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Abstract

Augmented renal clearance (ARC) is a recently reported condition in pathophysiology of critically ill patients in the intensive care unit. ARC refers to the enhanced renal elimination of circulating solutes. These patients are either young or previously healthy people who have undergone surgery or multiple trauma.

This case report describes an adjustment of dosing regime of vancomycin to a young patient, who demonstrated ARC with severe polytrauma, overcome crush syndrome and sepsis. This 16-year old male patient was crushed by a tractor, which caused severe tissue damaged in the right lower limb. He gradually developed a serious crush syndrome. When kidneys resumed their function, creatinine clearance reached the value that indicated ARC (339.81 mL/min/1.73 m2). Vancomycin was included in the patient’s treatment regime by administering conventional dose of 1 g per 12 hours. The residual measured levels were very low. The dose of vancomycin had to be adjusted to double and then to triple the conventional dose. Without the therapeutic drug monitoring (TDM) and subsequent interpretation of the results by the clinical pharmacists, such high doses would not have been considered for administration.

ARC responds strongly to sub-therapeutic serum vancomycin levels. Our case report confirms the significance of TDM and the consecutive interpretation of the results in critically ill patients.

The problem of low peak concentration of gentamicin in clinical practice

Aminoglycoside antibiotics have particular importance in the treatment of Gram-negative infections. Toxicity of gentamicin is well-known, but patients often receive insufficient dosage in clinical practice. The purpose of this study was to refer to the problem of insufficient dosages that were confirmed by low peak concentration and to determine relationship between low peak levels and pharmacokinetic parameters, renal function and body weight.

We studied 68 patients who were treated with gentamicin for one year (August 2010 - August 2011). Therapeutic drug monitoring (TDM) was applied for all the patients. Gentamicin peak and trough concentrations were measured by the FPIA (Fluorescence Polarization Immunoassay) method with an analyser, AxSYM of ABBOTT company. We divided the patients into 3 groups according to peak and trough levels.

Together 13 (19%) patients had high trough concentrations and optimal peak concentrations. Only 6 (9%) patients had optimal trough and peak levels in the first measurement of plasma concentrations. The third group included 49 patients (72%). These patients had optimal trough levels and low peak levels in the first measurement. 34 patients of the third group (28 males, 6 females) had optimal peak levels after adjustment of dosage in the second measurement. 15 patients, only males did not reach optimal peak levels even after adjustment of dosage in the second measurement.

The patients with low peak levels of gentamicin are more frequent than patients with toxic adverse effects in clinical practice. Especially, these are the patients with higher value of body weight and following increased pharmacokinetic parameters: creatinine clearance, total volume of distribution, total clearance and elimination rate constant. The clinical pharmacists have to adjust dosage regimens, especially according to Therapeutic drug monitoring (TDM) and clinical experience. The results of the study have confirmed that the clinical pharmacists must adjust dose regimen not only for patients who require reduced doses but more often for patients who require higher doses than are commonly used in clinical practice. These patients are at risk of underdosing of aminoglycoside antibiotics.

administration and one third of patients do not achieve total remission ( Cai et al., 2017 ). Therapeutic drug monitoring (TDM) is a beneficial patient management tool for quantification and subsequent interpretation of drug concentrations in blood in order to individualize and optimize pharmacotherapy. TDM enables individual dose adjustments according to the properties of the drug, patient characteristics, and measured concentration in blood. Therefore, it is considered as an important tool mainly in patients with variabilities in pharmacokinetics such as patients suffering

Abstract

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

Abstract

Background: Therapeutic drug monitoring (TDM) in patients with Chronic Kidney Disease (CKD) with kidney transplant, represents a major post transplant concern due to the characteristics of this special category of patients, particularities which can generate changes of the pharmacokinetic profile of the administered medication.

Material and methods: The current study is a retrospective pharmacokinetic study, over a period of 50 months, including a group of 36 kidney transplanted patients with CKD. Tacrolimus blood concentration was determined by a validated high-performance liquid chromatography method (HPLC), at a 12 hour time interval from the last administration of the immunosuppressive medication and before the following dose (Residual concentration, Cmin(trough)).

Results: During the monitoring of therapy, based on the pharmacokinetic criteria, 252 measurements of blood concentration were determined, 58 of these being outside the therapeutic window.

Conclusions: The results obtained show that it is mandatory to continue to monitor closely medical therapy based on the pharmacokinetic criteria in view of improving drug administration. The other ways of monitoring therapy: the clinical and biochemical criteria should not be overlooked. In addition, the interindividual variability of patients should be considered, as well as drug interaction which can alter the pharmacokinetics of tacrolimus.

