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A Study To Evaluate The Effect Of Rifampin On Pharmacokinetics Of PF-06463922 In Healthy Volunteers

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ClinicalTrials.gov Identifier: NCT02804399
Recruitment Status : Completed
First Posted : June 17, 2016
Results First Posted : January 25, 2019
Last Update Posted : January 25, 2019
Sponsor:
Information provided by (Responsible Party):
Pfizer

Brief Summary:
The purpose of this study is to estimate the effect of rifampin on the single dose PK of PF-06463922.

Condition or disease Intervention/treatment Phase
Healthy Drug: PF-06463922 Drug: rifampin Phase 1

Detailed Description:
This will be a Phase 1, open-label, 2-period, 2-treatment, fixed-sequence, cross-over study in approximately 12 healthy subjects employing administration of a single oral dose of PF-06463922 in the fasted state alone, and with multiple dosing of rifampin 600 mg once a day to estimate the effect of multiple dose rifampin on the single dose PK of PF-06463922.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 12 participants
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Other
Official Title: A Phase One, Open Label, Two-period, Two-treatment, Fixed Sequence, Cross-over Study To Estimate The Effect Of Multiple Dose Rifampin On The Single Dose Pharmacokinetics Of Pf-06463922 In Healthy Volunteers.
Actual Study Start Date : July 2016
Actual Primary Completion Date : October 2016
Actual Study Completion Date : October 2016

Resource links provided by the National Library of Medicine

Drug Information available for: Rifampin

Arm Intervention/treatment
Experimental: all subjects
subjects will receive a 100 mg single oral dose of PF-06463922 followed by a 100 mg single dose of PF-06463922 combined with 600 mg QD dose of rifampin with at least 10 days of washout period between two PF-06463922 doses.
Drug: PF-06463922
100 mg oral dose on day 1 in period 1 and on day 8 in period 2
Other Name: lorlatinib

Drug: rifampin
600 mg QD from day 1 to day 12 in period 2.
Other Name: rifampicin




Primary Outcome Measures :
  1. Plasma AUCinf for PF-06463922 Given Alone and With Rifampin [ Time Frame: Predose, 0.5, 1, 1.5, 2, 4, 6, 12, 24, 36, 48, 60, 72, 96, 120 hours postdose on Day 1 after PF-06463922 100 mg administration in Period 1, and at the same time points on Day 8 after PF-06463922 100 mg with rifampin administration in Period 2. ]
    AUCinf is the plasma area under the plasma concentration-time profile from time 0 extrapolated to infinite time. The pharmacokinetics (PK) parameter analysis population was defined as all participants enrolled and treated who have at least 1 of the PF-06463922 PK parameters of primary interest in at least 1 treatment period.

  2. Plasma Cmax for PF-06463922 Given Alone and With Rifampin [ Time Frame: Predose, 0.5, 1, 1.5, 2, 4, 6, 12, 24, 36, 48, 60, 72, 96, 120 hours postdose on Day 1 after PF-06463922 100 mg administration in Period 1, and at the same time points on Day 8 after PF-06463922 100 mg with rifampin administration in Period 2. ]
    Cmax is the maximum observed plasma concentration. PK parameter analysis population was defined as all participants enrolled and treated who have at least 1 of the PF-06463922 PK parameters of primary interest in at least 1 treatment period.


Secondary Outcome Measures :
  1. Plasma AUClast for PF-06463922 Given Alone and With Rifampin [ Time Frame: Predose, 0.5, 1, 1.5, 2, 4, 6, 12, 24, 36, 48, 60, 72, 96, 120 hours postdose on Day 1 after PF-06463922 100 mg administration in Period 1, and at the same time points on Day 8 after PF-06463922 100 mg with rifampin administration in Period 2. ]
    AUClast is the plasma area under the plasma concentration-time profile from time 0 to the time of the last quantifiable concentration. The PK parameter analysis population was defined as all participants enrolled and treated who have at least 1 of the PF-06463922 PK parameters of primary interest in at least 1 treatment period.

