Serum teriflunomide concentrations in routine multiple sclerosis therapy: A cross-sectional pilot study.

BACKGROUND: Teriflunomide is administered orally to treat relapsing-remitting multiple sclerosis. In this prospective pilot study, the free and total serum concentrations of teriflunomide obtained during routine health care were measured and their relationship with disease activity was evaluated. METHODS: Eighty-nine patients were included in this study. Blood samples were collected from April 2021 to February 2022, and free and total teriflunomide serum concentrations were measured. Patient assessment involved monitoring of blood counts and potential adverse effects of teriflunomide. RESULTS: In the steady-state group, total teriflunomide concentrations ranged from 14.7 to 144.2 mg/L, while free concentrations from 31.1 to 389.7 µg/L. In the non-steady-state group, the total concentration ranged from 2.2 to 59.3 mg/L, with free concentrations ranging from 6.8 to 143.5 µg/L. In the steady-state group, a significant inverse correlation was found between absolute peripheral blood lymphocyte count and both total and free teriflunomide serum concentrations. CONCLUSION: Although all patients were treated with the same dose, up to a 10-fold difference in total and free teriflunomide serum concentrations, and up to a 5-fold difference in steady-state trough concentrations were observed. This vast interindividual variability can potentially lead to toxicity or, conversely, to suboptimal therapeutic concentrations of teriflunomide, with the risk of further worsening of multiple sclerosis compensation.

Liquid chromatography-tandem mass spectrometry methods for quantification of total and free antibiotic concentrations in serum and exudate from patients with post-sternotomy deep sternal wound infection receiving negative pressure wound therapy.

BACKGROUND: Systemically administered antibiotics are thought to penetrate the wounds more effectively during negative pressure wound therapy (NPWT).To test this hypothesis total and free antibiotic concentrations were quantified in serum and wound exudate. METHODS: UHPLC-MS/MS methods were developed and validated for the determination of ceftazidime, cefepime, cefotaxime, cefuroxime, cefazolin, meropenem, oxacillin, piperacillin with tazobactam, clindamycin, ciprofloxacin, sulfamethoxazole/trimethoprim (cotrimoxazole), gentamicin, vancomycin, and linezolid. The unbound antibiotic fraction was obtained by ultrafiltration using a Millipore Microcon-30kda Centrifugal Filter Unit. Analysis was performed on a 1.7-µm Acquity UPLC BEH C18 2.1 × 100-mm column with a gradient elution. RESULTS: The validation was performed for serum, exudates and free fractions. For all matrices, requirements were met regarding linearity, precision, accuracy, limit of quantitation, and matrix effect. The coefficient of variation was in the range of 1.2-13.6%.and the recovery 87.6-115.6%, respectively. Among the 29 applications of antibiotics thus far, including vancomycin, clindamycin, ciprofloxacin, oxacillin, cefepime, cefotaxime, cotrimoxazole, and gentamicin, total and free antibiotic concentrations in serum and exudate were correlated. CONCLUSION: This method can accurately quantify the total and free concentrations of 16 antibiotics. Comparison of concentration ratios between serum and exudates allows for monitoring individual antibiotics' penetration capacity in patients receiving NPWT.

Therapeutic monitoring of lacosamide, perampanel, and zonisamide during breastfeeding.

OBJECTIVE: To provide additional information on the transport of the new anti-seizure medications lacosamide, perampanel, and zonisamide in breast milk and breastfed infants. METHODS: Between 2013 and 2022, concentrations of anti-seizure medications were measured in six women with epilepsy (each drug in two patients) using high-performance liquid chromatography. Additionally, concentrations were determined after two consecutive pregnancies in women receiving lacosamide and one woman receiving zonisamide. In all cases, anti-seizure medication concentrations were measured in the maternal serum and breast milk, and five cases, in the infant serum. RESULTS: For lacosamide, the ratios of breast milk/maternal serum concentration varied between 0.77 and 0.93, the ratios of infant/maternal serum concentrations were 0.16 and 0.35, and the ratios of infant serum/milk concentrations were 0.21 and 0.38. For perampanel, the ratios of breast milk/maternal serum concentration were 0.01 and 0.10 and the ratio of infant/maternal serum concentration was 0.36. For zonisamide, the ratios of breast milk/maternal serum concentration varied between 0.76 and 1.26, the ratios of infant/maternal serum concentrations between 0.44 and 0.85, and the ratios of infant serum/milk concentrations between 0.55 and 1.05. CONCLUSIONS: Breastfeeding is recommended for women using lacosamide, perampanel, and zonisamide. However, the actual exposure can only be accurately evaluated by determining the serum concentration of anti-seizure medication in breastfed infants.

