseline ≥ 30 to <60 msec | 0 Participants |
| Normal Function | Number of Participants With Electrocardiogram (ECG) Data Meeting Categorical Summarization Criteria | QTcF interval ≥ 480 msec | 0 Participants |
| Normal Function | Number of Participants With Electrocardiogram (ECG) Data Meeting Categorical Summarization Criteria | QT interval ≥ 500 msec | 0 Participants |
| Normal Function | Number of Participants With Electrocardiogram (ECG) Data Meeting Categorical Summarization Criteria | PR interval ≥ 200 to <240 msec | 0 Participants |
| Normal Function | Number of Participants With Electrocardiogram (ECG) Data Meeting Categorical Summarization Criteria | PR interval ≥ 200 to <220 msec | 0 Participants |
| Normal Function | Number of Participants With Electrocardiogram (ECG) Data Meeting Categorical Summarization Criteria | QRS interval percent change from baseline ≥ 50% | 0 Participants |
| Normal Function | Number of Participants With Electrocardiogram (ECG) Data Meeting Categorical Summarization Criteria | QRS interval >120 msec | 0 Participants |
| Normal Function | Number of Participants With Electrocardiogram (ECG) Data Meeting Categorical Summarization Criteria | PR interval ≥ 240 to <260 msec | 0 Participants |
| Normal Function | Number of Participants With Electrocardiogram (ECG) Data Meeting Categorical Summarization Criteria | QTcF interval ≥ 450 to <480 msec | 0 Participants |
| Normal Function | Number of Participants With Electrocardiogram (ECG) Data Meeting Categorical Summarization Criteria | PR interval percent change from baseline > 25% | 0 Participants |
| Normal Function | Number of Participants With Electrocardiogram (ECG) Data Meeting Categorical Summarization Criteria | PR interval change from baseline ≥ 80 msec | 0 Participants |
| Mild Impairment | Number of Participants With Electrocardiogram (ECG) Data Meeting Categorical Summarization Criteria | PR interval percent change from baseline > 25% | 0 Participants |
| Mild Impairment | Number of Participants With Electrocardiogram (ECG) Data Meeting Categorical Summarization Criteria | QTcF interval ≥ 450 to <480 msec | 0 Participants |
| Mild Impairment | Number of Participants With Electrocardiogram (ECG) Data Meeting Categorical Summarization Criteria | PR interval ≥ 200 to <220 msec | 0 Participants |
| Mild Impairment | Number of Participants With Electrocardiogram (ECG) Data Meeting Categorical Summarization Criteria | PR interval ≥ 200 to <240 msec | 0 Participants |
| Mild Impairment | Number of Participants With Electrocardiogram (ECG) Data Meeting Categorical Summarization Criteria | PR interval ≥ 240 to <260 msec | 0 Participants |
| Mild Impairment | Number of Participants With Electrocardiogram (ECG) Data Meeting Categorical Summarization Criteria | PR interval ≥ 260msec | 0 Participants |
| Mild Impairment | Number of Participants With Electrocardiogram (ECG) Data Meeting Categorical Summarization Criteria | QRS interval >120 msec | 0 Participants |
| Mild Impairment | Number of Participants With Electrocardiogram (ECG) Data Meeting Categorical Summarization Criteria | QT interval ≥ 500 msec | 0 Participants |
| Mild Impairment | Number of Participants With Electrocardiogram (ECG) Data Meeting Categorical Summarization Criteria | QTcF interval ≥ 480 msec | 0 Participants |
| Mild Impairment | Number of Participants With Electrocardiogram (ECG) Data Meeting Categorical Summarization Criteria | PR interval change from baseline ≥ 40 to <60 msec | 0 Participants |
| Mild Impairment | Number of Participants With Electrocardiogram (ECG) Data Meeting Categorical Summarization Criteria | PR interval change from baseline ≥ 60 to <80 msec | 0 Participants |
| Mild Impairment | Number of Participants With Electrocardiogram (ECG) Data Meeting Categorical Summarization Criteria | PR interval change from baseline ≥ 80 msec | 0 Participants |
| Mild Impairment | Number of Participants With Electrocardiogram (ECG) Data Meeting Categorical Summarization Criteria | QRS interval percent change from baseline ≥ 50% | 0 Participants |