  2. Plasma Tmax for PF-06463922 Given Alone and With Rifampin [ Time Frame: Predose, 0.5, 1, 1.5, 2, 4, 6, 12, 24, 36, 48, 60, 72, 96, 120 hours postdose on Day 1 after PF-06463922 100 mg administration in Period 1, and at the same time points on Day 8 after PF-06463922 100 mg with rifampin administration in Period 2. ]
    Tmax is the time for maximum observed plasma concentration (Cmax). The PK parameter analysis population was defined as all participants enrolled and treated who have at least 1 of the PF-06463922 PK parameters of primary interest in at least 1 treatment period.

  3. Plasma t1/2 for PF-06463922 Given Alone and With Rifampin [ Time Frame: Predose, 0.5, 1, 1.5, 2, 4, 6, 12, 24, 36, 48, 60, 72, 96, 120 hours postdose on Day 1 after PF-06463922 100 mg administration in Period 1, and at the same time points on Day 8 after PF-06463922 100 mg with rifampin administration in Period 2. ]
    Terminal plasma half-life (t1/2) is the time measured for the plasma concentration of drug to decrease by one half. The PK parameter analysis population is defined as all participants enrolled and treated who have at least 1 of the PF-06463922 PK parameters of primary interest in at least 1 treatment period.

  4. Plasma CL/F for PF-06463922 Given Alone and With Rifampin [ Time Frame: Predose, 0.5, 1, 1.5, 2, 4, 6, 12, 24, 36, 48, 60, 72, 96, 120 hours postdose on Day 1 after PF-06463922 100 mg administration in Period 1, and at the same time points on Day 8 after PF-06463922 100 mg with rifampin administration in Period 2. ]
    CL/F is the apparent oral clearance. The PK parameter analysis population was defined as all participants enrolled and treated who have at least 1 of the PF-06463922 PK parameters of primary interest in at least 1 treatment period.

  5. Plasma Vz/F for PF-06463922 Given Alone and With Rifampin [ Time Frame: Predose, 0.5, 1, 1.5, 2, 4, 6, 12, 24, 36, 48, 60, 72, 96, 120 hours postdose on Day 1 after PF-06463922 100 mg administration in Period 1, and at the same time points on Day 8 after PF-06463922 100 mg administration with rifampin in Period 2. ]
    Vz/F is the apparent volume of distribution (only after single dose).The PK parameter analysis population was defined as all participants enrolled and treated who have at least 1 of the PF-06463922 PK parameters of primary interest in at least 1 treatment period.

  6. Plasma AUClast for PF-06895751 When PF-06463922 Given Alone and With Rifampin [ Time Frame: Predose, 0.5, 1, 1.5, 2, 4, 6, 12, 24, 36, 48, 60, 72, 96, 120 hours postdose on Day 1 after PF-06463922 100 mg administration in Period 1, and at the same time points on Day 8 after PF-06463922 100 mg with rifampin administration in Period 2. ]
    AUClast was the plasma area under the plasma concentration-time profile from time 0 to the time of the last quantifiable concentration. The PK parameter analysis population was defined as all participants enrolled and treated who have at least 1 of the PF-06463922 PK parameters of primary interest in at least 1 treatment period. PF-06895751 was the metabolite of PF-06463922.

  7. Plasma AUCinf for PF-06895751 When PF-06463922 Given Alone and With Rifampin [ Time Frame: Predose, 0.5, 1, 1.5, 2, 4, 6, 12, 24, 36, 48, 60, 72, 96, 120 hours postdose on Day 1 after PF-06463922 100 mg administration in Period 1, and at the same time points on Day 8 after PF-06463922 100 mg with rifampin administration in Period 2. ]
    AUCinf was the area under the plasma concentration-time profile from time 0 extrapolated to infinite time. The PK parameter analysis population was defined as all participants enrolled and treated who have at least 1 of the PF-06463922 PK parameters of primary interest in at least 1 treatment period. PF-06895751 was the metabolite of PF-06463922.

