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1.	Bengtsson, Finn (författare) Therapeutic drug monitoring of psychotropic drugs - TDM "Nouveau" 2004 Ingår i: Therapeutic Drug Monitoring. - 0163-4356 .- 1536-3694. ; 26:2, s. 145-151 Tidskriftsartikel (refereegranskat)abstract TDM applied in psychiatry dates back several decades. The reason for this is that, after the advent of modem clinical psychopharmacology around the middle of the past century, an insight came to common knowledge about the existence of (1) a large inter-individual pharmacokinetic (PK) variability for virtually all psychoactive drugs and (2) a worse clinical efficacy not only in inadequate drug concentrations but also in excessively high concentrations. From this concept, the definition of a therapeutic concentration "window" was evidenced for a substantial number of, primarily, antidepressant drugs. However, with the further extensive development of the clinically available pharmacopoeia of psychoactive drugs from the later 1980s until today, the concept of less toxic compounds than before has commonly been launched in the marketing strategies for these newer drugs. This concept also led to the idea that TDM was no longer necessary for the newer types of psychoactive drugs, a position backed up by difficulties in unraveling concentration-effect relationships generally for these drugs in clinical trials. The present survey summarizes the background history for TDM in psychiatry and makes a critical appraisal of why a "lack" of definition of concentration-effect relationships for newer psychoactive drugs is now common. This survey also provides the reader with a novel concept challenging ambient TDM strategies (referred to as TDM "traditionelle") in psychiatry by forwarding a theoretical model called TDM "nouveau." In this model both inter- and intraindividual (over time) PK variation is suggested to be used for dose optimization by TDM in a naturalistic clinical setting. The previous concept of a simple, common concentration "window" existing for all such drugs is questioned by promotion of the use of available PK data merely as "guiding principles" rather than as "reference values" when interpreting the TDM outcome in individual cases.
2.	Blessborn, Daniel, et al. (författare) Determination of pyronaridine in whole blood by automated solid-phase extraction and high-performance liquid chromatography 2003 Ingår i: Therapeutic Drug Monitoring. - : Ovid Technologies (Wolters Kluwer Health). - 0163-4356 .- 1536-3694. ; 25:3, s. 264-270 Tidskriftsartikel (refereegranskat)abstract A new extraction procedure for the analysis of pyronaridine in whole blood is presented. A weak cation exchanger with a carboxylic acid (CBA) sorbent was found to be a suitable solid phase sorbent for the extraction of pyronaridine. High-performance liquid chromatography with UV detection at 278 nm and an electrochemical detector at +0.75 V is used. The electrochemical detector gives higher selectivity than the UV detector. The separation was performed using a C18 reversed phase column with mobile phase of acetonitrile-phosphate buffer (0.01 mol/L, pH 2.5)- sodium perchlorate (1.0 mol/L; 22:77:1, v/v/v). The within-day RSDs were below 5% at all concentration levels between 75 nmol/L and 1500 nmol/L, and the between-day RSDs were below 14% at all concentration levels. The limit of quantification was about 50 nmol/L in 1000 microL whole blood with an RSD of 20% or less on a day-to-day basis. The stability of pyronaridine is increased if the pH is less than 3 in water solutions. In whole blood, the concentration decreases by about 10% for each freeze-thaw cycle performed. At room temperature (about 22 degrees C), pyronaridine concentration in whole blood decreases by about 10% within 12 to 24 hours.
3.	Capiau, Sara, et al. (författare) Official International Association for Therapeutic Drug Monitoring and Toxicology guideline : Development and Validation of Dried Blood Spot-based Methods for Therapeutic Drug Monitoring 2019 Ingår i: Therapeutic Drug Monitoring. - 0163-4356 .- 1536-3694. ; 41:4, s. 409-430 Tidskriftsartikel (refereegranskat)abstract Dried blood spot (DBS) analysis has been introduced more and more into clinical practice to facilitate Therapeutic Drug Monitoring (TDM). To assure the quality of bioanalytical methods, the design, development and validation needs to fit the intended use. Current validation requirements, described in guidelines for traditional matrices (blood, plasma, serum), do not cover all necessary aspects of method development, analytical- and clinical validation of DBS assays for TDM. Therefore, this guideline provides parameters required for the validation of quantitative determination of small molecule drugs in DBS using chromatographic methods, and to provide advice on how these can be assessed. In addition, guidance is given on the application of validated methods in a routine context. First, considerations for the method development stage are described covering sample collection procedure, type of filter paper and punch size, sample volume, drying and storage, internal standard incorporation, type of blood used, sample preparation and prevalidation. Second, common parameters regarding analytical validation are described in context of DBS analysis with the addition of DBS-specific parameters, such as volume-, volcano-and hematocrit effects. Third, clinical validation studies are described, including number of clinical samples and patients, comparison of DBS with venous blood, statistical methods and interpretation, spot quality, sampling procedure, duplicates, outliers, automated analysis methods and quality control programs. Lastly, cross-validation is discussed, covering changes made to existing sampling- and analysis methods. This guideline of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology on the development, validation and evaluation of DBS-based methods for the purpose of TDM aims to contribute to high-quality micro sampling methods used in clinical practice.
4.	Delattre, Isabelle K., et al. (författare) Population Pharmacokinetic Modeling and Optimal Sampling Strategy for Bayesian Estimation of Amikacin Exposure in Critically Ill Septic Patients 2010 Ingår i: Therapeutic Drug Monitoring. - 0163-4356 .- 1536-3694. ; 32:6, s. 749-756 Tidskriftsartikel (refereegranskat)abstract Because the sepsis-induced pharmacokinetic (PK) modifications need to be considered in aminoglycoside dosing, the present study aimed to develop a population PK model for amikacin (AMK) in severe sepsis and to subsequently propose an optimal sampling strategy suitable for Bayesian estimation of the drug PK parameters. Concentration-time profiles for AMK were obtained from 88 critically ill septic patients during the first 24 hours of antibiotic treatment. The population PK model was developed using a nonlinear mixed effects modeling approach. Covariate analysis included demographic data, pathophysiological characteristics, and comedication. Optimal sampling times were selected based on a robust Bayesian design criterion. Taking into account clinical constraints, a two-point sampling approach was investigated. A two-compartment model with first-order elimination best fitted the AMK concentrations. Population PK estimates were 19.2 and 9.34 L for the central and peripheral volume of distribution and 4.31 and 2.21 L/h for the intercompartmental and total body clearance. Creatinine clearance estimated using the Cockcroft-Gault equation was retained in the final model. The two optimal sampling times were 1 hour and 6 hours after onset of the drug infusion. Predictive performance of individual Bayes estimates computed using the proposed optimal sampling strategy was reported: mean prediction errors were less than 5% and root mean square errors were less than 30%. The present study confirmed the significant influence of the creatinine clearance on the PK disposition of AMK during the first hours of treatment in critically ill septic patients. Based on the population estimates, an optimal sampling strategy suitable for Bayesian estimation of the drug PK parameters was developed, meeting the need of clinical practice.
5.	Dolores Cherma Yeste, Maria, et al. (författare) Therapeutic Drug Monitoring of Ziprasidone in a Clinical Treatment Setting 2008 Ingår i: Therapeutic Drug Monitoring. - 0163-4356 .- 1536-3694. ; 30:6, s. 682-688 Tidskriftsartikel (refereegranskat)abstract There is limited information on the pharmacokinetics of ziprasidone (ZIP) in naturalistic clinical settings. The objective of this study was to investigate the concentrations of ZIP and its active metabolite S-methyl-dihydroziprasidone (SMDZ), and the dose-normalized concentrations, using routine therapeutic drug monitoring (TDM) data. A high-performance liquid chromatographic method for determining serum concentrations of these substances for routine clinical use was established at the TDM Laboratory in Linkoping, Sweden. This analytical service was available to all physicians in Sweden. Between January 2001 and December 2004, 545 analyses, representing samples from 370 patients, were performed. The median daily ZIP dose was 120 mg (range 20-320 mg). In all, 121 steady-state trough specimens with essential clinical information were included in the pharmacokinetic evaluation. The median (25th to 75th percentile) serum concentration of ZIP was 125 nmol/L (82-188 nmol/L). The SMDZ:ZIP ratio decreased with increasing serum concentration of ZIP. The median (25th to 75th percentile) dose-normalized concentrations (nmol L-1 mg(-1) d(-1)) for ZIP and SMDZ were 1.13 (0.74-1.77) and 0.62 (0.45-0.86), respectively, with SMDZ:ZIP ratio of 0.57 (0.42-0.79). The overall coefficients of variation for close-normalized scruin concentrations of ZIP, SMDZ, and SMDZ:ZIP ratio were 62%, 56%, and 57%, respectively (n = 121). Smoking women had lower normalized ZIP concentrations than nonsmoking women. Twenty-eight patients with repeated eligible TDM analyses were studied for intraindividual variance over time. In summary, great interindividual and intraindividual differences in ZIP concentrations were observed. TDM of ZIP maybe used for individual dose adjustments and monitoring medication adherence.
6.	El-Khateeb, Eman, et al. (författare) Using Prior Knowledge on Systems Through PBPK to Gain Further Insight into Routine Clinical Data on Trough Concentrations: The Case of Tacrolimus in Chronic Kidney Disease 2023 Ingår i: Therapeutic Drug Monitoring. - : Ovid Technologies (Wolters Kluwer Health). - 0163-4356 .- 1536-3694. ; 45:6, s. 743-753 Tidskriftsartikel (refereegranskat)abstract Background: Routine therapeutic drug monitoring (TDM) relies heavily on measuring trough drug concentrations. Trough concentrations are affected not only by drug bioavailability and clearance, but also by various patient and disease factors and the volume of distribution. This often makes interpreting differences in drug exposure from trough data challenging. This study aimed to combine the advantages of top-down analysis of therapeutic drug monitoring data with bottom-up physiologically-based pharmacokinetic (PBPK) modeling to investigate the effect of declining renal function in chronic kidney disease (CKD) on the nonrenal intrinsic metabolic clearance (CLint) of tacrolimus as a case example.Methods: Data on biochemistry, demographics, and kidney function, along with 1167 tacrolimus trough concentrations for 40 renal transplant patients, were collected from the Salford Royal Hospital's database. A reduced PBPK model was developed to estimate CLint for each patient. Personalized unbound fractions, blood-to-plasma ratios, and drug affinities for various tissues were used as priors to estimate the apparent volume of distribution. Kidney function based on the estimated glomerular filtration rate (eGFR) was assessed as a covariate for CLint using the stochastic approximation of expectation and maximization method.Results: At baseline, the median (interquartile range) eGFR was 45 (34.5-55.5) mL/min/1.73 m2. A significant but weak correlation was observed between tacrolimus CLint and eGFR (r = 0.2, P < 0.001). The CLint declined gradually (up to 36%) with CKD progression. Tacrolimus CLint did not differ significantly between stable and failing transplant patients.Conclusions: Kidney function deterioration in CKD can affect nonrenal CLint for drugs that undergo extensive hepatic metabolism, such as tacrolimus, with critical implications in clinical practice. This study demonstrates the advantages of combining prior system information (via PBPK) to investigate covariate effects in sparse real-world datasets.
