Presence of tobramycin in blood and urine during selective decontamination of the digestive tract in critically ill patients, a prospective cohort study

Tobramycin is one of the components used for selective decontamination of the digestive tract (SDD), applied to prevent colonization and subsequent infections in critically ill patients. Tobramycin is administered in the oropharynx and gastrointestinal tract and is normally not absorbed. However, critical illness may convey gut barrier failure. The aim of the study was to assess the prevalence and amount of tobramycin leakage from the gut into the blood, to quantify tobramycin excretion in urine, and to determine the association of tobramycin leakage with markers of circulation, kidney function and other organ failure. This was a prospective observational cohort study. The setting was the 20-bed closed format-mixed ICU of a teaching hospital. The study population was critically ill patients with an expected stay of more than two days, receiving SDD with tobramycin, polymyxin-E and amphotericin-B four times daily in the oropharynx and stomach. Tobramycin concentration was measured in serum (sensitive high performance liquid chromatography - mass spectrometry/mass spectrometry (HLPC-MS/MS) assay) and 24-hour urine (conventional immunoassay), in 34 patients, 24 hours after ICU admission, and in 71 patients, once daily for 7 days. Tobramycin leakage was defined as tobramycin detected in serum at least once (> 0.05 mg/L). Ototoxicity was not monitored. Of the 100 patients with available blood samples, 83 had tobramycin leakage. Median highest serum concentration for each patient was 0.12 mg/L; 99% of the patients had at least one positive urinary sample (> 0.5 mg/L), 49% had a urinary concentration ≥ 1 mg/L. The highest tobramycin serum concentration was significantly associated with vasopressor support, renal and hepatic dysfunction, and C-reactive protein. At binary logistic regression analysis, high dopamine dose and low urinary output on Day 1 were the significant predictors of tobramycin leakage. Nephrotoxicity could not be shown. The majority of acute critically ill patients treated with enteral tobramycin as a component of SDD had traces of tobramycin in the blood, especially those with severe shock, inflammation and subsequent acute kidney injury, suggesting loss of gut barrier and decreased renal removal. Unexpectedly, urinary tobramycin was above the therapeutic trough level in half of the patients. Nephrotoxicity could not be demonstrated

A Randomised Controlled Trial Assessing the Effect of Oral Diazepam on F-18-FDG Uptake in the Neck and Upper Chest Region

A distinctive pattern of physiological symmetrical uptake of F-18-fluorodeoxyglucose (F-18-FDG) in the neck and upper chest region is a phenomenon that is sometimes observed on positron emission tomography (PET) scans of some oncologic patients. Initially, it was assumed to be muscle uptake secondary to patient anxiety or tension, which could be prevented by diazepam treatment. However, PET-computed tomography data have shown that F-18-FDG uptake is not restricted to the musculature but is also localised within the non-muscular soft tissue, such as brown adipose tissue. The efficacy of benzodiazepine treatment to reduce this uptake has not been well established. Therefore, a randomised controlled trial was conducted to decide whether diazepam would decrease physiological F-18-FDG uptake in the neck and upper chest region (FDG-NUC). A randomised, double-blind, placebo-controlled trial was conducted to assess the effect on FDG-NUC of 5 mg diazepam, given orally 1 h before F-18-FDG injection. Patients younger than 40 years, having or suspected to have a malignancy, were eligible for inclusion. The primary endpoint was FDG-NUC, as assessed by visual analysis of whole-body PET scans by two independent observers. The secondary endpoint was clinical relevance of FDG-NUC. Fifty-two patients were included between September 2003 and January 2005. Twenty-eight patients (54%) received placebo; 24 (46%) received diazepam. FDG-NUC was seen in 25% of the patients in the diazepam group versus 29% in the placebo group. This difference was not statistically significant. No beneficial effect of administration of diazepam could be established. Pre-medication with benzodiazepines to diminish physiological uptake of F-18-FDG in the neck and upper chest region is not indicate

A Systematic Evaluation of Cost-Saving Dosing Regimens for Therapeutic Antibodies and Antibody-Drug Conjugates for the Treatment of Lung Cancer