  8. Plasma Tmax for PF-06895751 When PF-06463922 Given Alone and With Rifampin. [ Time Frame: Predose, 0.5, 1, 1.5, 2, 4, 6, 12, 24, 36, 48, 60, 72, 96, 120 hours postdose on Day 1 after PF-06463922 100 mg administration in Period 1, and at the same time points on Day 8 after PF-06463922 100 mg with rifampin administration in Period 2. ]
    Tmax was the time for maximum observed plasma concentration (Cmax). The PK parameter analysis population was defined as all participants enrolled and treated who have at least 1 of the PF-06463922 PK parameters of primary interest in at least 1 treatment period. PF-06895751 was the metabolite of PF-06463922.

  9. Plasma t1/2 for PF-06895751 When PF-06463922 Given Alone and With Rifampin [ Time Frame: Predose, 0.5, 1, 1.5, 2, 4, 6, 12, 24, 36, 48, 60, 72, 96, 120 hours postdose on Day 1 after PF-06463922 100 mg administration in Period 1, and at the same time points on Day 8 after PF-06463922 100 mg with rifampin administration in Period 2. ]
    T1/2 was the terminal plasma half-life. The PK parameter analysis population was defined as all participants enrolled and treated who have at least 1 of the PF-06463922 PK parameters of primary interest in at least 1 treatment period. PF-06895751 was the metabolite of PF-06463922.

  10. Plasma Cmax for PF-06895751 When PF-06463922 Given Alone and With Rifampin [ Time Frame: Predose, 0.5, 1, 1.5, 2, 4, 6, 12, 24, 36, 48, 60, 72, 96, 120 hours postdose on Day 1 after PF-06463922 100 mg administration in Period 1, and at the same time points on Day 8 after PF-06463922 100 mg with rifampin administration in Period 2. ]
    Cmax was the maximum observed plasma concentration. The PK parameter analysis population was defined as all participants enrolled and treated who have at least 1 of the PF-06463922 PK parameters of primary interest in at least 1 treatment period. PF-06895751 was the metabolite of PF-06463922.

  11. Plasma Molecular Weight Adjusted Metabolite to Parent (M/P) Ratio for Cmax (MRCmax) of PF-06463922 and Its Metabolite: When PF-06463922 Given Alone and With Rifampin [ Time Frame: Predose, 0.5, 1, 1.5, 2, 4, 6, 12, 24, 36, 48, 60, 72, 96, 120 hours postdose on Day 1 after PF-06463922 100 mg administration in Period 1, and at the same time points on Day 8 after PF-06463922 100 mg with rifampin administration in Period 2. ]
    Cmax was the maximum observed plasma concentration of PF-06463922 and PF-06895751 ( metabolite of PF-06463922). The molecular weight adjusted metabolite/parent ratio (PF-06895751/PF-06463922) for Cmax was presented. The PK parameter analysis population was defined as all participants enrolled and treated who have at least 1 of the PF-06463922 PK parameters of primary interest in at least 1 treatment period.

  12. Plasma Molecular Weight Adjusted Metabolite to Parent (M/P) Ratio for AUClast (MRAUClast) of PF-06463922 and Its Metabolite: When PF-06463922 Given Alone and With Rifampin [ Time Frame: Predose, 0.5, 1, 1.5, 2, 4, 6, 12, 24, 36, 48, 60, 72, 96, 120 hours postdose on Day 1 after PF-06463922 100 mg administration in Period 1, and at the same time points on Day 8 after PF-06463922 100 mg with rifampin administration in Period 2. ]
    AUClast was the plasma area under the plasma concentration-time profile from time 0 to the time of the last quantifiable concentration of PF-06463922 and PF-06895751 ( metabolite of PF-06463922). The molecular weight adjusted metabolite/parent ratio (PF-06895751/PF-06463922) for AUClast was presented. The PK parameter analysis population was defined as all participants enrolled and treated who have at least 1 of the PF-06463922 PK parameters of primary interest in at least 1 treatment period. PF-06895751 was the metabolite of PF-06463922.

