[Therapeutic drug monitoring of clozapine]. / Suivi thérapeutique pharmacologique de la clozapine.

Clozapine is a prototypical atypical antipsychotic used to treat severe schizophrenia and for which a therapeutic drug monitoring (TDM) is quite commonly proposed. Clozapine is rapidly absorbed (maximum concentration reached within 1 to 4hours), and is extensively metabolized in the liver by CYP1A2 to an active metabolite (and to a lesser extent, to inactive metabolites via other enzymes). Its half-life is 8 to 16h. A therapeutic range has been proposed for clozapine as some studies have reported both a relationship between low plasmatic concentrations and resistance to treatment (threshold level is likely between 250 and 400µg/L), and a relationship between high plasmatic concentrations and an increase in the occurrence of toxicity (alert level=1000µg/L). Given the data obtained in different studies, the TDM was evaluated for this molecule, to recommended.

[Therapeutic drug monitoring of olanzapine]. / Suivi thérapeutique pharmacologique de l'olanzapine.

Olanzapine, atypical antipsychotic, is used to treat schizophrenia and bipolar disorder. Its therapeutic drug monitoring (TDM) is quite commonly done. Olanzapine is well absorbed orally (bioavailability: 85 %), with peak plasma occurring between 4 and 6hours after oral administration. It is extensively metabolized by different hepatic enzymes (including CYP1A2 and CYP2D6 isoforms) to a large number of inactive metabolites, and its half-life is between 30 and 60hours. No specific therapeutic range, or threshold concentration could not be a consensus, but the higher intra- and interindividual variability, as well as the existence of studies suggesting a correlation between circulating concentrations of olanzapine and occurrence of therapeutic relapse or toxic phenomena appear to justify the STP for this molecule. Given these data, the interest of the STP was evaluated for this molecule to: recommended with therapeutic window of 20µg/L to 80µg/L.

Subthalamic nucleus modulates social and anxogenic-like behaviors.

In Parkinson's disease, global social maladjustment and anxiety are frequent after subthalamic nucleus (STN) stimulation and are generally considered to be linked with sociofamilial alterations induced by the motor effects of stimulation. We hypothesized that the STN is per se involved in these changes and aimed to explore the role of STN in social and anxogenic-like behaviors using an animal model. Nineteen male Wistar rats with bilateral lesions of the STN were compared with 26 sham-lesioned rats by synchronizing an ethological approach based upon direct observation of social behaviors and a standardized approach, the elevated plus maze (EPM). Comparisons between groups were performed by a Mann-Whitney-Wilcoxon test. Lesioned rats showed impairments in their social (P=0.05) and aggressive behaviors with a diminution of attacking (P=0.04) and chasing (P=0.06). In the EPM, concerning the open arms, the percentage of distance, time, inactive time, and entry were significantly decreased in lesioned rats (P=0.02, P=0.01, P=0.04, and P=0.05). The time spent in non-protected head dips was also diminished in the lesioned rats (P=0.01). These results strongly implicate the STN in social behavior and anxogenic-like behavior. In human, as DBS induces changes in the underlying dynamics of the stimulated brain networks, it could create an abnormal brain state in which anxiety and social behavior are altered. These results highlight another level of complexity of the behavioral changes after stimulation.

[Therapeutic drug monitoring of primidone and phenobarbital]. / Suivi thérapeutique pharmacologique de la primidone et du phénobarbital.

Primidone is a minor first-generation antiepileptic drug, little currently prescribed for this indication, but except marketing authorization, remains a first-line treatment of essential tremor. Although it is metabolized in phenyl-ethyl-malondamide and phenobarbital, active metabolites that contribute also to its action, primidone is not a prodrug and is active by itself. The rate of conversion of primidone to phenobarbital is highly variable according to the subject. Generally accepted therapeutic range for primidone is between 5 and 10 mg/L (23-46 mmol/L). The therapeutic drug monitoring (TDM) of primidone must be accompanied by the determination of phenobarbital concentrations. The level of proof of the interest of the TDM primidone was estimated to be "probably useless". Phenobarbital, a very ancient anticonvulsant, is much less used today, for the benefit of other more recent compounds. It remains prescribed in neonatology and is one of the compounds used in status epilepticus. It is a molecule with a long half-life, metabolized in p-hydroxy-phenobarbital. It is a potent inducer of CYP3A4. Several side effects, especially drowsiness, are concentration-dependent. Generally accepted therapeutic range for phenobarbital is between 10 and 40 mg/L (43 - 172 mmol/L), without considering the type of crise. The level of proof of the interest of TDM of phenobarbital was evaluated as "recommended".

