Ignite Creation Date:
2024-05-06 @ 4:54 PM
Last Modification Date:
2024-10-26 @ 2:18 PM
Study NCT ID:
NCT05124678
Status:
UNKNOWN
Last Update Posted:
2022-01-25
First Post:
2021-10-01
Brief Title:
Pharmacogenetics-guided Isoniazid Dosing in TB-HIV
Sponsor:
Makerere University
Organization:
Makerere University
Study Overview
Official Title:
A Phase II Trial to Describe the Pharmacokinetics Safety and Efficacy of Pharmacogenetics-guided Dosing of Isoniazid in Patients With HIV-associated TB
Status:
UNKNOWN
Status Verified Date:
2021-10
Last Known Status:
RECRUITING
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
PHINX
Brief Summary:
The current TB treatment as recommended by World Health Organization WHO although capable of achieving 85 cure rates has limitations in particular drug interactions toxicities and the long treatment duration which increases the possibility of nonadherence
Sub-therapeutic isoniazid concentrations were demonstrated in several studies including our previous work carried out among patients with tuberculosis receiving the standard dose 5mgkg of isoniazid The investigators found 78 of patients with HIV had isoniazid concentrations below the recommended threshold Malabsorption drug-drug interactions poor adherence due to high pill burden may contribute to this Pharmacogenetic variation may compound these factors isoniazid displays inter-individual variation in serum concentrations and clearance due to differences in individual acetylator status
While patients who metabolize isoniazid slowly slow acetylators are at a higher risk of high drug concentrations and toxicities fast acetylators are more likely to have sub-therapeutic isoniazid concentrations
In other studies insufficient exposure with isoniazid one of the cornerstone drugs for TB treatment has been associated with delayed sputum clearance development of drug resistance and treatment failure
Isoniazid is metabolized by the enzyme N-acetyl transferase which in turn is controlled by the N-acetyl transferase-2 NAT-2 gene Polymorphisms in this gene are responsible for the N-acetylation phenotypes with the distribution of NAT-2 fast intermediate and slow acetylators being highly variable especially among African populations
Given that NAT2 acetylator status explains most of the variability in INH exposures knowledge of NAT2 status may be a simpler way to select the right dose for individual patients The investigators will therefore provide higher doses to fast acetylators and compare the isoniazid pharmacokinetics in these patients to slow acetylators who receive the standard dose who are more likely to already be achieving target concentrations
Sub-therapeutic isoniazid concentrations were demonstrated in several studies including our previous work carried out among patients with tuberculosis receiving the standard dose 5mgkg of isoniazid The investigators found 78 of patients with HIV had isoniazid concentrations below the recommended threshold Malabsorption drug-drug interactions poor adherence due to high pill burden may contribute to this Pharmacogenetic variation may compound these factors isoniazid displays inter-individual variation in serum concentrations and clearance due to differences in individual acetylator status
While patients who metabolize isoniazid slowly slow acetylators are at a higher risk of high drug concentrations and toxicities fast acetylators are more likely to have sub-therapeutic isoniazid concentrations
In other studies insufficient exposure with isoniazid one of the cornerstone drugs for TB treatment has been associated with delayed sputum clearance development of drug resistance and treatment failure
Isoniazid is metabolized by the enzyme N-acetyl transferase which in turn is controlled by the N-acetyl transferase-2 NAT-2 gene Polymorphisms in this gene are responsible for the N-acetylation phenotypes with the distribution of NAT-2 fast intermediate and slow acetylators being highly variable especially among African populations
Given that NAT2 acetylator status explains most of the variability in INH exposures knowledge of NAT2 status may be a simpler way to select the right dose for individual patients The investigators will therefore provide higher doses to fast acetylators and compare the isoniazid pharmacokinetics in these patients to slow acetylators who receive the standard dose who are more likely to already be achieving target concentrations
Detailed Description:
N-acetyl transferase genotyping will be performed on HIV infected patients diagnosed with T B Slow acetylators will be initiated on the standard dose of isoniazid 5mgkg while fast and intermediate acetylators will be initiated on 10mgkg of isoniazid All other TB drugs will be given at their standard doses