| Mild Impairment | Number of Participants With Electrocardiogram (ECG) Data Meeting Categorical Summarization Criteria | QTcF interval change from baseline ≥ 30 to <60 msec | 0 Participants |
| Mild Impairment | Number of Participants With Electrocardiogram (ECG) Data Meeting Categorical Summarization Criteria | QTcF interval change from baseline ≥ 60 msec | 0 Participants |
| Moderate Impairment | Number of Participants With Electrocardiogram (ECG) Data Meeting Categorical Summarization Criteria | QTcF interval ≥ 480 msec | 0 Participants |
| Moderate Impairment | Number of Participants With Electrocardiogram (ECG) Data Meeting Categorical Summarization Criteria | QTcF interval change from baseline ≥ 30 to <60 msec | 0 Participants |
| Moderate Impairment | Number of Participants With Electrocardiogram (ECG) Data Meeting Categorical Summarization Criteria | PR interval change from baseline ≥ 40 to <60 msec | 1 Participants |
| Moderate Impairment | Number of Participants With Electrocardiogram (ECG) Data Meeting Categorical Summarization Criteria | PR interval ≥ 260msec | 0 Participants |
| Moderate Impairment | Number of Participants With Electrocardiogram (ECG) Data Meeting Categorical Summarization Criteria | PR interval change from baseline ≥ 60 to <80 msec | 0 Participants |
| Moderate Impairment | Number of Participants With Electrocardiogram (ECG) Data Meeting Categorical Summarization Criteria | PR interval ≥ 200 to <220 msec | 0 Participants |
| Moderate Impairment | Number of Participants With Electrocardiogram (ECG) Data Meeting Categorical Summarization Criteria | PR interval change from baseline ≥ 80 msec | 0 Participants |
| Moderate Impairment | Number of Participants With Electrocardiogram (ECG) Data Meeting Categorical Summarization Criteria | PR interval ≥ 240 to <260 msec | 0 Participants |
| Moderate Impairment | Number of Participants With Electrocardiogram (ECG) Data Meeting Categorical Summarization Criteria | PR interval percent change from baseline > 25% | 1 Participants |
| Moderate Impairment | Number of Participants With Electrocardiogram (ECG) Data Meeting Categorical Summarization Criteria | PR interval ≥ 200 to <240 msec | 0 Participants |
| Moderate Impairment | Number of Participants With Electrocardiogram (ECG) Data Meeting Categorical Summarization Criteria | QRS interval percent change from baseline ≥ 50% | 0 Participants |
| Moderate Impairment | Number of Participants With Electrocardiogram (ECG) Data Meeting Categorical Summarization Criteria | QT interval ≥ 500 msec | 0 Participants |
| Moderate Impairment | Number of Participants With Electrocardiogram (ECG) Data Meeting Categorical Summarization Criteria | QTcF interval ≥ 450 to <480 msec | 0 Participants |
| Moderate Impairment | Number of Participants With Electrocardiogram (ECG) Data Meeting Categorical Summarization Criteria | QRS interval >120 msec | 0 Participants |
| Moderate Impairment | Number of Participants With Electrocardiogram (ECG) Data Meeting Categorical Summarization Criteria | QTcF interval change from baseline ≥ 60 msec | 0 Participants |
| Severe Impairment | Number of Participants With Electrocardiogram (ECG) Data Meeting Categorical Summarization Criteria | PR interval ≥ 200 to <240 msec | 0 Participants |
| Severe Impairment | Number of Participants With Electrocardiogram (ECG) Data Meeting Categorical Summarization Criteria | QTcF interval ≥ 480 msec | 0 Participants |
| Severe Impairment | Number of Participants With Electrocardiogram (ECG) Data Meeting Categorical Summarization Criteria | PR interval ≥ 260msec | 0 Participants |
| Severe Impairment | Number of Participants With Electrocardiogram (ECG) Data Meeting Categorical Summarization Criteria | PR interval ≥ 200 to <220 msec | 1 Participants |
| Severe Impairment | Number of Participants With Electrocardiogram (ECG) Data Meeting Categorical Summarization Criteria | PR interval percent change from baseline > 25% | 0 Participants |
| Severe Impairment | Number of Participants With Electrocardiogram (ECG) Data Meeting Categorical Summarization Criteria | PR interval change from baseline ≥ 40 to <60 msec | 0 Participants |
