Effects of Gastric pH on the Pharmacokinetics of Dasatinib

Effects of Gastric pH on the Pharmacokinetics of Dasatinib in Healthy Volunteers

The goal of this study is to evaluate the ability of a natural supplement (betaine hydrochloride) to affect the absorption of dasatinib in healthy volunteers. The investigators predict that betaine hydrochloride will increase the absorption of dasatinib, in volunteers pre-treated with proton-pump inhibitors (PPIs).

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Drug: Dasatinib; Drug: Dasatinib plus Rabeprazole; Drug: Dasatinib plus Rabeprazole AND Betaine Hydrochloride

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • San Francisco, California, United States, 94143
      • Clinical Research Center, UCSF

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 59 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male or female 18-59 years of age
• Healthy adult with no active medical problems or significant chronic diseases as determined by the study doctor based on history, physical exam and laboratory evaluations
• BMI between 18.5-30 kg/m2
• Taking no medications 2 weeks before and during the study enrollment, including drugs of abuse, prescription or over-the-counter (OTC) medications (except acetaminophen)
• Subjects able to maintain adequate birth control during the study independent of hormonal contraceptive use
• Be able to provide written informed consent and comply with requirements of the study
• Avoid eating grapefruit and drinking grapefruit juice from 7 days before the first study day until the completion of the entire study
• Abstinence from alcoholic beverages, caffeinated beverages and orange juice from 3pm the night before a study day until completion of that study day
• Fast from food and beverages at least 8 hours prior to medication dosing
• Be able to read, speak, and understand English

Exclusion Criteria:

• Subjects with a history of gastrointestinal disease including gastroesophageal reflux disease, gastritis, peptic ulcer disease, or dyspepsia
• Subjects with a fasting gastric pH of > 4 (i.e. hypochlorhydria)
• Subjects with a history of dysphagia, achalasia, or difficulty swallowing capsules, tablets, or pills
• Subjects on prescription or chronic over-the-counter (OTC) medications (including hormonal contraceptives)
• Subjects with known allergies to rabeprazole or any other proton pump inhibitors (PPI's) or betaine hydrochloride
• Subjects who smoke tobacco
• Subjects with ongoing alcohol or illegal drug use
• Subjects who are pregnant, lactating, or attempting to conceive
• Subjects unable to maintain adequate birth control during the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Dasatinib	Drug: Dasatinib; dasatinib (100mg) PO x1
Experimental: Dasatinib plus Rabeprazole	Drug: Dasatinib plus Rabeprazole; Rabeprazole (20mg) PO twice daily (Days 1-3); Dasatinib (100mg) PO x1 (Day 4)
Experimental: Dasatinib plus Rabeprazole AND Betaine Hydrochloride	Drug: Dasatinib plus Rabeprazole AND Betaine Hydrochloride; Rabeprazole (20mg) PO twice daily (Days 1-3); Betaine Hydrochloride (1500mg) PO x1 AND Dasatinib (100mg) PO x1 on Day 4

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area-Under-the Concentration Curve from zero-to-twenty two hours (AUC,0-22) of Dasatinib	The primary outcome measure will be dasatinib area-under-the-concentration curve (AUC) values from zero-to-twenty two (0-22) hours. Values from Experiemntal Arms of the study (Dasatinib plus Rabeprazole; Dasatinib plus Rabeprazole AND Betaine Hydrochloride) will be compared against the active comparator (dasatinib alone) and tested for statistical significance.	Day 4
Area-Under-the Concentration Curve from zero-to-infinity (AUC,0-inf) of Dasatinib	The primary outcome measure will be dasatinib area-under-the-concentration curve (AUC) values from zero-to-infinite time (0-inf). Values from Experiemntal Arms of the study (Dasatinib plus Rabeprazole; Dasatinib plus Rabeprazole AND Betaine Hydrochloride) will be compared against the active comparator (dasatinib alone) and tested for statistical significance.	Day 4

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Concentration of Dasatinib	The maximum plasma concentration (Cmax) will also be measured. Values from Experiemntal Arms of the study (Dasatinib plus Rabeprazole; Dasatinib plus Rabeprazole AND Betaine Hydrochloride) will be compared against the active comparator (Dasatinib alone) and tested for statistical significance.	Day 4

Collaborators and Investigators

• Sponsor: University of California, San Francisco
• Collaborators: Genentech, Inc.
• Investigators: Principal Investigator: Leslie Z Benet, Ph.D, University of California, San Francisco; Principal Investigator: Lynda Frassetto, M.D., University of California, San Francisco

Publications and helpful links

General Publications

• Yago MR, Frymoyer AR, Smelick GS, Frassetto LA, Budha NR, Dresser MJ, Ware JA, Benet LZ. Gastric reacidification with betaine HCl in healthy volunteers with rabeprazole-induced hypochlorhydria. Mol Pharm. 2013 Nov 4;10(11):4032-7. doi: 10.1021/mp4003738. Epub 2013 Sep 10.

Study record dates

Study Major Dates

• Study Start: August 1, 2011
• Primary Completion (Actual): February 1, 2014
• Study Completion (Actual): February 1, 2014

Study Registration Dates

• First Submitted: July 5, 2011
• First Submitted That Met QC Criteria: July 18, 2011
• First Posted (Estimate): July 20, 2011

Study Record Updates

• Last Update Posted (Estimate): April 28, 2015
• Last Update Submitted That Met QC Criteria: April 24, 2015
• Last Verified: April 1, 2015

More Information

Terms related to this study

• Keywords: healthy volunteer; pharmacokinetics; dasatinib; betaine; betaine hydrochloride
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites; Antineoplastic Agents; Gastrointestinal Agents; Hypolipidemic Agents; Lipid Regulating Agents; Protein Kinase Inhibitors; Anti-Ulcer Agents; Proton Pump Inhibitors; Lipotropic Agents; Rabeprazole; Dasatinib; Betaine
• Other Study ID Numbers: Dasatinib-63-03