Ignite Creation Date:
2024-05-06 @ 6:56 PM
Last Modification Date:
2024-10-26 @ 2:57 PM
Study NCT ID:
NCT05839613
Status:
NOT_YET_RECRUITING
Last Update Posted:
2023-05-03
First Post:
2023-04-20
Brief Title:
PhaRmacOgenetics and Therapeutic Drug Monitoring In SchizophrEnia
Sponsor:
Assistance Publique Hopitaux De Marseille
Organization:
Assistance Publique Hopitaux De Marseille
Study Overview
Official Title:
How Personalized Medicine Based on Pharmacogenetics and Therapeutic Drug Monitoring Can Reduce Relapse Rate in Patients WITH schizophreniA An Analytical Experimental Prospective Comparative Adaptive Randomized Open-label Multicenter Clinical Trial
Status:
NOT_YET_RECRUITING
Status Verified Date:
2023-04
Last Known Status:
None
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:
PROMISE
Brief Summary:
Schizophrenia is a severe chronic mental disorder with a long-term treatment Most antipsychotic AP drugs are effective for only 30 to 60 of patients and for many drugs treatment selection remains a trial-and-error processThe main result of treatment inefficiency is relapse the recurrence of acute symptoms after a period of partial or complete remission
Pharmacogenetics PG is the study of genetic differences in drug met-abolic pathways which can affect individual responses to drugs both in terms of therapeutic effect as well as adverse effects PG testing could therefore identify patients at potentially high risk of relapse allowing the opportunity of an individualized prescription In this study PG was shown to improve the safety profile of AP treatments in patients presenting PM or UM CYP variants by reducing associated side effects Therapeutic Drug Monitoring TDM is the quantification and interpretation of drug concentration in blood to optimize pharmacotherapy For drugs with established therapeutic reference ranges TRR or with a narrow therapeutic index it makes sense to measure drug concentrations in blood for dose titration after initial prescription or after dose change Non adherence is a recurrent problem in the management of schizophrenia leading to reduced quality of life and increased risk of relapse TDM is recognized as a direct reliable measure for drug adherence and can be an additional support after a therapy adjustment Additionally TDM can be useful to educate patients and make them more aware of their treatment Finally TDM is likely to ensure a better tolerance and fewer side effects for APs while allowing a better efficacy However evidence on the clinical impact of this tool in schizophrenic population is lacking and randomized clinical trials are needed to confirm it
Finally relapses occur frequently in schizophrenia and the cost for a relapsing schizophrenic patient is estimate over 4 times higher than for a non-relapsing patient highlighting the importance of cost-effective care strategies
When separately used PG testing or TDM alone might not be sufficient to ensure the clinical utility and cost-effectiveness of these tests We hypothesize that individualized medicine including the association of PG testing with TDM PGTDM intervention on the most commonly prescribed AP drugs can reduce relapse rate at one year while being cost-effective
Pharmacogenetics PG is the study of genetic differences in drug met-abolic pathways which can affect individual responses to drugs both in terms of therapeutic effect as well as adverse effects PG testing could therefore identify patients at potentially high risk of relapse allowing the opportunity of an individualized prescription In this study PG was shown to improve the safety profile of AP treatments in patients presenting PM or UM CYP variants by reducing associated side effects Therapeutic Drug Monitoring TDM is the quantification and interpretation of drug concentration in blood to optimize pharmacotherapy For drugs with established therapeutic reference ranges TRR or with a narrow therapeutic index it makes sense to measure drug concentrations in blood for dose titration after initial prescription or after dose change Non adherence is a recurrent problem in the management of schizophrenia leading to reduced quality of life and increased risk of relapse TDM is recognized as a direct reliable measure for drug adherence and can be an additional support after a therapy adjustment Additionally TDM can be useful to educate patients and make them more aware of their treatment Finally TDM is likely to ensure a better tolerance and fewer side effects for APs while allowing a better efficacy However evidence on the clinical impact of this tool in schizophrenic population is lacking and randomized clinical trials are needed to confirm it
Finally relapses occur frequently in schizophrenia and the cost for a relapsing schizophrenic patient is estimate over 4 times higher than for a non-relapsing patient highlighting the importance of cost-effective care strategies
When separately used PG testing or TDM alone might not be sufficient to ensure the clinical utility and cost-effectiveness of these tests We hypothesize that individualized medicine including the association of PG testing with TDM PGTDM intervention on the most commonly prescribed AP drugs can reduce relapse rate at one year while being cost-effective
Detailed Description:
