Concentrations In Therapeutic Range Research Articles

Assessing the impact of an electronic therapeutic drug monitoring record in the management of vancomycin through pharmacist intervention: a single‐centre study

AbstractBackgroundA gap in vancomycin therapeutic drug monitoring (TDM) electronic documentation, management, and related clinical pharmacist activities was identified by our clinical pharmacy team. In response, an electronic TDM (eTDM) template was planned, designed, and implemented by the pharmacy department team in collaboration with the electronic medical records team (EMR) and documentation committee.AimTo assess the impact of an electronic therapeutic drug monitoring (eTDM) template to measure the impact of adherence to vancomycin guidelines. Guideline adherence indicators include the number of vancomycin levels within the therapeutic range and the number of appropriate concentrations taken.MethodAn interventional, single‐centre study of vancomycin therapy in adult patients was performed from 2019–2021. Data were extracted from the electronic medical records and TDM paper‐based forms completed by clinical pharmacists. The number of concentrations within the therapeutic range and the number of appropriately taken levels were analysed by the chi‐square test. This study received an exemption from the Peninsula Health Human Research Ethics Commitee (QA/60523/PH‐2019/197291).ResultsThere was a total of 198 concentrations collected in the ‘before’ period and 125 concentrations collected in the ‘after’ period. The number of concentrations in therapeutic range increased from 34.8% to 43.2% (p = 0.132), not statistically significant. The number of concentrations taken appropriately increased from 33.8% to 55.2% (p < 0.001). The proportion of patients with pharmacist involvement increased from 43.0% to 57.0% (p = 0.868).ConclusionThe study shows that implementation of an electronic vancomycin monitoring template improved the proportion of appropriate levels taken and is the preferred method of documentation by clinical pharmacists. Future projects may benefit from analysing the cost associated with unnecessary vancomycin serum levels ordered or inclusion of pharmacists in the TDM of other narrow therapeutic medications.

Correlation between ABCB1 gene polymorphisms, antiepileptic drug concentrations and treatment response

Abstract Aim: A possible molecular mechanism of clinically defined multidrug-resistant epilepsy involves drug efflux transporters such as P glycoprotein (P-gp), a member of the ATP-binding cassette subfamily B1 (ABCB1). We have investigated the prevalence of the C3435T, G 2677T/A, and T129C single-nucleotide polymorphisms in the promoter region of MDR1 gene, in Romanian epileptic patients. Methods: 70 epileptic patients evaluated in the Neurology Department of Cluj County Hospital were included in the study. The response to treatment was assessed by reviewing the seizure diaries and the patients were classified as responders or non-responders. Antiepileptic drug (AED) plasmatic concentrations were measured and the patients were divided into 2 groups: first group with AED concentrations in therapeutic range and the second one with sub-optimal AED concentrations. Genotyping the DNA samples, we investigated MDR1 gene polymorphism by polymerase chain reaction (PCR). Results were expressed as genotype and allele frequencies per response group and compared between subgroups. Results: 33 patients (47.14%) were classified as responders, while the remaining 37 patients (52.86%) were classified as non-responders. A comparison of responders and non-responders revealed no significant difference in genotype frequency for any of the three mutations studied. The CT heterozygote for ABCB1 T129C had significantly lower AED concentrations (p=0.041), with no significant difference for the other polymorphisms studied. Conclusions: In our study we found an association of CT variant in ABCB1 C129T with lower AED plasmatic concentrations and no association between ABCB1 variants and the drug responsiveness.

Vancomycin pharmacokinetic–pharmacodynamic parameters to optimize dosage administration in critically ill children

Critically ill children may present changes in pharmacokinetic parameters and may not reach effective concentrations of vancomycin with current dosages. The objective of this study is to calculate vancomycin pharmacokinetic parameters in critically ill children and to estimate area under the curve at 24 hrs/minimal inhibitory concentration reached for Staphylococcus aureus. Children treated with vancomycin, hospitalized in the Intensive Care Unit of the Pediatric Hospital-Centro Hospitalario Pereira Rossell, were included. Samples to determine vancomycin serum concentration were obtained on first and third days of treatment, 1 hr after the end of the third daily dose administration (maximum drug concentration) and 15 mins before the fourth (minimum drug concentration). Half-life elimination, volume of distribution, clearance, and area under the curve at 24 hrs were estimated. Vancomycin concentration values of 20-40 μg/mL (maximum drug concentration) and 5-10 μg/mL (minimum drug concentration) were considered therapeutic. Twenty-two children were included. On day 1, seven of 18 children for maximum drug concentration and 16 of 22 for minimum drug concentration reached concentrations in therapeutic range; on day 3, seven of 16 children for maximum drug concentration and 11 of 17 for minimum drug concentration did. Mean values of maximum drug concentration and minimum drug concentration were higher in children with negative water balance. Mean value of half-life elimination increased from day 1 to day 3. Considering a value of minimal inhibitory concentration for S. aureus of 1 μg/mL, nine of 18 children reached a relationship area under the curve at 24 hrs/minimal inhibitory concentration >400 on day 1 and seven of 15 on day 3. Considering a minimal inhibitory concentration of 2 μg/mL, one child reached it on day 1 and one on day 3. Critically ill children show changes in pharmacokinetic parameters. Serum concentration monitorization is necessary for dosage individualization. Most children do not reach an area under the curve at 24 hrs/minimal inhibitory concentration >400 with current dosage.

