Evidence for Therapeutic Drug Monitoring of Atypical Antipsychotics.

Second-generation antipsychotics (SGAs), also known as atypical antipsychotics, are a newer class of antipsychotic drugs used to treat schizophrenia, bipolar disorder, and related psychiatric conditions. The plasma concentration of antipsychotic drugs is a valid measure of the drug at its primary target structure in the brain, and therefore determines the efficacy and safety of these drugs. However, despite the well-known high variability in pharmacokinetics of these substances, psychiatric medication is usually administered in uniform dosage schedules. Therapeutic drug monitoring (TDM), as the specific method that can help personalised medicine in dose adjustment according to the characteristics of the individual patient, minimizing the risk of toxicity, monitoring adherence, and increasing cost-effectiveness in the treatment, thus seems to be an elegant tool to solve this problem. Non-response to therapeutic doses, uncertain adherence to medication, suboptimal tolerability, or pharmacokinetic drug-drug interactions are typical indications for TDM of SGAs. This review aims to summarize an overview of the current knowledge and evidence of the possibilities to tailor the dosage of selected SGAs using TDM, including the necessary pharmacokinetic parameters for personalised pharmacotherapy.

Do clinical pharmacists contribute to fall prevention in healthcare facilities also in the Czech Republic? 10 years of monitoring and experience from ÚVN Prague.

Clinical pharmacists are encouraged to participate in falls prevention programs in many healthcare facilities. A uniform methodology for the work of clinical pharmacist in fall prevention has not yet been established in the Czech Republic. The aim of this work is to offer the methodology based on our own data analysis. Retrospective clinical pharmacist's output analysis was performed in two areas: fall's pharmacoprevention and post-fall drug audits. In the results 78 % of patients who fell during hospitalization were over 65 years of age. Age was subsequently taken as the basic criterion for the patient's medication evaluation with regard to the risk of falling. Thanks to the widespread expansion of clinical pharmaceutical care and the newly introduced fall prevention and monitoring system at ÚVN Prague, there was a positive trend in the incidence of medication's adverse effects on patient's falls: in 2017 it was 34 % of cases, in 2020 only 13 %. Based on our data and experience, we offer a methodology for the clinical pharmacist's activity in fall prevention: 1. performing revision of medication also with regard to the risk of falls in patients over 65 years of age, 2. ensuring the automatic requests sending to the clinical pharmacy department in the case of a patient's fall in a medical facility.

Do we care enough about the medication in the elderly? (Case of the geriatric care facility at Military University Hospital Prague).

OBJECTIVE: The aim of this paper is a complex evaluation of clients medication in the geriatric care facility Domov Vlčí mák (DVM) with regard to the most common drug related risk factors in elderly. The paper shows ways of identification, resolution and prevention of drug related problems from the perspective of a clinical pharmacist. METHODS: The medication was evaluated in 74 DVM clients. The sample consisted of 45 women (61 %) and 29 men (39 %) with an average age of 90 years. The project took place in the period from April to June 2020. Patients pharmacotherapy was graded as low, medium or high risk in accordance with the methodology and concept of clinical pharmaceutical care in the Czech Republic developed by the Czech Professional Society of Clinical Pharmacy ČLS JEP. For all clients, medication was also assessed in terms of the risk of falls. RESULTS: There was a total of 62 (84 %) high, 4 (5 %) medium and 8 (11 %) low risk clients. A plan for medication adjustments was proposed for a total of 67 clients in the form of pharmacotherapeutic recommendations. A total of 170 drug related problems was identified and pharmacotherapeutic intervention was performed. The most common problem (in 42 % of cases) was a missing drug in terms of effective therapy. Medication discontinuation was recommended in 33 % of cases, mainly due to the risk of side effects, missing indications or drug necessity. Inadequate dosing was found in 15 % of cases, usually it was recommended to reduce the dose to the so-called “senior dose”. In 6 % of cases laboratory testing was indicated and in 4 % of cases timing of the drug administration was changed. CONCLUSION: Identified drug related problems did not represent major errors that could endanger the quality or safety of the healthcare provided. One of the reasons for the good outcome is an established multidisciplinary cooperation in this facility.

