Valproate Comedication Research Articles

Therapeutic Drug Monitoring of Olanzapine: Effects of Clinical Factors on Plasma Concentrations in Psychiatric Patients.

Therapeutic drug monitoring (TDM) is strongly recommended for olanzapine due to its high pharmacokinetic variability. This study aimed to investigate the impact of various clinical factors on olanzapine plasma concentrations in patients with psychiatric disorders. The study used TDM data from the PsyMetab cohort, including 547 daily dose-normalized, steady-state, olanzapine plasma concentrations (C:D ratios) from 248 patients. Both intrinsic factors (eg, sex, age, body weight) and extrinsic factors (eg, smoking status, comedications, hospitalization) were examined. Univariate and multivariable, linear, mixed-effects models were employed, with a stepwise selection procedure based on Akaike information criterion to identify the relevant covariates. In the multivariable model (based on 440 observations with a complete data set), several significant findings emerged. Olanzapine C:D ratios were significantly lower in smokers (β = -0.65, P < 0.001), valproate users (β = -0.53, P = 0.002), and inpatients (β = -0.20, P = 0.025). Furthermore, the C:D ratios decreased significantly as the time since the last dose increased (β = -0.040, P < 0.001). The male sex had a significant main effect on olanzapine C:D ratios (β = -2.80, P < 0.001), with significant interactions with age (β = 0.025, P < 0.001) and body weight (β = 0.017, P = 0.011). The selected covariates explained 30.3% of the variation in C:D ratios, with smoking status accounting for 7.7% and sex contributing 6.9%. The overall variation explained by both the fixed and random parts of the model was 67.4%. The model facilitated the prediction of olanzapine C:D ratios based on sex, age, and body weight. The clinical factors examined in this study, including sex, age, body weight, smoking status, and valproate comedication, remarkably influence olanzapine C:D ratios. Considering these factors, in addition to TDM and the clinical situation, could be important for dose adjustment.

Levetiracetam pharmacokinetics and its covariates: proposal for optimal dosing in the paediatric population

ObjectivesLevetiracetam is an anticonvulsive drug increasingly used in paediatric populations. Ontogenesis may alter its pharmacokinetics, demanding dose individualisation of levetiracetam in paediatric populations. We therefore aimed to explore levetiracetam pharmacokinetics...

A Retrospective Analysis of Steady-State Olanzapine Concentrations in Chinese Patients Using Therapeutic Drug Monitoring: Effects of Valproate and Other Factors.

The objective of this study was to investigate the serum concentrations of olanzapine in relation to age, sex, and other factors in Chinese patients aged between 10 and 90 years. Data for 884 olanzapine patients, deposited between 2016 and 2017, were retrieved from the therapeutic drug monitoring database of the Affiliated Brain Hospital of Guangzhou Medical University. The effects of covariates on serum olanzapine concentration, dose-normalized concentration (C/D ratio), and normalized concentration (C/D/weight) were investigated. Generally, male patients had lower olanzapine concentration, C/D ratio, and C/D/weight than female patients (P < 0.001). Smoking and drinking reduced olanzapine concentration, C/D ratio, and C/D/weight (P < 0.001). Coadministration with valproate decreased olanzapine concentration, C/D ratio, and C/D/weight by about 16%, 30%, and 40%, respectively (P < 0.001). Patients younger than 60 years had higher olanzapine concentrations (P < 0.05) but lower C/D ratios and C/D/weight (P < 0.001) than patients older than 60 years. Age was correlated with olanzapine concentration (r = -0.082, P < 0.05), C/D ratio (r = 0.196, P < 0.001), and C/D/weight (r = 0.169, P < 0.001). Sample timing after dose and diagnostic factors also contributed to the olanzapine concentrations. Multiple linear regression analysis revealed significant influences of dosage, age, sex, valproate comedication, smoking, postdose interval, and schizophrenia (vs bipolar affective disorders) on serum olanzapine concentrations. The metabolism of olanzapine may be altered by several factors. Patients characterized with a combination of factors may benefit from therapeutic drug monitoring for the adjustment of olanzapine dose to minimize adverse reactions.