Liquid chromatography - tandem mass spectrometry method for determination of natalizumab in serum and cerebrospinal fluid of patients with multiple sclerosis.

Natalizumab is a humanized recombinant monoclonal IgG4 antibody used in the treatment of multiple sclerosis. Commonly used methods for natalizumab and anti-natalizumab antibodies quantification are enzyme-linked immunosorbent assay (ELISA) and radioimmunoassay, respectively. Measurement of therapeutic monoclonal antibodies can be challenging due to the resemblance to human plasma immunoglobulins. Recent developments in mass spectrometry enables to analyze vast variety of large protein molecules. The aim of this study was to develop a LC-MS/MS method for determining natalizumab in human serum and cerebrospinal fluid (CSF) and apply it to clinical settings. For successful quantification, it was necessary to find specific sequences of peptides in natalizumab. This immunoglobulin was treated with dithiothreitol and iodoacetamide, cleaved with trypsin into short specific peptides and determined on a UPLC-MS/MS system. An Acquity UPLC BEH C18 column at 55 °C and gradient elution was used for analysis. Intra- and interassay accuracies and precisions were tested at four concentration levels. Precision was determined by coefficients of variation and was in the range of 0.8-10.2 %, with accuracy in the range of 89.8-106.4 %. The concentration of natalizumab in patient samples ranged from 1.8 to 193.3 µg/mL. The method was validated according to the European Medicines Agency (EMA) guideline, met all acceptance criteria for accuracy and precision, and is suitable for clinical applications. In comparison to immunoassay, which can be elevated by cross-reaction with endogenous immunoglobulins, the results of developed LC-MS/MS method are more accurate and specific.

Liquid chromatography-tandem mass spectrometry method for determination of total and free teriflunomide concentration in serum of patients with multiple sclerosis.

Teriflunomide belongs to disease-modifying drugs and is used in treatment of multiple sclerosis. According to in vitro studies more than 99.4 % of drug is binding to plasma proteins and only less than 1 % is free for clinical activity. The rapid and simple ultra-performance liquid chromatography-tandem mass spectrometry method (UPLC-MS/MS) was developed and validated for determination of total and free teriflunomide (TFM) in serum of patients with multiple sclerosis. To determine the total teriflunomide samples were precipitated with a precipitation reagent consisting of 11 % solution of ZnSO4 in acetonitrile/methanol (40:60, v/v). To determine the free fraction of teriflunomide, an ultracentrifugation method was used. The analysis was performed on a UPLC system connected to a XEVO TQ-XS mass spectrometer. Chromatographic separation was carried out on an Acquity UPLC BEH C18 1.7 µm (100 × 2.1 mm) column heated to 30 °C and teriflunomide-D4 was used as an internal standard. Ionization was performed by electrospray in negative ion mode. The developed methods were validated according to the rules of the European Medicines Agency (EMA) for the analytical method validation of bioanalytical methods. The coefficients of variation were in the range of 0.53-14.84 % and the recovery 97.92-108.33 %, respectively. Share of free teriflunomide was 0.15-0.40 % (mean 0.25 ± 0.05 %) of total teriflunomide and there was a significant correlation between free and total teriflunomide r2 = 0.9083 (p < 0.0001). This newly developed method allows the rapid and easy determination of the teriflunomide concentration with high sensitivity and can be applied to clinical samples of patients with multiple sclerosis.

Therapeutic monitoring of serum concentrations of acyclovir and its metabolite 9-(carboxymethoxymethyl) guanine in routine clinical practice.