[Therapeutic drug monitoring of ethosuximide]. / Suivi thérapeutique pharmacologique de l'éthosuximide.

Ethosuximide is a minor antiepileptic drug, available in France since 1965, indicated in the epilepsy absence, whose interest was reassessed from recent clinical trials, showing that it was the first choice, in term of risk benefit relationship, in this indication. It is a chiral molecule that presents a high bioavailability, a lack of protein binding, hepatic metabolism and urinary excretion. Its elimination half-life is long, between 40 and 60 h in adults, 30 and 40 h in children. The therapeutic range is established at 40-100 mg/L (283-708 µmol/L), but the upper limit is probably underestimated. The clinical studies of relation exposure effects, although ancient (from the 1970s) and realized with methodologies that do not meet current criteria, show concentration-efficacy and -toxicity relationship and the risk of drug interactions is proven. It is a drug preponderantly prescribed in children, a vulnerable population with physiological change with age. To benefit at best of its effectiveness, it is necessary to have relatively high plasma concentrations. Despite these arguments and due to the lack of studies providing a sufficient level of evidence, the recommendation can only be "potentially useful", assessment probably underestimated.

[Level of evidence for therapeutic drug monitoring of ceftriaxone]. / Niveau de preuve du suivi thérapeutique pharmacologique de la ceftriaxone.

Ceftriaxone is a third generation cephalosporin with an original pharmacokinetics based on a long elimination half-life among cephalosporins, a high protein binding and a dual renal and biliary elimination. Also the pharmacokinetic parameters of ceftriaxone are highly variable in clinical situations such as severe renal insufficiency, liver and renal insufficiency, the elderly, the neonates less than 1 week of age and critically ill patients. In these clinical situations associated or not with high minimal inhibitory concentration (MIC) level, the relationship concentration-clinical outcome based on the ratio between trough plasma concentration and MIC can allow a dose adjustment. Consequently, therapeutic drug monitoring (TDM) of ceftriaxone could be possibly useful in these situations, whereas the necessity of TDM has still to be demonstrated to monitor toxicity.

[Therapeutic drug monitoring of stiripentol]. / Suivi thérapeutique pharmacologique du stiripentol.

Stiripentol is a third generation antiepileptic, marketed since 2007 under the name of Diacomit(®). It is indicated, always in combination, in the treatment of severe myoclonic epilepsy in infancy or Dravet syndrome. Its pharmacokinetics is not linear. It is a potent inhibitor of CYP3A4, 1A2 and 2C19 and increases the plasma concentrations of many other antiepileptic drugs. Without this being considered as a validated therapeutic range, the trough plasma concentrations at steady-state, corresponding to the usual doses are between 10 and 15 mg/L. The concentration-efficacy relationship is not established, but there is some evidence for a concentration-related toxicity. However, because of its non-linear kinetics, stiripentol should be a good candidate for therapeutic drug monitoring (TDM). Nonetheless, the current level of evidence for the advantage of TDM is "remains to be estimated".

[Therapeutic drug monitoring of rufinamide]. / Suivi thérapeutique pharmacologique du rufinamide.

Rufinamide is a third-generation antiepileptic drug, available since early 2010 in France. It is indicated in combination therapy in the Lennox-Gastaut syndrome from the age of 4. It has orphan drug status. The bioavailability of rufinamide is high, but decreases with the dose and increases with food intake. Rufinamide is not metabolized by cytochromes but hydrolyzed by a carboxylesterase in an inactive carboxylic derivative. Elimination is mainly renal. The half-life varies from 6 to 10h. Although established from relatively few studies, exposure efficacy and exposure toxicity relationships are argued. A plasma concentration of 15 mg/L, obtained with a standard regimen, reduces the number of seizures of 25%. Few factors of intrinsic variability are described. There are few clinically significant pharmacokinetic interactions and they concern combinations with other antiepileptic drugs, especially valproate. Although there is no validated therapeutic range, the level of evidence for this therapeutic drug monitoring has been estimated at "possibly useful".

[Therapeutic drug monitoring of lacosamide]. / Suivi thérapeutique pharmacologique du lacosamide.

Lacosamide is a third generation antiepileptic drug, available in France since 2008. It is indicated in combination therapy for the treatment of inadequately controlled focal seizures, from the age of 16. The bioavailability of lacosamide is 100% and is unaffected by food intake; protein binding is low; it is metabolized by CYP2C19 into inactive O-desmethyl lacosamide. It does not inhibit or induce cytochromes; the elimination is renal with a half-life of approximately 13 h. The relationship between dose and plasma concentration is established, but there does not appear to be any clear relationship between concentration and efficacy. However, the main side effects are concentration dependent. The potential for drug-drug interaction of lacosamide is low and variability between individuals is minimal. Accordingly, the level of evidence for the therapeutic drug monitoring has been estimated at "probably of no use".