| Severe Impairment | Number of Participants With Electrocardiogram (ECG) Data Meeting Categorical Summarization Criteria | QTcF interval ≥ 450 to <480 msec | 0 Participants |
| Severe Impairment | Number of Participants With Electrocardiogram (ECG) Data Meeting Categorical Summarization Criteria | QTcF interval change from baseline ≥ 30 to <60 msec | 0 Participants |
| Severe Impairment | Number of Participants With Electrocardiogram (ECG) Data Meeting Categorical Summarization Criteria | QTcF interval change from baseline ≥ 60 msec | 0 Participants |
| Severe Impairment | Number of Participants With Electrocardiogram (ECG) Data Meeting Categorical Summarization Criteria | PR interval change from baseline ≥ 60 to <80 msec | 0 Participants |
| Severe Impairment | Number of Participants With Electrocardiogram (ECG) Data Meeting Categorical Summarization Criteria | PR interval ≥ 240 to <260 msec | 0 Participants |
| Severe Impairment | Number of Participants With Electrocardiogram (ECG) Data Meeting Categorical Summarization Criteria | QT interval ≥ 500 msec | 0 Participants |
| Severe Impairment | Number of Participants With Electrocardiogram (ECG) Data Meeting Categorical Summarization Criteria | QRS interval percent change from baseline ≥ 50% | 0 Participants |
| Severe Impairment | Number of Participants With Electrocardiogram (ECG) Data Meeting Categorical Summarization Criteria | PR interval change from baseline ≥ 80 msec | 0 Participants |
| Severe Impairment | Number of Participants With Electrocardiogram (ECG) Data Meeting Categorical Summarization Criteria | QRS interval >120 msec | 0 Participants |
Secondary
Number of Participants With Laboratory Test Abnormalities Without Regard to Baseline Abnormalities
The hematology, chemistry and urinalysis tests were included in the laboratory examination. Hematology evaluation included hemoglobin, hematocrit, red blood cell count, platelet count, white blood cell count, total neutrophils, eosinophils, monocytes, basophils, lymphocytes, erythrocyte mean corpuscular volume, erythrocyte mean corpuscular hemoglobin concentration and erythrocyte mean corpuscular hemoglobin. Chemistry evaluation included blood urea nitrogen, creatinine, glucose, calcium, sodium, potassium, chloride, total bicarbonate, aspartate aminotransferase, alanine aminotransferase, total bilirubin, alkaline phosphatase, uric acid albumin, total protein, lipase and amylase. Urinalysis evaluation included decimal logarithm of reciprocal of hydrogen ion activity \[pH\], glucose, protein, blood, ketones, microscopy, ketones, nitrite, leukocyte esterase, urobilinogen, urine bilirubin and bacteria. The lab abnormalities were reported in accordance with the sponsor reporting standards.
Time frame: Screening, Day -1, Day 2 and Day 6
Population: The analysis population included all participants who received at least 1 dose of study medication.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Normal Function | Number of Participants With Laboratory Test Abnormalities Without Regard to Baseline Abnormalities | 4 Participants |
| Mild Impairment | Number of Participants With Laboratory Test Abnormalities Without Regard to Baseline Abnormalities | 2 Participants |
| Moderate Impairment | Number of Participants With Laboratory Test Abnormalities Without Regard to Baseline Abnormalities | 8 Participants |
| Severe Impairment | Number of Participants With Laboratory Test Abnormalities Without Regard to Baseline Abnormalities | 5 Participants |
Secondary
Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
An adverse event (AE) was any untoward medical occurrence in a study participant administered a product or medical device; the event did not need to have a causal relationship with the treatment or usage. A serious adverse event (SAE) was any untoward medical occurrence at any dose that resulted in death; was life threatening; required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; resulted in congenital anomaly/birth defect. AEs included both SAEs and AEs. TEAEs were AEs occurred following the start of treatment or AEs increasing in severity during treatment. Number of participants with both all-causality and treatment-related TEAEs are presented below.