OBJECTIVE: To obtain information on the serum concentrations of acyclovir and its metabolite in routine health care with respect to the renal function. METHODS: This prospective study analyzed data from 27 patients receiving acyclovir intravenously between June 2019 and October 2021. Patients were divided into two subgroups according to the estimated glomerular filtration rate. Serum concentrations of acyclovir and its metabolite 9-(carboxymethoxymethyl) guanine were mainly analyzed on day 5 after the initiation of treatment before the morning dose (trough concentration) and 30 min after the end of the infusion (peak concentration). RESULTS: Trough acyclovir concentrations ranged from 0.8 to 7.6 mg/L and peak concentrations from 6.3 to 25.7 mg/L, and trough metabolite concentrations ranged from 0.12 to 2.30 mg/L and peak concentrations from 0.47 to 2.70 mg/L, respectively. The ratio of trough metabolite and acyclovir concentrations ranged from 0.07 to 0.63 and the ratio of peak concentrations from 0.03 to 0.24. Patients in the subgroup with reduced renal function were significantly older, smaller, and of lower body weight and received significantly lower doses of acyclovir. CONCLUSIONS: A 10-fold difference in the weight-adjusted apparent clearance of acyclovir was observed between patients. This wide interindividual variability in acyclovir pharmacokinetics can lead not only to toxicity but also to suboptimal acyclovir concentrations in severe infections. Therefore, therapeutic monitoring of serum concentrations of acyclovir and its metabolite may be important for optimizing pharmacotherapy, especially in patients with severe clinical conditions.

Comparison of Mw\Pharm 3.30 and Mw\Pharm ++ (Windows version) software for PK/PD monitoring of vancomycin: A priori modeling.

OBJECTIVE: To evaluate the possibility of population-based dose optimization with the aid of MwPharm modeling and to find the best model in the Windows version (WIN). MATERIALS: 25 patients repeatedly examined for vancomycin (mean age 63 ± 14 years, body weight 88 ± 21 kg, median dose 1 g/12 h). METHODS: Trough concentrations predicted by WIN models "vancomycin_adult_k_C2", "#vancomycin_adult_C2", "vancomycin_adult_C2", and "vancomycin adult" DOS model (DOS) were compared with the measured value. STATISTICS: The percentage prediction error (%PE) calculated as (predicted - measured)/measured values, Blandt-Altman plot, root mean square error (RMSE), Pearson's coefficient of rank correlation (R). Data is presented as mean ± SD. Student's t-test was used for prediction precision evaluation. RESULTS: The %PE varied from +44.4 ± 65.2% to +76.5 ± 84.3%, p < 0.001. "#vancomycin_adult_C2" model produced the lowest %PE among WIN models as well as the lowest RMSE (79) and Blandt-Altman bias (-4.01 ± 7.59), but the Pearson's correlation (0.6843, p = 0.0002) was less tight. DOS model produced the second lowest RMSE (81), %PE (+45.9 ± 66.6%), and Blandt-Altman bias (-4.83 ± 6.97) and highest Pearson's R (0.7847, p < 0.0001). "vancomycin_adult_C2" produced the third best prediction: RMSE (113), %PE (62.8 ± 92.6%), Blandt-Altman bias (-6.78 ± 11.2) but Pearson's R was the poorest (0.5773, p = 0.0025). CONCLUSION: The lowest %PE and highest Pearson's R were achieved by the "#vancomycin_adult_C2" model. Due to the poor predictive performance of all MwPharm versions and models, we find all of them unsuitable for a priori vancomycin dosing management. Other software should be evaluated for routine use.

Carbamazepine and carbamazepine-epoxide concentrations in mothers, colostrum, and breastfed newborns: Comparison with concentrations determined during delivery and in the mature milk period.

