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Relative Bioavailability Of A Crizotinib Oral Liquid Formulation To Crizotinib Formulated Capsule

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ClinicalTrials.gov Identifier: NCT01297595
Recruitment Status : Completed
First Posted : February 17, 2011
Results First Posted : February 8, 2012
Last Update Posted : February 16, 2012
Sponsor:
Information provided by (Responsible Party):
Pfizer

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Crossover Assignment;   Masking: None (Open Label);   Primary Purpose: Basic Science
Condition Healthy
Intervention Drug: crizotinib
Enrollment 22
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Crizotinib 250 mg FC First, Then Crizotinib 250 mg OLF Crizotinib 250 mg OLF First, Then Crizotinib 250 mg FC
Hide Arm/Group Description Single oral dose of crizotinib 250 milligram (mg) formulated capsule (FC) in first intervention period; and single oral dose of crizotinib 250 mg oral liquid formulation (OLF) in second intervention period. A washout period of at least 14 days was maintained between each crizotinib dose. Single oral dose of crizotinib 250 mg OLF in first intervention period; and single oral dose of crizotinib 250 mg FC in second intervention period. A washout period of at least 14 days was maintained between each crizotinib dose.
Period Title: First Intervention Period
Started 11 11
Completed 11 11
Not Completed 0 0
Period Title: Washout Period (At Least 14 Days)
Started 11 11
Completed 11 11
Not Completed 0 0
Period Title: Second Intervention Period
Started 11 11
Completed 11 11
Not Completed 0 0
Arm/Group Title Entire Study Population
Hide Arm/Group Description Includes participants randomized to receive crizotinib 250 mg FC first and crizotinib 250 mg OLF first.
Overall Number of Baseline Participants 22
Hide Baseline Analysis Population Description
[Not Specified]
Age Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 22 participants
38.0  (11.9)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 22 participants
Female
0
   0.0%
Male
22
 100.0%
1.Primary Outcome
Title Area Under the Curve From Time Zero to Infinite Time [AUC (0 - ∞)]
Hide Description AUC (0 - ∞) = Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - ∞). It is obtained from AUC (0 - t) plus AUC (t - ∞).
Time Frame 0 (pre-dose), 1, 2, 3, 4, 5, 6, 8, 10, 12, 24, 48, 72, 96 and 144 hours (hrs) post crizotinib dose
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic (PK) parameter analysis population included all participants randomized and treated who had at least 1 of the PK parameters of primary interest in at least 1 treatment period.
Arm/Group Title Crizotinib 250 mg FC Crizotinib 250 mg OLF
Hide Arm/Group Description:
Single oral dose of crizotinib 250 mg FC [Reference] in either first intervention period or second intervention period.
Single oral dose of crizotinib 250 mg OLF [Test] in either first intervention period or second intervention period.
Overall Number of Participants Analyzed 22 22
Geometric Mean (Standard Deviation)
Unit of Measure: ng*hr/mL
2833  (1099) 2821  (1086)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Crizotinib 250 mg FC, Crizotinib 250 mg OLF
Comments Natural log transformed AUC (0 - ∞) of crizotinib was analyzed using a mixed effect model with sequence, period and treatment as a fixed effects and participant within sequence as a random effect. The adjusted mean differences and 90% confidence intervals (CIs) for the differences were exponentiated to provide estimates of the ratio of adjusted geometric means (Test/Reference) and 90% CIs for the ratios. This was an estimation study and there was no formal statistical hypothesis.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Ratio of Adjusted Means
Estimated Value 99.58
Confidence Interval (2-Sided) 90%
91.08 to 108.87
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Time to Reach Maximum Observed Plasma Concentration (Tmax)
Hide Description [Not Specified]
Time Frame 0 (pre-dose), 1, 2, 3, 4, 5, 6, 8, 10, 12, 24, 48, 72, 96 and 144 hrs post crizotinib dose
Hide Outcome Measure Data
Hide Analysis Population Description
PK parameter analysis population included all participants randomized and treated who had at least 1 of the PK parameters of primary interest in at least 1 treatment period.
Arm/Group Title Crizotinib 250 mg FC Crizotinib 250 mg OLF
Hide Arm/Group Description:
Single oral dose of crizotinib 250 mg FC [Reference] in either first intervention period or second intervention period.
Single oral dose of crizotinib 250 mg OLF [Test] in either first intervention period or second intervention period.
