A Phase I Study To Estimate The Effect Of Ketoconazole And Omeprazole On The Pharmacokinetics Of Dimebon In Healthy Subjects Who Are Normal Or Poor CYP2D6 Metabolizers

Study Overview
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Brief Summary
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This study will evaluate the potential for a drug-drug interaction of Dimebon with ketoconazole and omeprazole, potent inhibitors of the drug metabolizing enzymes CYP3A4 and CYP2C19, respectively.

Official Title
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A Phase I, Open-Label, Three-Period, Fixed-Sequence Study To Estimate The Steady-State Effect Of Ketoconazole And Omeprazole On The Single-Dose Pharmacokinetics Of Dimebon [PF-01913539] In Healthy CYP2D6 EM And PM Subjects

Conditions
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Alzheimer's Disease, Huntington's Disease

Intervention / Treatment
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* Drug: Dimebon alone
* Drug: Dimebon + Ketoconazole
* Drug: Dimebon + Omeprazole


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures. Subjects must have either a CYP2D6 EM (n=12) or PM (n=12) status based on genotyping at screening. Subjects must have a CYP2C19 EM status based on status at screening. Exclusion Criteria: Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, or allergic disease. Subjects with any history of a previous seizure or convulsion or significant head trauma. Subjects specifically allergic to imidazole antifungal agents. Subjects specifically allergic to omeprazole or other proton pump inhibitors. Any condition possibly affecting drug absorption (eg, gastrectomy). Subjects with hypersensitivity reactions to Dimebon or other antihistamines. Consumption of grapefruit or grapefruit containing products within 7 days prior to the first dose of study medication. Subjects currently taking omeprazole, other proton pump inhibitors, antacids, H2-blockers or CYP2C19 inhibitors. Pregnant or nursing females; females of childbearing potential who are unwilling or unable to use an acceptable method of nonhormonal contraception as outlined in this protocol from at least 14 days prior to the first dose of study medication.

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

Allocation: Non-Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Period 1<br> | Drug: Dimebon alone<br>* Pharmacokinetics of a single oral dose of 10 mg Dimebon (tablet) will be assessed in subjects with a CYP2D6 extensive and poor metabolizer status based on genotyping as screening<br>|
| Experimental: Period 2<br> | Drug: Dimebon + Ketoconazole<br>* Pharmacokinetics of a single oral dose of 10 mg Dimebon (tablet) will be assessed on Day 4 during the daily administration of ketoconazole (400 mg, Day 1-11) in subjects with a CYP2D6 extensive and poor metabolizer status based on genotyping as screening<br>|
| Experimental: Period 3<br> | Drug: Dimebon + Omeprazole<br>* Pharmacokinetics of a single oral dose of 10 mg Dimebon (tablet) will be assessed on Day 5 during the daily administration of omeprazole(40 mg, Day 1-12) in subjects with a CYP2D6 extensive and poor metabolizer status based on genotyping as screening<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dimebon alone: Dimebon PK in CYP2D6 EMs and PMs (Cmax, Tmax, AUCinf (as data permit), AUClast, and t1/2 (as data permit), CL/F (as data permit) and V/F (as data permit)) |  | Period 1 Day 1 | 
| Dimebon + keto: Dimebon PK in CYP2D6 EMs and PMs (Cmax, Tmax, AUCinf (as data permit), AUClast, and t1/2 (as data permit), CL/F (as data permit) and V/F (as data permit)) |  | Period 2 Day 4 | 
| Dimebon + omeprazole: Dimebon PK in CYP2D6 EMs and PMs (Cmax, Tmax, AUCinf (as data permit), AUClast, and t1/2 (as data permit), CL/F (as data permit) and V/F (as data permit)) |  | Period 3 Day 5 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dimebon alone: Safety and tolerability (AE's, ECG, vital signs, safety labs) |  | Period 1 Day 1-7 | 
| Dimebon + keto: Safety and tolerability (AE's, ECG, vital signs, safety labs) |  | Period 2 Day 1-12 | 
| Dimebon + omeprazole: Safety and tolerability (AE's, ECG, vital signs, safety labs) |  | Period 3 Day 1-13 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Drug Interactions, pharmacokinetics, CYP2D6, CYP2C19, ketoconazole, omeprazole