Relationship Between UGT1A4 and UGT2B7 Polymorphisms and the Steady-State Plasma Concentrations of Lamotrigine in Patients With Treatment-Resistant Depressive Disorder Receiving Lamotrigine as Augmentation Therapy.

In a previous study, the authors had shown that in treatment-resistant depressive disorder, an early therapeutic response to lamotrigine augmentation therapy is dependent on its plasma concentrations. Lamotrigine is mainly metabolized by UGT1A4 and UGT2B7, and polymorphisms of said UGTs that affect enzyme activities have been reported. This study investigated the effect of these polymorphisms on the steady-state plasma concentrations (Css) of lamotrigine in patients with treatment-resistant depressive disorder receiving lamotrigine as augmentation therapy. The subjects were 103 depressed patients who had already shown insufficient response to at least 3 psychotropics including antidepressants, mood stabilizers, and atypical antipsychotics. The diagnoses were major depressive disorder (n = 46), bipolar II disorder (n = 44), and bipolar I disorder (n = 13). They received augmentation therapy with lamotrigine for 8 weeks. The final doses of lamotrigine were 100 mg/d for 67 subjects who were not taking valproate and 75 mg/d for 36 subjects taking valproate, respectively. Blood sampling was performed at the 8th week. Plasma concentrations of lamotrigine were measured by high-performance liquid chromatography. The genotypes of UGT1A4 142T>G, UGT2B7 -161C>T, and UGT2B7 372A>G were identified by polymerase chain reaction analyses. There were no significant relationships between these polymorphisms and the Css of lamotrigine in the subjects regardless of valproate comedication. This study suggests that these genetic polymorphisms do not affect the Css of lamotrigine in patients with treatment-resistant depressive disorder receiving lamotrigine as augmentation therapy.

Success of tardive electroconvulsive therapy sessions after loxapine-induced malignant syndrome in the context of very poor metabolisation

We report the success of tardive electroconvulsive therapy in a case of loxapine malignant syndrome with catatonia. Loxapine and its metabolites were measured in biological samples by liquid chromatography coupled to tandem mass spectrometry. Genes were studied by sequencing and quantitative polymerase chain reaction (PCR). Plasmatic drug concentrations showed a supratherapeutic concentration of loxapine with a very low 8-hydroxyloxapine/loxapine ratio (range from 0.32 to 0.66, normal value>2 for 100mg) and a very long elimination half-life of loxapine (half-life>140h, normal value from 1 to 4hours). We tried to explain this kinetics by exploring the main pharmacogenes implicated in the metabolism of loxapine. No genetic abnormality for CYP1A2 was observed. The study of associated treatments showed the potential contribution of valproate. Pharmacokinetics and pharmacogenetics investigations revealed a blockade of the CYP1A2 metabolic pathway without genetic abnormalities, probably due to valproate co-medication. Toxicological monitoring of loxapine and its metabolites helped to explain the persistence of symptoms and to adapt the therapeutic management.

Effect of valproate on the plasma concentrations of aripiprazole in bipolar patients

Objective. There is very limited documentation available on the effects of valproate co-medication on the pharmacokinetics of aripiprazole in a naturalistic setting. The aim of the present study was to investigate the effect of co-medication with valproate on serum concentrations of aripiprazole in bipolar disorder patients in a clinical setting. Method. Plasma samples of bipolar disorder patients (n = 69) on a stable dose of aripiprazole 20 mg/day were analyzed by a liquid chromatography-mass spectrometry method in a routine therapeutic drug monitoring setting. Therapeutic drug monitoring was done for the entire study group before and after valproate co-administration. Results. We observed a statistically significant difference between the aripiprazole monotherapy and aripiprazole-valproate combination with respect to total aripiprazole plasma levels (p < 0.01). However, no statistically significant differences were noted in aripiprazole levels between the first week and the second week of valproate co-administration. Conclusion. In conclusion, concurrent treatment with valproate resulted in changes in the total aripiprazole plasma levels by 23%. But a lower total aripiprazole concentration during co-medication with valproate, caused by protein binding displacement, is reported being clinically insignificant in previous studies. The results from these studies are important in order to clarify clinical safety and efficacy.

