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To establish the relationship between human MAAI haplotype and DCA and tyrosine metabolism. This aim test the postulates that MAAI haplotype determines, and thus can predict,1) dose-dependent DCA kinetics and biotransformation.
The arms of the study involves determining the haplotype of individuals enrolled. Then participants were divided into two groups based on their genotype. The groups include a genotype with an EGT alle and a group of genotype without an EGT alle. All subjects first took a low dose of DCA 2.5ug/kg for 5 days then wait 30 days and take a therapeutic dose of DCA 25mg/kg for 5 days On the first day and on the 5th day of taking DCA kinetics were be done. A total of 16 blood samples were obtained through an intravenous catheter. Urine collection will also occur.
Population pharmacogenetic analysis of MAI allelic frequencies and the GC or LC-MS/MS techniques for blood or urinary metabolites were used in this investigation. Pharmacokinetic data was used to determine metabolism rate of DCA for each allele
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| No EGT Allele, slow metabolizers for DCA | Experimental | Individuals were genotyped at the beginning of the study and their haplotypes were defined. Dichloroacetate 2.5.ug/kg (non-clinical dose) will be administered for five days in the clinical research center. On day 5 with the dose of DCA a pharmacokinetics test will be performed for 24 hours. 30 days later the individuals will return to the clinic and receive Dichloroacetate 25mg/kg (clinical dose) for five days. On day 1 and day 5 Pharmacokinetics will be performed to determine the relationship between DCA metabolism and haplotype. |
|
| 1+ EGT Allele, fast metabolizers for DCA | Experimental | Individuals were genotyped at the beginning of the study and their haplotypes were defined. Dichloroacetate 2.5.ug/kg (non-clinical dose) will be administered for five days in the clinical research center. On day 5 with the dose of DCA a pharmacokinetics test will be performed for 24 hours. 30 days later the individuals will return to the clinic and receive Dichloroacetate 25mg/kg (clinical dose) for five days. On day 1 and day 5 Pharmacokinetics will be performed to determine the relationship between DCA metabolism and haplotype. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Dichloroacetate (DCA) | Drug | Dichloroacetate 2.5.ug/kg will be administered for five days in the clinical research center. On day 5 with the dose of DCA a pharmacokinetics test will be performed for 24 hours. 30 days later the individuals will return to the clinic and receive Dichloroacetate 25mg/kg (clinical dose) for five days. On day 1 and day 5 Pharmacokinetics will be performed to determine the relationship between DCA metabolism and haplotype. |
| Measure | Description | Time Frame |
|---|---|---|
| Hypothesize That Subject's Genotype Will Determine How DCA is Metabolized. | Terminal half-life (the amount of time needed to clear one-half of dose of the drug). | 24 hours for analysis on Day 5, Clinical dose |
| Measure | Description | Time Frame |
|---|---|---|
| Terminal Half-life (the Amount of Time Needed to Clear One-half of the Dose of Drug)for Environmental Dose 2.5 ug/kg/Day. | Terminal half-life (the amount of time needed to clear one-half of the dose of drug)for the environmental dose 2.5 ug/kg/day. | 24 hours for analysis on Day 5, Environmental dose |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Peter W Stacpoole, PhD, MD | University of Florida | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Florida Shands Hospital | Gainesville | Florida | 32610 | United States |
21 subjects were consented to the study; however, 7 were excluded before being assigned to a group for the following reasons: works at night, on contraindicated medication, history of mitral valve prolapse, obesity, started smoking, and elevated liver enzymes.
Subjects were recruited from a list of individuals who had already been genotyped. Subjects were called on the telephone to see if they wanted to participate in this study.
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| ID | Title | Description |
|---|---|---|
| FG000 | Lack Any EGT Allele on GSTz1/MAAI Region of Chromosome 14q24.3 | Both dichloroacetate 2.5ug and 25mg per kg per day and is administered for five days. (Biologic randomization) Dichloroacetate 2.5ug/kg (Environmental) and 25mg/kg (clinical) are administered daily for 5 days in all subjects. Subjects are admitted to the clinical research center for 6 nights. The first day subjects are administer 2.5ug/kg/day. Frequent blood samples are collected over a 24 hour period. On days 2, 3, 4 the subjects receive a dose of DCA each day. On day 5 they receive a dose of DCA and pharmacokinetics are done for 24 hours then subjects are discharged. |
| FG001 | 1+ EGT Allele on GSTz1/MAAI Region of Chromosome 14q24.3 | Both dichloroacetate 2.5ug and 25mg per kg per day and is administered for five days. (Biologic randomization) Dichloroacetate 2.5ug/kg (Environmental) and 25mg/kg (clinical) are administered daily for 5 days in all subjects. Subjects are admitted to the clinical research center for 6 nights. The first day subjects are administer 2.5ug/kg/day. Frequent blood samples are collected over a 24 hour period. On days 2, 3, 4 the subjects receive a dose of DCA each day. On day 5 they receive a dose of DCA and pharmacokinetics are done for 24 hours then subjects are discharged. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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|
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| ID | Title | Description |
|---|---|---|