Perioperative management of metformin: is there something new?

Metformin is the drug of choice in the treatment of type 2 diabetes mellitus. Diabetic patients treated with metformin, who are scheduled for surgery, have always been subjects to discussion regarding the perioperative management of metformin because of the risk of developing lactic acidosis. The article presents the basic informations about this adverse event, describes new approach to the metformin treatment in the perioperative period, and summarizes the recommendations of professional societies and expert groups.

Clinically significant drug interactions of antiretrovirals.

Evaluating of the clinical significance of drug interactions is one of the domains of clinical pharmacist expertise. Drug interactions are discussed when two or more drugs co-administer and the effect of one of them changes. Drug interactions can be a serious cause of toxicity and side effects. They can also lead to the failure of the treatment. On the other hand, they can also play a positive role, e. g. in the treatment of people living with HIV. The combination of some antiretrovirals with boosters is based on the principle of drug interaction. The article presents pharmacokinetic drug interactions of antiretrovirals. Their occurrence is not unique in the clinical practice. The pharmacokinetic profiles of the individual antiretrovirals, whose knowledge is essential for the correct assessment of the clinical significance of drug interactions, are reviewed.

[A Case of a patient with AIDS and pneumocystis pneumonia complicated by cytomegalovirus pneumonitis].

We report a case of a 39-year-old male admitted for respiratory failure. On admission, the patient was diagnosed with advanced HIV infection and Pneumocystis jirovecii pneumonia (PJP). The patient's condition improved following specific PJP therapy but then deteriorated. The patient was subsequently diagnosed with cytomegalovirus pneumonitis and treated with ganciclovir. The severe course of both opportunistic infections required long-term care at an intensive care unit. Despite complications, the patient was discharged after 108 inpatient days in a stable clinical condition. The case demonstrates a rare coincidence of PJP and cytomegalovirus pneumonitis while also emphasizing the importance of correct diagnosis, treatment and interdisciplinary care which, despite poor prognosis, may lead to successful cure of serious simultaneous opportunistic infections in AIDS.

Vancomycin population pharmacokinetics and dosing proposal for the initial treatment in obese adult patients.

Aim: The aim of this study was to develop a vancomycin population pharmacokinetic model in adult obese patients and propose covariate-based dosing individualization in order to maximize the achievement of the newly recommended PK/PD target, according to a revised consensus guideline from 2020. Methods: Therapeutic drug monitoring data from initial vancomycin therapy (first 3 days of treatment) in adult obese (BMI ≥ 30 kg/m2) patients from 2013 to 2022 were analyzed using a non-linear mixed-effects modeling method, and Monte Carlo simulations were then used to find the optimal dosage maximizing the PK/PD target attainment. Results: A total of 147 vancomycin serum levels obtained from 138 patients were included in the analysis. Based on the covariate model diagnosis among all tested variables, no reliable predictor of vancomycin volume of distribution (Vd) was identified, while clearance (CL) was positively correlated with eGFR and lean body mass. Creatinine-based eGFR predicted vancomycin CL better than cystatin C-based eGFR. The median (interquartile range) value from conditional modes of individual estimates of Vd, CL, and elimination half-life in our population was 74.0 (70.5-75.4) L, 6.65 (4.95-8.42) L/h, and 7.7 (6.0-10.0) h, respectively. Conclusion: We proposed dosing individualization based on the covariate found in order to maximize the achievement of the newly recommended PK/PD target of the AUC/MIC ratio of 400-600. Clinical pharmacy/pharmacology interventions may lead to an improvement in vancomycin dosing with a reflection in PK/PD target attainment.

Vancomycin loading dose individualization in a population of obese patients undergoing haemodialysis based on population pharmacokinetic model.