7.	Elens, Laure, et al. (författare) Genetic Predisposition to Poor Opioid Response in Preterm Infants : Impact of KCNJ6 and COMT Polymorphisms on Pain Relief after Endotracheal Intubation 2016 Ingår i: Therapeutic Drug Monitoring. - 0163-4356 .- 1536-3694. ; 38:4, s. 525-533 Tidskriftsartikel (refereegranskat)abstract Background: Single-nucleotide polymorphisms in genes involved in pain control might predispose to exaggerated sensitivity or difference in opioid analgesic effect. The relevance of the KCNJ6 -1250G>A (rs6517442, c.-1787G>A) and the catecholamine-O-methyltransferase (COMT) c.472G>A (rs4680, Val 158 Met) single-nucleotide polymorphisms were studied in preterm infants needing intubation and randomized to a premedication strategy including remifentanil (n 17) or morphine (n 17). Methods: Pain was scored with Astrid Lindgren and Lund Children's Hospital Pain Assessment Scale every 30 minutes for 6 hours. The pain relief provided by the opioids was compared between the different KCNJ6 and COMT genotypes. Results: Infants homozygous for the KCNJ6 -1250A allele had an increased duration after intubation to achieve a score indicating no pain compared with infants with the A/G or G/G genotypes (182 ± 30, 109 ± 29, and 60 ± 21 minutes, respectively; Logrank 7.5, P 0.006). Similarly, the duration was increased in individuals with the COMT Val/Val alleles compared with Val/Met and Met/Met (285 ± 37, 137 ± 25, and 63 ± 15 minutes, respectively; Logrank 14.4, P 0.0021). Cox proportional hazards analysis confirmed that the variation in both genes was independently associated with susceptibility to respond to therapy. Conclusion: We conclude that the KCNJ6 -1250A and COMT 158 Val alleles are predisposing preterm newborns to diminished opioid-induced pain relief.
8.	Elkayal, Omar, et al. (författare) A Population Pharmacokinetic Modeling and Simulation Study of Posaconazole Oral Suspension in Immunocompromised Pediatric Patients : A Short Communication 2021 Ingår i: Therapeutic Drug Monitoring. - : Wolters Kluwer. - 0163-4356 .- 1536-3694. ; 43:4, s. 512-518 Tidskriftsartikel (refereegranskat)abstract Background: Posaconazole oral suspension emerged as a promising candidate for prophylaxis of invasive fungal infections in immunocompromised children. Its pharmacodynamic advantages include a broad-spectrum activity and a favorable safety profile; however, they are overshadowed by its large pharmacokinetic (PK) variability, which might cause subtherapeutic exposure. The aim of this study was to develop a population (pop) PK model based on rich sampling data to better understand the PK of posaconazole oral suspension in pediatric patients. Methods: Data were obtained from a prospective interventional study involving hospitalized pediatric patients with a hematologic malignancy and prophylactically treated with posaconazole oral suspension. After constructing the popPK model, the probability of target attainment (PTA; 100% T >= 0.7 mg/L) for prophylaxis under fixed, body weight-based, and body surface area-based dosing was evaluated using Monte Carlo simulation. Results: Fourteen patients contributed 112 posaconazole plasma concentrations. The PK of posaconazole was adequately described by a 1-compartment model with lag time 2.71 hours [13%]; nonlinear bioavailability ED50 99.1 mg/m(2) (fixed); first-order absorption rate constant 0.325 hour(-1) [27%]; apparent volume of distribution 1150 L [34%]; and apparent clearance 15.4 L/h [24%] (similar to 70-kg individual). The bioavailability decreased in the presence of diarrhea and co-treatment with a proton pump inhibitor (PPI). The unexplained interindividual variability in posaconazole PK remained large. The PTA was <85%, irrespective of the simulated dosing strategy. Patients without diarrhea and not administered a PPI had the highest PTA (85% under the fixed 300-mg dosing 4 times per day). Conclusions: Therapeutic drug monitoring is recommended during prophylactic posaconazole therapy in immunocompromised pediatric patients. Large-scale comparative studies are needed to characterize the PK variability between different posaconazole formulations in this cohort.
9.	Gunes, Arzu, et al. (författare) ABCB1 polymorphisms influence steady-state plasma levels of 9-hydroxyrisperidone and risperidone active moiety 2008 Ingår i: Therapeutic Drug Monitoring. - 0163-4356 .- 1536-3694. ; 30:5, s. 628-633 Tidskriftsartikel (refereegranskat)abstract Risperidone is metabolized to its active metabolite, 9-hydroxy risperidone, mainly by the cytochrome P450 enzymes CYP2D6 and 3A4. Its antipsychotic effect is assumed to be related to the active moiety, that is, the sum of risperidone and 9-hydroxyrisperidone. Both risperidone and 9-hydroxyrisperidone are substrates of P-glycoprotein (P-gp), a transport protein involved in drug absorption, distribution, and elimination. The aim of the present study was to evaluate the influence of polymorphisrns in genes encoding CYP3A5 and P-gp (ABCB1) on the steady-state plasma levels of risperidone, 9-hydroxyrisperidone, and the active moiety, taking CYP2D6 genotype status into account. Forty-six white patients with schizophrenia treated with risperidone (1-10 mg/d) in monotherapy for 4-6 weeks were genotyped, and their plasma concentrations of risperidone and 9-hydroxyrisperidone were measured. Dose-corrected plasma concentrations (C/D) of risperidone, 9-hydroxyrisperidone, and active moiety showed up to 68-, 9-, and 10-fold interindividual variation, respectively. Six patients carried 1 CYP3A5*1 allele and therefore were likely to express the CYP3A5 enzyme. The CYP3A5 genotype did not influence risperidone, 9-hydroxyrisperidone, or active moiety C/Ds. The CYP2D6 genotype in these 46 patients was again associated with risperidone C/D (P = 0.001) but not with 9-hydroxyrisperidone C/D or active moiety C/D, as previously shown by our group in 37 of these patients. Patients homozygous for the ABCB1 3435T/2677T/1236T haplotype had significantly lower C/Ds of 9-hydroxyrisperidone (P = 0.026) and active moiety (P = 0.028) than patients carrying other ABCB1 genotypes. In conclusion, our results confirmed the significant effect of CYP2D6 genotype oil the steady-state plasma levels of risperidone and showed that ABCB1 polymorphisins have a moderate effect oil those of 9-hydroxyrisperidone and the active moiety.
10.	Haglund, Sofie, et al. (författare) The Role of Inosine-5'-Monophosphate Dehydrogenase in Thiopurine Metabolism in Patients With Inflammatory Bowel Disease. 2011 Ingår i: Therapeutic Drug Monitoring. - : Lippincott Williams & Wilkins. - 0163-4356 .- 1536-3694. ; 33:2, s. 200-208 Tidskriftsartikel (refereegranskat)abstract BACKGROUND:: There is a large interindividual variability in thiopurine metabolism. High concentrations of methylthioinosine-5'-monophosphate (meTIMP) and low concentrations of 6-thioguanine nucleotides (6-TGNs) have been associated with a lower response rate and an increased risk of adverse events. In this study, the role of inosine-5'-monophosphate dehydrogenase (IMPDH) for differences in metabolite patterns of thiopurines was investigated. METHODS:: IMPDH activity and thiopurine metabolite concentrations were determined in patients with inflammatory bowel disease and a normal thiopurine methyltransferase (TPMT) phenotype and meTIMP/6-TGN concentration ratio > 20 (n = 26), in patients with a metabolite ratio ≤20 (n = 21), in a subgroup with a metabolite ratio <4 (n = 6), and in 10 patients with reduced TPMT activity. In vitro studies were conducted on human embryonic kidney cells (HEK293) with genetically engineered IMPDH and TPMT activities. RESULTS:: Patients with metabolite ratios >20 had lower IMPDH activity than those with ratios ≤20 (P < 0.001). Metabolic ratios >20 were only observed in patients with normal TPMT activity. Downregulation of IMPDH activity in HEK293 cells was associated with an increase in the concentration of meTIMP (fold change: 17 up to 93, P < 0.001) but, unexpectedly, also of 6-thioguanosine monophosphate (fold change: 2.6 up to 5.0, P < 0.001). CONCLUSIONS:: These data question the general view of IMPDH as the rate-limiting enzyme in the phosphorylation of thiopurines. Investigations of other mechanisms are needed to more fully explain the various metabolite patterns and outcomes in patients under treatment.
11.	Hamberg, Anna-Karin, 1964-, et al. (författare) Is Trough Concentration of Vancomycin Predictive of the Area Under the Curve? : A Commentary 2017 Ingår i: Therapeutic Drug Monitoring. - 0163-4356 .- 1536-3694. ; 39:3, s. 303-303 Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
12.	Hindorf, U., et al. (författare) Assessment of thiopurine methyltransferase and metabolite formation during thiopurine therapy : Results from a large swedish patient population 2004 Ingår i: Therapeutic Drug Monitoring. - : Ovid Technologies (Wolters Kluwer Health). - 0163-4356 .- 1536-3694. ; 26:6, s. 673-678 Tidskriftsartikel (refereegranskat)abstract This study examined thiopurine methyltransferase (TPMT) and the relationship to thioguanine nucleotides (TGN) and methylthioinosine monophosphate (meTIMP) in a large Swedish patient population. The current hypothesis is that the cytotoxic effects of thiopurine drugs are mediated by the incorporation of TGN into DNA. The authors assayed the TPMT activity in red blood cells from 1151 subjects and the concentrations of TGN (n = 602) and meTIMP (n = 593) from patients treated with thiopurine drugs. The TPMT frequency distribution in both adults and children showed some differences from what had been found in unselected general populations. Children had lower median TPMT activity than adults (12.0 versus 12.9 U/mL RBC, P < 0.001). Relative differences in both TGN formation [medians: normal TPMT, 1.3, intermediate TPMT, 3.3, low TPMT, 47.9 pmol/8 × 108 RBC per mg azathioprine (AZA), P < 0.001] and meTIMP formation (medians: normal TPMT, 13, intermediate TPMT, 7.3, low TPMT, 0 pmol/8 × 108 RBC per mg AZA, P = 0.001) per 1 mg administered drug were noted among the 3 TPMT activity groups. Women formed higher concentrations of both TGN (1.5 versus 1.3 pmol/8 × 108 RBC per mg AZA, P = 0.01) and meTIMP (14.4 versus 10.7 pmol/8 × 108 RBC per mg AZA, P = 0.01) than men did. There was a significant correlation between the AZA dose and the meTIMP concentrations (r = 0.45, P < 0.001). Furthermore, dose alterations made in subjects with normal TPMT (n = 84) and intermediate TPMT (n = 22) activity resulted in more pronounced increases in TGN concentrations (170 versus 30 pmol/8 × 10 8 RBC, P < 0.001) in intermediate TPMT activity, whereas in normal TPMT activity changes in meTIMP concentrations were more pronounced (1.3 versus 0 nmol/8 × 108 RBC, P < 0.001). In normal TPMT activity both metabolites increased in a dose-dependent fashion, whereas in intermediate TPMT activity only TGN concentrations increased. The results of this study demonstrate the dynamic nature of thiopurine metabolism and its importance for thiopurine dosing.