Time frame: Baseline up to 28 days after last dose of study treatment (approximately 29 days)
Population: The analysis population included all participants who received at least 1 dose of study medication.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Normal Function | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Treatment-related AEs | 3 Participants |
| Normal Function | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Treatment-related SAEs | 0 Participants |
| Normal Function | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | All-causality SAEs | 0 Participants |
| Normal Function | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | All-causality AEs | 5 Participants |
| Mild Impairment | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | All-causality SAEs | 0 Participants |
| Mild Impairment | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | All-causality AEs | 2 Participants |
| Mild Impairment | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Treatment-related AEs | 2 Participants |
| Mild Impairment | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Treatment-related SAEs | 0 Participants |
| Moderate Impairment | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Treatment-related SAEs | 0 Participants |
| Moderate Impairment | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | All-causality AEs | 4 Participants |
| Moderate Impairment | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | All-causality SAEs | 0 Participants |
| Moderate Impairment | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Treatment-related AEs | 1 Participants |
| Severe Impairment | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Treatment-related AEs | 1 Participants |
| Severe Impairment | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | All-causality SAEs | 0 Participants |
| Severe Impairment | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | All-causality AEs | 1 Participants |
| Severe Impairment | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Treatment-related SAEs | 0 Participants |
Secondary
Number of Participants With Vital Signs Data Meeting Categorical Summarization Criteria
Vital signs evaluations included supine diastolic blood pressure (DBP), and supine systolic blood pressure (SBP) were measured with the participant's arm supported at the level of the heart and recorded to the nearest mmHg after approximately 5 minutes of rest. Number of participants with vital signs data meeting the categorical summarization criteria is presented. The pre-specified criteria of vital signs data were categorized as follows: SBP (minimum) \<90 mmHg, maximum of decrease and increase from baseline for SBP \>=30 mmHg; DBP (minimum) \<50 mmHg, maximum of decrease and increase from baseline for DBP\>=20 mmHg.
Time frame: Baseline up to 28 days after last dose of study treatment (approximately 29 days)
Population: The analysis population included all participants who received at least 1 dose of study medication.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Normal Function | Number of Participants With Vital Signs Data Meeting Categorical Summarization Criteria | Supine SBP ≥ 30 mmHg decrease | 1 Participants |
| Normal Function | Number of Participants With Vital Signs Data Meeting Categorical Summarization Criteria | Supine SBP < 90 mmHg | 0 Participants |
| Normal Function | Number of Participants With Vital Signs Data Meeting Categorical Summarization Criteria | Supine SBP ≥ 30 mmHg increase | 0 Participants |
| Normal Function | Number of Participants With Vital Signs Data Meeting Categorical Summarization Criteria | Supine DBP < 50 mmHg | 0 Participants |
| Normal Function | Number of Participants With Vital Signs Data Meeting Categorical Summarization Criteria | Supine DBP ≥ 20 mmHg increase | 0 Participants |
| Normal Function | Number of Participants With Vital Signs Data Meeting Categorical Summarization Criteria | Supine DBP ≥ 20 mmHg decrease | 0 Participants |
