I. Kacirova

Therapeutic drug monitoring of atypical antipsychotic drugs.

Abstract Schizophrenia is a severe psychiatric disorder often associated with cognitive impairment and affective, mainly depressive, symptoms. Antipsychotic medication is the primary intervention for stabilization of acute psychotic episodes and prevention of recurrences and relapses in patients with schizophrenia. Typical antipsychotics, the older class of antipsychotic agents, are currently used much less frequently than newer atypical antipsychotics. Therapeutic drug monitoring (TDM) of antipsychotic drugs is the specific method of clinical pharmacology, which involves measurement of drug serum concentrations followed by interpretation and good cooperation with the clinician. TDM is a powerful tool that allows tailor-made treatment for the specific needs of individual patients. It can help in monitoring adherence, dose adjustment, minimizing the risk of toxicity and in cost-effectiveness in the treatment of psychiatric disorders. The review provides complex knowledge indispensable to clinical pharmacologists, pharmacists and clinicians for interpretation of TDM results.

Vancomycin removal during low-flux and high-flux extended daily hemodialysis in critically ill septic patients

AIMS To determine the extent of vancomycin removal and vancomycin pharmacokinetics in septic patients with AKI using daily hemodialysis with polysulphone high-flux and low-flux membrane. METHODS Five patients received 6 h daily dialysis with low-flux polysulphone membrane, four patients with high-flux polysulphone membrane. Vancomycin was administered over the last hour of dialysis. The maintenance dose was adjusted based on pre-hemodialysis serum concentrations. Patients were followed up for two days. RESULTS Median percentage of vancomycin removal by low-flux membrane dialysis was 17% (8-38%) and by high-flux membrane dialysis was 31% (13-43%). Vancomycin clearance was only moderately higher in high-flux membrane dialysis (median 3.01 L/h, range 2.34-3.5 L/h) compared to low-flux dialysis (median 2.48 L/h, range 0.53-5.68 L/h) in the first day of the study. About two-fold higher vancomycin clearance in high-flux dialysis (median 3.62 L/h, range 1.37-5.07 L/h) was observed on the second day of the study than low-flux dialysis (median 1.74 L/h, range 0.75-30.94 L/h). CONCLUSIONS Both high-flux and low-flux membrane dialysis remove considerable amounts of vancomycin in critically ill septic patients with AKI. Application of vancomycin after each dialysis was required to maintain therapeutic concentrations.

Therapeutic monitoring of psychoactive drugs - antidepressants: A review

BACKGROUND Major depression, is one of the most prevalent mental disorders in Europe and the USA. The dramatic rise in pharmacological antidepressants is mainly due to increase in use of selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors and other new generation antidepressants. In clinical practice, optimum individual doses are often guided by trial-and-error. This article reviews the available literature on therapeutic monitoring of antidepressant drugs. METHODS A search using MEDLINE (english-language reports, 1983 - August 2012) with the key words for antidepressant drugs and therapeutic drug monitoring. RESULTS There is a need for monitoring antidepressants due to wide interindividual pharmacokinetic variability. At the same drug dose, a more than 20-fold variation in steady state concentration of drug in the body may result: people differ in their ability to absorb, distribute, metabolise and excrete drugs for reasons of concurrent disease, age, gender, smoking and eating habits, concomitant medication and genetics. CONCLUSIONS Monitoring of antidepressant drugs enables us to individualise drug doses based on rational therapy, minimalise side effects, reduce morbidity and mortality and cut the cost of health care. Phenotyping and genotyping could increase therapeutic drug monitoring furthere.

Serum levels of lamotrigine during delivery in mothers and their infants

PURPOSE We followed up lamotrigine transport through the placenta and analyzed maternal and umibilical cord concentrations, its ratio and maternal lamotrigine clearance in monotherapy and in combinations. METHODS Maternal and umbilical cord concentrations were analyzed during delivery in a cohort of 63 women between 2001 and 2009. The request forms for routine therapeutic drug monitoring were used as the data source. Maternal concentrations were used for the estimation of apparent oral clearance and paired infant and maternal concentrations for estimation of the infant (umibilical cord)/maternal serum concentration ratio. RESULTS The lamotrigine infant/maternal serum concentration ratio ranged in monotherapy from 0.40 to 1.38 (median 0.91). The ratio in monotherapy showed a possible distribution to two subgroups. Concomitant administration of valproic acid significantly increased both maternal and infant lamotrigine concentrations and significantly decreased lamotrigine clearance by about 65%. Co-medication with carbamazepine increased lamotrigine clearance non-significantly. Highly significant correlations were found between maternal and umbilical cord lamotrigine concentrations, both in monotherapy and in the lamotrigine+valproic acid combination. Infant concentrations of valproic acid were found to be about 30% higher and infant concentrations of carbamazepine were found to be about 20% lower than maternal concentrations. CONCLUSIONS Our data from the large cohort showed the interindividual variability of umbilical cord/maternal serum concentration ratio in lamotrigine monotherapy caused probably by the different activity of the placental lamotrigine metabolizing enzymes UGT1A4 and 2B7 associated with genetic polymorphism. The potential teratogenic effect of lamotrigine combination with valproic acid could be associated with the higher lamotrigine and valproic acid concentrations in the fetus.