| BG000 | Lack Any EGT Allele on GSTz1/MAAI Region of Chromosome 14q24.3 | This study is a biological randomization for dichloroacetate pharmacodynamics for those with at least one EGT vs. without any EGT haplotype of the GSTZ1/MAAI gene which is located on chromosome 14q24.3. |
| BG001 | 1+ EGT Allele on GSTz1/MAAI Region of Chromosome 14q24.3 |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Hypothesize That Subject's Genotype Will Determine How DCA is Metabolized. | Terminal half-life (the amount of time needed to clear one-half of dose of the drug). | All completing subjects (2 withdrawals have no pharmacokinetic data on this parameter) The intent was to accrue 12 per group but the grant ended before that could be achieved. Subjects were recruited from a large pool but the two genetically defined subgroups are rare. | Posted | Median | Inter-Quartile Range | Minutes | 24 hours for analysis on Day 5, Clinical dose |
|
Adverse events were collected from 5/2008 to 2/2009
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Lack Any EGT Allele on GSTz1/MAAI Region of Chromosome 14q24.3 | This study is a biological randomization for dichloroacetate pharmacodynamics for those with at least one EGT vs. without any EGT haplotype of the GSTZ1/MAAI gene which is located on chromosome 14q24.3. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Rash | Skin and subcutaneous tissue disorders | Systematic Assessment | Subject had developed a rash on his right arm where the Tegraderm from his IV was applied. It was determined he had an allergic reaction to the Tegraderm. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| sleepiness | General disorders | Non-systematic Assessment | Eleven subjects on 25mg/kg of DCA complained of sleepiness following taking the drug |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Peter Stacpoole/Principal Investigator | University of Florida | 1-352-273-9023 | pws@ufl.edu |
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| ID | Term |
|---|---|
| D003999 | Dichloroacetic Acid |
| D005838 | Genotype |
| D005819 | Genetic Markers |
| D006239 | Haplotypes |
| ID | Term |
|---|---|
| D062845 | Chloroacetates |
| D000085 | Acetates |
| D000144 | Acids, Acyclic |
| D002264 | Carboxylic Acids |
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|
|
| Genetic Marker on Chromosome 14q24.3 | Genetic | Individuals were genotyped at the beginning of the study and their haplotypes were defined. The study is looking at individuals with genetic markers on Chromosome 14q24.3 to determine if there will be a difference in how the DCA will be metabolized. |
|
|
This study is a biological randomization for dichloroacetate pharmacodynamics for those with at least one EGT vs. without any EGT haplotype of the GSTZ1/MAAI gene which is located on chromosome 14q24.3. |
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| OG001 | 1+ EGT Allele on GSTz1/MAAI Region of Chromosome 14q24.3 | Both dichloroacetate 2.5ug and 25mg per kg per day and is administered for five days. (Biologic randomization) Dichloroacetate 2.5.ug/kg (Environmental) and 25mg/kg (clinical) are administered daily for 5 days in all subjects. Subjects are admitted to the clinical research center for 6 nights. The first day subjects are administer 2.5ug/kg/day. Frequent blood samples are collected over a 24 hour period. On days 2, 3, and 4 the subjects receive a dose of DCA each day. On day 5 they receive a dose of DCA and pharmacokinetics are done for 24 hours then subjects are discharged. |
|
|
|
| Secondary | Terminal Half-life (the Amount of Time Needed to Clear One-half of the Dose of Drug)for Environmental Dose 2.5 ug/kg/Day. | Terminal half-life (the amount of time needed to clear one-half of the dose of drug)for the environmental dose 2.5 ug/kg/day. | same as Primary | Posted | Median | Inter-Quartile Range | minutes | 24 hours for analysis on Day 5, Environmental dose |
|
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| 1 |
| 6 |
| 5 |
| 6 |
| EG001 | 1+ EGT Allele on GSTz1/MAAI Region of Chromosome 14q24.3 | This study is a biological randomization for dichloroacetate pharmacodynamics for those with at least one EGT vs. without any EGT haplotype of the GSTZ1/MAAI gene which is located on chromosome 14q24.3. | 0 | 8 | 5 | 8 |
|
|
| abdominal cramping and diarrhea | Gastrointestinal disorders | Non-systematic Assessment | Subject complained of abdominal cramping and diarrhea which lasted for 2 days |
|
| Hives | Immune system disorders | Systematic Assessment | Subject complained of having hives. When examined by the principal investigator one hive was found on her right arm and was fading |
|
| Wheezing | Respiratory, thoracic and mediastinal disorders | Systematic Assessment | Subject had wheezes in his lower lobes of his lungs and stated he was spitting up yellow sputum. He had been having a cold when he entered the study |
|
| Constipation | Gastrointestinal disorders | Non-systematic Assessment | Complained of constipation but subject was not dehydrated. A stool softener was order which resolved the problem |
|
| slow clearance of DCA | Metabolism and nutrition disorders | Non-systematic Assessment | Following completion of the study when the results were being analyzed it showed that subject did not clear DCA as rapidly as other subject. It was attributed to his genotype. |
|
| headache | Musculoskeletal and connective tissue disorders | Non-systematic Assessment | Subject complained of a headache. It was resolved after she took a nap |
|
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| D009930 |
| Organic Chemicals |
| D006843 | Hydrocarbons, Chlorinated |
| D006846 | Hydrocarbons, Halogenated |
| D006838 | Hydrocarbons |
| D055614 | Genetic Phenomena |
| D015415 | Biomarkers |
| D001685 | Biological Factors |
| D010641 | Phenotype |