OBJECTIVE: To obtain information on the transport of carbamazepine and its active metabolite carbamazepine-epoxide from mother to colostrum and breastfed newborns. METHODS: In this cohort study, carbamazepine and carbamazepine-epoxide concentrations in maternal serum (162 women), milk (i.e., colostrum) and breastfed newborn serum were analysed between the 1st and 5th days after delivery from November 1990 to February 2021. The measured concentrations were compared with the delivery and mature milk periods. The effect of the combination with both enzyme-inducing antiseizure medication and valproic acid was also evaluated. RESULTS: Carbamazepine concentrations varied from 1.0 to 11.2 mg/L (epoxide 0.3-4.4 mg/L) in maternal serum, from 0.5 to 6.8 mg/L (epoxide 0.3-2.4 mg/L) in milk and from 0.5 to 4.7 mg/L (epoxide 0.3-1.7 mg/L) in newborn serum. The median milk/maternal serum concentration ratio of carbamazepine was 0.45 (epoxide 0.71), the median newborn/maternal serum concentration ratio of carbamazepine was 0.20 (epoxide 0.41), and the median newborn serum/milk concentration ratio of carbamazepine was 0.38 (epoxide 0.50). A highly significant correlation was found between the milk and maternal serum concentrations of both carbamazepine and carbamazepine-epoxide and between the milk and newborn serum concentrations of carbamazepine. CONCLUSIONS: In the serum of breastfed newborns, only one concentration of carbamazepine reached the reference range used for the general epileptic population, and more than half was below the lower limit of quantification. Routine monitoring of serum carbamazepine concentrations is not required in breastfed newborns. However, observation of newborns is desirable, and if signs of potential adverse reactions are noted, the serum concentrations in newborns should be measured.

Monitoring of lamotrigine concentrations in mothers, colostrum, and breastfed newborns during the early postpartum period.

OBJECTIVE: To analyse the concentrations of lamotrigine in maternal serum, colostrum, and serum of breastfed newborns, and to evaluate the effect of comedication with enzyme-inducing antiseizure medication and valproic acid. METHODS: This cohort study collected data from 158 women and 143 breastfed newborns. Maternal serum, milk (i.e., colostrum), and newborn serum samples were collected between the 2nd and 5th postnatal days, and lamotrigine concentrations were measured by high-performance liquid chromatography. RESULTS: The median lamotrigine concentrations were 2.7 mg/L in maternal serum, 1.4 mg/L in milk, and 1.7 mg/L in newborn serum. The median milk/maternal serum concentration ratio was 0.60, the median newborn/maternal serum concentration ratio was also 0.60, and the median newborn serum/milk concentration ratio was 1.00. A significant correlation was observed between milk and maternal serum concentrations and between newborn serum and milk concentrations, maternal serum concentrations, maternal daily dose, and dose related to maternal body weight. CONCLUSIONS: Exposure to lamotrigine in breastfed newborns is lower than exposure during pregnancy. However, by the same dose by the same mother, lamotrigine concentrations in both maternal serum and milk increase significantly after delivery. This finding, together with the immature function of eliminating enzymes in newborns, may be the reason for reaching concentrations in the reference range used for the general epileptic population in breastfed newborns. Therapeutic monitoring of breastfed newborns serum concentrations of lamotrigine is not mandatory; however, if signs of possible adverse events are noted, newborn serum concentrations should be analysed.

Expression and 7-day time course of circulating microRNAs in septic patients treated with nephrotoxic antibiotic agents.

BACKGROUND: Through regulation of signaling pathways, microRNAs (miRNAs) can be involved in sepsis and associated organ dysfunction. The aims of this study were to track the 7-day time course of blood miRNAs in patients with sepsis treated with vancomycin, gentamicin, or a non-nephrotoxic antibiotic and miRNA associations with neutrophil gelatinase-associated lipokalin (NGAL), creatinine, procalcitonin, interleukin-6, and acute kidney injury (AKI) stage. METHODS: Of 46 adult patients, 7 were on vancomycin, 20 on gentamicin, and 19 on another antibiotic. Blood samples were collected on days 1, 4, and 7 of treatment, and miRNAs were identified using quantitative reverse transcription PCR. RESULTS: The results showed no relationship between miRNA levels and biochemical variables on day 1. By day 7 of gentamicin treatment miR-15a-5p provided good discrimination between AKI and non-AKI (area under curve, 0.828). In patients taking vancomycin, miR-155-5p and miR-192-5p positively correlated with creatinine and NGAL values, and miR-192-5p and miR-423-5p positively correlated with procalcitonin and interleukin-6 in patients treated with a non-nephrotoxic antibiotic. In patients together we found positive correlation between miR-155-5p and miR-423-5p and all biochemical markers. CONCLUSION: The results suggest that these four miRNAs may serve as diagnostic or therapeutic tool in sepsis, renal injury and nephrotoxic treatment. TRIAL REGISTRATION: ClinicalTrials.gov , ID: NCT04991376 . Registered on 27 July 2021.