[Therapeutic drug monitoring of quinine]. / Suivi thérapeutique pharmacologique de la quinine.

Quinine is an antimalarial agent whose main mechanism of action on Plasmodium is to inhibit the transformation of toxic haem to polymeric non-toxic haemozoin. After oral and intramuscular administration, quinine is well absorbed, with peak plasma concentration reached in 1 to 3 hours. The pharmacokinetic of quinine differs depending on the severity of the disease: the volume of distribution and the clearance decrease proportionally to the infection, while the half-life increases. Plasma concentrations are approximately 50% higher in patients in the acute phase than in convalescence. Quinine is metabolized primarily by CYP3A4, implying changing the dosage when combined with inhibitors or inducers of CYP. The efficacy of quinine has been proved for residual concentrations above 5 mg/L (15 µmol/L) throughout the duration of treatment. Some side effects are concentration-dependent and a concentration of 20 mg/L (60 µmol/L) is considered as the threshold for toxicity. The 2007 consensus conference of the French Language Infectious Diseases Society calls for daily monitoring of plasma concentrations during the first 3 days of treatment targeting a trough concentration between 10 and 12 mg/L (30-36 µmol/L). For this compound, the level of evidence of the interest of therapeutic drug monitoring has been evaluated and the latter is recommended.

Simultaneous determination of 12 beta-lactam antibiotics in human plasma by high-performance liquid chromatography with UV detection: application to therapeutic drug monitoring.

A rapid and specific high-performance liquid chromatography method with UV detection (HPLC-UV) for the simultaneous determination of 12 beta-lactam antibiotics (amoxicillin, cefepime, cefotaxime, ceftazidime, ceftriaxone, cloxacillin, imipenem, meropenem, oxacillin, penicillin G, piperacillin, and ticarcillin) in small samples of human plasma is described. Extraction consisted of protein precipitation by acetonitrile. An Atlantis T3 analytical column with a linear gradient of acetonitrile and a pH 2 phosphoric acid solution was used for separation. Wavelength photodiode array detection was set either at 210 nm, 230 nm, or 298 nm according to the compound. This method is accurate and reproducible (coefficient of variation [CV] < 8%), allowing quantification of beta-lactam plasma levels from 5 to 250 µg/ml without interference with other common drugs. This technique is easy to use in routine therapeutic drug monitoring of beta-lactam antibiotics.

[Aripiprazole use in children and adolescent psychiatric patients]. / Prescription de l'aripiprazole chez l'enfant et l'adolescent.

Aripiprazole inaugurates a new generation of antipsychotics called dopamine-serotonin system stabilizers. Its mechanism of action is different as aripiprazole is a partial dopamine D(2) and serotonin 5-HT(1A) receptor agonist and 5-HT(2A) receptor antagonist. Therefore, aripiprazole is thought to have an antagonistic action in the mesolimbic pathway but an agonistic action in the mesocortical pathway, tending to normalize the dopaminergic transmission regardless of the type of imbalance. Clinical trials involving children and adolescents have demonstrated the efficacy of aripiprazole in bipolar disorders, schizophrenia, mood disorders associated with pervasive developmental disorders, in tics and Tourette's. The most frequent side effects are extrapyramidal symptoms and sleepiness and are dose-dependent. Nevertheless, contrary to other second-generation antipsychotics available in France, it induces little weight gain, does not modify lipid and glucidic profiles, does not increase prolactin levels, or induce QTc lengthening. The main advantage of aripiprazole is its good safety profile, with different toxicity targets to other second-generation antipsychotics available in France. Aripiprazole appears to be an alternative for children and adolescents who are vulnerable to these side effects and are having trouble coping with them.

[Level of evidence for therapeutic drug monitoring of low dose methotrexate in inflammatory diseases]. / Suivi thérapeutique pharmacologique du méthotrexate à faible dose dans les maladies inflammatoires.