Overall Number of Participants Analyzed 22 22
Median (Full Range)
Unit of Measure: hr
5.00
(2.00 to 6.00)
5.00
(2.00 to 6.00)
3.Secondary Outcome
Title Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast)
Hide Description Area under the plasma concentration time-curve from zero (pre-dose) to the last measured concentration (AUClast).
Time Frame 0 (pre-dose), 1, 2, 3, 4, 5, 6, 8, 10, 12, 24, 48, 72, 96 and 144 hrs post crizotinib dose
Hide Outcome Measure Data
Hide Analysis Population Description
PK parameter analysis population included all participants randomized and treated who had at least 1 of the PK parameters of primary interest in at least 1 treatment period.
Arm/Group Title Crizotinib 250 mg FC Crizotinib 250 mg OLF
Hide Arm/Group Description:
Single oral dose of crizotinib 250 mg FC [Reference] in either first intervention period or second intervention period.
Single oral dose of crizotinib 250 mg OLF [Test] in either first intervention period or second intervention period.
Overall Number of Participants Analyzed 22 22
Geometric Mean (Standard Deviation)
Unit of Measure: ng*hr/mL
2696  (1073) 2679  (1069)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Crizotinib 250 mg FC, Crizotinib 250 mg OLF
Comments Natural log transformed AUClast of crizotinib was analyzed using a mixed effect model with sequence, period and treatment as a fixed effects and participant within sequence as a random effect. The adjusted mean differences and 90% CIs for the differences were exponentiated to provide estimates of the ratio of adjusted geometric means (Test/Reference) and 90% CIs for the ratios. This was an estimation study and there was no formal statistical hypothesis.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Ratio of Adjusted Means
Estimated Value 99.35
Confidence Interval (2-Sided) 90%
90.51 to 109.07
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Maximum Observed Plasma Concentration (Cmax)
Hide Description [Not Specified]
Time Frame 0 (pre-dose), 1, 2, 3, 4, 5, 6, 8, 10, 12, 24, 48, 72, 96 and 144 hrs post crizotinib dose
Hide Outcome Measure Data
Hide Analysis Population Description
PK parameter analysis population included all participants randomized and treated who had at least 1 of the PK parameters of primary interest in at least 1 treatment period.
Arm/Group Title Crizotinib 250 mg FC Crizotinib 250 mg OLF
Hide Arm/Group Description:
Single oral dose of crizotinib 250 mg FC [Reference] in either first intervention period or second intervention period.
Single oral dose of crizotinib 250 mg OLF [Test] in either first intervention period or second intervention period.
Overall Number of Participants Analyzed 22 22
Geometric Mean (Standard Deviation)
Unit of Measure: ng/mL
121.0  (38.9) 117.2  (36.1)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Crizotinib 250 mg FC, Crizotinib 250 mg OLF
Comments Natural log transformed Cmax of crizotinib was analyzed using a mixed effect model with sequence, period and treatment as a fixed effects and participant within sequence as a random effect. The adjusted mean differences and 90% CIs for the differences were exponentiated to provide estimates of the ratio of adjusted geometric means (Test/Reference) and 90% CIs for the ratios. This was an estimation study and there was no formal statistical hypothesis.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Ratio of Adjusted Means
Estimated Value 96.84
Confidence Interval (2-Sided) 90%
88.22 to 106.32
Estimation Comments [Not Specified]
5.Secondary Outcome
Title Plasma Terminal Half-Life (t1/2)
Hide Description Plasma terminal half-life is the time measured for the plasma concentration to decrease by one half.
Time Frame 0 (pre-dose), 1, 2, 3, 4, 5, 6, 8, 10, 12, 24, 48, 72, 96 and 144 hrs post crizotinib dose
Hide Outcome Measure Data
Hide Analysis Population Description
PK parameter analysis population included all participants randomized and treated who had at least 1 of the PK parameters of primary interest in at least 1 treatment period.
Arm/Group Title Crizotinib 250 mg FC Crizotinib 250 mg OLF
Hide Arm/Group Description:
Single oral dose of crizotinib 250 mg FC [Reference] in either first intervention period or second intervention period.
Single oral dose of crizotinib 250 mg OLF [Test] in either first intervention period or second intervention period.
Overall Number of Participants Analyzed 22 22
Mean (Standard Deviation)
Unit of Measure: hr
35.58  (6.12) 36.35  (5.64)
6.Secondary Outcome
Title Apparent Oral Clearance (CL/F)
Hide Description Drug clearance (CL) is a quantitative measure of the rate at which a drug substance is removed from the plasma. Clearance obtained after oral dose (apparent oral clearance [CL/F]) is influenced by the fraction of the dose absorbed (F).