13.	Janssen, Julie M, et al. (författare) Evaluation of Extrapolation Methods to Predict Trough Concentrations to Guide Therapeutic Drug Monitoring of Oral Anticancer Drugs. 2020 Ingår i: Therapeutic Drug Monitoring. - 0163-4356 .- 1536-3694. ; 42:4, s. 532-539 Tidskriftsartikel (refereegranskat)abstract BACKGROUND: For oral anticancer drugs, trough concentration (Cmin) is usually used as a target in therapeutic drug monitoring (TDM). Recording of Cmin is highly challenging in outpatients, in whom there is typically a variability in sample collection time after dosing. Various methods are used to estimate Cmin from the collected samples. This simulation study aimed to evaluate the performance of 3 different methods in estimating the Cmin of 4 oral anticancer drugs for which TDM is regularly performed.METHODS: Plasma concentrations of abiraterone, dabrafenib, imatinib, and pazopanib at a random time (Ct,sim) and at the end of the dosing interval (Cmin,sim) were simulated from population pharmacokinetic models including 1000 patients, and the values were converted into simulated observed concentrations (Ct,sim,obs and Cmin,sim,obs) by adding a residual error. From Ct, sim,obs, Cmin was predicted (Cmin,pred) by the Bayesian estimation (method 1), taking the ratio of the Ct,sim,obs and typical population concentration and multiplying this ratio with the typical population value of Cmin,sim (method 2), and log-linear extrapolation (method 3). Target attainment was assessed by comparing Cmin,pred with the proposed pharmacokinetic targets related to efficacy and calculating the positive predictive and negative predictive values.RESULTS: The mean relative prediction error and root mean squared relative prediction error results showed that method 3 was out-performed by method 1 and 2. Target attainment was adequately predicted by all 3 methods (the respective positive predictive value of method 1, 2, and 3 was 92.1%, 92.5%, and 93.1% for abiraterone; 87.3%, 86.9%, and 99.1% for dabrafenib; 79.3%, 79.3%, and 75.9% for imatinib; and 72.5%, 73.5%, and 67.6% for pazopanib), indicating that dose adjustments were correctly predicted.CONCLUSIONS: Both method 1 and 2 provided accurate and precise individual Cmin,pred values. However, method 2 was easier to implement than method 1 to guide individual dose adjustments in TDM programs.
14.	Johansson, Åsa M., et al. (författare) A Population Pharmacokinetic/Pharmacodynamic Model of Methotrexate and Mucositis Scores in Osteosarcoma 2011 Ingår i: Therapeutic Drug Monitoring. - 0163-4356 .- 1536-3694. ; 33:6, s. 711-718 Tidskriftsartikel (refereegranskat)abstract Methotrexate, when used in high doses (12 g/m(2)) in the treatment of osteosarcoma, shows wide between-subject variability (BSV) in its pharmacokinetics. High-dose methotrexate is associated with severe toxicity; therefore, therapeutic drug monitoring (TDM) is carried out to guide rescue therapy and monitor for nephrotoxicity. Mucositis is a commonly encountered dose-limiting toxicity that often leads to delays in subsequent courses of chemotherapy. This, in turn, results in a reduction in the dosing intensity, which is essential in the treatment of osteosarcoma. The aims of this study were to develop a population pharmacokinetic (PK) model from TDM using physiologically relevant covariates and to investigate the correlation between mucositis scores and methotrexate pharmacokinetics. In total, 46 osteosarcoma patients (30 men and 16 women; age, 4-51 years) were recruited, and blood samples were collected for routine TDM once every 24 hours. Mucositis scores, graded according to the National Cancer Institute Common Toxicity Criteria, were recorded for 28 of the patients (18 men and 10 women; age, 8-51 years) predose and postdose. A population PK model was developed in NONMEM VI. A 2-compartment PK model was chosen, and clearance (CL) was divided into filtration and secretion/metabolism components. All parameters were scaled with body weight, and, in addition, total CL was scaled with age-and sex-adjusted serum creatinine. Between-subject variability was modeled for all parameters, and betweenoccasion variability was included in CL. For a typical 70 kg man of 18 years or older, the parameter estimates for the final model were CL(filt) = 2.69 L/h/70 kg, CL(sec) = 10.9 L/h/70 kg, V(1) = 74.3 L/70 kg, Q = 0.110 L/h/70 kg, and V(2) = 4.10 L/70 kg. Sequential pharmacodynamic modeling consisted of mucositis scores as 5-point ordered categorical data. A significant linear relationship between individual area under the curve (AUC) and mucositis score probability was found, and the probability of having mucositis score >= 1 increased with increasing AUC and was almost 50% at the average cumulative AUC after 2 consecutive methotrexate doses.
15.	Jones, A Wayne, 1945-, et al. (författare) Concentrations of scheduled prescription drugs in blood of impaired drivers : Considerations for interpreting the results 2007 Ingår i: Therapeutic Drug Monitoring. - 0163-4356 .- 1536-3694. ; 29:2, s. 248-260 Tidskriftsartikel (refereegranskat)abstract We report the concentrations of scheduled prescription drugs in blood samples from people arrested in Sweden for driving under the influence of drugs (DUID). The investigation covered a 2 year period 2004 (N = 7052 cases) and 2005 (N = 7759 cases) and was prompted by recent legislation stipulating zero-concentration limits in blood for controlled substances. However, prescription drugs are exempt from the zero-limit law provided that the medication was being used in accordance with a doctor's prescription. The blood concentrations of various psychoactive substances were compared with the limits of quantitation of the analytic method used and the so-called therapeutic concentration range according to various reference books and tabulations. Diazepam [N = 1950 (26%)] and nordazepam [N = 2168 (28%)] were the therapeutic agents most frequently identified in these forensic blood samples along with other benzodiazepines such as alprazolam [N = 430 (5.6%)], flunitrazepam [N = 308 (4.0%)], and nitrazepam [N = 222 (2.9%)]. The newer hypnotics, exemplified by zolpidem [N = 148 (1.9%)] and zopiclone [N = 111 (1.5%)], were also high on the list of psychoactive substances identified. Interpreting the concentration of a prescription drug in blood in relation to whether the person had taken an overdose or was abusing the substance in question is not always easy. The age, gender, degree of obesity, and ethnicity of the person concerned, the pharmacokinetic profile of the drug, polymorphism of drug-metabolizing enzymes as well as liver and kidney function and blood hematocrit need to be considered. Among preanalytic factors, stability of the drug in blood after sampling, the type of tubes and preservatives used, the dosage form and route of administration deserve consideration. When therapeutic drug monitoring concentrations are compared with forensic toxicology results, then the plasma-to-whole blood distribution ratio of the drug also needs to be considered. In blood samples from DUID suspects, the concentrations of many commonly used sedatives and hypnotics exceeded the accepted therapeutic limits, which gives an indication of the abuse potential of these types of medications. © 2007 Lippincott Williams & Wilkins, Inc.
16.	Jones, A Wayne, 1945-, et al. (författare) Distribution of diazepam and nordiazepam between plasma and whole blood and the influence of hematocrit 2004 Ingår i: Therapeutic Drug Monitoring. - : Ovid Technologies (Wolters Kluwer Health). - 0163-4356 .- 1536-3694. ; 26:4, s. 380-385 Tidskriftsartikel (refereegranskat)abstract The binding of drugs to plasma proteins is important to consider when concentrations in whole blood (eg, in forensic toxicology) are compared with therapeutic and toxic concentrations based on the analysis of plasma or serum. The plasma to whole blood distribution of diazepam (D) and its major metabolite nordiazepam (ND) was investigated under in vitro and ex vivo conditions. Studies in vitro were done by spiking whole blood with D and ND to give concentrations ranging from 0.1 to 1.0 μg/g. Venous blood was also obtained from hospital blood donors (n = 66) after informed consent. The hematocrit, hemoglobin, and water content of blood specimens were determined by routine procedures before D and ND were added to produce target concentrations of ∼0.5 μg/g for each substance. The ex vivo work was done with blood specimens from hospital outpatients who were being medicated with D. Concentrations of D and ND were determined in body fluids by capillary column gas chromatography after adding prazepam as internal standard and solvent extraction with butyl acetate. The method limit of quantitation was 0.03 μg/g for both D and ND. The concentrations of D and ND were highest in plasma and lowest in erythrocytes. The plasma/blood (P/B) distribution ratios did not depend on drug concentration between 0.1 and 1.0 μg/g. The mean P/B ratios were 1.79:1 for D and 1.69:1 for ND when hematocrit was 45%. Furthermore, the P/B ratio for D (y) was positively correlated with blood hematocrit (x) and the regression equation was y = 0.636 + 0.025x (r = 0.86, P < 0.001). A similar strong association was found between the P/B ratio and hematocrit for ND (r = 0.79). P/B ratios of D and ND, blood hematocrit, hemoglobin, and the water content differed between sexes (P < 0.001). The overall mean P/B ratios for D and ND were 1.69 ± 0.097 (± SD) and 1.62 ± 0.08 (P < 0.001, n = 66) respectively when the mean hematocrit was 42.9 ± 3.4 (± SD). For forensic purposes, it would be better to forgo making any conversion of a drug concentration measured in whole blood to that expected in plasma or serum, instead, therapeutic and toxic concentrations should be established for the actual specimens received.
17.	Jönsson, Anna K., et al. (författare) A Compilation of Serum Concentrations of 12 Antipsychotic Drugs in a Therapeutic Drug Monitoring Setting 2019 Ingår i: Therapeutic Drug Monitoring. - : LIPPINCOTT WILLIAMS & WILKINS. - 0163-4356 .- 1536-3694. ; 41:3, s. 348-356 Tidskriftsartikel (refereegranskat)abstract BACKGROUND: No comprehensive collection of routine therapeutic drug monitoring data for antipsychotic drugs has been published. METHODS: In this compilation, data on 12 antipsychotics are presented. The drugs included are amisulpride (n = 506), aripiprazole (n = 1610), clozapine (n = 1189), flupentixol (n = 215), haloperidol (n = 390), olanzapine (n = 10,268), perphenazine (n = 1065), quetiapine (n = 5853), risperidone (n = 3255), sertindole (n = 111), ziprasidone (n = 1235), and zuclopenthixol (n = 691). Because only one sample per patient is included, the number of patients equals the number of samples. For each drug, median serum concentrations as well as that of the 10th and 90th percentiles are given for a range of daily doses. Comparisons are made between males and females, between patients younger than 65 years and 65 years and older, and between those treated with a low and a high dose of each drug. The concentration-to-dose (C/D) ratio is the primary variable used in these comparisons. Coefficients of variation (CVs) for the serum concentrations of each drug within and between subjects are presented. RESULTS: In general, the C/D ratios were higher in females than in males, higher in those 65 years and older than in younger subjects, and lower in those treated with higher doses than in those treated with lower doses. CVs between individuals were larger than within subjects, and the CVs were highest for the drugs with short elimination half-lives. CONCLUSIONS: For each antipsychotic drug, the results presented can serve as a reference tool for pharmacokinetic interpretation of the individual patient's serum drug level. The compiled serum concentrations and the C/D ratios can support the physician's decision when individualizing dosing and determining treatment strategies for a specific patient.