Methotrexate is prescribed to low-dose, ranging from 7.5 mg to 15 mg and until 25 mg if necessary, pulse once a week, in inflammatory pathologies, in particular in rheumatoid arthritis and psoriasis. The therapeutic answer and the frequency of adverse reactions are very variable from a patient to the other one, consequences of a large interindividual variability of the pharmacokinetic parameters of methotrexate, in particular bioavailability, suggesting a genetic support. Numerous polymorphisms being involved (carriers of influx and efflux, enzymes of the metabolism and of the mechanism of action of methotrexate), their determination with the aim of an individualized prescription does not seem realistic at the moment. On the other hand, an exposure-effect relationship, not so much by considering the plasma concentrations of methotrexate, but those of its polyglutamate derivatives in red blood cells, was described. Their determination should be able to contribute to a faster adaptation of dosages, or to a well-argued change of molecule in case of non clinical response. Although other studies are necessary to specify which markers would be the most relevant, which would be the best moment for their determination and to refine the therapeutic range, this approach seems promising. But currently, the level of proof of the therapeutic drug monitoring of low dose methotrexate in inflammatory disease was classified "remaining to evaluate".

Acute and chronic anxiogenic-like response to fluoxetine in rats in the elevated plus-maze: modulation by stressful handling.

While antidepressants are widely prescribed to humans for the treatment of anxiety, the results achieved with animal anxiety models are conflicting. The experimental procedure and the prior test history of the animals are critical parameters that are largely susceptible to influence the results and their interpretation. We compared the effect of 5mg fluoxetine administered to six groups of rats subjected to the psychopharmacological test of the elevated plus-maze, under experimental conditions designed to demonstrate the effect of handling and one daily injection on the response to fluoxetine. The results show that for animals with the same recent experience, fluoxetine, when administered once or over a period of 15 days, induces anxiogenic-like behaviour. On the other hand, our results also show that stressful handling has an anxiolytic-like effect modulating the anxiogenic-like effect of fluoxetine, without eliminating it altogether.

Determination of daptomycin in human plasma by liquid chromatography-tandem mass spectrometry. Clinical application.

BACKGROUND: Daptomycin is a recently developed cyclic lipopeptide antibiotic active against most Gram-positive pathogens including vancomycin-resistant enterococci and methicillin-resistant Staphylococcus aureus. To optimize treatment efficacy and safety, especially in patients undergoing multiple drug regimens and/or co-morbidities, a specific liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed for the quantification of daptomycin in plasma. METHODS: A C18 column was used for separation, with a mobile phase initially consisting of 0.1% formic acid, water, and acetonitrile (ACN) in a linear gradient from 20% to 70%. After protein precipitation with ACN, the clear upper layer was diluted in water:ACN (50:50, v/v) before injection. Detection was performed using an electrospray ionization technique. MS/MS transitions, monitored in the positive ion mode were m/z 811.1 → m/z 313.1 for daptomycin, and m/z 609.4 → m/z 194.9 for reserpine, used as internal standard. RESULTS: Elution of daptomycin and reserpine occurred at 4.5 and 3.9 min, respectively. The method was validated over a range of concentrations from 1 mg/L to 120 mg/L. The assay met recommended acceptance criteria: coefficients of variation were <6.3% and <7.4%, and accuracies were between -5.9% and +11.2% and between -3.5% and +3.7%, for intra- and inter-day validations, respectively. CONCLUSIONS: This method appears well-adapted to routine hospital practice for therapeutic drug monitoring of daptomycin considering its time of analysis, range of concentrations measured, precision and accuracy.

[Not Available]. / Prescription de l'aripiprazole chez l'enfant et l'adolescent.

Aripiprazole inaugurates a new generation of antipsychotics called dopamine-serotonin system stabilizers. Its mechanism of action is different as aripiprazole is a partial dopamine D2 and serotonin 5-HT1A receptor agonist and 5-HT2A receptor antagonist. Therefore, aripiprazole is thought to have an antagonistic action in the mesolimbic pathway but an agonistic action in the mesocortical pathway, tending to normalize the dopaminergic transmission regardless of the type of imbalance. Clinical trials involving children and adolescents have demonstrated the efficacy of aripiprazole in bipolar disorders, schizophrenia, mood disorders associated with pervasive developmental disorders, in tics and Tourette's. The most frequent side effects are extrapyramidal symptoms and sleepiness and are dose-dependant. Nevertheless, contrary to other second-generation antipsychotics available in France, it induces little weight gain, does not modify lipid and glucidic profiles, does not increase prolactin levels, or induce QTc lengthening. The main advantage of aripiprazole is its good safety profile, with different toxicity targets to other secondgeneration antipsychotics available in France. Aripiprazole appears to be an alternative for children and adolescents who are vulnerable to these side effects and are having trouble coping with them.

[Therapeutic drug monitoring of clonazepam]. / Suivi thérapeutique pharmacologique du clonazépam.