Gentamicin pharmacokinetics during continuous venovenous hemofiltration in critically ill septic patients

Abstract Objective: Current dosing recommendations for administration of gentamicin to septic patients with acute kidney injury (AKI) on continuous venovenous hemofiltration (CVVH) at a filtration rate of 45 ml/kg/h are missing. Aim: To describe gentamicin pharmacokinetics and to find an optimal dosing regimen in patients on CVVH. Methods: Seven adult patients were included. Patients received loading dose of 240 mg followed by application of maintenance dose every 24 hours. Maintenance dose was adjusted according to gentamicin Cmax/MIC ratio and drug levels simulation using a pharmacokinetic programme. Results: Median total clearance (0·59–0·79 ml/min/kg) was similar to patients with normal renal function; median volume of distribution was higher than observed in non-septic patients (about 0·5 l/kg versus 0·25 l/kg). Patients with diuresis required an increase of gentamicin dose to reach Cmax/MIC ratio. Conclusion: Septic patients with AKI on CVVH (45 ml/kg/h) require a loading dose of 240 mg, followed by therapeutic drug monitoring to optimize maintenance dose.

Vancomycin pharmacokinetics during high-volume continuous venovenous hemofiltration in critically ill septic patients.

AIMS To assess the influence of continuous venovenous hemofiltration (CVVH) at a filtration rate of 45 mL/kg/h on vancomycin pharmacokinetics in critically ill septic patients with acute kidney injury (AKI). METHODS Seventeen adult septic patients with acute kidney injury treated with CVVH and vancomycin were included. All patients received first dose of 1.0 g intravenously followed by 1.0 g/12 h if not adjusted. In sixteen patients vancomycin was introduced on the day of the start of CRRT therapy. Blood samples and ultrafiltrates were obtained before and 0.5, 1, 6 and 12 h after vancomycin administration. RESULTS On the first day, the median total vancomycin clearance (Cltot) was 0.89 mL/min/kg (range 0.31 - 2.16). CRRT clearance accounted for around 50-60% of the total clearance of vancomycin found in a population with normal renal function (0.97 mL/min/kg). Vancomycin serum concentrations after the first dose were below the required target of 10 mg/L as early as 6 h in 10 patients, AUC0-24/MIC ≥ 400 ratio was achieved in 10 patients on the first day. CONCLUSIONS CVVH at a filtration rate of 45 mL/kg/h leads to high and rapid extracorporeal removal of vancomycin in critically ill patients. Due to the rapid change in patient clinical status it was impossible to predict a fixed dosage regimen. We recommend blood sampling as early as 6 h after first vancomycin dose with maintenance dose based on vancomycin serum level monitoring.

Fast simultaneous LC/MS/MS determination of 10 active compounds in human serum for therapeutic drug monitoring in psychiatric medication

A UPLC/MS/MS method with simple protein precipitation has been validated for the fast simultaneous analysis of agomelatine, asenapine, amisulpride, iloperidone, zotepine, melperone, ziprasidone, vilazodone, aripiprazole and its metabolite dehydro-aripiprazole in human serum. Alprenolol was applied as an internal standard. A BEH C18 (2.1 × 50 mm, 1.7 µm) column provided chromatographic separation of analytes using a binary mobile phase gradient (A, 2 mmol/L ammonium acetate, 0.1% formic acid in 5% acetonitrile, v/v/v; B, 2 mmol/L ammonium acetate, 0.1% formic acid in 95% acetonitrile, v/v/v). Mass spectrometric detection was performed in the positive electrospray ionization mode and ion suppression owing to matrix effects was evaluated. The validation criteria were determined: linearity, precision, accuracy, recovery, limit of detection, limit of quantification, reproducibility and matrix effect. The concentration range was as follows: 0.25-1000 ng/mL for agomelatine; 0.25-100 ng/mL for asenapine and iloperidone; 2.5-1000 ng/mL for amisulpride, aripiprazole, vilazodone and zotepine; 2.3-924.6 ng/mL for dehydroaripiprazole; 2.2-878.4 ng/mL for melperone; and 2.2-883.5 ng/mL for ziprasidone. Limits of quantitation below a therapeutic reference range were achieved for all analytes. Intra-run precision of 0.4-5.5 %, inter-run precision of 0.6-8.2% and overall recovery of 87.9-114.1% were obtained. The validated method was successfully implemented into routine practice for therapeutic drug monitoring in our hospital.