Therapeutic drug monitoring guided fluconazole therapy in a patient with cholangitis sepsis.

Candida and other fungal species play an increasing role in nosocomial infections, including cholangitis and cholangiosepsis. Early diagnosis and prompt treatment are essential in successful patient outcomes. Fluconazole is an antifungal of choice in fluconazole-sensitive Candida infections. Little information is known about the fluconazole biliary excretion. Decreased tissue penetration may be one of the possible causes of treatment failure. Due to favorable pharmacokinetics, therapeutic drug monitoring of this antifungal has not been recommended routinely. In the presented case we report the successful therapeutic drug monitoring-guided fluconazole treatment in a patient with cholangitis and cholangiosepsis caused by fluconazole-sensitive Candida spp.

Lay abstract A successful fluconazole treatment of Candida cholangitis based on therapeutic drug monitoring, is described in our case study. Unlike other azole antimycotic agents, fluconazole is not considered a desirable candidate for therapeutic drug monitoring. However, as shown in our case study, a fixed dosage regimen might not lead to adequate fluconazole exposure in every patient and a personalized dosing regimen might be useful in the achievement of adequate fluconazole exposure and the successful treatment of Candida infection.

Comparison of Mw\Pharm 3.30 and Mw\Pharm ++, a Windows version of pharmacokinetic software for PK/PD monitoring of vancomycin. Part 1: A-posteriori modelling.

BACKGROUND AND OBJECTIVES: For a long time, the Mw\Pharm software suite (MEDI\WARE, Prague, Czech Republic/ Groningen, Netherlands) has been used for PK/PD modelling in therapeutic drug monitoring (TDM). The aim of this study was to find the best model in the newer Windows Mw\Pharm++ 1.3.5.558 version (WIN). METHODS: 25 patients were repeatedly examined for vancomycin (mean age 63±14 years, body weight 88±21 kg, median dose 1 g/12 h). Trough concentrations predicted a-posteriori by WIN models "vancomycin_adult_k_C2", "#vancomycin_adult_C2", "vancomycin_adult_C2" were compared with the measured value and "vancomycin adult" DOS 3.30 model (DOS). STATISTICS: Percentage prediction error (%PE) calculated as (predicted-measured)/measured values, or WIN-DOS/DOS - data presented as mean±SD, RMSE, Blandt-Altman plot - data presented as bias±SD (95% limits of agreement), Pearson's coefficient of rank correlation (R), Student's t-test. Statistical analysis was performed using GraphPad Prism version 5.00 for Windows. RESULTS: The mean%PE in vancomycin predicted values varied from -4.5% ± 33.6 to -8.2% ± 39.3. The%PE between WIN and DOS models varied from -0.2% ± 24.5% to 4.4 ± 21.4%. Model "vancomycin_adult_C2" was closest both to measured vancomycin trough concentration and DOS model:%PE -4.5 ± 33.6% vs +4.2 ± 20.3%, RMSE 33.7 vs 20.6, Blandt-Altman bias +2.19 ± 6.17 (-9.9 - 14.3) vs -0.29 ± 3.25 (-6.7 - 6.1), resp. "#vancomycin_adult_C2" model produced largest%PE (-8.2%), RMSE (40.0) as well as Blandt-Altman bias +2.82 ± 6.76 (-10.4 - 16.1). The Pearson's R of predicted and measured vancomycin concentration, and of values predicted by WIN and DOS models, varied from 0.5135 to 0.5854, P<0.0001 and from 0.7869 to 0.8462, P<0.0001, resp. CONCLUSIONS: Three Windows vancomycin models and one DOS model in the Mw\Pharm software were compared. The best outcomes, i.e. lowest%PE, RMSE and highest Pearson's R, were reached with "vancomycin_adult_C2" model.

Was it necessary to change the therapeutic range of topiramate?