The variability of treatment response for both efficacy and side effects is multifactorial Non-pharmacological aspects such as psychological and social implications influence drug response but at the pharmacological level drug response results from the interaction of genetic eg drug-metabolizing enzymes drug transporters drug targets personal eg age sex disease states treatment adherence and environmental factors eg smoking diet alcohol habits drug-drug interactions that produce interindividual differences in term of pharmacokinetics and pharmacodynamics de Leon 2009 Moreover non-adherence is linked to the pathology itself and also to adverse drug reactions Because the development of new APs is slow it is of paramount importance to use the currently available drugs as effectively as possible An important aspect of effective use is dose personalization because owing to interindividual differences in drug metabolism the dose required to achieve optimal concentration of APs varies substantially between patients Jukic et al 2019 Two main tools are available for the optimization of APs exposure PG testing and TDM
PG testing can help reduce the uncertainty inherent in psychiatric pharmacotherapy by detecting genetic factors that predict clinical response and side effects such as genetic variations that impact drug-metabolizing enzymes drug transporters or drug targets Evans et Johnson 2001 Evans et Relling 1999 PG is the study of genetic differences in drug metabolic pathways which can affect individual responses to drugs both in terms of therapeutic effect as well as adverse effects Nebert 1999 In France PG is now well implanted in university hospitals and anti-cancer institutions as well as in certain private medical laboratories Picard et al 2017 According to the medical and scientific report of the Biomedecine Agency ABM 56 laboratories reported PG activity in 2019 compared with 47 laboratories with such activity in 2015 and 38091 patients were tested in 2019 vs 18777 in 2015 Annual activity report of postnatal genetic ABM 2019 Interpretation requires expertise in genetics and in pharmacology Depending on the degree of enzymatic deficiency treatment can be reduced from onset or an alternative drug can be proposed if the deficiency is severe The therapeutic attitude will be modulated depending on the clinical context disease gravity existence or not of a therapeutic alternative
The identification of robust clinical criteria and biomarkers eg genetic variants for guiding treatment choice has been the objective of a number of research efforts and part of the resulting findings were recently incorporated in guidelines In a recent review authors aims to provide an overview of the available studies focused on the genetic predictors of antidepressants response the current clinical applications of antidepressants PG and possible future developments Zanardi et al 2020 The future clinical approach in psychiatry as well as in other fields of medicine is indeed represented by precision medicine that aims to integrate genetic environmental clinical and lifestyle individual factors in order to personalize treatments
Cytochromes P450 2D6 and 2C19 genetic polymorphisms are well-known to influence APs pharmacokinetics Crettol et al 2014 CYP2D6 and CYP2C19 haplotypes are assigned a star-allele nomenclature to allow for the standardization of genetic polymorphism annotation Robarge et al 2007 Then diplotype which is the summary of inherited maternal and paternal star-alleles allows to categorized CYP2D6 and CYP2C19 into functional groups based on the predicted activity of the encoded enzyme Hicks et al 2017 2015 The predicted phenotype is influenced by the expected function of each reported allele in the diplotype making it possible to differentiate four groups of phenotypes extensive metabolizer EM who have classically two functional alleles intermediate metabolizer IM with classically one inactive allele and one causing a reduced rate of metabolism poor metabolizer PM carrying two inactive alleles with no functional activity and ultrarapid metabolizer UM who have classically an increased enzymatic function Bondy et Spellmann 2007 To date the interest of identification of PM and UM is recently growing and should help to individualize therapeutic regimens and current guidelines of the CPIC and DPWG require dose adjustment according to CYP2D6 CYP2C19 or CYP3A43A5 genetic variants wwwpharmGKBorg Based on the currently available information Arranz Salazar et Hernández 2021 has presented that PG intervention should be reduced to APs dose adjustment according to the genetically predicted metabolic status CYPs profile of the patient Growing evidence suggests that such interventions will reduce APs side-effects and increase treatment safety Despite this evidence the use of PG in psychiatric wards is minimal Hopefully further evidence on the clinical and economic benefits the development of clinical protocols based on PG information and improved and cheaper genetic testing will increase the implementation of PG guided prescription in clinical settings