Serum levels of valproic acid during delivery in mothers and in umbilical cord - correlation with birth length and weight

AIMS The data on the valproic acid transplacental transfer and risk to the fetus of exposure, remain sparse and only a limited number of studies have reported umbilical cord blood levels. MATERIALS AND METHODS Maternal and umbilical cord serum levels were analyzed at delivery in a cohort of 58 women, between the years 1991 - 2013. The request forms for routine therapeutic drug monitoring were used as the data source. Maternal levels and dosing information were used for estimating the maternal apparent oral clearance and the paired umbilical cord and maternal levels for estimation of umbilical cord/maternal level ratios. RESULTS The levels varied from 5.3 - 59.5 mg/L in maternal and 5.4 - 72.1 mg/L in umbilical cord serum. The umbilical cord/maternal level ratios ranged from 0.64 - 2.49. Significant correlation was found between maternal and umbilical cord levels. Significant inverse correlations were found between birth length, and both maternal and umbilical cord levels in monotherapy. CONCLUSIONS There were large individual variations in umbilical cord/maternal level ratios of valproic acid. Neonatal length and weight were inversely related to maternal and umbilical cord levels, but not to dose. Therefore, therapeutic drug monitoring in mothers is more useful than the given dose for the estimation of fetal exposure and minimization of the risk of fetal effects.

Concentrations of carbamazepine and carbamazepine-10,11-epoxide in maternal and umbilical cord blood at birth: Influence of co-administration of valproic acid or enzyme-inducing antiepileptic drugs

BACKGROUND Carbamazepine is one of the three most frequently prescribed antiepileptic drugs in pregnancy. However, data relating to both carbamazepine and carbamazepine-10,11-epoxide transplacental passage remain sparse. MATERIAL AND METHODS We have analysed in a cohort of 114 women carbamazepine and carbamazepine-10,11-epoxide levels in maternal and umbilical cord serum at birth during 25 years retrospectively. The carbamazepine maternal apparent oral clearance, ratio of the umbilical cord/maternal level and ratio of the carbamazepine-10,11-epoxide/carbamazepine ratio were estimated. The influence of co-medication with valproic acid or enzyme-inducing antiepileptic drugs was evaluated. RESULTS The maternal carbamazepine levels varied from 0.6 to 11.8mg/L (carbamazepine-10,11-epoxide 0.1-2.5mg/L) and in umbilical cord between 0.1 and 10.5mg/L (carbamazepine-10,11-epoxide 0.1-2.2mg/L). The ratio the of umbilical cord/maternal level of carbamazepine ranged from 0.03 to 2.23 (median 0.80) and of carbamazepine-10,11-epoxide between 0.17 and 2.00 (median 0.83). Concomitant administration with enzyme inducers significantly increased the maternal apparent oral clearance by approximately 50% and co-administration with valproic acid approximately by 70%. Combination with valproic acid significantly increased the rate of carbamazepine-10,11-epoxide to the parent drug both in maternal serum (by approximately 80%) and in umbilical cord (by 100%). CONCLUSIONS The data showed the wide interindividual variability of the ratio of the umbilical cord/maternal level of both carbamazepine and carbamazepine-10,11-epoxide. It is the first study showing the significant increase of the ratio of umbilical cord/maternal level of carbamazepine-10,11-epoxide and carbamazepine-10,11-epoxide/carbamazepine ratio not only in maternal serum but also in umbilical cord in addition of valproic acid. The present study demonstrates that a concomitant administration of enzyme-inducing antiepileptics and valproic acid increases the maternal apparent oral clearance of carbamazepine significantly.

Cytochrome P450 2D6 phenotype and genotype in hypertensive patients on long-term therapy with metoprolol.

OBJECTIVE The aim was to compare cytochrome P450 2D6 phenotype and genotype using metoprolol as a probe drug. Further, to investigate the influence of P450 2D6 activity on metoprolol pharmacokinetics and pharmacodynamics in patients on metoprolol therapy. BACKGROUND Cytochrome P450 2D6 is a highly polymorphic enzyme that contributes to the variability of metoprolol. However, environmental factors also modify drug disposition. METHODS Forty-nine hypertensive patients were enrolled. Serum metoprolol and α-hydroxymetoprolol concentrations, resting heart rate were measured before, 1, 3 and 4 hours post-dose. RESULTS Significantly higher normalized metoprolol serum concentrations, normalized metoprolol AUC0-4 and metoprolol oral clearance were observed in patients with lower P450 2D6 metabolic activity. A trend towards a lower resting heart rate before metoprolol intake was also observed in this group of patients. The differences in metoprolol disposition were more expressed when P450 2D6 phenotype instead of genotype was determined. CONCLUSION Significant variations exist in metoprolol disposition in hypertensive patients. Both genotyping and phenotyping provides a valuable method in determining the enzymatic activity and in optimising metoprolol therapy (Tab. 3, Fig. 8, Ref. 35).