Clinical predictors of serum clozapine levels in patients with treatment-resistant schizophrenia

Fixed oral doses of clozapine produce up to 45-fold interindividual variability among its serum levels in patients with treatment-resistant schizophrenia. Although the relationship between serum clozapine level and its therapeutic response is uncertain, the presence of a therapeutic window and level-dependent adverse effects require the estimation of serum clozapine levels. As routine therapeutic drug monitoring of clozapine is not feasible in many clinical settings, identification of clinical predictors of serum clozapine levels is desirable. Hence, we aimed to evaluate the clinical variables associated with serum clozapine levels. We assessed the sociodemographic and clinical profiles, cognition, disability and psychopathology of 101 consecutive patients with treatment-resistant schizophrenia on a stable dose of clozapine, using standard assessment schedules. We determined their serum clozapine levels using high-performance liquid chromatography with ultraviolet detection. While employing multivariate robust regression models, oral clozapine dose (P<0.001), caffeine intake (P=0.04) and Valproate comedication (P=0.005) were associated with serum clozapine levels. Serum clozapine levels above 750 ng/ml increased the risk of seizures (odds ratio 5.15; P=0.03). Clinical variables are useful to model a dosing nomogram for serum clozapine levels. The importance of caffeine consumption and Valproate comedication should be considered during clozapine dose adjustments to enhance its therapeutic response and safety profile.

Lamotrigine Serum Concentrations under Valproate Comedication: “Contraindication” or “Safe Combination”?

In our laboratory we analyse the concentrations of various psychopharmaceuticals from serum samples, which are sent to us from a broad spectrum of hospitals. Among a total number of 685 lamotrigine serum samples analysed in our laboratory between March 2005 and April 2007, 117 specimens (11.7% of all lamotrigine specimens) were identified that were obtained from patients under valproate comedication [10]. In Germany, both drugs are licensed for the treatment of epilepsy. Valproate has an additional indication for the treatment of acute mania as well as for prevention of bipolar disorders, while lamotrigine is the choice for the prevention of depressive episodes in bipolar disorders [1] [2] [3]. Lamotrigine is a phenyltriazine derivative and structurally different from all other antiepileptic drugs. The half-life of lamotrigine is reported to be 24.1±5.7 h under monotherapy [7]. Its biotransformation involves direct glucuronidation by UGT1A4 (uridine-glucuronyltransferase isoenzyme 1A4) to the pharmacologically inactive 2N-glucuronide, with the oxidative liver enzymes (the cytochrome P450 system) not being involved [9]. Valproate is known to be a potent inhibitor of this metabolic pathway resulting in a three-fold increase of the lamotrigine elimination half-life, whereas valproate concentrations are not significantly changed under lamotrigine comedication [15] [16]. The combined use of the two drugs therefore results in significantly higher lamotrigine serum concentrations and the risk of severe side effects [8] [19]. Nevertheless, combination is possible and of certain benefit in bipolar disorders [20]. A tentative therapeutic reference range of 1-4 mg/L has been suggested for lamotrigine when used as antiepileptic drug to prevent grand mal seizures [6] [17]. There is so far no therapeutic reference range for its use in psychiatry for relapse prevention in bipolar disorders. Until better evidence is available, the therapeutic reference range for its use as an antiepileptic substance is been tentatively applied for the application of lamotrigine in bipolar disorders, too.

Influence of age, gender, body weight and valproate comedication on quetiapine plasma concentrations

Quetiapine is a second-generation antipsychotic with a favourable risk/benefit profile that is increasingly used in psychiatric patients. Similar to other antipsychotics, the efficacy and adverse effects of quetiapine depend much more on the actual plasma concentration of the active drug than on the prescribed dose. The present study investigated whether age, gender, body weight or certain comedications influence quetiapine plasma concentration by determining quetiapine plasma levels by tandem mass spectrometry in 94 (36 male and 58 female) patients aged 42.2 +/- 20.0 years. Older age was a significant predictor of a higher quetiapine plasma concentration, with a mean increase of weight-corrected concentration/dose ratio of 11% per 10 years of age (P = 0.003). In females, the concentration/dose (C/D) ratio was 35.4% higher than in males (adjusted mean 0.144 ng/ml/mg for males versus 0.195 ng/ml/mg for females, respectively; P = 0.035). However, after correction for weight, the gender difference in C/D ratio dropped to 22% and significance was lost (P = 0.133). Valproate comedication was associated with a 77% increase in quetiapine plasma levels (P = 0.016). In conclusion, older age, body weight and comedication with valproate have to be considered when prescribing quetiapine. Higher plasma levels in female patients need to be replicated in larger samples.

