Clinical Trial Details
— Status: Not yet recruiting
Administrative data
| NCT number |
NCT05839613 |
| Other study ID # |
2022-A01015-38 |
| Secondary ID |
|
| Status |
Not yet recruiting |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
May 2023 |
| Est. completion date |
May 2027 |
Study information
| Verified date |
April 2023 |
| Source |
Assistance Publique Hopitaux De Marseille |
| Contact |
Olivier BLIN, Pr |
| Phone |
04 91 38 75 63 |
| Email |
olivier.blin[@]ap-hm.fr |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial 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" process.The 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 (PG/TDM intervention), on the most commonly
prescribed AP drugs, can reduce relapse rate at one year while being cost-effective.
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 (e.g. drug-metabolizing enzymes, drug transporters, drug targets), personal (e.g.
age, sex, disease states, treatment adherence) and environmental factors (e.g. 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 38,091 patients were tested in 2019 (vs 18,777 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 (e.g., 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, author's
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 CYP3A4/3A5 genetic variants
(www.pharmGKB.org). 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, i.e.
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 (i.e. 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 drug/drug or drug/food 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 metabolite(s), 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.