| Mild Impairment | Number of Participants With Vital Signs Data Meeting Categorical Summarization Criteria | Supine DBP ≥ 20 mmHg increase | 0 Participants |
| Mild Impairment | Number of Participants With Vital Signs Data Meeting Categorical Summarization Criteria | Supine SBP < 90 mmHg | 1 Participants |
| Mild Impairment | Number of Participants With Vital Signs Data Meeting Categorical Summarization Criteria | Supine SBP ≥ 30 mmHg increase | 0 Participants |
| Mild Impairment | Number of Participants With Vital Signs Data Meeting Categorical Summarization Criteria | Supine DBP ≥ 20 mmHg decrease | 1 Participants |
| Mild Impairment | Number of Participants With Vital Signs Data Meeting Categorical Summarization Criteria | Supine DBP < 50 mmHg | 1 Participants |
| Mild Impairment | Number of Participants With Vital Signs Data Meeting Categorical Summarization Criteria | Supine SBP ≥ 30 mmHg decrease | 1 Participants |
| Moderate Impairment | Number of Participants With Vital Signs Data Meeting Categorical Summarization Criteria | Supine DBP ≥ 20 mmHg increase | 1 Participants |
| Moderate Impairment | Number of Participants With Vital Signs Data Meeting Categorical Summarization Criteria | Supine SBP ≥ 30 mmHg decrease | 0 Participants |
| Moderate Impairment | Number of Participants With Vital Signs Data Meeting Categorical Summarization Criteria | Supine DBP ≥ 20 mmHg decrease | 0 Participants |
| Moderate Impairment | Number of Participants With Vital Signs Data Meeting Categorical Summarization Criteria | Supine SBP < 90 mmHg | 0 Participants |
| Moderate Impairment | Number of Participants With Vital Signs Data Meeting Categorical Summarization Criteria | Supine SBP ≥ 30 mmHg increase | 2 Participants |
| Moderate Impairment | Number of Participants With Vital Signs Data Meeting Categorical Summarization Criteria | Supine DBP < 50 mmHg | 0 Participants |
| Severe Impairment | Number of Participants With Vital Signs Data Meeting Categorical Summarization Criteria | Supine DBP ≥ 20 mmHg decrease | 0 Participants |
| Severe Impairment | Number of Participants With Vital Signs Data Meeting Categorical Summarization Criteria | Supine SBP ≥ 30 mmHg increase | 1 Participants |
| Severe Impairment | Number of Participants With Vital Signs Data Meeting Categorical Summarization Criteria | Supine SBP ≥ 30 mmHg decrease | 0 Participants |
| Severe Impairment | Number of Participants With Vital Signs Data Meeting Categorical Summarization Criteria | Supine DBP < 50 mmHg | 0 Participants |
| Severe Impairment | Number of Participants With Vital Signs Data Meeting Categorical Summarization Criteria | Supine DBP ≥ 20 mmHg increase | 1 Participants |
| Severe Impairment | Number of Participants With Vital Signs Data Meeting Categorical Summarization Criteria | Supine SBP < 90 mmHg | 0 Participants |
Other Pre-specified
Apparent Clearance After Oral Dose (CL/F) of Lorlatinib
CL/F was calculated by Dose/AUCinf.
Time frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 48, 72, 96 and 120 hours postdose
Population: The analysis population included all participants dosed who had at least 1 of the PK parameters of primary interest.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Normal Function | Apparent Clearance After Oral Dose (CL/F) of Lorlatinib | 12.02 L/hr | Geometric Coefficient of Variation 33 |
| Mild Impairment | Apparent Clearance After Oral Dose (CL/F) of Lorlatinib | 11.51 L/hr | Geometric Coefficient of Variation 29 |
| Moderate Impairment | Apparent Clearance After Oral Dose (CL/F) of Lorlatinib | 10.11 L/hr | Geometric Coefficient of Variation 27 |
| Severe Impairment | Apparent Clearance After Oral Dose (CL/F) of Lorlatinib | 8.51 L/hr | Geometric Coefficient of Variation 37 |
Other Pre-specified
Apparent Volume of Distribution Following Oral Dose (Vz/F) of Lorlatinib
Vz/F was calculated by Dose/(AUCinf\*kel). kel was the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve.