The Influence of Lepirudin, Bivalirudin and Dabigatran on the Calibrated Automated Thrombogram (CAT)

In a two centre study (laboratories in Diagnostica Stago and Biomnis) we compared the in vitro effect on thrombin generation (TG) of Dabigatran and Bivalirudin (reversible direct anti-IIa inhibitors) with that of Lepirudin (an irreversible direct anti-IIa inhibitor) spiked into normal pool plasma. The effect of Lepirudin, Bivalirudin and Dabigatran were evaluated in both centres using the CAT (Diagnostica Stago, France) TG method in a concentration ranges up to 5, 20 and 1 μg/mL respectively. Testing was done in triplicate and repeated over 2 days. To reduce assay variability both centres used the same reagents lots and the same normal pool plasma (George King, USA). The range of each drug tested extended well above the therapeutic range concentrations normally found in patient plasma (0.5 to 1.0 μg/mL, 5 to 10 μg/mL and 0.1 to 0.3 μg/mL respectively for Lepirudin, Bivalirudin and Dabigatran). To see the effect of increasing activation forces, TG was performed at 3 different final concentrations of Tissue Factor (TF) - 1, 5 and 20 pM. All reagents were used as recommended by the manufacturer (Thrombinoscope, The Netherlands). A prolongation in the lag time (LT) is observed with all 3 drugs with all 3 concentrations of TF, but this is more marked for Lepirudin and Bivalirudin than it is for Dabigatran. In the therapeutic range Dabigatran (at 5pM TF) shows both an increase in LT and a decrease in peak thrombin and the ETP. At low concentration of Bivalirudin or Lepirudin, there is a paradoxical increase in peak height, which is even more pronounced at low TF concentration. At 1pM TF, this paradoxical peak increase is also observed with Dabigatran.Results obtained in both laboratories are similar and complement our previous results and those reported elsewhere (1–4). The effect of Lepirudin and Bivalirudin on TG is different from that of Dabigatran. We also note that at lower TF concentration the anticoagulant effect on TG initiation is more intense but the test becomes less reproducible.

Quinidine and procainamide inhibit murine macrophage uptake of apoptotic and necrotic cells: A novel contributing mechanism of drug-induced-lupus

A number of mechanisms have been proposed to explain the etiology of drug-induced lupus (DIL) but the effect of apoptotic and necrotic cell handling has not been previously examined. To evaluate the effect of quinidine and procainamide at therapeutic range concentrations, on the uptake of apoptotic and necrotic thymocytes by murine peritoneal macrophages and on macrophage survival, as a novel mechanism for DIL. Thymocytes were stained and induced to undergo apoptosis by serum withdrawal. Apoptosis was evaluated using annexin V and propidum iodide (PI) and PI staining. Necrosis was induced by heating. Peritoneal macrophages were treated with quinidine or procainamide at a range of therapeutic concentrations and incubated with stained apoptotic and necrotic thymocytes. Apoptotic and necrotic cell uptake was evaluated by flow cytometry using double staining of thymocytes and macrophages and by confocal microscopy. Green fluorescent latex beads were used as controls for phagocytosis. Significantly decreased uptake of apoptotic and necrotic cells was seen in the presence of quinidine and procainamide. The documented effect was mainly on the number of apoptotic/necrotic cells per macrophage. Uptake of fluorescent latex beads offered to resident macrophages was not significantly affected by quinidine or procainamide. No pro-apoptotic effect of quinidine or procainamide on macrophages was seen. Quinidine and procainamide at therapeutic range concentrations specifically inhibit clearance of apoptotic and necrotic cells by peritoneal macrophages. Altered handling of apoptotic and necrotic cells may represent a contributing mechanism for DIL.

Solid phase extraction and high performance liquid chromatographic determination of doxophylline in plasma

A sensitive and selective high performance liquid chromatographic doxophylline assay with ultraviolet detection has been developed for plasma samples. The drug is isolated from biological samples with a reversed phase C18 disposable extraction column. Plasma standard curves are linear for concentrations of doxophylline from 0.03 to 10 mg/L. At the therapeutic range concentrations, the recoveries are better than 96.9%. The coefficients of variation for the procedure are 4.1% and 2.7% for the concentrations 0.03 mg/L and 10 mg/L, respectively. By this method, pharmacokinetic profiles are obtained for six adult volunteers.