Two recent randomized clinical trial failed to demonstrate the impact of PG alone on clinical improvement in schizophrenic patients Jürgens et al 2019 described a randomized clinical trial witch the aim was to assess whether routine genetic testing for CYP2D6 and CYP2C19 CYP testing improves AP drug treatment in patients with schizophrenia in terms of improved drug persistence a surrogate for tolerability and effectiveness compared with clinically guided treatment The authors concluded that routine CYP2D6 and CYP2C19 genotyping had no effect on AP drug persistence In the study of Arranz et al 2019 no evidence of greater efficacy of PG intervention was observed However results show that PG may improve the safety profile of AP treatments in patients presenting PM or UM CYP variants by reducing associated side effects The PG intervention described in this study may be particularly useful when considering treatment with APs with one major metabolic pathway and therefore more susceptible to be affected by functional variants of CYP metabolizing enzymes These recent studies confirm the fact that PG alone can only partially explain the variability pharmacokinetic of APs
TDM has a long standing history in clinical psychiatry and has been proved to be a reasonably adequate tool for the management of individual variability in psychotropic drug response Albers et Ozdemir 2004 Hiemke et al 2018 Non-response at therapeutic doses uncertain drug adherence suboptimal tolerability or pharmacokinetic drug-drug interactions are typical indications for TDM Hiemke et al 2018 Additionally TDM can be useful to educate patients and make them more aware of their treatment Finally TDM is likely to ensure a better tolerance and fewer side effects for antipsychotics drugs while allowing a better efficacy
For drugs with established TRR or with a narrow therapeutic index it makes sense to measure drug concentrations in blood for dose titration after initial prescription or after dose change Even without a specific problem there is sufficient evidence that TDM has beneficial effects for patients treated with the following drugs lithium tricyclic antidepressants several APs or anticonvulsants Hiemke et al 2018 de Leon Armstrong et Cozza 2006 Indeed since more than a decade the TDM task force of the working group on neuropsychopharmacology Arbeitsgemeinschaft fuer Neuropsychopharmakologie und Pharmakopsychiatrie AGNP has worked out consensus guidelines to assist psychiatrists and laboratories involved in psychotropic drug analysis to optimise the use of TDM of psychotropic drugs and recommendations for genotyping Baumann et al 2004 Hiemke et al 2018 Schoretsanitis et al 2020 Five research-based levels of recommendation were defined with regard to routine monitoring of plasma concentrations for dose titration of 65 psychoactive drugs 1 strongly recommended 2 recommended 3 useful 4 probably useful and 5 not recommended Baumann et al 2004 A list of recommended TRR was also established table 4 of the guideline AP strongly recommended 1 and recommended 2 are amisulpride aripiprazole bromperidol not available in France chlorpromazine clozapine flupentixol fluphenazine haloperidol olanzapine paliperidone perazine not available in France perphenazine not available in France quetiapine risperidone sertindole not available in France since 2007 sulpiride and ziprasidone not available in France
To conclude measuring drug concentrations in blood is advantageous compared to other methods since it tells the prescribing psychiatrist whether the drug is in the body at a concentration that is potentially sufficient to provide the expected clinical response ie pharmacodynamics effect However evidence on the clinical impact of this tool in schizophrenic population is lacking and randomized clinical trials are needed to confirm it
Taking together PG and TDM display marked synergy in the following areas of medical therapeutics Albers et Ozdemir 2004 Ozdemir Shear et Kalow 2001
To explain the mechanism of pharmacodynamic variability related to drug targets
To provide pharmacokinetic exposure beyond the study sample in various populations including evaluations in population extreme metabolizers ie UM and PM
To explain and predict drug distribution to tissues outside the plasma compartment by genetic testing of drug transporters
To provide drug exposure prior to drug administration and make appropriate dose adjustments early in the course of pharmacotherapy thereby reducing the time-lag for therapeutic response and avoiding acute drug toxicity that may occur after several doses of atypical APs
To provide the risk for inhibitory and inductive drugdrug or drugfood interaction potential by genetic testing and elucidation of the drug metabolism pathways that contribute to APs disposition in vivo
The most important indications for combining CYP450 genotyping and TDM are presented by Zanardi et al 2020 1 when prescribing a drug with a narrow therapeutic index and high risk of toxicity 2 when a drug has wide interindividual variability in metabolism and a considerable risk of toxicity 3 a post hoc genotyping when the patient presents unusual plasma concentrations of the drug or its metabolites indicating a possible alternation of drug metabolism or the lack of adherence to the prescribed dose so-called pseudo-resistance the latter should of course be checked before CYP450 genotyping
Therefore on APs area on the one hand PG biomarkers included in prescribing guidelines could represented an important step towards precision psychiatry On the other hand TDM important and cost-effective tool Hiemke et al 2018 should be integrated with genetic testing and clinical evaluation in order to adjust dose and optimize pharmacotherapy