  13. Plasma Molecular Weight Adjusted Metabolite to Parent (M/P) Ratio for AUCinf (MRAUCinf) of PF-06463922 and Its Metabolite: When PF-06463922 Given Alone and With Rifampin [ Time Frame: Predose, 0.5, 1, 1.5, 2, 4, 6, 12, 24, 36, 48, 60, 72, 96, 120 hours postdose on Day 1 after PF-06463922 100 mg administration in Period 1, and at the same time points on Day 8 after PF-06463922 100 mg with rifampin administration in Period 2. ]
    AUCinf was the plasma area under the plasma concentration-time profile from time 0 extrapolated to infinite time of PF-06463922 and PF-06895751 ( metabolite of PF-06463922). The molecular weight adjusted metabolite/parent ratio (PF-06895751/PF-06463922) for AUCinf was presented. The PK parameter analysis population was defined as all participants enrolled and treated who have at least 1 of the PF-06463922 PK parameters of primary interest in at least 1 treatment period.


Other Outcome Measures:
  1. Number of Participants With End of Study Abnormal Laboratory Findings Meeting the Criteria of Potentially Significant Clinical Concern [ Time Frame: Baseline to about 18 days after the first PF-06463922 dose ]
    The total number of participants with laboratory test abnormalities was assessed. Clinical laboratory tests included hematology, chemistry, urinalysis and some other tests (including follicle-simulating hormone[FSH], urine drug screening, hepatitis B surface antigen [HBsAg], hepatitis B core antibody [HBcAb], hepatitis C virus antibody [HCVAb] and human immunodeficiency virus [HIV]. Clinical significance was judged by the investigator.

  2. Number of Participants With Physical Examination Findings Meeting the Criteria of Potentially Significant Clinical Concern [ Time Frame: Baseline to about 18 days after the first PF-06463922 dose. ]
    A full physical examination included head, ears, eyes, nose, mouth, skin, heart and lung examinations, lymph nodes, gastrointestinal, musculoskeletal, and neurological systems. The limited or abbreviated physical examination focused on general appearance, the respiratory and cardiovascular systems, as well as towards participant reported symptoms. Clinical significance was judged by the investigator.

  3. Number of Participants With Changes From Baseline and Absolute Values in Vital Signs Meeting the Criteria of Potentially Significant Clinical Concerns [ Time Frame: Baseline to about 18 days after the first PF-06463922 dose. ]
    Criteria for potentially clinically important changes in vital signs were defined as: supine and standing systolic blood pressure (SBP) of less than (<90) millimeters of mercury (mm Hg) or change in supine and standing SBP more than or equal to (>=) 30 mm Hg; supine and standing diastolic blood pressure (DBP) of < 50 mm Hg or change in supine and standing DBP of >= 20 mm Hg; supine and standing pulse rate of < 40 or >120 beats per minute (bpm). Figure "99999" signifies data not measurable/applicable. Maximum Decrease is abbreviated as Max.Dec., and Maximum Increase is abbreviated as Max.Inc. n is the number of participants contributing to the parameter, not applicable is abbreviated as N/A.

  4. Number of Participants With Electrocardiogram (ECG) Findings Meeting the Criteria of Potentially Significant Clinical Concerns [ Time Frame: Baseline to about 18 days after the first PF-06463922 dose. ]
    PR interval was the interval between the start of the P wave and the start of the QRS complex, corresponding to the time between the onset of the atrial depolarization and onset of ventricular depolarization. Criteria for potentially clinically important changes (chg) in ECG were defined as: absolute values of PR interval >=200 to <220 msec, >=220 to <240 msec, >=240 to <260 msec and >=260 msec. Increase from baseline >=40, <60, >=60 and <80, >=80, and relative change from baseline >25%. The beginning of the Q wave to the end of the T wave corresponding to electrical systole (QT) interval corrected using the Fridericia formular (QTCF) of 450 to <480 msec, 480 to <500 msec and >=500 msec, or an increase of 30 to <60 msec of >=60 msec. Maximum is abbreviated as Max.