AIMS: The Norwegian Association for Clinical Pharmacology in their National Guidelines decreased the therapeutic range (TR) of topiramate (TPM) from 5-20 mg/L to 2-10 mg/L. The objective of this study is to ascertain which TR produces better clinical outcomes. METHODS: The data sources were request forms for routine therapeutic drug monitoring (TDM) of TPM. Concentration dependent adverse drug reactions (ADRs) were evaluated in 1721 samples taken pre-dose. Seizure frequency analysis was performed in 294 samples of monotherapy. Statistical analysis was performed using Prism 5.0, GraphPad Instatt: One-way ANOVA with Bonferroni correction for median plasma level (PL) and χ2 -test with Bonferroni correction for seizure frequency and for distribution of PL according to TR 5-20 mg/L and intervals <2, 2-5, 5-10, 10-20, >20 mg/L. RESULTS: Better seizure control was found in children both in the whole cohort (without seizure 49% vs 37% adults), as well as in monotherapy (56% vs 44%), in children with PL 5-20 mg/L vs <5 mg/L (65% vs 44%) and in children with PL 5-10 mg/L vs <2 mg/L (63 vs 14%). PL in seizure-free patients did not differ from those with seizure. Seizure control was poorer in the period 2003-2005 compared to 2006-2011. ADRs reported in 38 samples (2.8%) were not related to PL. CONCLUSIONS: Change of TR is not recommended.

Valproic Acid Concentrations in Mothers, Colostrum and Breastfed Infants during the Early Postpartum Period: Comparison with Concentrations Determined during Delivery and in the Mature Milk Period.

To obtain information on the transport of valproic acid from mothers to colostrum and breastfed infants, in this cohort study, valproic acid concentrations in maternal serum (90 subjects), colostrum and the serum of breastfed infants were analyzed in years 1993-2018, between the 2nd and 5th postnatal days. Valproic acid concentrations ranged from 4.3 to 66.5 mg/L (mean 31.2 ± 13.6 mg/L) in maternal serum, from 0.5 to 5.9 mg/L (mean 1.1 ± 1.2 mg/L) in milk, and from 0.5 to 42.9 mg/L (mean 15.4 ± 9.4 mg/L) in infant serum. The milk/maternal serum concentration ratio ranged from 0.01 to 0.22 (mean 0.04 ± 0.04), and the infant/maternal serum concentration ratio ranged from 0.01 to 1.61 (mean 0.51 ± 0.28). A significant correlation was found between serum concentrations of breastfed infants and milk concentrations, maternal serum concentrations, maternal daily dose, and dose related to maternal body weight. Valproic acid concentrations in milk and infant serum did not reach the lower limit of the reference range used for the general epileptic population, and three-quarters of the concentrations in milk were lower than the lower limit of quantification. Routine monitoring of serum concentrations of breastfed infants is not necessary. If signs of potential adverse reactions are noted, serum concentrations of the infants should be measured.

Liquid chromatography-tandem mass spectrometry method for quantification of gentamicin and its individual congeners in serum and comparison results with two immunoanalytical methods (fluorescence polarization immunoassay and chemiluminiscent microparticle immunoassay).

BACKGROUND: Total gentamicin is a sum of five congeners C1, C1a, C2, C2a and minor C2b, which differ from each other in their methylation on the purpurosamine ring. Liquid chromatography with mass detection (LC-MS/MS) and specified calibration material enables the concentration of total gentamicin and its individual congeners to be analysed. METHODS: 50 µL serum was precipitated with acetonitrile in the presence of 0.5 mol/L formic acid. A RP BEH C18 1.7 µm 2.1x50 mm column maintained at 30 °C and tobramicin as the internal standard were used. Mass detection was performed in positive electrospray. The gentamicin results were compared with fluorescence polarization immunoassay (FPIA) and chemiluminiscent microparticle immunoassay (CMIA). Passing-Bablock regression analysis and Bland-Altman analysis were used. RESULTS: Calibration curves for individual gentamicin congeners were linear with correlation coefficients between 0.997 and 0.998. Recovery was 91.6-102.0% and the coefficients of variation 1.4-8.4%. The total gentamicin concentration was compared with immunoassay FPIA (LC-MSgen = 0.9798xPFIAgen) and CMIA (LC MSgen = 0.9835xCMIAgen) both with significant correlation (p < 0.001). CONCLUSION: The LC-MS/MS method is fast and precise and can be applied to routine TDM in patients. Comparing it to immunoassays makes it possible to measure concentration of gentamicin congeners, which may be important in the case of their different pharmacokinetics.