Time Frame 0 (pre-dose), 1, 2, 3, 4, 5, 6, 8, 10, 12, 24, 48, 72, 96 and 144 hrs post crizotinib dose
Hide Outcome Measure Data
Hide Analysis Population Description
PK parameter analysis population included all participants randomized and treated who had at least 1 of the PK parameters of primary interest in at least 1 treatment period.
Arm/Group Title Crizotinib 250 mg FC Crizotinib 250 mg OLF
Hide Arm/Group Description:
Single oral dose of crizotinib 250 mg FC [Reference] in either first intervention period or second intervention period.
Single oral dose of crizotinib 250 mg OLF [Test] in either first intervention period or second intervention period.
Overall Number of Participants Analyzed 22 22
Geometric Mean (Standard Deviation)
Unit of Measure: Liter/hour (L/hr)
88.21  (30.17) 88.61  (28.96)
7.Secondary Outcome
Title Apparent Volume of Distribution (Vz/F)
Hide Description 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 absorbed.
Time Frame 0 (pre-dose), 1, 2, 3, 4, 5, 6, 8, 10, 12, 24, 48, 72, 96 and 144 hrs post crizotinib dose
Hide Outcome Measure Data
Hide Analysis Population Description
PK parameter analysis population included all participants randomized and treated who had at least 1 of the PK parameters of primary interest in at least 1 treatment period.
Arm/Group Title Crizotinib 250 mg FC Crizotinib 250 mg OLF
Hide Arm/Group Description:
Single oral dose of crizotinib 250 mg FC [Reference] in either first intervention period or second intervention period.
Single oral dose of crizotinib 250 mg OLF [Test] in either first intervention period or second intervention period.
Overall Number of Participants Analyzed 22 22
Geometric Mean (Standard Deviation)
Unit of Measure: Liter
4473  (2089) 4593  (2108)
8.Secondary Outcome
Title Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) for Crizotinib Metabolite (PF-06260182)
Hide Description Area under the plasma concentration time-curve from zero (pre-dose) to the last measured concentration (AUClast) of Crizotinib metabolite (PF-06260182).
Time Frame 0 (pre-dose), 1, 2, 3, 4, 5, 6, 8, 10, 12, 24, 48, 72, 96 and 144 hrs post crizotinib dose
Hide Outcome Measure Data
Hide Analysis Population Description
PK parameter analysis population included all participants randomized and treated who had at least 1 of the PK parameters of primary interest in at least 1 treatment period.
Arm/Group Title Crizotinib 250 mg FC Crizotinib 250 mg OLF
Hide Arm/Group Description:
Single oral dose of crizotinib 250 mg FC [Reference] in either first intervention period or second intervention period.
Single oral dose of crizotinib 250 mg OLF [Test] in either first intervention period or second intervention period.
Overall Number of Participants Analyzed 22 22
Geometric Mean (Standard Deviation)
Unit of Measure: ng*hr/mL
429.5  (242.3) 439.1  (271.5)
9.Secondary Outcome
Title Area Under the Curve From Time Zero to Infinite Time [AUC (0 - ∞)] for Crizotinib Metabolite (PF-06260182)
Hide Description AUC (0 - ∞)= Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - ∞). It is obtained from AUC (0 - t) plus AUC (t - ∞) of crizotinib metabolite (PF-06260182).
Time Frame 0 (pre-dose), 1, 2, 3, 4, 5, 6, 8, 10, 12, 24, 48, 72, 96 and 144 hrs post crizotinib dose
Hide Outcome Measure Data
Hide Analysis Population Description
PK parameter analysis population included all participants randomized and treated who had at least 1 of the PK parameters of primary interest in at least 1 treatment period. 'N' = Number of participants contributing to the mean.
Arm/Group Title Crizotinib 250 mg FC Crizotinib 250 mg OLF
Hide Arm/Group Description:
Single oral dose of crizotinib 250 mg FC [Reference] in either first intervention period or second intervention period.
Single oral dose of crizotinib 250 mg OLF [Test] in either first intervention period or second intervention period.
Overall Number of Participants Analyzed 21 22
Geometric Mean (Standard Deviation)
Unit of Measure: ng*hr/mL
454.4  (242.1) 446.7  (273.1)
10.Secondary Outcome
Title Maximum Observed Plasma Concentration (Cmax) for Crizotinib Metabolite (PF-06260182)
Hide Description [Not Specified]
Time Frame 0 (pre-dose), 1, 2, 3, 4, 5, 6, 8, 10, 12, 24, 48, 72, 96 and 144 hrs post crizotinib dose
Hide Outcome Measure Data
Hide Analysis Population Description
PK parameter analysis population included all participants randomized and treated who had at least 1 of the PK parameters of primary interest in at least 1 treatment period.