PG testing or TDM alone might not be sufficient to ensure the clinical utility and cost-effectiveness of these tests when separately used in patients suffering from schizophrenia
Combined PG and TDM testing should improve acute and long-term treatment prediction of therapeutic response possible correlations with treatment outcome reduction of side effects and monitoring of treatment compliance
PG testing can help reduce the uncertainty inherent in psychiatric pharmacotherapy by detecting genetic factors that predict clinical response and side effects such as genetic variations that impact drug-metabolizing enzymes drug transporters or drug targets Evans et Johnson 2001 Evans et Relling 1999 PG is the study of genetic differences in drug metabolic pathways which can affect individual responses to drugs both in terms of therapeutic effect as well as adverse effects Nebert 1999 In France PG is now well implanted in university hospitals and anti-cancer institutions as well as in certain private medical laboratories Picard et al 2017 According to the medical and scientific report of the Biomedecine Agency ABM 56 laboratories reported PG activity in 2019 compared with 47 laboratories with such activity in 2015 and 38091 patients were tested in 2019 vs 18777 in 2015 Annual activity report of postnatal genetic ABM 2019 Interpretation requires expertise in genetics and in pharmacology Depending on the degree of enzymatic deficiency treatment can be reduced from onset or an alternative drug can be proposed if the deficiency is severe The therapeutic attitude will be modulated depending on the clinical context disease gravity existence or not of a therapeutic alternative
The identification of robust clinical criteria and biomarkers eg genetic variants for guiding treatment choice has been the objective of a number of research efforts and part of the resulting findings were recently incorporated in guidelines In a recent review authors aims to provide an overview of the available studies focused on the genetic predictors of antidepressants response the current clinical applications of antidepressants PG and possible future developments Zanardi et al 2020 The future clinical approach in psychiatry as well as in other fields of medicine is indeed represented by precision medicine that aims to integrate genetic environmental clinical and lifestyle individual factors in order to personalize treatments
Cytochromes P450 2D6 and 2C19 genetic polymorphisms are well-known to influence APs pharmacokinetics Crettol et al 2014 CYP2D6 and CYP2C19 haplotypes are assigned a star-allele nomenclature to allow for the standardization of genetic polymorphism annotation Robarge et al 2007 Then diplotype which is the summary of inherited maternal and paternal star-alleles allows to categorized CYP2D6 and CYP2C19 into functional groups based on the predicted activity of the encoded enzyme Hicks et al 2017 2015 The predicted phenotype is influenced by the expected function of each reported allele in the diplotype making it possible to differentiate four groups of phenotypes extensive metabolizer EM who have classically two functional alleles intermediate metabolizer IM with classically one inactive allele and one causing a reduced rate of metabolism poor metabolizer PM carrying two inactive alleles with no functional activity and ultrarapid metabolizer UM who have classically an increased enzymatic function Bondy et Spellmann 2007 To date the interest of identification of PM and UM is recently growing and should help to individualize therapeutic regimens and current guidelines of the CPIC and DPWG require dose adjustment according to CYP2D6 CYP2C19 or CYP3A43A5 genetic variants wwwpharmGKBorg Based on the currently available information Arranz Salazar et Hernández 2021 has presented that PG intervention should be reduced to APs dose adjustment according to the genetically predicted metabolic status CYPs profile of the patient Growing evidence suggests that such interventions will reduce APs side-effects and increase treatment safety Despite this evidence the use of PG in psychiatric wards is minimal Hopefully further evidence on the clinical and economic benefits the development of clinical protocols based on PG information and improved and cheaper genetic testing will increase the implementation of PG guided prescription in clinical settings
Two recent randomized clinical trial failed to demonstrate the impact of PG alone on clinical improvement in schizophrenic patients Jürgens et al 2019 described a randomized clinical trial witch the aim was to assess whether routine genetic testing for CYP2D6 and CYP2C19 CYP testing improves AP drug treatment in patients with schizophrenia in terms of improved drug persistence a surrogate for tolerability and effectiveness compared with clinically guided treatment The authors concluded that routine CYP2D6 and CYP2C19 genotyping had no effect on AP drug persistence In the study of Arranz et al 2019 no evidence of greater efficacy of PG intervention was observed However results show that PG may improve the safety profile of AP treatments in patients presenting PM or UM CYP variants by reducing associated side effects The PG intervention described in this study may be particularly useful when considering treatment with APs with one major metabolic pathway and therefore more susceptible to be affected by functional variants of CYP metabolizing enzymes These recent studies confirm the fact that PG alone can only partially explain the variability pharmacokinetic of APs
