A Phase 1 Absolute Bioavailability Study For Oral Crizotinib In Healthy Volunteers

Pfizer14 enrolled

Overview

This study will be an open-label, randomized, 2-period, 2-treatment, 2-sequence, cross-over single-dose study to test the absolute bioavailability of oral crizotinib formulation to IV formulation in healthy adult volunteers. Fourteen (14) subjects will be enrolled to obtain at least 12 evaluable subjects who complete the study. Each subject will receive two treatments (A and B) with a washout period of at least 14 days between each treatment.

evaluate the absolute bioavailability of oral crizotinib to IV crizotinib.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Masking

NONE

Enrollment

Conditions

Healthy

Interventions

crizotinibDRUG

Treatment A: Intravenous dose of 50 mg crizotinib will be administered as directed.

crizotinibDRUG

Treatment B: Oral dose of 250 mg crizotinib as 1 × 50-mg Immediate Release Tablet and 2 × 100-mg Immediate Release Tablets will be administered in the fasted state as directed.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 55 YearsHealthy volunteers:

Medical Language ↔ Plain English

Inclusion Criteria: * Healthy male and/or female of non-childbearing potential subjects between the ages of 18 and 55 years, inclusive (Healthy is defined as no clinically relevant abnormalities identified by a detailed medical history, full physical examination, including blood pressure and pulse rate measurement, 12-lead ECG and clinical laboratory tests). * Body Mass Index (BMI) of 17.5 to 30.5 kg/m\^2; 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 (including drug allergies, but excluding untreated, asymptomatic, seasonal allergies at time of dosing). * Any condition possibly affecting drug absorption (eg, gastrectomy). * A positive urine drug screen. * History of regular alcohol consumption exceeding 14 drinks/week for females or 21 drinks/week for males within 6 months of screening. * Treatment with an investigational drug within 30 days (or as determined by the local requirement, whichever is longer) or 5 half-lives preceding the first dose of study medication. * 12-lead ECG demonstrating QTc \>450 msec at Screening. * Pregnant or nursing females; females of childbearing potential, including those with tubal ligation. * Use of prescription or nonprescription drugs and dietary supplements within 7 days or 5 half-lives (whichever is longer) prior to the first dose of study medication. Herbal supplements and hormone replacement therapy must be discontinued 28 days prior to the first dose of study medication. * Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for entry into this study. * A positive serology for Hepatitis B or Hepatitis C. * Subjects who are currently smoking.

Locations (1)

Pfizer Investigational Site

Brussels, Belgium

Outcomes

Primary Outcomes

Dose Normalized Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUC [0 - ∞][dn])

AUC \[0 - ∞\]\[dn\] = Dose normalized area under the plasma concentration versus time curve (AUC\[dn\]) from time zero (pre-dose) to extrapolated infinite time (0 - ∞). It is obtained from AUC (0 - ∞) divided by dose.

Time frame: 0 (pre-dose), 1, 2, 2.5, 3, 4, 6, 8, 12, 24, 36, 48, 72, 96, and 144 hours (hrs) post IV crizotinib dose in Treatment A and 0 (pre-dose), 1, 2, 4, 5, 6, 8, 10, 12, 24, 36, 48, 72, 96, and 144 hrs post oral crizotinib dose in Treatment B

Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUC [0 - ∞])

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, 2.5, 3, 4, 6, 8, 12, 24, 36, 48, 72, 96, and 144 hrs post IV crizotinib dose in Treatment A and 0 (pre-dose), 1, 2, 4, 5, 6, 8, 10, 12, 24, 36, 48, 72, 96, and 144 hrs post oral crizotinib dose in Treatment B

Secondary Outcomes

Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast)

Area under the plasma concentration time-curve from zero (pre-dose) to the last measured concentration (AUClast).

Dose Normalized Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast[dn])

AUClast\[dn\] = Dose normalized area under the plasma concentration time-curve (AUC\[dn\]) from zero to the last measured concentration.

Data from ClinicalTrials.gov

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Maximum Observed Plasma Concentration (Cmax)

Time to Reach Maximum Observed Plasma Concentration (Tmax)

Time frame: 0 (pre-dose), 1, 2, 4, 5, 6, 8, 10, 12, 24, 36, 48, 72, 96, and 144 hrs post oral crizotinib dose in Treatment B

Plasma Decay Half Life (t1/2)

Plasma decay half life is the time measured for the plasma concentration to decrease by one half.

Apparent Oral Clearance (CL/F)

Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the body. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed.

Time frame: 0 (pre-dose), 1, 2, 4, 5, 6, 8, 10, 12, 24, 36, 48, 72, 96, and 144 hrs post oral crizotinib dose in Treatment B

Systemic Clearance (CL)

CL is a quantitative measure of the rate at which a drug substance is removed from the body.

Time frame: 0 (pre-dose), 1, 2, 2.5, 3, 4, 6, 8, 12, 24, 36, 48, 72, 96, and 144 hrs post IV crizotinib dose in Treatment A

Apparent Volume of Distribution (Vz/F)

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, 4, 5, 6, 8, 10, 12, 24, 36, 48, 72, 96, and 144 hrs post oral crizotinib dose in Treatment B

Volume of Distribution at Steady State (Vss)

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 blood concentration of a drug. Steady state volume of distribution (Vss) is the apparent volume of distribution at steady-state.

Time frame: 0 (pre-dose), 1, 2, 2.5, 3, 4, 6, 8, 12, 24, 36, 48, 72, 96, and 144 hrs post IV crizotinib dose in Treatment A

Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) for Crizotinib Metabolite (PF-06260182)

Area under the plasma concentration time-curve from zero (pre-dose) to the last measured concentration (AUClast) of crizotinib metabolite (PF-06260182).

Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUC [0 - ∞]) for Crizotinib Metabolite (PF-06260182)

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, 4, 5, 6, 8, 10, 12, 24, 36, 48, 72, 96, and 144 hrs post oral crizotinib dose in Treatment B

Maximum Observed Plasma Concentration (Cmax) for Crizotinib Metabolite (PF-06260182)

Time to Reach Maximum Observed Plasma Concentration (Tmax) for Crizotinib Metabolite (PF-06260182)

Time frame: 0 (pre-dose), 1, 2, 4, 5, 6, 8, 10, 12, 24, 36, 48, 72, 96, and 144 hrs post oral crizotinib dose in Treatment B

Metabolite to Parent Ratio of Area Under the Curve From Time Zero to Last Quantifiable Concentration for Crizotinib Metabolite Ratio (MRAUClast)

Molar ratio of metabolite to parent area under the plasma concentration time-curve from zero (pre-dose) to the last measured concentration (MRAUClast).

Metabolite to Parent Ratio Area Under the Curve From Time Zero to Extrapolated Infinite Time (MRAUC [0-∞])

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, 4, 5, 6, 8, 10, 12, 24, 36, 48, 72, 96, and 144 hrs post oral crizotinib dose in Treatment B

Metabolite to Parent Ratio Maximum Observed Plasma Concentration (MRCmax)

Metabolite to parent molar ratio of maximum observed plasma concentration (MRCmax).