18.	Karlsson, Kristin C., et al. (författare) A population pharmacokinetic model of gabapentin developed in nonparametric adaptive grid and nonlinear mixed effects modeling 2009 Ingår i: Therapeutic Drug Monitoring. - 0163-4356 .- 1536-3694. ; 31:1, s. 86-94 Tidskriftsartikel (refereegranskat)abstract Gabapentin is used in analgesic treatment of neuropathic pain, and large interindividual variation has been observed in the pharmacokinetics (PK) of the drug. The aim of this study was to develop a population PK model for gabapentin appropriate for monitoring patients with neuropathic pain and for individualizing their dose regimens. Steady-state serum concentrations of gabapentin, distributed over a dosage interval, were obtained from 16 adult patients. Data were analyzed with an iterative 2-stage Bayesian and a nonparametric adaptive grid algorithm (NPAG) (USC*PACK) and with nonlinear mixed effects modeling (NONMEM). Compartmental population models for gabapentin PK were developed in NPAG and NONMEM using creatinine clearance and body weight as covariates. Bioavailability was included in the models as a function of dose by using a hyperbolic function derived from data previously reported in the literature. The mean population parameter estimates from the final NPAG model predicted individual serum concentrations reasonably well. The models developed in NONMEM provided additional information about the relevance of the various possible covariates and also allowed for further evaluation by simulation from the model. The population PK model may be utilized in the MM-USCPACK monitoring software (MM: multiple model dosage design) for predicting and achieving individually optimized steady-state serum concentrations of gabapentin.
19.	Kasai, Hidefumi, et al. (författare) Pharmacodynamic Model-Based Safety Management of Eribulin-Induced Myelosuppression in Patients With Breast Cancer 2023 Ingår i: Therapeutic Drug Monitoring. - 1536-3694 .- 0163-4356. ; 45:3, s. 318-326 Tidskriftsartikel (refereegranskat)abstract BACKGROUND: Neutropenia is a major dose-limiting toxicity of cancer chemotherapy. Semimechanistic mathematical models have been applied to describe the time course of neutrophil counts. The objectives of this study were to develop a mathematical model describing changes in neutrophil counts during eribulin treatment, to apply the empirical Bayes method to predict the probability of developing neutropenia ≥ grade 3 during eribulin treatment in each patient, and to propose the implementation of this mathematical tool in clinical practice for individual safety management. METHODS: The present model analysis and subsequent external evaluation were performed using the data of 481 patients with breast cancer, previously obtained from a postmarketing surveillance (training set) and a phase 2 clinical study (validation set). The model we previously reported (Kawamura et al 2018) was modified to improve its predictive capability. The individual time course of neutrophil changes during the treatment period was predicted by the empirical Bayes method using the observed neutrophil counts at baseline and the first measurement after the first eribulin dose. To evaluate the predictability of this method, the predicted neutrophil counts were compared with those of the observed values. RESULTS: The developed model provided good individual predictions, as indicated by the goodness-of-fit plots between the predicted and observed neutrophil counts, especially for a lower neutrophil count range. Days required to reach the nadir after the dose were also well-predicted. The sensitivity, specificity, and accuracy of the prediction of neutropenia grade ≥3 were 76%, 53%, and 71%, respectively. CONCLUSIONS: We developed a mathematical method for predicting and managing the risk of neutropenia during eribulin treatment. This method is generally applicable to other cases of chemotherapy-induced neutropenia and can be a new practical tool for individual safety management.
20.	Klaasen, Rolf Anton, et al. (författare) A Fully Automated Method for the Determination of Serum Belatacept and Its Application in a Pharmacokinetic Investigation in Renal Transplant Recipients 2019 Ingår i: Therapeutic Drug Monitoring. - : LIPPINCOTT WILLIAMS & WILKINS. - 0163-4356 .- 1536-3694. ; 41:1, s. 11-18 Tidskriftsartikel (refereegranskat)abstract Background: Belatacept (Nulojix; Bristol-Myers Squibb, New York, NY) is a biological immunosuppressive drug used for the prophylaxis of acute rejection after renal transplantation. Few studies have described belatacept pharmacokinetics, and the effect of therapeutic drug monitoring has not been investigated. We have developed a drug-capture assay (using drug target) to measure belatacept in serum and applied this assay in a pharmacokinetic study in renal transplant recipients. Methods: CD80 was used to trap belatacept onto streptavidin-coated wells. Captured drug was quantified using Eu3+-labeled protein A and time-resolved fluorescence. The assay was applied in a pilot pharmacokinetic study in renal transplanted patients receiving belatacept infusions. Belatacept serum concentrations were determined at several time points between belatacept infusions. A simple population pharmacokinetic model was developed to visualize measured and predicted belatacept serum concentrations. Results: The assay range was 0.9-30 mg/L with accuracy within 91%-99% and coefficients of variation ranging from 1.2% to 3.6%. Predilution extended the measurement range to 130 mg/L with an accuracy of 90% and coefficients of variation of 3.8%. Samples were stable during storage at 48 degrees C for 15 days and during 2 freeze-thaw cycles. Belatacept concentrations were determined in a total of 203 serum samples collected during 26 infusion intervals from 5 renal transplant recipients. The population pharmacokinetic model visualized both measured and predicted concentrations. Conclusions: We have developed an automated, accurate, and precise assay for the determination of belatacept serum concentrations. The assay was successfully applied in a pharmacokinetic study in renal transplant recipients receiving belatacept infusions.
21.	Kronstrand, Robert, et al. (författare) A Screening Method for 30 Drugs in Hair Using Ultrahigh-Performance Liquid Chromatography Time-of-Flight Mass Spectrometry 2013 Ingår i: Therapeutic Drug Monitoring. - : Lippincott, Williams and Wilkins. - 0163-4356 .- 1536-3694. ; 35:3, s. 288-295 Tidskriftsartikel (refereegranskat)abstract Objectives: The objectives of this study were to develop and to validate a qualitative screening method that met the new Society of Hair Testing (SoHT) guideline criteria for thresholds. less thanbrgreater than less thanbrgreater thanMethods: Extraction of 20 mg hair was performed by a previously validated procedure using overnight incubation in a mixture of methanol:acetonitrile:formiate buffer pH 3 (10:10:80). Analysis was performed on an Agilent 6540 quadrupole time-of-flight mass spectrometer in combination with an Agilent 1290 Infinity ultrahigh-performance liquid chromatography system. Separation was achieved with a 12-minute linear gradient chromatography on a high-strength silica T3 column at acidic conditions. An in-house database containing 30 compounds from the groups amphetamines, opiates, opioids, cocaine, benzodiazepines, and other sedatives including 6 deuterated internal standards was built by analyzing solutions from certified standards. Data were extracted using mass accuracy of +/- 10 ppm, retention time deviation of +/- 0.15 minutes, and area of andgt;= 30,000 counts. Identification was based on scoring of retention time, accurate mass measurement, and isotopic pattern. Validation included selectivity, repeatability of analyte area, and the scoring parameters at the proposed thresholds and a method comparison with the present liquid chromatography-mass spectrometry-mass spectrometry method using 50 authentic hair samples. A daily cutoff calibrator was used to identify positive samples. less thanbrgreater than less thanbrgreater thanResults: All cutoffs could be met with imprecisions of less than 5% for most parameters and analytes. Hair from drug-free subjects did not produce any positive results and the method comparison agreed in more than 90% of the cases. less thanbrgreater than less thanbrgreater thanConclusions: We conclude that the developed method meets the criteria of the new SoHT guidelines for screening cutoffs. Even though no thresholds have been suggested for benzodiazepines, we conclude that thresholds between 0.05 and 0.1 ng/mg should be sufficient to determine regular use of these substances.
22.	Kugelberg, Fredrik, et al. (författare) Disposition of the enantiomers of citalopram and its demethylated metabolites in rats 2003 Ingår i: Therapeutic Drug Monitoring. - 0163-4356 .- 1536-3694. ; 25:4, s. 163- Konferensbidrag (övrigt vetenskapligt/konstnärligt)
23.	Lindegårdh, Niklas, et al. (författare) Automated Solid-Phase Extraction Method for the Determination of Piperaquine in Whole Blood by Rapid Liquid Chromatography 2003 Ingår i: Therapeutic Drug Monitoring. - 0163-4356 .- 1536-3694. ; 25:5, s. 544-551 Tidskriftsartikel (refereegranskat)
24.	Lindegårdh, N, et al. (författare) Automated solid-phase extraction method for the determination of piperaquine in whole blood by rapid liquid chromatography. 2003 Ingår i: Therapeutic drug monitoring. - 0163-4356 .- 1536-3694. ; 25:5, s. 544-51 Tidskriftsartikel (refereegranskat)abstract A bioanalytic method for the determination of piperaquine in whole blood by solid-phase extraction and rapid liquid chromatography has been developed and validated. Whole blood was hemolyzed with deionized water, and an internal standard was added to the samples before they were loaded onto a PRS cation-exchange solid-phase extraction column. Piperaquine and internal standard were analyzed by liquid chromatography on a Chromolith Performance (100 x 4.6 mm) column with mobile phase acetonitrile:phosphate buffer, I = 0.1, pH 2.5 (8:92, vol/vol), flow rate 4 mL x min-1, and UV detection at 345 nm. The intraassay precision for whole blood was 3.2% at 3.00 microM and 12.3% at 0.100 microM. The interassay precision for whole blood was 1.8% at 3.00 microM and 5.2% at 0.100 microM. The lower limit of quantification and the limit of detection were 0.050 microM and 0.010 microM, respectively.
25.	Linder, Camilla, et al. (författare) Dried Blood Spot Self-Sampling by Guardians of Children With Epilepsy Is Feasible : Comparison With Plasma for Multiple Antiepileptic Drugs 2019 Ingår i: Therapeutic Drug Monitoring. - : Lippincott Williams & Wilkins. - 0163-4356 .- 1536-3694. ; 41:4, s. 509-518 Tidskriftsartikel (refereegranskat)abstract BACKGROUND: Dried blood spot (DBS) is an attractive matrix alternative to plasma for the measurement of antiepileptic drug concentrations with the possibility of self-sampling at home. The aim of this study was to evaluate whether DBS concentrations from a children population could be used as an alternative to plasma concentrations in a clinical routine laboratory.METHODS: Children with epilepsy using carbamazepine (CBZ), lamotrigine (LTG), levetiracetam (LEV), or valproic acid (VPA) had capillary blood collected for routine plasma analysis. DBS samples were collected by guardians or nurses, and the quality of sampling was compared between the groups. DBS samples were analyzed with liquid chromatography-tandem mass spectrometry methods and plasma samples with immunochemical methods. In the comparison between DBS and plasma concentrations, previously analyzed sample data were pooled with data in this study and resulted in 190 comparison pairs. A bioanalytical cross-validation according to European Medicines Agency was performed. Clinicians evaluated the results to understand if a DBS concentration was linked to a different clinical dose recommendation for the patient in comparison with plasma concentrations.RESULTS: Comparison of DBS sample quality showed that 2.3% of the capillary DBS collected by guardians were rejected and 8.0% of the capillary DBS collected by nurses. For DBS, a conversion factor of 0.85 for CBZ and 1.65 for VPA was applied for the comparison with plasma. LTG and LEV results were directly comparable. In the cross-validation, 88% of CBZ, 75% of LTG, 74% of LEV, and 94% of VPA comparisons were within 20% of the difference of the mean, although LEV had a few major differences (+31% to -40%). In 4 of the 190 comparisons, the clinical evaluation indicated a risk of conflicting decisions regarding the need for dose adjustment when using DBS concentrations. However, the risk of negative patient outcomes was considered negligible.CONCLUSIONS: Our study demonstrates that a combination of bioanalytical cross-validation and clinical evaluation is an effective way to describe the applicability of DBS as an alternative to plasma, taking into account how therapeutic drug monitoring is used in specific patient groups. For LTG, converted CBZ and VPA, DBS is a feasible alternative for self-sampling at home. DBS for LEV can only be recommended for nonadherence queries due to the high variability of the plasma/DBS concentration ratios.