Background: Expensive novel anticancer drugs put a serious strain on healthcare budgets, and the associated drug expenses limit access to life-saving treatments worldwide. Objective: We aimed to develop alternative dosing regimens to reduce drug expenses. Methods: We developed alternative dosing regimens for the following monoclonal antibodies used for the treatment of lung cancer: amivantamab, atezolizumab, bevacizumab, durvalumab, ipilimumab, nivolumab, pembrolizumab, and ramucirumab; and for the antibody-drug conjugate trastuzumab deruxtecan. The alternative dosing regimens were developed by means of modeling and simulation based on the population pharmacokinetic models developed by the license holders. They were based on weight bands and the administration of complete vials to limit drug wastage. The resulting dosing regimens were developed to comply with criteria used by regulatory authorities for in silico dose development. Results: We found that alternative dosing regimens could result in cost savings that range from 11 to 28%, and lead to equivalent pharmacokinetic exposure with no relevant increases in variability in exposure. Conclusions: Dosing regimens based on weight bands and the use of complete vials to reduce drug wastage result in less expenses while maintaining equivalent exposure. The level of evidence of our proposal is the same as accepted by regulatory authorities for the approval of alternative dosing regimens of other monoclonal antibodies in oncology. The proposed alternative dosing regimens can, therefore, be directly implemented in clinical practice.</p

An economic evaluation of vial sharing of expensive drugs in automated compounding

Background Manual compounding of expensive cytotoxic drugs often leads to drug wastage, due to residual product in vials not being used. Aim To determine the cost savings that can be achieved by implementing an automated compounding process with a vial sharing strategy, instead of manually compounding drugs. Method The drug wastage during automated compounding was compared with that of three simulation scenarios using manual compounding, in a general teaching hospital. All automatically compounded preparations of rituximab, pemetrexed, bevacizumab, and trastuzumab from September 2019 and up until February 2020 were included. A vial sharing strategy was implemented during the automated compounding process (scenario 1). In this scenario, all residual drugs could be reused for up to seven days. Two of the simulation scenarios for manual compounding were executed using a batch compounding strategy, for an entire working day (scenario 2), and twice a day (scenario 3). The third manual compounding simulation was executed without making use of a batch compounding strategy (scenario 4). Results There was no drug wastage during automated compounding with vial sharing (scenario 1). The cost of drug wastage for 1001 preparations, over a period of six months for rituximab, pemetrexed, bevacizumab, and trastuzumab combined, were € 34,133 for scenario 2, € 46,688 for scenario 3, and € 88,255 for scenario 4. The estimated total cost savings between 2017, when the compounding robot was commissioned, and 2021, was more than € 280,000. Conclusion Vial sharing of expensive drugs during automated compounding can prevent drug wastage, resulting in an economic and environmental advantage as opposed to manual compounding

Analysis of production time and capacity for manual and robotic compounding scenarios for parenteral hazardous drugs

BACKGROUND: The increasing amount of hazardous preparations in combination with shortages leads to a call for more efficient compounding methods. This research aims to evaluate the required amount of time, production capacity and direct labour costs of the manual, manual software-supported and robotic compounding of parenteral hazardous drugs. METHODS: This multicentre study was conducted at the clinical pharmacy departments of three Dutch hospitals with different compounding methods: St Antonius hospital (manual software-supported compounding), Amsterdam University Medical Centre (Amsterdam UMC) (both robotic compounding and manual compounding without software support) and OLVG (robotic compounding). Time measurements of individual hazardous drugs were performed in all three hospitals. At Amsterdam UMC and St Antonius hospital, the times per compounding phase, the production capacity and the direct labour costs per preparation were also determined. To reflect real-world situations, the combination of robotic and manual compounding was also studied. RESULTS: The total compounding process, including the actions before compounding and the release-time and cleaning time, lasted 6:44 min with robotic compounding and was faster than manual compounding with and without software support (6:48 and 9:48 min, respectively). The production capacity of one full-time equivalent (FTE) on 1 day (P1FTE1day) was 15 preparations per FTE per day with manual compounding with and without software support, and 57 preparations per FTE per day with only robotic compounding. If manual and robotic compounding were combined, the production capacity was 30 preparations per FTE per day. In this setting, the direct labour costs per preparation were €5.21, while these costs were €13.18 with only manual compounding. CONCLUSION: Compared with manual compounding, robotic compounding was faster over the total compounding process. A combination of manual compounding and robotic compounding could lead to 100% more preparations per FTE and 2.5 times lower direct labour costs compared with manual compounding

Case report: Pharmacokinetics of pembrolizumab in a patient with stage IV non?small cell lung cancer after a single 200 mg administration