Time frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 48, 72, 96 and 120 hours postdose
Population: The analysis population included all participants dosed who had at least 1 of the PK parameters of primary interest.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Normal Function | Apparent Volume of Distribution Following Oral Dose (Vz/F) of Lorlatinib | 436.9 L | Geometric Coefficient of Variation 24 |
| Mild Impairment | Apparent Volume of Distribution Following Oral Dose (Vz/F) of Lorlatinib | 462.9 L | Geometric Coefficient of Variation 27 |
| Moderate Impairment | Apparent Volume of Distribution Following Oral Dose (Vz/F) of Lorlatinib | 566.2 L | Geometric Coefficient of Variation 21 |
| Severe Impairment | Apparent Volume of Distribution Following Oral Dose (Vz/F) of Lorlatinib | 503.8 L | Geometric Coefficient of Variation 36 |
Other Pre-specified
Area Under the Plasma Concentration-time Profile From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) of Lorlatinib
AUClast was calculated by linear/Log trapezoidal method.
Time frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 48, 72, 96 and 120 hours postdose
Population: The analysis population included all participants dosed who had at least 1 of the PK parameters of primary interest.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Normal Function | Area Under the Plasma Concentration-time Profile From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) of Lorlatinib | 8015 ng*hr/mL | Geometric Coefficient of Variation 32 |
| Mild Impairment | Area Under the Plasma Concentration-time Profile From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) of Lorlatinib | 8307 ng*hr/mL | Geometric Coefficient of Variation 28 |
| Moderate Impairment | Area Under the Plasma Concentration-time Profile From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) of Lorlatinib | 8867 ng*hr/mL | Geometric Coefficient of Variation 24 |
| Severe Impairment | Area Under the Plasma Concentration-time Profile From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) of Lorlatinib | 10310 ng*hr/mL | Geometric Coefficient of Variation 36 |
Other Pre-specified
Renal Clearance (CLR) of Lorlatinib
CLR was calculated by Ae/AUClast. Ae was cumulative amount of drug recovered unchanged in urine, which was calculated by sum of (urine concentration × sample volume) for each collection interval from 0 to time 120 hours postdose. Sample volume = (urine weight in g/1.020), where 1.020 g/mL is the approximate specific gravity of urine.
Time frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 48, 72, 96 and 120 hours postdose
Population: The analysis population included all participants dosed who had at least 1 of the PK parameters of primary interest.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Normal Function | Renal Clearance (CLR) of Lorlatinib | 0.1095 L/hr | Geometric Coefficient of Variation 42 |
| Mild Impairment | Renal Clearance (CLR) of Lorlatinib | 0.1382 L/hr | Geometric Coefficient of Variation 50 |
| Moderate Impairment | Renal Clearance (CLR) of Lorlatinib | 0.08199 L/hr | Geometric Coefficient of Variation 55 |
| Severe Impairment | Renal Clearance (CLR) of Lorlatinib | 0.06872 L/hr | Geometric Coefficient of Variation 45 |
Other Pre-specified
Terminal Elimination Plasma Half-life (t½) of Lorlatinib
t1/2 was calculated by ln(2)/kel.
Time frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 48, 72, 96 and 120 hours postdose
Population: The analysis population included all participants dosed who had at least 1 of the PK parameters of primary interest.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Normal Function | Terminal Elimination Plasma Half-life (t½) of Lorlatinib | 25.64 hours | Standard Deviation 4.75 |
| Mild Impairment | Terminal Elimination Plasma Half-life (t½) of Lorlatinib | 28.08 hours | Standard Deviation 3.5156 |
| Moderate Impairment | Terminal Elimination Plasma Half-life (t½) of Lorlatinib | 39.40 hours | Standard Deviation 7.1019 |
| Severe Impairment | Terminal Elimination Plasma Half-life (t½) of Lorlatinib | 41.66 hours | Standard Deviation 7.6081 |
Other Pre-specified
Time for Cmax (Tmax) of Lorlatinib
Tmax was observed directly from data as time of first occurrence.
Time frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 48, 72, 96 and 120 hours postdose
Population: The analysis population included all participants dosed who had at least 1 of the PK parameters of primary interest.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Normal Function | Time for Cmax (Tmax) of Lorlatinib | 1.50 hours |
| Mild Impairment | Time for Cmax (Tmax) of Lorlatinib | 1.00 hours |
| Moderate Impairment | Time for Cmax (Tmax) of Lorlatinib | 1.25 hours |
| Severe Impairment | Time for Cmax (Tmax) of Lorlatinib | 1.00 hours |