26.	Lofgren, C., et al. (författare) High activity and incomplete cross resistance of nucleoside analogues cladribine and fludarabine versus ara-C on leukemic cells from patients with AML 2005 Ingår i: Therapeutic Drug Monitoring. - : Ovid Technologies (Wolters Kluwer Health). - 0163-4356 .- 1536-3694. ; 27:5, s. 641-646 Tidskriftsartikel (refereegranskat)abstract The in vitro activity and cross-resistance pattern of the purine analogues cladribine and fludarabine and the pyrimidine analogue cytarabine on leukemic cells from 170 patients with AML was evaluated using a bioluminescence assay. In in vivo mimicking concentrations, cladribine (50 nmol/L) and fludarabine (2 µmol/L) were more cytotoxic than cytarabine (0.5 µmol/L). The cytotoxic effect of fludarabine correlated weakly to cytarabine (r = 0.37, P < 0.001). The cytotoxic effect of cladribine correlated better to cytarabine (r = 0.49, P = 0.0002) but best to fludarabine (r = 0.82, P < 0.001). There was an absence of correlation between either cladribine or fludarabine and daunorubicin (0.2 µmol/L). Of 45 highly Ara-C-resistant samples, cladribine exerted high or intermediate effect in 54% and fludarabine in 52%. These in vitro data indicate that cladribine and fludarabine are active drugs in the treatment of AML. The cross resistance to cytarabine was not complete, and the drugs can be valuable either as alternatives to Ara-C or in combination therapy for treatment of leukemia resistant to standard therapy. Copyright © 2005 by Lippincott Williams & Wilkins.
27.	Lundmark, Jöns, 1953-, et al. (författare) Serum concentrations of fluoxetine in the clinical treatment setting 2001 Ingår i: Therapeutic Drug Monitoring. - : Ovid Technologies (Wolters Kluwer Health). - 0163-4356 .- 1536-3694. ; 23:2, s. 139-147 Tidskriftsartikel (refereegranskat)abstract This article discusses fluoxetine serum concentrations as displayed in a clinical setting. A racemic serum fluoxetine and norfluoxetine high-performance liquid chromatography method, including ultraviolet light detection, was used for routine therapeutic drug monitoring (TDM) purposes. In all, 508 samples were analyzed. For the scientific investigation, predefined inclusion and exclusion criteria were applied and 150 samples representative of trough values in steady-state conditions with essential clinical information provided on the assay request forms were evaluated. Fluoxetine plus norfluoxetine concentration-to-dose (C/D) ratio showed Gaussian distribution. Interindividual coefficients of variation of fluoxetine and norfluoxetine serum concentrations after different doses were found to be 40-63%. Intraindividual fluoxetine TDM variability was low. The Spearman rank correlation coefficient for fluoxetine and norfluoxetine C/D ratios in first and second samples was 0.68. Minor increases in norfluoxetine C/D and fluoxetine plus norfluoxetine C/D ratios were found in elderly patients compared with younger adult patients. A higher body-mass index was associated with minor decreases in fluoxetine and fluoxetine plus norfluoxetine C/D ratios. New fluoxetine pharmacokinetic data are added to the results from earlier phases of drug development. Moreover, the results of this study support the usefulness of a fluoxetine TDM procedure for individual dose optimization, detection of drug interactions, and assessments of patient compliance.
28.	Lundmark, Jöns, 1953-, et al. (författare) Therapeutic drug monitoring of sertraline : Variability factors as displayed in a clinical setting 2000 Ingår i: Therapeutic Drug Monitoring. - : Ovid Technologies (Wolters Kluwer Health). - 0163-4356 .- 1536-3694. ; 22:4, s. 446-454 Tidskriftsartikel (refereegranskat)abstract This report describes sertraline pharmacokinetics derived from routine therapeutic drug monitoring (TDM) data. A high-performance liquid chromatographic method with ultraviolet detection was established for routine sertraline TDM, and 924 analyses were performed from April 1995 to May 1997. Extensive predefined inclusion/exclusion criteria were applied to increase the validity of scientifically evaluated data. Subsequently, 605 samples (65.5%) were excluded. The remaining 319 samples from 319 patients, representative of steady state through specimens and accompanied by essential clinical information provided on request forms, were scrutinized. A pronounced interindividual variability was observed. Smokers had significantly lower concentration-to-dose (C/D) mean ratios of serum sertraline (s-sert) and its main metabolite desmethylsertraline (s-dsert) than nonsmokers. Higher s-sert and s-dsert C/D mean ratios were found in elderly patients than in adults aged less than 65 years. In a subset of 20 patients in whom repeated TDM analyses were performed, observed intraindividual sertraline TDM outcome variability was low. The results highlight sertraline TDM as a tool for individual dose optimization and evaluation of patient drug compliance as well as drug-drug interactions.
29.	Löfgren, Christina, et al. (författare) Higher plasma but not intracellular concentrations after infusion with liposomal daunorubicin compared with conventional daunorubicin in adult acute myeloid leukemia 2007 Ingår i: Therapeutic Drug Monitoring. - New York : Raven P.. - 0163-4356 .- 1536-3694. ; 29:5, s. 626-631 Tidskriftsartikel (refereegranskat)abstract To investigate the plasma and intracellular pharmacokinetics of liposomal daunorubicin (DaunoXome) in comparison with conventional daunorubicin, 14 patients aged 28 to 60 years with newly diagnosed acute myeloid leukemia were treated for 1 day with DaunoXome (50 mg/m) and for 2 days with daunorubicin (50 mg/m) with concomitant Ara-C (7 days, 200 mg/m, continuous IV). Eleven of the 14 patients entered complete remission; 9 are still alive. Pharmacokinetic profiles were obtained by blood sampling at appropriate intervals on days 1 to 4. Daunorubicin and daunorubicinol concentrations in plasma and in peripheral leukemic blast cells were measured by high-performance liquid chromatography. Following liposomal daunorubicin administration, the peak values and plasma area under the curve (AUC) were more than 100 times higher than after administration of conventional daunorubicin (AUC, 176 vs. 0.98 micromol/L x hour), but the intracellular AUCs were comparable (759 vs. 715 micromol/L x hour). Intracellular concentrations after DaunoXome peaked later and half as high as after daunorubicin. After DaunoXome versus daunorubicin, plasma clearance was 0.001 versus 0.4 micromol/h, respectively. The volume of distribution was 5.5 L for DaunoXome, versus 3640 L for daunorubicin, indicating low tissue affinity for the liposomal formulation. The authors conclude that liposomal daunorubicin, DaunoXome, yields 2-log higher plasma concentrations but similar intracellular concentrations of daunorubicin and its metabolite daunorubicinol than does free daunorubicin.
30.	Molenaar-Kuijsten, Laura, et al. (författare) Everolimus Concentration in Saliva to Predict Stomatitis : A Feasibility Study in Patients with Cancer. 2022 Ingår i: Therapeutic Drug Monitoring. - : Ovid Technologies (Wolters Kluwer Health). - 0163-4356 .- 1536-3694. ; 44:4, s. 520-526 Tidskriftsartikel (refereegranskat)abstract BACKGROUND: Most patients with cancer treated with everolimus experience stomatitis, which seriously affects the quality of life. The salivary concentrations of everolimus may predict the incidence and severity of stomatitis. The authors aimed to examine whether it was feasible to quantify the everolimus concentration in saliva and subsequently use it to predict stomatitis.METHODS: Saliva and whole blood samples were taken from patients with cancer, who were treated with everolimus in the dosage of either 10 mg once a day or 5 mg twice a day. Everolimus concentrations in saliva samples were measured by liquid chromatography-tandem mass spectrometry. A published population pharmacokinetic model was extended with the everolimus concentration in saliva to assess any association between everolimus in the blood and saliva. Subsequently, the association between the occurrence of stomatitis and the everolimus concentration in saliva was studied.RESULTS: Eleven patients were included in this study; saliva samples were available from 10 patients, including 3 patients with low-grade stomatitis. Everolimus concentrations were more than 100-fold lower in saliva than in whole blood (accumulation ratio 0.00801 and relative standard error 32.5%). Interindividual variability (67.7%) and residual unexplained variability (84.0%) were high. The salivary concentration of everolimus tended to be higher in patients with stomatitis, 1 hour postdose ( P = 0.14).CONCLUSIONS: Quantification of the everolimus concentration in saliva was feasible and revealed a nonsignificant correlation between everolimus concentration in the saliva and the occurrence of stomatitis. If future research proves this relationship to be significant, the everolimus concentration in the saliva may be used as an early predictor of stomatitis without invasive sampling. Thereby, in patients with high salivary everolimus concentrations, precautions can be taken to decrease the incidence and severity of stomatitis.
31.	Panagiotidis, Georgios, et al. (författare) Depot haloperidol treatment in outpatients with schizophrenia on monotherapy : impact of CYP2D6 polymorphism on pharmacokinetics and treatment outcome 2007 Ingår i: Therapeutic Drug Monitoring. - 0163-4356 .- 1536-3694. ; 29:4, s. 417-422 Tidskriftsartikel (refereegranskat)abstract Haloperidol and several other antipsychotic drugs are at least partially metabolized by the polymorphic cytochrome P450 2D6 (CYP2D6). The interindividual variation in metabolic capacity of CYP2D6 might be of importance when dosing. In this study, 26 outpatients with schizophrenia and depot haloperidol as monotherapy were genotyped. The authors found 1 patient with no functional alleles, 8 with one functional allele, 16 with two functional alleles, and 1 with three functional alleles. The daily dose of haloperidol ranged from 0.45 to 14.29 mg. Steady state plasma concentrations were measured at peak (range, 1.6-67 nmol/L) and at trough (range, 1.0-49 nmol/L). The Positive and Negative Syndrome scale for Schizophrenia and the Extrapyramidal Symptom Rating Scale were used to evaluate the clinical effect. The authors found a clear correlation between haloperidol plasma concentration and number of active CYP2D6 alleles. No correlation was found between plasma concentration of haloperidol or number of CYP2D6 alleles and treatment outcome or side effects. A model to predict plasma concentration from dose and number of active CYP2D6 alleles was formed from the obtained data by means of multiple linear regression.