This study aimed to develop a vancomycin population pharmacokinetic model in obese adult patients treated with intermittent haemodialysis and propose a model-based loading dose strategy ensuring attainment of newly recommended AUC-based PK/PD target. Retrospective cross-sectional analysis was performed among obese haemodialysis dependent adult patients treated with intravenous vancomycin. A pharmacokinetic population model was developed using a nonlinear mixed-effects modelling approach and Monte Carlo simulations were used to identify the optimal loading dose for PK/PD target attainment during the first 48 h of treatment. Therapeutic drug monitoring data from 27 patients with a BMI of 30.2-52.9 kg/m2 were analysed. Among all tested variables, only LBM as a covariate of vancomycin Vd significantly improved the model, while vancomycin CL did not correlate with any of the tested variables. The median (IQR) value from the conditional mean of individual estimates of Vd and CL was 68.4 (56.6-84.2) L and 0.86 (0.79-0.90) L/h, respectively. To ensure optimal vancomycin exposure during the first 48 h of therapy, the vancomycin loading dose of 1500, 1750, 2000, 2250, 2500 and 2750 mg should be administered to obese patients with a lean body mass of ˂50, 50-60, 60-70, 70-80, 80-85 and >85 kg, respectively.

Population Pharmacokinetic Analysis Proves Superiority of Continuous Infusion in PK/PD Target Attainment with Oxacillin in Staphylococcal Infections.

Considering its very short elimination half-life, the approved oxacillin dosage might not be sufficient to maintain the pharmacokinetic/pharmacodynamics (PK/PD) target of time-dependent antibiotics. This study aimed to describe the population pharmacokinetics of oxacillin and to explore the probability of PK/PD target attainment by using various dosing regimens with oxacillin in staphylococcal infections. Both total and unbound oxacillin plasma concentrations retrieved as a part of routine therapeutic drug-monitoring practice were analyzed using nonlinear mixed-effects modeling. Monte Carlo simulations were used to generate the theoretical distribution of unbound oxacillin plasma concentration-time profiles at various dosage regimens. Data from 24 patients treated with oxacillin for staphylococcal infection have been included into the analysis. The volume of distribution of oxacillin in the population was 11.2 L, while the elimination rate constant baseline of 0.73 h-1 increased by 0.3 h-1 with each 1 mL/s/1.73 m2 of the estimated glomerular filtration rate (eGFR). The median value of oxacillin binding to plasma proteins was 86%. The superiority of continuous infusion in achieving target PK/PD values was demonstrated and dosing according to eGFR was proposed. Daily oxacillin doses of 9.5 g, 11 g, or 12.5 g administered by continuous infusion have been shown to be optimal for achieving target PK/PD values in patients with moderate, mild, or normal renal function, respectively.

Meropenem population pharmacokinetics and model-based dosing optimisation in patients with serious bacterial infection.

OBJECTIVES: The objective of this study was to develop a population pharmacokinetic model of meropenem in a heterogeneous population of patients with a serious bacterial infection in order to propose dosing optimisation leading to improved achievement of the pharmacokinetic/pharmacodynamic (PK/PD) target. METHODS: A total of 174 meropenem serum levels obtained from 144 patients during therapeutic drug monitoring were analysed using a non-linear mixed-effects modelling approach and Monte Carlo simulation was then used to compare various dosing regimens in order to optimise PK/PD target attainment. RESULTS: The meropenem volume of distribution of the patient population was 54.95 L, while clearance started at 3.27 L/hour and increased by 0.91 L/hour with each 1 mL/s/1.73 m2 of estimated glomerular filtration rate. Meropenem clearance was also 0.31 L/hour higher in postoperative patients with central nervous system infection. Meropenem administration by continuous infusion showed a significantly higher probability of attaining the PK/PD target than a standard 30 min infusion (95.3% vs 49.5%). CONCLUSIONS: A daily meropenem dose of 3 g, 6 g and 10.5 g administered by continuous infusion was shown to be accurate for patients with moderate to severe renal impairment, normal renal function to mild renal impairment and augmented renal clearance, respectively.