Arm/Group Title Crizotinib 250 mg FC Crizotinib 250 mg OLF
Hide Arm/Group Description:
Single oral dose of crizotinib 250 mg FC [Reference] in either first intervention period or second intervention period.
Single oral dose of crizotinib 250 mg OLF [Test] in either first intervention period or second intervention period.
Overall Number of Participants Analyzed 22 22
Geometric Mean (Standard Deviation)
Unit of Measure: ng/mL
30.98  (10.39) 32.56  (10.75)
11.Secondary Outcome
Title Time to Reach Maximum Observed Plasma Concentration (Tmax) for Crizotinib Metabolite (PF-06260182)
Hide Description [Not Specified]
Time Frame 0 (pre-dose), 1, 2, 3, 4, 5, 6, 8, 10, 12, 24, 48, 72, 96 and 144 hrs post crizotinib dose
Hide Outcome Measure Data
Hide Analysis Population Description
PK parameter analysis population included all participants randomized and treated who had at least 1 of the PK parameters of primary interest in at least 1 treatment period.
Arm/Group Title Crizotinib 250 mg FC Crizotinib 250 mg OLF
Hide Arm/Group Description:
Single oral dose of crizotinib 250 mg FC [Reference] in either first intervention period or second intervention period.
Single oral dose of crizotinib 250 mg OLF [Test] in either first intervention period or second intervention period.
Overall Number of Participants Analyzed 22 22
Median (Full Range)
Unit of Measure: hr
5.00
(4.00 to 6.00)
5.00
(4.00 to 6.00)
12.Secondary Outcome
Title Metabolite to Parent Ratio of Maximum Observed Plasma Concentration (MRCmax)
Hide Description Metabolite (PF-06260182) to parent (crizotinib) molar ratio of maximum observed plasma concentration (MRCmax).
Time Frame 0 (pre-dose), 1, 2, 3, 4, 5, 6, 8, 10, 12, 24, 48, 72, 96 and 144 hrs post crizotinib dose
Hide Outcome Measure Data
Hide Analysis Population Description
PK parameter analysis population included all participants randomized and treated who had at least 1 of the PK parameters of primary interest in at least 1 treatment period.
Arm/Group Title Crizotinib 250 mg FC Crizotinib 250 mg OLF
Hide Arm/Group Description:
Single oral dose of crizotinib 250 mg FC [Reference] in either first intervention period or second intervention period.
Single oral dose of crizotinib 250 mg OLF [Test] in either first intervention period or second intervention period.
Overall Number of Participants Analyzed 22 22
Geometric Mean (Standard Deviation)
Unit of Measure: Ratio
0.2482  (0.0349) 0.2694  (0.0532)
13.Secondary Outcome
Title Metabolite to Parent Ratio of Area Under the Curve From Time Zero to Last Quantifiable Concentration (MRAUClast)
Hide Description Molar ratio of metabolite to parent area under the plasma concentration time-curve from time zero (pre-dose) to the last measured concentration (MRAUClast).
Time Frame 0 (pre-dose), 1, 2, 3, 4, 5, 6, 8, 10, 12, 24, 48, 72, 96 and 144 hrs post crizotinib dose
Hide Outcome Measure Data
Hide Analysis Population Description
PK parameter analysis population included all participants randomized and treated who had at least 1 of the PK parameters of primary interest in at least 1 treatment period.
Arm/Group Title Crizotinib 250 mg FC Crizotinib 250 mg OLF
Hide Arm/Group Description:
Single oral dose of crizotinib 250 mg FC [Reference] in either first intervention period or second intervention period.
Single oral dose of crizotinib 250 mg OLF [Test] in either first intervention period or second intervention period.
Overall Number of Participants Analyzed 22 22
Geometric Mean (Standard Deviation)
Unit of Measure: Ratio
0.1546  (0.0275) 0.1589  (0.0274)
14.Secondary Outcome
Title Metabolite to Parent Ratio of Area Under the Curve From Time Zero to Infinite Time [MRAUC (0- ∞)]
Hide Description Molar ratio of metabolite to parent area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0- ∞) [MRAUC (0- ∞)].