Background: Pembrolizumab is a well-tolerated biologic agent with a potentially stable and durable anti-tumor response. Unfortunately, discontinuation of therapy can occur as a consequence of immune-related adverse effects (irAEs). These irAEs appear independent of dose and exposure. However, such irAEs might also result from pembrolizumab’s highly specific mechanism of action and current dosing regimens. However, the currently available pharmacokinetic (PK) and pharmacodynamic (PD) data to reassess dosing strategies are insufficient. To highlight the importance of additional PK/PD studies, we present a case describing the complexity of pembrolizumab’s PK/PD after a single 200 mg pembrolizumab dose in a treatment-naive patient with non–small cell lung cancer (NSCLC). Case description: A 72-year-old man with stage IV NSCLC presented hepatotoxic symptoms 19 days after receiving the first 200 mg pembrolizumab dose. Hence, pembrolizumab therapy was paused, and prednisolone therapy was initiated, which successfully inhibited the toxic effect of pembrolizumab. However, repeated flare-ups due to prednisolone tapering suggest that the toxic effect of pembrolizumab outlasts the presence of pembrolizumab in the bloodstream. This further suggests that the T-cell–mediated immune response outlasts the programmed cell death protein 1 (PD-1) receptor occupancy by pembrolizumab, which challenges the need for the current fixed-interval strategies and their stop criteria. Furthermore, a validated ELISA quantified pembrolizumab levels in 15 samples within 123 days after administration. A shift in the pembrolizumab clearance rate was evident ensuing day 77 (0.6 µg/mL) after administration. Pembrolizumab levels up to day 77 (9.1–0.6 µg/mL) strongly exhibited a linear, first-order clearance (R 2 = 0.991), whereas after day 77, an accelerated non-linear clearance was observed. This transition from a linear to non-linear clearance was most likely a result of full target receptor saturation to non-full target receptor saturation, in which the added effect of target-mediated drug disposition occurs. This suggests that pembrolizumab’s targets were fully saturated at levels above 0.6 µg/mL, which is 43 to 61 times lower than the steady-state trough levels (C trough,ss) of the currently registered fixed-dosing regimens (3–5)

Validation of a multiwell gamma-counter for measuring high-pressure liquid chromatography metabolite profiles

OBJECTIVES: The purpose of this study was to verify the accuracy and reproducibility of a multiwell counter to assess its suitability for use within human PET studies in which metabolizing (11)C tracers are used. Such tracers often require metabolite analysis for deriving plasma metabolite-corrected input curves. High-pressure liquid chromatography (HPLC) with on-line activity measurement is often unreliable for later plasma samples due to the poor sensitivity of the on-line activity detector. Fraction collector obtained HPLC samples that are counted in a separate high-sensitivity well counter can be an alternative to overcome poor counting statistics. METHODS: Several experiments to evaluate background counting, reproducibility, and linearity were performed to validate the accuracy, precision, and detection limits of the well counter. In addition, measurements on a series of samples resembling activity profiles as seen within human (11)C-flumazenil studies were performed to evaluate the performance of the well counter for clinically relevant data. RESULTS: The tests proved that the well counter detection limit, linearity, and reproducibility were more than sufficient in circumstances as seen during patient studies for samples with both high and low activity. CONCLUSION: The use of a multiwell counter is a good alternative for the on-line activity detector of the HPLC, allowing derivation of plasma metabolite fractions with high accuracy and reproducibility

Validation of a multiwell γ-counter for measuring high-pressure liquid chromatography metabolite profiles

Objectives: The purpose of this study was to verify the accuracy and reproducibility of a multiwell counter to assess its suitability for use within human PET studies in which metabolizing 11C tracers are used. Such tracers often require metabolite analysis for deriving plasma metabolite-corrected input curves. High-pressure liquid chromatography (HPLC) with on-line activity measurement is often unreliable for later plasma samples due to the poor sensitivity of the on-line activity detector. Fraction collector obtained HPLC samples that are counted in a separate high-sensitivity well counter can be an alternative to overcome poor counting statistics. Methods: Several experiments to evaluate background counting, reproducibility, and linearity were performed to validate the accuracy, precision, and detection limits of the well counter. In addition, measurements on a series of samples resembling activity profiles as seen within human 11C-flumazenil studies were performed to evaluate the performance of the well counter for clinically relevant data. Results: The tests proved that the well counter detection limit, linearity, and reproducibility were more than sufficient in circumstances as seen during patient studies for samples with both high and low activity. Conclusion: The use of a multiwell counter is a good alternative for the on-line activity detector of the HPLC, allowing derivation of plasma metabolite fractions with high accuracy and reproducibility