Summary

Immunosuppressive drugs play a crucial role in the inhibition of immune reaction and prevention of graft rejection as well as in the pharmacotherapy of autoimmune disorders. Effective immunosuppression should provide an adequate safety profile and improve treatment outcomes and the patients’ quality of life. High-risk transplant recipients may be identified, but a definitive prediction model has still not been recognized. Therapeutic drug monitoring (TDM) for immunosuppressive drugs is an essential, but at the same time insufficient tool due to low predictability of drug exposition and marked pharmacokinetic variability. Parallel therapeutic, biochemical and clinical monitoring may successfully optimize and individualize therapy for transplanted recipients, providing optimal medical outcomes. Modern pharmacotherapy management should include new biomarkers with better sensitivity and specificity that can identify early cell damage. The aim of this study was to point out the importance of finding new biomarkers that would enable early detection of adverse drug events and cell damage in organ transplant recipients. We wanted to confirm the importance of routine biochemical monitoring in improving the safety of immunosuppressive treatment.

Summary

Background

Due to wide intra- and inter-individual pharmacokinetic variability and narrow therapeutic index of sirolimus, the therapeutic drug monitoring (TDM) of sirolimus with detailed biochemical and clinical monitoring is necessary for dose individualization in kidney transplant patients. The purpose of the study was to explore and identify factors that contribute to pharmacokinetic variability by developing and validating a population model using routine TDM data and routinely monitored biochemical and clinical parameters.

Methods

The data obtained by routine monitoring of 38 patients over a period of one year from the sirolimus treatment initiation, were collected from patients’ records. Population analysis was performed using the software NONMEM®. The validity of the model was tested by the internal and external validation techniques.

Results

The pharmacokinetic variability was partially explained with patient’s age and liver function. CL/F was found to decrease with age. According to the developed model, sirolimus CL/F decreases by, in average, 37% in patients with aspartate aminotransferase (AST) greater than 37 IU/L. The internal and external validation confirmed the satisfactory prediction of the developed model.

Conclusions

The population modeling of routinely monitored data allowed quantification of the age and liver function influence on sirolimus CL/F. According to the final model, patients with compromised liver function expressed via AST values require careful monitoring and dosing adjustments. Proven good predictive performance makes this model a useful tool in everyday clinical practice.

Abstract

Introduction A gentamicin dose, which the physicians select, frequently does not take any pharmacokinetic parameters into consideration.

Aim To analyse the results of therapeutic drug monitoring (TDM) of gentamicin for those patients who have not had the gentamicin dose adjusted at the beginning of therapy (first group) and for those patients who had the gentamicin dose adjusted at the beginning of therapy (second group).

Methods We acquired the basic data about patients from the requests for laboratory examination of levels of gentamicin. We measured all the gentamicin concentrations mentioned in this work using the FPIA method.

Results The monitored set included 379 hospitalized patients during a 4-year period. We divided the monitored set into 2 groups. First group was composed of patients without dose adjustment of gentamicin at the beginning of therapy, and the second group was composed of patients with dose adjustment of gentamicin by the clinical pharmacist at the beginning of therapy. In addition, the patients in each group were divided according to the body mass index (BMI). In the first group of patients, a low percentage of patients had both optimal levels (trough, peak levels). As for patients with BMI > 25 m2/kg, there were only 17 % such cases, and the patients with BMI ≤ 25 m2/kg were only 18.8 %. In the second group, the patients had all trough and peak levels in optimal therapeutic range at obese patients, overweight patients and also at patients with normal weight (p < 0.001).

Conclusion Adjustment of dosage regimens immediately at the beginning of therapy will provide for administering sufficient doses of antibiotics at the beginning of therapy, which is a pre-condition for a successful anti-infective therapy. Therapeutic monitoring of levels allows for administration of sufficient dose of gentamicin without fear of any undesirable effects.

Summary

Background: Busulfan (Bu) requires therapeutic drug monitoring (TDM) in subjects undergoing a conditioning regimen for hematopoietic stem cell transplantation (HSCT). To speed up the procedure and increase reproducibility, we improved our routine LC-MS/MS assay using the on-line solid-phase extraction (SPE) of samples.

Methods: A protein precipitation (PP) step was performed before the on-line SPE of Bu from 200 μL of plasma spiked with octa-deuterated Bu (D8-Bu) as the internal standard. Bias was assessed with respect to our routine LC-MS/MS Bu assay with off-line extraction using the Passing-Bablok robust regression. Root cause of bias for individual samples was assessed by analyzing the regression residuals.

Results: The method was linear in the range 37.75-2,416 ng/mL (r2>0.999), with 19.74 ng/mL LLOQ and 10.5% CV at 20 ng/mL. Precision and accuracy were both within ±5%, and neither appreciable matrix nor carryover effects were observed. The Passing-Bablok regression analysis returned a 0.99 slope (95% Cl: 0.97 to 1.01) and -6.82 intercept (95% Cl: -15.23 to 3.53). Residuals analysis against the 2.5th-97.5th percentiles range showed four samples with significant bias individually.

Conclusions: The method presented can be successfully employed for the routine analysis of Bu in plasmatic samples, and can replace the LC-MS/MS method with off-line extraction without any statistically significant overall bias. In this regard, samples with individual significant bias were reasonably produced by preanalytical issues which had no relation with the conversion to the on-line SPE extraction.