32.	Pettersson, B, et al. (författare) Differences between children and adults in thiopurine methyltransferase activity and metabolite formation during thiopurine therapy : Possible role of concomitant methotrexate 2002 Ingår i: Therapeutic Drug Monitoring. - : Ovid Technologies (Wolters Kluwer Health). - 0163-4356 .- 1536-3694. ; 24:3, s. 351-358 Tidskriftsartikel (refereegranskat)abstract This study examined the role of thiopurine methyltransferase (TPMT) polymorphism in the metabolism and clinical effects of azathioprine and 6-mercaptopurine in the treatment of inflammatory bowel disease and childhood leukemia. The current hypothesis is that the cytotoxic effects of thiopurines are caused by the incorporation of thioguanine nucleotides into DNA. In this context, S-methylation catalyzed by TPMT can be regarded as a competing metabolic pathway. The authors assayed the TPMT activity in red blood cells from 122 patients treated with azathioprine or 6-mercaptopurine (83 adults with inflammatory bowel disease and 39 children with acute lymphoblastic leukemia) and in 290 untreated controls (219 adult blood donors and 71 children). The concentrations of thioguanine nucleotides and methylthioinosine monophosphate were also assayed in red blood cells from the patients. The TPMT activity and the concentrations of methylthioinosine monophosphate and thioguanine nucleotides were higher in children than in adults. All children but no adult patient received concomitant methotrexate. Interaction between methotrexate and 6-mercaptopurine has been described, and may explain the results. Low TPMT activity in adult patients with inflammatory bowel disease correlated to an increased incidence of adverse drug reactions. However, there was no correlation between TPMT activity and the red blood cell concentrations of methylthioinosine monophosphate or thioguanine nucleotides, or between the concentrations of these metabolites and the occurrence of adverse effects. The results show that the role of thiopurine metabolism for drug effects is complex.
33.	Reis, Margareta, et al. (författare) Inter- and intraindividual pharmacokinetic variations of mirtazapine and its N-demethyl metabolite in patients treated for major depressive disorder : A 6-month therapeutic drug monitoring study 2005 Ingår i: Therapeutic Drug Monitoring. - : Ovid Technologies (Wolters Kluwer Health). - 0163-4356 .- 1536-3694. ; 27:4, s. 469-477 Tidskriftsartikel (refereegranskat)abstract Mirtazapine pharmacokinetic (PK) data from patients on long-term treatment for major depression have never been investigated. For this reason, in a large naturalistic outpatient study (prospective, multicenter, open-labeled, and noncomparative) conducted in Sweden in the period 2000-2002, one of the main objectives was to outline the inter- as well as intraindividual PK variance of mirtazapine and demethylmirtazapine serum concentrations in a patient cohort treated up to 6 (optionally 12) months. A total of 192 male and female outpatients aged 18 years or older were included. Serum samples of mirtazapine and demethylmirtazapine were collected, by the means of therapeutic drug monitoring, at weeks 1, 4, 8, and 24 (52). Altogether 683 serum samples were analyzed. A pronounced interindividual variability of mirtazapine and demethylmirtazapine, and the demethylmirtazapine/mirtazapine ratio was seen. The coefficient of variation was about 38%, 33%, and 36%, respectively. The intraindividual variation over time was low, about 20% on all variables. At the population level, no accumulation of mirtazapine, demethylmirtazapine, or change of the demethylmirtazapine/mirtazapine ratio was observed over time. Women had significantly higher dose-corrected concentrations of mirtazapine and demethylmirtazapine and demethylmirtazapine/mirtazapine ratio than men. Patients above 65 years of age had higher concentrations than their younger counterparts. Among patients with adverse events, lower demethylmirtazapine concentrations were observed than in patients with no adverse events. Patients on multiple drug treatment had higher dose-corrected mirtazapine and demethylmirtazapine serum concentrations than patients taking only mirtazapine. Weight and BMI had a significant negative correlation with demethylmirtazapine concentrations and with the demethylmirtazapine/mirtazapine ratio. Continued efforts are warranted to perform PK studies in a natural clinical setting to learn and understand inter- and intraindividual PK variances in real patients treated for longer periods of time. For mirtazapine as well as for most antidepressant drugs only relatively short term PK is available. To help clinicians improve their treatment of patients with major depressive disorder, the possible implications on the PK with a long-term treatment are important to study. Copyright © 2005 by Lippincott Williams & Wilkins.
34.	Reis, Margareta, et al. (författare) Therapeutic Drug Monitoring of Escitalopram in an outpatient setting 2007 Ingår i: Therapeutic Drug Monitoring. - 0163-4356 .- 1536-3694. ; 29:6, s. 758-766 Tidskriftsartikel (refereegranskat)abstract The main objectives of this study were to outline the inter- and intraindividual and overall pharmacokinetic variability of S-citalopram, S-desmethylcitalopram, and S-didesmethylcitalopram in serum by means of therapeutic drug monitoring, and to investigate potential correlations between the serum concentration and simultaneously collected clinical data. The study was conducted on outpatients in Sweden in 2002 to 2005. Included in the pharmacokinetic evaluation were 155 patients (68% women and 32% men) aged 17 to 95 years (average, 51 years). One serum sample per patient, taken as a trough value in steady state, was assessed. For the inter- and intraindividual variation calculation, 16 patients were included with two eligible samples each. The median daily dose was 20 mg/day (range, 5-40 mg). Extensive overall serum concentration variability was seen for all dose levels. The interindividual coefficient of variation for dose-normalized concentrations was 71% for S-citalopram, 36% for S-desmethylcitalopram, and 50% for S- didesmethylcitalopram. The intraindividual variations over time for the same parameters were approximately 30%, except for the ratio S-desmethylcitalopram/S- citalopram, which was 23%. The median S-desmethylcitalopram level was approximately 60% of the parent substance and the S-didesmethylcitalopram level approximately 9%. Higher age was correlated with higher serum concentrations, but no gender-related concentration differences were found. A majority (76%) of the patients took one or more drugs in addition to escitalopram, but concomitant medication did not seem to interact with escitalopram. However, women taking oral contraceptives showed a lower metabolic ratio compared with age-matched women. As a result of the wide range of the ratio in this population, these findings are not considered of clinical relevance.
35.	Reis, Margareta, 1959-, et al. (författare) Therapeutic drug monitoring of racemic citalopram : a 5-year experience in Sweden, 1992-1997 2003 Ingår i: Therapeutic Drug Monitoring. - : Ovid Technologies (Wolters Kluwer Health). - 0163-4356 .- 1536-3694. ; 25:2, s. 183-191 Tidskriftsartikel (refereegranskat)abstract Racemic citalopram (CIT) was introduced in Sweden in 1992 for management of major depression. During a 5-year period, 1992 to 1997, serum samples of CIT and desmethylcitalopram (DCIT) were collected for therapeutic drug monitoring (TDM) from patients from all over Sweden. These samples were accompanied by clinical information on a specially designed TDM request form. They represented men and women of various ages (11-94 years) usually on multiple concomitant medications and treated in a naturalistic setting. The TDM samples eligible for evaluation (n = 749), all trough values at steady state, were studied with respect to inter- and intraindividual pharmacokinetic variability. Extensive, interindividual serum concentration variability was seen on all dose levels. For dose-corrected concentrations (C/D) and for clearance (C1) we found the coefficient of variation (CV) to be approximately 55% for all variables (C/D CIT, C/D DCIT, the ratio DCIT to CIT, and for C1 CIT). The intraindividual variations over time for the same parameters were 30% to 35%. On a population level, signs of a possible saturation of CYP2D6 associated with increasing DCIT-to-CIT ratios with increasing daily doses was observed. Age and gender affected the pharmacokinetics of CIT and DCIT. Women showed significantly higher C/D CIT and C/D DCIT and lower C1 CIT values compared with men, and patients aged more than 65 years had higher C/D CIT and C/D DCIT and lower C1 CIT values compared with younger patients. Finally, concomitant medication affected the outcome of serum concentrations by a general increase in C/D CIT and C/D DCIT but without alteration in the DCIT-to-CIT ratio. Thus, this tendency of changes in the CIT disposition when multiple drugs are used (and multiple diseases are prevailing?) seems more general in character than specific for a certain drug or type of drugs.
36.	Reis, Margareta, 1959-, et al. (författare) Therapeutic drug monitoring of racemic venlafaxine and its main metabolites in an everyday clinical setting 2002 Ingår i: Therapeutic Drug Monitoring. - : Ovid Technologies (Wolters Kluwer Health). - 0163-4356 .- 1536-3694. ; 24:4, s. 545-553 Tidskriftsartikel (refereegranskat)abstract When Efexor® (venlafaxine) became available in Sweden, a therapeutic drug monitoring (TDM) service was developed in the authors' laboratory. This analytical service was available to all physicians in the country. From March 1996, to November 1997, 797 serum concentration analyses of venlafaxine (VEN) and its main metabolites, O-desmethylvenlafaxine (ODV), N-desmethylvenlafaxine (NDV), and N,O-didesmethylvenlafaxine (DDV) were requested. These samples, each of which was accompanied by clinical information on a specially designed request form, represented 635 inpatients or outpatients, comprising all ages, treated in a naturalistic setting. The first sample per patient, drawn as a trough value in steady state and with documented concomitant medication, was further evaluated pharmacokinetically (n= 187). The doses prescribed were from 37.5 mg/d to 412.5 mg/d. There was a wide interindividual variability of serum concentrations on each dose level, and the mean coefficient of variation of the dose-corrected concentrations (C/D) was 166% for C/D VEN, 60% for C/D ODV, 151% for C/D NDV, and 59% for C/D DDV. The corresponding CV for the ratio ODV/VEN was 110%. However, within patients over time, the C/D VEN and ODV/VEN variation was low, indicating stability in individual metabolizing capacity. Patients over 65 years of age had significantly higher concentrations of C/D VEN and C/D ODV than the younger patients. Women had higher C/D NDV and C/D DDV, and a higher NDV/VEN ratio than men, and smokers showed lower C/D ODV and C/D DDV than nonsmokers. A number of polycombinations of drugs were assessed for interaction screening, and a trend for lowered ODV/VEN ratio was found, predominantly with concomitant medication with CNS-active drug(s) known to inhibit CYP2D6.