Time Frame 0 (pre-dose), 1, 2, 3, 4, 5, 6, 8, 10, 12, 24, 48, 72, 96 and 144 hrs post crizotinib dose
Hide Outcome Measure Data
Hide Analysis Population Description
PK parameter analysis population included all participants randomized and treated who had at least 1 of the PK parameters of primary interest in at least 1 treatment period. 'N' = Number of participants contributing to the mean.
Arm/Group Title Crizotinib 250 mg FC Crizotinib 250 mg OLF
Hide Arm/Group Description:
Single oral dose of crizotinib 250 mg FC [Reference] in either first intervention period or second intervention period.
Single oral dose of crizotinib 250 mg OLF [Test] in either first intervention period or second intervention period.
Overall Number of Participants Analyzed 21 22
Geometric Mean (Standard Deviation)
Unit of Measure: Ratio
0.1514  (0.0254) 0.1535  (0.0259)
Time Frame [Not Specified]
Adverse Event Reporting Description The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
 
Arm/Group Title Crizotinib 250 mg FC Crizotinib 250 mg OLF
Hide Arm/Group Description Single oral dose of crizotinib 250 mg FC [Reference] in either first intervention period or second intervention period. Single oral dose of crizotinib 250 mg OLF [Test] in either first intervention period or second intervention period.
All-Cause Mortality
Crizotinib 250 mg FC Crizotinib 250 mg OLF
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Hide Serious Adverse Events
Crizotinib 250 mg FC Crizotinib 250 mg OLF
Affected / at Risk (%) Affected / at Risk (%)
Total   0/22 (0.00%)   0/22 (0.00%) 
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Crizotinib 250 mg FC Crizotinib 250 mg OLF
Affected / at Risk (%) Affected / at Risk (%)
Total   17/22 (77.27%)   17/22 (77.27%) 
Ear and labyrinth disorders     
Ear pain * 1  0/22 (0.00%)  1/22 (4.55%) 
Gastrointestinal disorders     
Abdominal distension * 1  1/22 (4.55%)  0/22 (0.00%) 
Abdominal pain * 1  4/22 (18.18%)  7/22 (31.82%) 
Abdominal pain upper * 1  1/22 (4.55%)  0/22 (0.00%) 
Diarrhoea * 1  9/22 (40.91%)  10/22 (45.45%) 
Dyspepsia * 1  0/22 (0.00%)  2/22 (9.09%) 
Eructation * 1  0/22 (0.00%)  2/22 (9.09%) 
Faeces discoloured * 1  1/22 (4.55%)  0/22 (0.00%) 
Flatulence * 1  1/22 (4.55%)  0/22 (0.00%) 
Gastrointestinal sounds abnormal * 1  2/22 (9.09%)  1/22 (4.55%) 
Nausea * 1  6/22 (27.27%)  6/22 (27.27%) 
General disorders     
Fatigue * 1  1/22 (4.55%)  1/22 (4.55%) 
Feeling cold * 1  0/22 (0.00%)  1/22 (4.55%) 
Influenza like illness * 1  0/22 (0.00%)  1/22 (4.55%) 
Infections and infestations     
Gastroenteritis * 1  1/22 (4.55%)  0/22 (0.00%) 
Nasopharyngitis * 1  1/22 (4.55%)  1/22 (4.55%) 
Nervous system disorders     
Dizziness * 1  2/22 (9.09%)  0/22 (0.00%) 
Dizziness postural * 1  1/22 (4.55%)  0/22 (0.00%) 
Headache * 1  5/22 (22.73%)  7/22 (31.82%) 
Hypersomnia * 1  0/22 (0.00%)  1/22 (4.55%) 
Somnolence * 1  0/22 (0.00%)  1/22 (4.55%) 
Psychiatric disorders     
Abnormal dreams * 1  1/22 (4.55%)  1/22 (4.55%) 
Initial insomnia * 1  0/22 (0.00%)  1/22 (4.55%) 
Insomnia * 1  1/22 (4.55%)  0/22 (0.00%) 
Respiratory, thoracic and mediastinal disorders     
Rhinorrhoea * 1  1/22 (4.55%)  0/22 (0.00%) 
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA 13.1
[Not Specified]
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Pfizer ClinicalTrials.gov Call Center
Organization: Pfizer, Inc.
Phone: 1-800-718-1021
EMail: ClinicalTrials.gov_Inquiries@pfizer.com
Layout table for additonal information
Responsible Party: Pfizer
ClinicalTrials.gov Identifier: NCT01297595    
Other Study ID Numbers: A8081019
First Submitted: February 15, 2011
First Posted: February 17, 2011
Results First Submitted: January 5, 2012
Results First Posted: February 8, 2012
Last Update Posted: February 16, 2012