TDM has a long standing history in clinical psychiatry and has been proved to be a reasonably adequate tool for the management of individual variability in psychotropic drug response Albers et Ozdemir 2004 Hiemke et al 2018 Non-response at therapeutic doses uncertain drug adherence suboptimal tolerability or pharmacokinetic drug-drug interactions are typical indications for TDM Hiemke et al 2018 Additionally TDM can be useful to educate patients and make them more aware of their treatment Finally TDM is likely to ensure a better tolerance and fewer side effects for antipsychotics drugs while allowing a better efficacy
For drugs with established TRR or with a narrow therapeutic index it makes sense to measure drug concentrations in blood for dose titration after initial prescription or after dose change Even without a specific problem there is sufficient evidence that TDM has beneficial effects for patients treated with the following drugs lithium tricyclic antidepressants several APs or anticonvulsants Hiemke et al 2018 de Leon Armstrong et Cozza 2006 Indeed since more than a decade the TDM task force of the working group on neuropsychopharmacology Arbeitsgemeinschaft fuer Neuropsychopharmakologie und Pharmakopsychiatrie AGNP has worked out consensus guidelines to assist psychiatrists and laboratories involved in psychotropic drug analysis to optimise the use of TDM of psychotropic drugs and recommendations for genotyping Baumann et al 2004 Hiemke et al 2018 Schoretsanitis et al 2020 Five research-based levels of recommendation were defined with regard to routine monitoring of plasma concentrations for dose titration of 65 psychoactive drugs 1 strongly recommended 2 recommended 3 useful 4 probably useful and 5 not recommended Baumann et al 2004 A list of recommended TRR was also established table 4 of the guideline AP strongly recommended 1 and recommended 2 are amisulpride aripiprazole bromperidol not available in France chlorpromazine clozapine flupentixol fluphenazine haloperidol olanzapine paliperidone perazine not available in France perphenazine not available in France quetiapine risperidone sertindole not available in France since 2007 sulpiride and ziprasidone not available in France
To conclude measuring drug concentrations in blood is advantageous compared to other methods since it tells the prescribing psychiatrist whether the drug is in the body at a concentration that is potentially sufficient to provide the expected clinical response ie pharmacodynamics effect However evidence on the clinical impact of this tool in schizophrenic population is lacking and randomized clinical trials are needed to confirm it
Taking together PG and TDM display marked synergy in the following areas of medical therapeutics Albers et Ozdemir 2004 Ozdemir Shear et Kalow 2001
To explain the mechanism of pharmacodynamic variability related to drug targets
To provide pharmacokinetic exposure beyond the study sample in various populations including evaluations in population extreme metabolizers ie UM and PM
To explain and predict drug distribution to tissues outside the plasma compartment by genetic testing of drug transporters
To provide drug exposure prior to drug administration and make appropriate dose adjustments early in the course of pharmacotherapy thereby reducing the time-lag for therapeutic response and avoiding acute drug toxicity that may occur after several doses of atypical APs
To provide the risk for inhibitory and inductive drugdrug or drugfood interaction potential by genetic testing and elucidation of the drug metabolism pathways that contribute to APs disposition in vivo
The most important indications for combining CYP450 genotyping and TDM are presented by Zanardi et al 2020 1 when prescribing a drug with a narrow therapeutic index and high risk of toxicity 2 when a drug has wide interindividual variability in metabolism and a considerable risk of toxicity 3 a post hoc genotyping when the patient presents unusual plasma concentrations of the drug or its metabolites indicating a possible alternation of drug metabolism or the lack of adherence to the prescribed dose so-called pseudo-resistance the latter should of course be checked before CYP450 genotyping
Therefore on APs area on the one hand PG biomarkers included in prescribing guidelines could represented an important step towards precision psychiatry On the other hand TDM important and cost-effective tool Hiemke et al 2018 should be integrated with genetic testing and clinical evaluation in order to adjust dose and optimize pharmacotherapy
PG testing or TDM alone might not be sufficient to ensure the clinical utility and cost-effectiveness of these tests when separately used in patients suffering from schizophrenia
Combined PG and TDM testing should improve acute and long-term treatment prediction of therapeutic response possible correlations with treatment outcome reduction of side effects and monitoring of treatment compliance
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