37.	Rosenqvist, Ulrika, et al. (författare) An interaction between sertraline and carbamazepine which resluted in sub-therapeutic concentrations of sertraline and N-desmethylsertraline in serum 2003 Ingår i: Therapeutic Drug Monitoring. - 0163-4356 .- 1536-3694. ; 25:4, s. 166- Konferensbidrag (övrigt vetenskapligt/konstnärligt)
38.	Skogh, Elisabeth, 1952-, et al. (författare) Could discontinuing smoking be hazardous for patients administered clozapine medication? A case report. 1999 Ingår i: Therapeutic Drug Monitoring. - 0163-4356 .- 1536-3694. ; 21, s. 580-582 Tidskriftsartikel (refereegranskat)
39.	Skogh, Elisabeth, 1952-, et al. (författare) Therapeutic drug monitoring data on olanzapine and its N-demethyl metabolite in the naturalistic clinical setting 2002 Ingår i: Therapeutic Drug Monitoring. - : Ovid Technologies (Wolters Kluwer Health). - 0163-4356 .- 1536-3694. ; 24, s. 518- Tidskriftsartikel (refereegranskat)abstract Olanzapine (Zyprexa(R)) was approved for general prescription in Sweden in November 1996, and an HPLC-based therapeutic drug monitoring (TDM) routine for serum olanzapine (OLA) and its major metabolite. N-demethylolanzapine (DMO) was established in February 1997. During 1997 to 1999, a total of 753 TDM requests for a total of 545 Swedish patients was analyi.ed. Additional patient information oil certain clinical variables was collected on specifically designed TDM request forms. After the exclusion process. samples from 194 patients were found to be eligible for further scrutiny. The concentration-to-dose (C/D) ratio for OLA varied 25-fold and that of DMO 22-fold. Women had a higher (P < 0.01) median C/D ratio for OLA than men (median, 7.2 nmol/L/mg, vs 5.2 nmol/L/mg). Nonsmokers had a higher (P < 0.001) C/D ratio for OLA than smokers (median, 9.2 nmol/L/mg vs 4.0 nmol/L/mg). Smokers got higher prescribed (P < 0.05) doses of OLA than nonsmokers did. In the group with reported side effects, the median serum OLA concentration was 22% higher (P < 0.05) than in the group without side effects. Patients co-medicated with carbamazepine had a 71% lower median C/D ratio for OLA than patients on OLA monotherapy. The present TDM-based follow-up suggests that the influence of gender, smoking habits. and certain drug interactions may need to be considered for optimal dosage of OLA. TDM may be used for this purpose more readily in the future.
40.	Skoglund, Karin, et al. (författare) In vivo CYP3A activity and pharmacokinetics of imatinib in relation to therapeutic outcome in chronic myeloid leukemia patients 2016 Ingår i: Therapeutic Drug Monitoring. - 0163-4356 .- 1536-3694. ; 38:2, s. 230-238 Tidskriftsartikel (refereegranskat)abstract BACKGROUND: CYP3A metabolic activity varies between individuals and is therefore a possible candidate of influence on the therapeutic outcome of the tyrosine kinase inhibitor imatinib in chronic myeloid leukemia (CML) patients. The aim of this study was to investigate the influence of CYP3A metabolic activity on the plasma concentration and outcome of imatinib in CML patients.METHODS: Forty-three CML patients were phenotyped for CYP3A activity using quinine as a probe drug and evaluated for clinical response parameters. Plasma concentrations of imatinib and its main metabolite, CGP74588, were determined using liquid chromatography-mass spectrometry.RESULTS: Patients with optimal response to imatinib after 12 months of therapy did not differ in CYP3A activity compared to non-optimal responders (quinine metabolic ratio of 14.69 and 14.70, respectively; P=0.966). Neither the imatinib plasma concentration nor the CGP74588/imatinib ratio was significantly associated with CYP3A activity.CONCLUSIONS: CYP3A activity does not influence imatinib plasma concentrations or the therapeutic outcome. These results indicate that even though imatinib is metabolized by CYP3A enzymes, this activity is not the rate-limiting step in imatinib metabolism and excretion. Future studies should focus on other pharmacokinetic processes so as to identify the major contributor to patient variability in imatinib plasma concentrations.
41.	Skoglund, Karin, et al. (författare) In Vivo Cytochrome P450 3A Isoenzyme Activity and Pharmacokinetics of Imatinib in Relation to Therapeutic Outcome in Patients With Chronic Myeloid Leukemia 2016 Ingår i: Therapeutic Drug Monitoring. - : LIPPINCOTT WILLIAMS & WILKINS. - 0163-4356 .- 1536-3694. ; 38:2, s. 230-238 Tidskriftsartikel (refereegranskat)abstract Background: Cytochrome P450 3A (CYP3A) isoenzyme metabolic activity varies between individuals and is therefore a possible candidate of influence on the therapeutic outcome of the tyrosine kinase inhibitor imatinib in patients with chronic myeloid leukemia (CML). The aim of this study was to investigate the influence of CYP3A metabolic activity on the plasma concentration and outcome of imatinib in patients with CML. Methods: Forty-three patients with CML were phenotyped for CYP3A activity using quinine as a probe drug and evaluated for clinical response parameters. Plasma concentrations of imatinib and its main metabolite, CGP74588, were determined using liquid chromatography-mass spectrometry. Results: Patients with optimal response to imatinib after 12 months of therapy did not differ in CYP3A activity compared to nonoptimal responders (quinine metabolic ratio of 14.69 and 14.70, respectively; P = 0.966). Neither the imatinib plasma concentration nor the CGP74588/imatinib ratio was significantly associated with CYP3A activity. Conclusions: The CYP3A activity does not influence imatinib plasma concentrations or the therapeutic outcome. These results indicate that although imatinib is metabolized by CYP3A enzymes, this activity is not the rate-limiting step in imatinib metabolism and excretion. Future studies should focus on other pharmacokinetic processes so as to identify the major contributor to patient variability in imatinib plasma concentrations.
42.	Skov-Skov Bergh, Marianne, et al. (författare) Distinguishing Between Cyclopropylfentanyl and Crotonylfentanyl by Methods Commonly Available in the Forensic Laboratory 2019 Ingår i: Therapeutic Drug Monitoring. - : LIPPINCOTT WILLIAMS & WILKINS. - 0163-4356 .- 1536-3694. ; 41:4, s. 519-527 Tidskriftsartikel (refereegranskat)abstract Background: The opioid analgesic fentanyl and its analogues pose a major health concern due to its high potency and the increasing number of overdose deaths worldwide. The analogues of fentanyl may differ in potency, toxicity, and legal status, and it is therefore important to develop analytical methods for their correct identification. This can be challenging since many fentanyl analogues are structural isomers. Two fentanyl isomers that have been in the spotlight lately due to difficulties regarding separation and identification are cyclopropylfentanyl and crotonylfentanyl, which have been reported to display nearly identical fragmentation patterns and chromatographic behavior. Methods: Chromatographic separation of cyclopropylfentanyl and crotonylfentanyl by ultra-high-performance liquid chromatography was investigated using 3 different stationary phases (high strength silica T3, ethylsiloxane/silica hybrid C-18, and Kinetex biphenyl) using gradient elution with a mobile phase consisting of 10 mM ammonium formate pH 3.1 and MeOH. Detection was performed by tandem mass spectrometry. In addition, the major metabolites of the 2 compounds formed on incubation with human liver microsomes were identified by ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry analysis. Results: Baseline separation of cyclopropylfentanyl and crotonylfentanyl was achieved on the ethylsiloxane/silica hybrid C-18 column with retention times of 6.79 and 7.35 minutes, respectively. The major metabolites of the 2 analogues formed by human liver microsomes differed, with the main biotransformation being N-dealkylation and carboxylation for cyclopropylfentanyl and crotonylfentanyl, respectively. We demonstrated the usefulness of the 2 approaches by unambiguously identifying cyclopropylfentanyl, as well as its metabolites, in 2 authentic postmortem blood samples. Conclusions: In this study, we successfully demonstrated that cyclopropylfentanyl and crotonylfentanyl can be distinguished by methods commonly available in forensic laboratories.
43.	Toepper, Christoph, et al. (författare) Variable Linezolid Exposure in Intensive Care Unit PatientsPossible Role of Drug-Drug Interactions 2016 Ingår i: Therapeutic Drug Monitoring. - 0163-4356 .- 1536-3694. ; 38:5, s. 573-578 Tidskriftsartikel (refereegranskat)abstract Background:Standard doses of linezolid may not be suitable for all patient groups. Intensive care unit (ICU) patients in particular may be at risk of inadequate concentrations. This study investigated variability of drug exposure and its potential sources in this population.Methods:Plasma concentrations of linezolid were determined by high-performance liquid chromatography in a convenience sample of 20 ICU patients treated with intravenous linezolid 600 mg twice daily. Ultrafiltration applying physiological conditions (pH 7.4/37 degrees C) was used to determine the unbound fraction. Individual pharmacokinetic (PK) parameters were estimated by population PK modeling. As measures of exposure to linezolid, area under the concentration-time curve (AUC) and trough concentrations (C-min) were calculated and compared with published therapeutic ranges (AUC 200-400 mgh/L, C-min 2-10 mg/L). Coadministered inhibitors or inducers of cytochrome P450 and/or P-glycoprotein were noted.Results:Data from 18 patients were included into the PK evaluation. Drug exposure was highly variable (median, range: AUC 185, 48-618 mgh/L, calculated C-min 2.92, 0.0062-18.9 mg/L), and only a minority of patients had values within the target ranges (6 and 7, respectively). AUC and C-min were linearly correlated (R = 0.98), and classification of patients (underexposed/within therapeutic range/overexposed) according to AUC or C-min was concordant in 15 cases. Coadministration of inhibitors was associated with a trend to higher drug exposure, whereas 3 patients treated with levothyroxine showed exceedingly low drug exposure (AUC approximate to 60 mg*h/L, C-min <0.4 mg/L). The median unbound fraction in all 20 patients was 90.9%.Conclusions:Drug exposure after standard doses of linezolid is highly variable and difficult to predict in ICU patients, and therapeutic drug monitoring seems advisable. PK drug-drug interactions might partly be responsible and should be further investigated; protein binding appears to be stable and irrelevant.
44.	Van der Heijden, Lisa T., et al. (författare) Development of a Therapeutic Drug Monitoring Strategy for the Optimization of Vincristine Treatment in Pediatric Oncology Populations in Africa 2023 Ingår i: Therapeutic Drug Monitoring. - : Ovid Technologies (Wolters Kluwer Health). - 0163-4356 .- 1536-3694. ; 45:3, s. 354-363 Tidskriftsartikel (refereegranskat)abstract Background:Recent studies have reported ethnic differences in vincristine exposure and outcomes such as toxicity. This resulted in the hypothesis of subtherapeutic dosing in African children. To optimize individual treatment, a strategy to identify subtherapeutic exposure using therapeutic drug monitoring is essential. The aim of the current study was to develop a strategy for therapeutic drug monitoring of vincristine in African children to meet the following criteria: (1) identify patients with low vincristine exposure with sufficient sensitivity (>70%), (2) determine vincristine exposure with a limited sampling strategy design of 3 samples, and (3) allow all samples to be collected within 4 hours after administration.Methods:An in silico simulation study was performed using a previously described population pharmacokinetic model and real-life demographic dataset of Kenyan and Malawian pediatric oncology patients. Two different therapeutic drug monitoring strategies were evaluated: (1) Bayesian approach and (2) pharmacometric nomogram. The sampling design was optimized using the constraints described above. Sensitivity analysis was performed to investigate the influence of missing samples, erroneous sampling times, and different boundaries on the nomogram weight bands.Results:With the Bayesian approach, 43.3% of the estimated individual exposure values had a prediction error of & GE;20% owing to extremely high shrinkage. The Bayesian approach did not improve with alternative sampling designs within sampling constraints. However, the pharmacometric nomogram could identify patients with low vincristine exposure with a sensitivity, specificity, and accuracy of 75.1%, 76.4%, and 75.9%, respectively. The pharmacometric nomogram performed similarly for different weight bands.Conclusions:The pharmacometric nomogram was able to identify patients with low vincristine exposure with high sensitivity, with 3 blood samples collected at 1, 1.5, and 4 hours after administration. Missing samples should be avoided, and the 3 scheduled samples should be collected within 15, 5, and 15 minutes of 1, 1.5, and 4 hours after administration, respectively.
