Congenital Lactic Acidosis
Conditions
Keywords
DCA, Dichloroacetate, Trichloroacetate
Brief summary
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.
Detailed description
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
Interventions
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.
GENETICGenetic Marker on Chromosome 14q24.3
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.
Sponsors
University of Florida
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
21 Years to 50 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy volunteers
Exclusion criteria
* Pregnancy * Other medications * Psychiatric illness on meds * Abnormal labs
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Hypothesize That Subject's Genotype Will Determine How DCA is Metabolized. | 24 hours for analysis on Day 5, Clinical dose | Terminal half-life (the amount of time needed to clear one-half of dose of the drug). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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. | 24 hours for analysis on Day 5, Environmental dose | 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. |
Countries
United States
Participant flow
Recruitment details
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.
Pre-assignment details
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.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 6 |
| 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. | 8 |
| Total | 14 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | Lack Any EGT Allele on GSTz1/MAAI Region of Chromosome 14q24.3 | Total | 1+ EGT Allele on GSTz1/MAAI Region of Chromosome 14q24.3 |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 6 Participants | 14 Participants | 8 Participants |
| Age, Continuous | 26.0 years STANDARD_DEVIATION 4.6 | 26.9 years STANDARD_DEVIATION 7.3 | 28.2 years STANDARD_DEVIATION 10.4 |
| Region of Enrollment United States | 6 participants | 14 participants | 8 participants |
| Sex: Female, Male Female | 3 Participants | 8 Participants | 5 Participants |
| Sex: Female, Male Male | 3 Participants | 6 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 5 / 6 | 5 / 8 |
| serious Total, serious adverse events | 1 / 6 | 0 / 8 |
Outcome results
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).
Time frame: 24 hours for analysis on Day 5, Clinical dose
Population: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lack Any EGT Allele on GSTz1/MAAI Region of Chromosome 14q24.3 | Hypothesize That Subject's Genotype Will Determine How DCA is Metabolized. | 1592 Minutes |
| 1+ EGT Allele on GSTz1/MAAI Region of Chromosome 14q24.3 | Hypothesize That Subject's Genotype Will Determine How DCA is Metabolized. | 232 Minutes |
Comparison: We used a Wilcoxon test (and accompanying Kendal's Tau B) because these outcomes are outlier prone.p-value: 0.02395% CI: [0.35, 0.85]Wilcoxon (Mann-Whitney)
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.
Time frame: 24 hours for analysis on Day 5, Environmental dose
Population: same as Primary
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lack Any EGT Allele on GSTz1/MAAI Region of Chromosome 14q24.3 | 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. | 65.4 minutes |
| 1+ EGT Allele on GSTz1/MAAI Region of Chromosome 14q24.3 | 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. | 74.3 minutes |
Comparison: This is the same analysis as the previous, except we use the day 5 pharmacogenetics on the amount of time needed to clear one-half of dose of the drug. This is for the environmental dose. A positive (negative) Kendall's Tau is associated with the EGT allele being faster (slower) than lacking EGT in terms of metabolization of DCA.p-value: 0.4295% CI: [-0.23, 0.69]Wilcoxon (Mann-Whitney)