  5. Number of Participants With Concomitant Treatments Meeting the Criteria of Potentially Significant Clinical Concerns [ Time Frame: Baseline to about 18 days after the first PF-06463922 dose. ]
    Participants abstained from all concomitant treatments, except for the treatment of adverse events. Limited use of non-prescription medications that were not believed to affect participant safety or the overall results of the study might be permitted on a case by case basis following approval by the sponsor. All participants were questioned about concomitant treatment at each clinic visit. Treatments taken within 28 days before the first dose of study investigational product were documented as a prior treatment. Treatment taken after the first dose of study investigational product were documented as concomitant treatments. Females taking hormone replacement therapy might be eligible to participate in this study if they were willing to discontinue therapy at least 28 days prior to the first dose of study treatment and remained off hormonal therapy for duration of the study. Clinical significance was judged by the investigator.

  6. Number of Participants With Treatment-Emergent Adverse Events (TEAEs) (All Causalities and Treatment-Related) [ Time Frame: Baseline to about 18 days after the first PF-06463922 dose. ]
    An adverse event (AE) was any untoward medical occurrence in a clinical investigation participant administered a product or medical device; the event need not necessarily have a casual relationship with the treatment or usage. A serious adverse event (SAE) was any untoward medical occurrence at any dose that: 1) resulted in death; 2) was life threatening (immediate risk of death); 3) required inpatient hospitalization or prolongation of existing hospitalization; 4) resulted in persistent or significant disability/incapacity (substantial disruption of the ability to conduct normal life functions); 5) resulted in congenital anomaly/birth defect. TEAE included both non-serious adverse events and serious adverse events.



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Ages Eligible for Study:   18 Years to 55 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Healthy female subjects of non-childbearing potential and/or male subjects who, at the time of screening, are between the ages of 18 and 55 years, inclusive
  • Body Mass Index (BMI) of 17.5 to 30.5 kg/m2; and a total body weight >50 kg (110 lbs)

Exclusion Criteria:

  • Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, or allergic disease
  • Any condition possibly affecting drug absorption
  • Positive urine drug screen
  • History of HIV, Hep B or Hep C
  • History of regular alcohol consumption
  • History of cardiac arrhythmia, history of AV block, history of symptomatic bradycardia, history of QTc prolongation
  • History of pancreatitis or hyperlipidemia, elevated lipase

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02804399


Locations
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United States, Connecticut
Pfizer New Haven Clinical Research Unit
New Haven, Connecticut, United States, 06511
Sponsors and Collaborators
Pfizer
Investigators
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Study Director: Pfizer CT.gov Call Center Pfizer

Additional Information:
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Responsible Party: Pfizer
ClinicalTrials.gov Identifier: NCT02804399     History of Changes
Other Study ID Numbers: B7461011
RIFAMPIN DDI STUDY ( Other Identifier: Alias Study Number )
First Posted: June 17, 2016    Key Record Dates
Results First Posted: January 25, 2019
Last Update Posted: January 25, 2019
Last Verified: August 2018
Keywords provided by Pfizer:
rifampin
pharmacokinetics
PF-06463922
drug interaction
Additional relevant MeSH terms:
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Rifampin
Antibiotics, Antitubercular
Antitubercular Agents
Anti-Bacterial Agents
Anti-Infective Agents
Leprostatic Agents
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Cytochrome P-450 CYP2B6 Inducers
Cytochrome P-450 Enzyme Inducers
Cytochrome P-450 CYP2C8 Inducers
Cytochrome P-450 CYP2C19 Inducers
Cytochrome P-450 CYP2C9 Inducers
Cytochrome P-450 CYP3A Inducers