Determination of acyclovir and its metabolite 9-carboxymethoxymethylguanide in human serum by ultra-high-performance liquid chromatography-tandem mass spectrometry.

A simple and rapid ultra-high-performance liquid chromatography coupled with mass spectrometry method was developed for acyclovir and its metabolite 9-carboxymethoxymethylguanine in human serum. After precipitation of serum samples with 0.1% formic acid in acetonitrile/methanol (40:60, v/v), components were separated on a Luna Omega C18 column (1.6 µm; 2.1 × 150 mm) at 40°C. Mobile phase A (2 mmol/L ammonium acetate, 0.1% formic acid in 5% acetonitrile, v/v/v) and mobile phase B (2 mmol/L ammonium acetate, 0.1% formic acid in 95% acetonitrile, v/v/v) were used for gradient elution. A linear calibration curve was obtained over the range of 0.05-50 mg/L, and the correlation coefficients were better than 0.999. The limit of quantitation was 0.05 mg/L for both analytes. The intra- and interday accuracy and precision at three concentration levels ranged between 1.6 and 13.3%, and recoveries were achieved with a range between 92.2 and 114.2%. This method was developed and validated for the therapeutic monitoring of acyclovir in patients.

Therapeutic monitoring of amiodarone and desethylamiodarone after surgical ablation of atrial fibrillation-evaluation of the relationship between clinical effect and the serum concentration.

BACKGROUND: Association between clinical effect and serum concentration of amiodarone (AMI) and its active metabolite desethylamidarone (DEA) in patients after surgical ablation (SA) of atrial fibrillation (AF) has not yet been studied. AIMS: We wanted to find a correlation between AMI and DEA serum concentration and maintaining sinus rhythm (SR) after SA of AF. METHODS: Sixty eight patients with AF who had undergone surgical ablation between 2014 and 2017 were included in a single-centre, prospective, observational study. Maintaining of SR was evaluated by standard 12-lead ECG and 24-hour Holter ECG monitoring at months 1, 3, 6 and 12 following surgery. Therapeutic monitoring of AMI and DEA concentrations was done to optimize therapy and adverse effects were followed up. RESULTS: We have noticed a high success rate in maintaining of SR (overall 83%). The median of serum concentration of AMI was 0.81 mg/L (range 0.16-2.35 mg/L) and DEA 0.70 mg/l (range 0.19-2.63 mg/L). No significant differences were found in the serum concentratration of AMI, DEA or DEA/AMI concentratration ratios between patients with SR and persistent supraventricular tachyarrhythmia except on the second outpatient visit. We observed significant correlation between serum concentration of DEA and thyroid-stimulating hormone elevation. CONCLUSION: We confirmed the efficacy of AMI and DEA at the measured serum concentrations. However, analysis of these concentrations alone cannot replace assessment of the clinical response for treatment. Establishment of individual AMI (and DEA) concentrations at which the optimal therapeutic response is achieved seems to be advantageous. Therapeutic monitoring of AMI and DEA is helpful in personalised pharmacotherapy after SA of AF.

Umbilical Cord, Maternal Milk, and Breastfed Infant Levetiracetam Concentrations Monitoring at Delivery and during Early Postpartum Period.

(1) To obtain objective information about levetiracetam transplacental passage and its transport into colostrum, mature milk, and breastfed infants, we analyzed data from women treated for epilepsy between October 2006 and January 2021; (2) in this cohort study, maternal, umbilical cord, milk, and infant serum concentrations were measured at delivery, 2-4 days postpartum (colostrum) and 7-31 days postpartum (mature milk). Paired umbilical cord serum, maternal serum, breastfed infant serum, and milk concentrations were used to assess the ratios of umbilical cord/maternal serum, milk/maternal serum, and infant/maternal serum concentrations. The influence of combined treatment with enzyme-inducing antiseizure medication carbamazepine was assessed; (3) the umbilical cord/maternal serum concentration ratio ranged between 0.75 and 1.78 (mean 1.10 ± 0.33), paired maternal and umbilical cord serum concentrations were not significantly different, and a highly significant correlation was found between both concentrations. The mean milk/maternal serum concentration ratio was 1.14 ± 0.27 (2-4 days postpartum) and 1.04 ± 0.24 (7-31 days postpartum) while the mean infant/maternal serum concentration ratio was markedly lower (0.19 ± 0.13 and 0.14 ± 0.05, respectively); (4) levetiracetam was found in the umbilical cord at a concentration similar to those in maternal serum. All of the breastfed infant serum concentrations were below the reference range used for the general epileptic population.