Clonazepam is a 1-4 benzodiazepine mainly used to treat epilepsy and epileptiform convulsion state. Rapidly absorbed after oral administration, it is widely distributed in the organism and is extensively converted in metabolites, poorly or not active, eliminated mainly in urine (70%) and feces. Elimination half-life is long, around 40 h. In adult and child, several studies showed a concentration-effect relation. Meanwhile, a large inter-individual variability in the dose-concentration relation was observed. A 15-50 microg/L range of clonazepam blood concentrations appears to be retained as an acceptable target to control a majority of epileptic seizures. The Therapeutic Drug Monitoring (TDM) of clonazepam can be considered as possibly useful in case of association with CYP450 inducers or inhibitors, suspicion of poor observance, or toxicity signs.

[Therapeutic drug monitoring of clobazam]. / Suivi thérapeutique pharmacologique du clobazam.

Clobazam is a 1,5 benzodiazepine available in France since 1975, used in add-on with the other anticonvulsant drugs in the treatment of refractory epilepsies of child and adult and for the treatment of anxiety of adult. It is mainly metabolized in desmethylclobazam, or norclobazam, active metabolite, present in a concentration approximately eight times superior to that of the parent drug, but with an activity of the order of 20 to 40% of that of clobazam. Elimination half-life of clobazam is of 18 h while that of norclobazam is from 40 to 50 h. There is a large interindividual variability in the plasma concentrations. Furthermore, clobazam being prescribed in add-on with the other anticonvulsant drugs in resistant epilepsies, concentration-effect relationship is difficult to bring to light, since, in many studies, the patients who did not answer received the highest doses. Adverse reactions are moderated, appearing more often for the highest concentrations; also the phenomenon of tolerance seems more frequent in high concentrations. However, because of the kinetic interactions, a dosage of clobazam and norclobazam can be useful in certain cases. There is no validated therapeutic range, but the usual concentrations are in the range of 100-300 microg/L for the parent drug and about ten times more for the metabolite. The level of proof of the interest of the Therapeutic Drug Monitoring for this molecule is estimated in: rather useless.

[Therapeutic drug monitoring of valproate]. / Suivi thérapeutique pharmacologique du valproate.

Valproic acid is an anticonvulsant drug available in France since 1967. It is a broad spectrum molecule indicated in various forms of epilepsy of the adult and the child, but it is also prescribed in the treatment of different other pathologies of nervous system. The divalproate sodium is indicated in the treatment of bipolar disorders. The valproic acid is marketed under various pharmaceutical forms, with different corresponding tmax values. But, whatever the administered preparation, the circulating active molecule is the ion valproate. Elimination half-life is from 11 to 20 h. Metabolization of valproate is important and represents its main route of elimination. Valpromide is comparable to a prodrug which metabolizes in valproate. The inter and intraindividual variability of the plasma concentrations are important. Several studies show a concentration-effect relationship, but two interventional trials ended in the lack of interest of the Therapeutic Drug Monitoring (TDM), although it is of current practice. However, numerous drug interactions may modify the plasma concentrations of valproate. The therapeutic range is from 50 to 100 mg/L (346-693 micromol/L). The level of proof of the interest of the TDM for this molecule was estimated in: recommended.

Liquid chromatography-tandem mass spectrometry method for simultaneous quantification of four triazole antifungal agents in human plasma.

BACKGROUND: Invasive fungal infections are an increasing cause of morbidity and mortality. Triazole antifungal agents are recommended for the prevention and treatment of such infections. Their broad inter- and intra-individual pharmacokinetic variability and the high probability of drug-drug interactions justify therapeutic drug monitoring (TDM). We developed a liquid chromatography-tandem mass spectrometry method for the simultaneous quantification of four triazole antifungal agents (fluconazole, itraconazole, posaconazole, voriconazole) and one of their metabolites (hydroxy-itraconazole) in human plasma. METHODS: After protein precipitation with acetonitrile (ACN), a C18 column was used for separation with a mobile phase consisting of 0.1% formic acid, water and ACN in a linear gradient from 20% to 70%, over 10 min. Detection was performed by electrospray ionization and quantification was performed using selected reaction monitoring transitions. RESULTS: Total run time was 15 min. The method was validated for a range of 0.1-12 µg/mL. Coefficients of variation were <9.5% and <13.8%, and accuracies were between -5.4% and +7.7% and between -10.8% and +10.4%, for intra- and inter-day validations, respectively. CONCLUSIONS: This method appears to be well suited to routine hospital practice for the TDM of triazole antifungal agents considering its time of analysis, range of concentrations measured, precision and accuracy.