Evaluation of VPA dose and concentration effects on lamotrigine pharmacokinetics: implications for conversion to lamotrigine monotherapy

Objective: Lamotrigine (LTG) is approved for monotherapy following withdrawal from enzyme-inducing antiepileptic drugs. LTG is also frequently used in combination with sodium valproate (VPA), and withdrawal to monotherapy in this setting is also frequently desirable. Given the known pharmacokinetic interaction between these two drugs, clinically relevant questions that should be answered include (1) at what dose and/or concentration of VPA does this interaction begin, and (2) at what dose of VPA does maximal inhibition occur. Methods: LTG pharmacokinetics was evaluated using single-dose LTG (25 mg) given before and following low-dose VPA co-medication (125, 250, 375, 500 mg per day VPA) in healthy subjects. Serial blood samples were obtained over 120 h post-dose in order to calculate LTG kinetic parameters including area under the concentration–time curve, apparent oral clearance, elimination half-life and percent inhibition of LTG clearance at each dosage level of VPA. Pharmacodynamic modeling was used to calculate EC 50 values for this interaction. Results: LTG pharmacokinetic parameters were evaluated in adult healthy female & male volunteers. Mean trough VPA concentrations at doses of 125, 250, 375 and 500 mg per day were 6.5, 13.9, 16.1 and 31.9 μg/ml, respectively. Maximal theoretical inhibition of LTG oral clearance by VPA is approximately 65%, with an EC 50 concentration value of approximately 5.6 μg/ml of VPA. Mean inhibition of LTG oral clearance during concomitant treatment with VPA 125, 250, 375 and 500 mg per day was 30.8, 51.5, 52.8 and 50.3%, respectively. Conclusions: These data suggest that VPA inhibition of LTG clearance begins at very low VPA doses and concentrations. Importantly, maximal inhibition can be expected at VPA doses of approximately 500 mg per day, with the magnitude of inhibition diminishing at doses below this. These data provide useful information to develop a dosing algorithm to facilitate conversion to LTG monotherapy.

The 10,11-Epoxide-10,11-diol Pathway of Carbamazepine in Early Pregnancy in Maternal Serum, Urine, and Amniotic Fluid

Epoxide metabolites of carbamazepine (CBZ) have been suggested to play a role in the occurrence of congenital malformations observed in infants exposed to CBZ. We have investigated the 10,11-epoxide-10,11-diol pathway of CBZ in pregnant epileptic patients receiving CBZ alone or in combination with other antiepileptic drugs in relation to the outcome of pregnancy in a prospective manner. The women were referred to our clinic before 16 weeks of gestation for prenatal diagnosis of fetal malformations, including neural tube defects, by ultrasound and amniocentesis. The availability of amniotic fluid samples enabled us to determine to what extent CBZ and its main metabolites reached the amniotic fluid. In 100 pregnancies with first trimester CBZ exposure (including 7 with malformed outcome), parent drug and metabolite concentrations in maternal serum were evaluated. CBZ-10,11-epoxide concentrations increased with increasing dose. Comedication with phenobarbital led to lower 10,11-epoxide concentrations in maternal serum and a higher percentage of the dose recovered in urine as 10,11-diol. Valproate comedication led to slightly higher 10,11-epoxide concentrations in maternal serum, in combination with lower CBZ concentrations and a lower percentage of the dose recovered in the urine as 10,11-diol. In amniotic fluid, concentrations of CBZ and its main metabolites in most patients were 2 to 2.5 times higher than the free concentrations in maternal serum. Metabolites and parent drug concentrations in amniotic fluid correlated with their free concentration in maternal serum, but stronger with each other in amniotic fluid. No significant differences in levels of CBZ and its metabolites were observed between pregnancies with normal and malformed outcome.