Monitoring for toxicities will be performed every two weeks including ALT and screening for peripheral neuropathy and isoniazid concentrations will be measured four weeks after initiating treatment at Ohr 30mins 1 hr Thr and 4hr following observed drug intake
Patients will be continued on standard dose isoniazid after completing the first 8 weeks of treatment intensive phase
Sputum cultures for mycobacteria will be performed at baseline week 2 4 and week 8 TB treatment outcome will be assessed after 6 months of treatment
Non-linear mixed effects modelling will be used to model PK-PD data taking into account clinical and demographic factors like age sex and BMI The investigators will develop a model to establish the population parameters for isoniazid for example clearance absorption rate constant and volume of distribution and the variability around these primary PK parameters The investigators will then use the model to derive secondary PK parameters namely area under the concentration-time curve AUC and maximum concentrations Cmax of isoniazid for each participant The investigators will compare the PK parameters of isoniazid in fastintermediate acetylators taking 10mgkg and slow acetylators taking 5mgkg of isoniazid
In addition to the main objectives of the study the investigators will also compare the PK in patients in the PG guided isoniazid dosing group to those in the historical cohort while matching for NAT2 status age and sex In the historical cohort NAT-2 acetlyator genotyping was performed but patients received standard dosing regardless of NAT-2 acetylator status In this trial the investigators will use pharmacogenetic guided therapy for all participants The investigators will therefore be able to compare the pharmacokinetic data above safety and efficacy in patients who received pharmacogenetic therapy and those who did not
The investigators will use PK-PD models to describe the relationship between concentrations and pharmacodynamic data including toxicities and sputum conversion at week 8 in patients on the different doses In addition to this the investigators will also make this same comparison for patients in this study and those who did not receive PG guided therapy from the historical cohort The investigators will also compare the number of grade 3-5 adverse events and time to sputum culture conversion in patients in patients who did and did not receive PG guided therapy while matching for NAT2 status age and sex
Monitoring for toxicities will be performed every two weeks including ALT and screening for peripheral neuropathy and isoniazid concentrations will be measured four weeks after initiating treatment at Ohr 30mins 1 hr Thr and 4hr following observed drug intake
Patients will be continued on standard dose isoniazid after completing the first 8 weeks of treatment intensive phase
Sputum cultures for mycobacteria will be performed at baseline week 2 4 and week 8 TB treatment outcome will be assessed after 6 months of treatment
Non-linear mixed effects modelling will be used to model PK-PD data taking into account clinical and demographic factors like age sex and BMI The investigators will develop a model to establish the population parameters for isoniazid for example clearance absorption rate constant and volume of distribution and the variability around these primary PK parameters The investigators will then use the model to derive secondary PK parameters namely area under the concentration-time curve AUC and maximum concentrations Cmax of isoniazid for each participant The investigators will compare the PK parameters of isoniazid in fastintermediate acetylators taking 10mgkg and slow acetylators taking 5mgkg of isoniazid
In addition to the main objectives of the study the investigators will also compare the PK in patients in the PG guided isoniazid dosing group to those in the historical cohort while matching for NAT2 status age and sex In the historical cohort NAT-2 acetlyator genotyping was performed but patients received standard dosing regardless of NAT-2 acetylator status In this trial the investigators will use pharmacogenetic guided therapy for all participants The investigators will therefore be able to compare the pharmacokinetic data above safety and efficacy in patients who received pharmacogenetic therapy and those who did not
The investigators will use PK-PD models to describe the relationship between concentrations and pharmacodynamic data including toxicities and sputum conversion at week 8 in patients on the different doses In addition to this the investigators will also make this same comparison for patients in this study and those who did not receive PG guided therapy from the historical cohort The investigators will also compare the number of grade 3-5 adverse events and time to sputum culture conversion in patients in patients who did and did not receive PG guided therapy while matching for NAT2 status age and sex
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None