Effect Of Modafinil And Pioglitazone On The Pharmacokinetics Of Palbociclib (PD-0332991)

Study Overview
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Brief Summary
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This study is designed to evaluate the potential effect of the moderate CYP3A inducer modafinil and the weak CYP3A inducer pioglitazone on the pharmacokinetics of palbociclib.

Official Title
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A Phase 1, Open-label, Fixed-sequence, 2-cohort, 2-period Study To Investigate The Effect Of Modafinil And Pioglitazone Given As Multiple Doses On Single Dose Pharmacokinetics Of Palbociclib (Pd-0332991) In Healthy Volunteers

Conditions
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Healthy

Intervention / Treatment
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* Drug: Palbociclib alone
* Drug: Palbociclib plus Modafinil
* Drug: Palbociclib alone
* Drug: Palbociclib plus pioglitazone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy male and/or female subjects of non childbearing potential 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). 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. 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 (eg, gastrectomy). Subjects with a self-reported history of addiction, especially to stimulants. A positive urine drug screen or alcohol breath test. Pregnant female subjects; breastfeeding female subjects; female subjects of childbearing potential; male subjects with partners currently pregnant; male subjects of childbearing potential who are unwilling or unable to use a highly effective method of contraception as outlined in this protocol for the duration of the study and for 90 days after the last dose of investigational product.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Non-Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Fixed sequence modafinil DDI arm (Cohort 1)<br>Fixed sequence study with treatment A of palbociclib alone, followed by treatment B of palbociclib with modafinil in Cohort 1. | Drug: Palbociclib alone<br>* A single 125 mg dose of palbociclib free base capsule given orally alone in the fed state, followed by 120 hours of PK sample collection.<br>* Other names: Palbociclib, PD-0332991;Drug: Palbociclib plus Modafinil<br>* For Cohort 1, modafinil 200 mg once daily for 7 days, followed by 400 mg once daily for 25 days; on Day 28, a single oral 125 mg dose of palbociclib will be given with modafinil after a meal, followed by 120 hours of PK sample collection.<br>* Other names: Palbociclib (PD-0332991); Modafinil (Provigil);|
| Experimental: Fixed sequence pioglitazone DDI arm (Cohort 2)<br>For Cohort 2, fixed sequence study with treatment A of palbociclib alone, followed by treatment C of palbociclib with pioglitazone. | Drug: Palbociclib alone<br>* A single 125 mg dose of palbociclib free base capsule given orally alone in the fed state, followed by 120 hours of PK sample collection.<br>* Other names: Palbociclib, PD-0332991;Drug: Palbociclib plus pioglitazone<br>* For Cohort 2, pioglitazone 45 mg once daily for a total of 19 days; On Day 15, a single oral 125 mg dose of palbociclib will be given with pioglitazone after a meal, followed by 120 hours of PK sample collection.<br>* Other names: Palbociclib (PD-0332991); Pioglitazone (Actos);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - 8)] | AUC (0 - 8)= Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - 8). It is obtained from AUC (0 - t) plus AUC (t - 8). | 0-120 hours | 
| Maximum Observed Plasma Concentration (Cmax) |  | 0-120 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma Palbociclib Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) | Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast) | 0 to 120 hours | 
| Plasma Palbociclib Time to Reach Maximum Observed Plasma Concentration (Tmax) |  | 0 to 120 hours | 
| Plasma Palbociclib Decay Half-Life (t1/2) | Plasma decay half-life is the time measured for the plasma concentration to decrease by one half. | 0 to 120 hours | 
| Apparent Oral Clearance (CL/F) of Palbociclib | Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Clearance was estimated from population pharmacokinetic (PK) modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. | 0 to 120 hours | 
| Apparent Volume of Distribution (Vz/F) of Palbociclib | 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. | 0 to 120 hours | 
| Trough Plasma Concentrations of Modafinil, Modafinil sulfone, pioglitazone, hydroxy derivative of pioglitazone, and keto derivative of pioglitazone |  | 0 to 120 hours | 
| Time of last quantifiable concentration for palbociclib |  | 0 to 120 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Palbociclib, Modafinil, Pioglitazone, Pharmacokinetics, Drug-Drug Interaction Study, Healthy Volunteers, CYP3A Inducers