Plasma Levels of Long-Acting Injectable Antipsychotics in Outpatient Care: A Retrospective Analysis.

PURPOSE: Antipsychotic efficacy in schizophrenia depends on its availability in the body. Although therapeutic outcomes remain still far from satisfactory, therapeutic drug monitoring is not a common part of clinical practice during treatment with long-acting injectable antipsychotics (LAI AP). The real effectiveness of LAI AP is thus uncertain. PATIENTS AND METHODS: We made a retrospective evaluation of plasma levels of LAI AP. Collection of blood samples was performed just before the drug application and one week later. Forty patients with a stabilized clinical condition and steady-state plasma levels were included. RESULTS: In the observed cohort of patients, flupentixol decanoate (n = 23) was the most often used drug, followed by fluphenazine decanoate (n = 7), haloperidol decanoate (n = 5), paliperidone palmitate (n = 3), and risperidone microspheres (n = 2). Just 5 of 40 patients were treated with a monotherapy. In the period before the application, 60% of the patients did not reach the therapeutic reference range (TRR) and 20% of the patients had an undetectable plasma level. At the time of collection of the second blood samples performed after 7 days, 24% of the patients were under the TRR. CONCLUSION: We have found a surprisingly high incidence of plasma levels under the TRR in patients treated with LAI AP. Notwithstanding individual variability in pharmacokinetics, it seems that LAI AP may be underdosed in usual clinical practice.

Monitoring topiramate concentrations at delivery and during lactation.

OBJECTIVE: To determine transplacental passage of topiramate and its transport to colostrum, mature maternal milk and breastfed infants, we examined data from 27 women treated with topiramate from 2004 to 2020. METHODS: In this cohort study, maternal serum, umbilical cord serum, milk and infant serum levels were measured by gas chromatography in the delivery subgroup, the colostrum subgroup (3-4 days postpartum) and the mature milk subgroup (7-30 days postpartum). Paired umbilical cord serum, maternal serum, breastfed infant serum, and milk levels were used to assess the ratios of umbilical cord/maternal serum, milk/maternal serum and infant/maternal serum levels. RESULTS: Topiramate levels varied from 1.0 to 7.1 mg/L in maternal serum and from 0.8 to 6.2 mg/L in umbilical cord serum, and the mean umbilical cord/maternal serum ratio was 0.93 ± 0.11. At 3-4 days after delivery, topiramate concentrations were 1.4-8.4 mg/L in maternal serum, 1.5-8.6 mg/L in milk and 0.3-4.4 mg/L in infant serum. The mean milk/maternal serum ratio was 0.99 ± 0.45, and the mean infant/maternal serum ratio was 0.25 ± 0.15. At 7-30 days after delivery, maternal serum levels varied from 1.9 to 9.7 mg/L, milk levels ranged from 2.3 to 10.6 mg/L and infant serum levels ranged from 0.3 to 6.5 mg/L. The mean milk/maternal serum ratio was 1.07 ± 0.31, and the mean infant/maternal serum ratio was 0.51 ± 0.27. CONCLUSIONS: We extended information about free transplacental passage of topiramate and its extensive transport to maternal milk with lower serum concentrations in breastfed infants in the largest group of patients ever reported to our knowledge. DATA AVAILABILITY STATEMENT: Authors declare that take full responsibility for the data, the analyses and interpretation, and the conduct of the research; that they have full access to all of the data; and that they have the right to publish all data. Authors were not participations in industry-sponsored research and corporate activities for evaluation of a manuscript.