45.	Vikingsson, Svante, et al. (författare) Monitoring of thiopurine metabolites in patients with inflammatory bowel disease-what is actually measured? 2009 Ingår i: Therapeutic Drug Monitoring. - 0163-4356 .- 1536-3694. ; 31:3, s. 345-50 Tidskriftsartikel (refereegranskat)abstract Azathioprine and 6-mercaptopurine are often used in the treatment of patients with inflammatory bowel disease (IBD). They are prodrugs and undergo a complex metabolism to active and inactive metabolites. Thiopurine treatment is monitored in many laboratories by measuring metabolite concentrations in erythrocytes (red blood cells). The metabolites of interest are not measured directly but as hydrolysis products, which can be produced from several metabolites. The aim of this study was to examine which metabolites are actually measured during routine monitoring. Samples from 18 patients treated with a thiopurine were analyzed by a typical routine high-performance liquid chromatography method for therapeutic drug monitoring and by a newly developed specific method measuring thioguanosine monophosphate (TGMP), thioguanosine diphosphate (TGDP), and thioguanosine triphosphate (TGTP), as well as methylthioinosine monophosphate (meTIMP), and the results were compared. 6-Thioguanine nucleotide (TGN) values detected by the routine method were 69% (range 40%-90%) of the sum of TGMP, TGDP, and TGTP measured by the specific method. TGTP and TGDP contributed 85% (range 78%-90%) and 14% (range 10%-21%) of the TGN total, respectively. Thioguanosine was not found in any patient sample. The concentration of meTIMP obtained by the routine method was 548% of the value obtained by the specific method (range 340%-718%). The difference in TGN measurements between the routine and specific methods can be explained by low hydrolysis efficiency in the routine method, although the most likely explanation for the difference in meTIMP values is that not yet identified metabolites are codetermined in the routine high-performance liquid chromatography method. Concentrations reported as TGN during therapeutic drug monitoring of thiopurine metabolites consist of TGDP and TGTP with a minor contribution of the TGMP. Concentrations reported as meTIMP or methyl mercaptopurine consist in part of meTIMP, but other not yet identified metabolites are codetermined.
46.	von Euler, Mia, 1967-, et al. (författare) Differential diagnosis of central nervous system involvement in a patient treated with acyclovir 2013 Ingår i: Therapeutic Drug Monitoring. - : Lippincott Williams & Wilkins. - 0163-4356 .- 1536-3694. ; 35:4, s. 417-419 Tidskriftsartikel (refereegranskat)abstract Acyclovir-induced neuropsychiatric symptoms (AINSs) may resemble several diseases of the central nervous system. Laboratory testing of acyclovir may be critical in supporting the diagnosis of AINSs when there is doubt. We present a case of suspected herpes encephalitis in which the diagnosis of AINSs was supported by therapeutic drug monitoring of plasma and cerebrospinal fluid concentrations of acyclovir and its main metabolite 9-carboxymethoxymethylguanine.
47.	von Euler, Mia, 1967-, et al. (författare) Interpretation of the presence of 6-monoacetylmorphine in the absence of morphine-3-glucuronide in urine samples : evidence of heroin abuse 2003 Ingår i: Therapeutic Drug Monitoring. - : Wolters Kluwer. - 0163-4356 .- 1536-3694. ; 25:5, s. 645-648 Tidskriftsartikel (refereegranskat)abstract The presence of morphine in a urinary sample may be caused not only by intake of heroin but also by intake of poppy-seed-containing food shortly before urine sampling or intake of drugs containing morphine, ethyl morphine, or codeine. To facilitate the interpretation, the heroin-specific metabolite 6-monoacetylmorphine (6-MAM) can be analyzed along with morphine-3-glucuronide (M3G) in an LC-MS verification analysis. In sporadic samples positive in the immunologic opiate screening test, 6-MAM, but not M3G, was found. To systematically analyze the finding all specimens with positive 6-MAM and/or M3G found during a 1-year period were investigated (n = 1923). Of these, 423 were positive for 6-MAM. In 32 (7.6%) of the samples 6-MAM was detected while the M3G concentrations were below cutoff (300 ng/mL) and in some cases even below the limit of detection (15 ng/mL). The 32 samples with this excretion pattern came from 13 different individuals, all but one with previously known heroin abuse. Eleven urine samples, nine containing M3G and 6-MAM and two with only 6-MAM, were also analyzed for the presence of heroin. In six samples, including the two with only 6-MAM, heroin was detected. There are several plausible explanations for these findings. The intake may have taken place shortly before urine sampling. High concentrations of heroin and 6-MAM may inhibit UGT 2B7, the enzyme responsible for glucuronidation of morphine. The hydrolyzation of 6-MAM to morphine may be disturbed by either internal or external causes. To elucidate this, further studies are required. Nevertheless, our finding demonstrates that routine measurement of 6-MAM when verifying opioid-positive immunologic screening results facilitates interpretation of low concentrations of M3G in urine specimens.
48.	Wallin, Johan E, et al. (författare) Population pharmacokinetics of tacrolimus in pediatric liver transplantation : early posttransplantation clearance 2011 Ingår i: Therapeutic Drug Monitoring. - 0163-4356 .- 1536-3694. ; 33:6, s. 663-672 Tidskriftsartikel (refereegranskat)abstract BACKGROUND: Tacrolimus is an immunosuppressant with a narrow therapeutic window, with considerable pharmacokinetic variability. Getting sufficient concentrations in pediatric liver transplantation is imperative, but it has proven difficult in the immediate posttransplantation period in particular. A predictive pharmacokinetic model could be the basis for development of a novel initial dose schedule, and therapeutic drug monitoring with Bayesian methodology. METHODS: The predictive capacity of 2 previously developed population pharmacokinetic models of tacrolimus in pediatric liver transplant recipients was tested in 20 new patients using Bayesian forecasting. Predictive performance was poor in the immediate posttransplant period with tacrolimus pharmacokinetics changing rapidly. A new population pharmacokinetic model, focusing on the immediate posttransplant period, was subsequently developed in 73 patients. RESULTS: An increase in the apparent clearance of tacrolimus in the first few weeks after transplant was evident. Typical apparent clearance of tacrolimus was 0.148 L·h·kg immediately after transplantation, increasing to a maximum of 1.37 L·h·kg. Typical apparent distribution volume was 27.2 L/kg. Internal and external validation studies confirmed the predictive capabilities of the developed model. Simulation studies reveal that in 60% of subjects the current initial standard dose without subsequent dosage adjustments overshoot the desired trough concentration range of 10-20 ng/mL. An alternative dosing schedule was developed based on allometric scaling with an initial loading dose followed by a maintenance dose increasing with time. CONCLUSIONS: A population pharmacokinetic model for tacrolimus was developed, to better describe the early posttransplantation phase. This model has the potential to aid therapeutic drug monitoring and was also used to suggest a revised dosing scheme in the intended population.
49.	Wallin, Johan, 1974-, et al. (författare) Population pharmacokinetics of tacrolimus in paediatric haematopoietic stem cell transplant recipients : New initial dosage suggestions and a model based dosage adjustment tool 2009 Ingår i: Therapeutic Drug Monitoring. - Philadelphia PA, US : Lippincott Williams & Wilkins. - 0163-4356 .- 1536-3694. ; 31:4, s. 457-466 Tidskriftsartikel (refereegranskat)abstract The population pharmacokinetics of tacrolimus was described in 22 paediatric haematopoietic stem cell transplant recipients and a model-based dosage adjustment tool that may assist with therapy in new patients was developed. Patients received tacrolimus by continuous intravenous infusion (0.03mg/kg/day) starting two days before transplantation, with conversion to oral therapy 2-3 weeks post-transplant. Population pharmacokinetic analysis was performed using NONMEM. A dosage adjustment tool that searches for individual parameter estimates to describe concentration measurements, counter-balanced by the final population model, was created in Excel. Typical clearance was 106 mL/h/kg0.75, typical distribution volume was 3.71 L/kg and typical bioavailability was 15.7%. Tacrolimus clearance decreased with increasing serum creatinine and bioavailability decreased with post-operative day. Predictions from the model showed that current intravenous dose recommendations of 0.03 mg/kg/day may produce potentially toxic drug concentrations in the patient population, whereas current oral conversion of four times the adjusted intravenous dose may lead to subtherapeutic concentrations. We suggest a dose of 0.035mg/kg0.75/day to ensure satisfactory levels, and an oral conversion factor of six times the intravenous dose. A dosage adjustment tool was developed that is capable of suggesting an initial infusion rate based on patient weight and serum creatinine and of devising a further individualised dosage as individual drug concentration measurements become available. The tool also allows the clinicia to graphically examine the concentration-time profile of tacrolimus under different infusion rates, with or without a loading dose.
50.	Woksepp, Hanna, et al. (författare) Simultaneous Measurement of 11 Antibiotics for Use in the Intensive Care Unit by Ultra-High Performance Liquid Chromatography-Tandem Mass Spectrometry 2022 Ingår i: Therapeutic Drug Monitoring. - : Lippincott Williams & Wilkins. - 0163-4356 .- 1536-3694. ; 44:2, s. 308-318 Tidskriftsartikel (refereegranskat)abstract Background: Recent studies indicate that a high proportion of patients in the intensive care unit fail to attain adequate antibiotic levels. Thus, there is a need to monitor the antibiotic concentration to ensure effective treatment. In this article, the authors aimed to develop an ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method for the simultaneous quantification of antimicrobials to assess individualized therapeutic drug monitoring. Methods: A UHPLC-MS/MS method with 11 antibiotics (ciprofloxacin, moxifloxacin, benzylpenicillin, levofloxacin, linezolid, rifampicin, meropenem, cloxacillin, cefotaxime, clindamycin, and piperacillin) was developed. Chromatographic separation was performed using a Kinetex Biphenyl reversed-phase column, with gradient elution using 0.1% formic acid and methanol with 0.1% formic acid. Sample preparation was performed using methanol protein precipitation. The total run time was 5 minutes. Results: For all analytes, the interassay inaccuracies for calibrators were <= 5%. The interday inaccuracies for the quality controls (QCs) were <= 5% for all analytes. The interassay precision for calibration standards ranged between 1.42% and 6.11%. The interassay imprecision for QCs of all antibiotics and concentrations ranged between 3.60% and 16.1%. Interassay inaccuracy and imprecision for the QCs and calibration standards were <= 15% for all drugs, except benzylpenicillin. Conclusions: A rapid UHPLC-MS/MS method was developed for the simultaneous quantification of 11 different antibiotics. Minimal sample preparation was required to ensure a rapid turnaround time. The method was applied to clinical samples collected from 4 intensive care units.

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