Dosing Therapeutic Radiopharmaceuticals in Obese Patients

The prevalence of obesity has increased dramatically in the Western population. Obesity is known to influence not only the proportion of adipose tissue but also physiological processes that could alter drug pharmacokinetics. Yet, there are no specific dosing recommendations for radiopharmaceuticals in this patient population. This could potentially lead to underdosing and thus suboptimal treatment in obese patients, while it could also lead to drug toxicity due to high levels of radioactivity. In this review, relevant literature is summarized on radiopharmaceutical dosing and pharmacokinetic properties, and we aimed to translate these data into practical guidelines for dosing of radiopharmaceuticals in obese patients. For radium-223, dosing in obese patients is well established. Furthermore, for samarium-153-ethylenediaminetetramethylene (EDTMP), dose-escalation studies show that the maximum tolerated dose will probably not be reached in obese patients when dosing on MBq/kg. On the other hand, there is insufficient evidence to support dose recommendations in obese patients for rhenium-168-hydroxyethylidene diphosphonate (HEDP), sodium iodide-131, iodide 131-metaiodobenzylguanidine (MIBG), lutetium-177-dotatate, and lutetium-177-prostate-specific membrane antigen (PSMA). From a pharmacokinetic perspective, fixed dosing may be appropriate for these drugs. More research into obese patient populations is needed, especially in the light of increasing prevalence of obesity worldwide.

Excessive unbound cefazolin concentrations in critically ill patients receiving veno-arterial extracorporeal membrane oxygenation (vaECMO): an observational study

The scope of extracorporeal membrane oxygenation (ECMO) is expanding, nevertheless, pharmacokinetics in patients receiving cardiorespiratory support are fairly unknown leading to unpredictable drug concentrations. Currently, there are no clear guidelines for antibiotic dosing during ECMO. This study aims to evaluate the pharmacokinetics (PK) of cefazolin in patients undergoing ECMO treatment. Total and unbound plasma cefazolin concentration of critically ill patients on veno-arterial ECMO were determined. Observed PK was compared to dose recommendations calculated by an online available, free dosing software. Concentration of cefazolin varied broadly despite same dosage in all patients. The mean total and unbound plasma concentration were high showing significantly (p = 5.8913 E−09) greater unbound fraction compared to a standard patient. Cefazolin clearance was significantly (p = 0.009) higher in patients with preserved renal function compared with CRRT. Based upon the calculated clearance, the use of dosing software would have led to lower but still sufficient concentrations of cefazolin in general. Our study shows that a “one size fits all” dosing regimen leads to excessive unbound cefazolin concentration in these patients. They exhibit high PK variability and decreased cefazolin clearance on ECMO appears to compensate for ECMO- and critical illness-related increases in volume of distribution.

Transition from Methylphenidate to Atomoxetine: reasons for switching and clinical outcome

AimsAttention Deficit Hyperactivity Disorder (ADHD) is a behavior disorder originating in childhood comprising of a constellation of features including inattention, impulsivity, and hyperactivity. The National Institute of Clinical Excellence (NICE) Guidelines 2018 recommends methylphenidate as a first line pharmacological agent for treatment of children aged 5 years and over with ADHD. Lisdexamfetamine, dexamfetamine and atomoxetine are recommended in this order if methylphenidate is not tolerated or if symptoms did not respond to separate 6-week trials. Our aim was to, assess the transition of methylphenidate to atomoxetine, the reasons for switching and its clinical outcome in order to make recommendations to current practice regarding treatment of ADHD.MethodThe study examined a total of 53 children between 0-16 years of age who were being treated for ADHD with atomoxetine at CYPS till September 2018. Data was collected from patients’ files retrospectively by using a proforma based on the NICE guidelines 2018 ADHD: diagnosis and management.ResultOut of 53 patients’ on atomoxetine in September 2018, 49 were included in the study. Results recorded side-effects as the main reason for switching from methylphenidate to atomoxetine. Unwanted side-effects were documented in 71.7% of patients of which 57.9% exhibited more than 1 side-effect with the two commonest side-effects documented being weight loss and decreased appetite. The audit highlighted the fact that the correct dose of atomoxetine was only administered in 17.2% of children with 56.9% of patient's being given a higher dose than recommended. Initial weight was not documented in 19% and hence, ideal dose could not be calculated. Overall, atomoxetine was shown to be an effective treatment. Out of the 40 patients documented to have hyperactivity this symptom was decreased in 82.5% whilst 82.9% were shown to have increased concentration. 35 patients had documented impulsivity and this was decreased in 62.9% of cases. 11 patients had documented anxiety with 72.7% being treated effectively with atomoxetine. 31% of patients’ had documented side-effects with 16% of these being tics. 20% of patient's required augmentation.ConclusionThe results indicate that the majority of doctors at CYPS in Malta adhered to the NICE guidelines 2018 and atomoxetine was proven to be efficacious as a second line drug in the treatment of ADHD. However, better adherence to NICE guidelines is required when it comes to the calculation of appropriate dosage. Our prediction is had dose recommendations according to weight been adhered to there may have been less side-effects documented.

Evaluating the Impact of Education on Pharmacist Tobramycin Dose Recommendations for Cystic Fibrosis and a Review of Perceptions on Pharmacist-Led Charting

Background: Pharmacists routinely interpret and optimize tobramycin dosing for people with cystic fibrosis (PwCF). Objectives: To determine the impact of tobramycin therapeutic drug monitoring (TDM) education on pharmacist dose recommendations, and to explore nurses’ and medical doctors’ perceptions toward pharmacist-led TDM charting. Methods: This study involved 3 phases: a 12-month retrospective audit of PwCF prescribed tobramycin to identify the appropriateness of pharmacists’ dose recommendations, a pharmacist tobramycin educational intervention utilizing a voiceover presentation with pre- and post-online tobramycin TDM assessment (involving multiple choice pharmacokinetics and case-based scenario questions), and a cross-sectional survey of respiratory nurses’ and doctors’ perceptions toward pharmacist-led TDM charting. The pharmacists’ dose recommendations, in the audit and case-based questions, were considered appropriate if subsequent levels achieved the targeted area under the curve (AUC). Results: Audit results revealed that 44.4% of the 277 pharmacist dose recommendations identified were appropriate. The pre- and post-interventional assessments were completed by 51 and 52 pharmacists, respectively. Post intervention, correct scores were significantly higher than pre-intervention, evident in both the pharmacokinetics (median score 75% vs 100%; P = 0.048) and case-based scenario (median score 60% vs 90%; P < 0.0001) questions. Of the 54 nurses and medical doctors surveyed, 92.6% supported the implementation of pharmacist-led tobramycin charting. Conclusion: The study demonstrated an increased accuracy and appropriateness of pharmacists’ tobramycin pharmacokinetics knowledge and TDM dose recommendations post-educational intervention and highlighted nurses’ and medical doctors’ support of pharmacist-led tobramycin TDM charting.

Phase I dose-escalation oncology trials with sequential multiple schedules

Background Conventional methods for phase I dose-escalation trials in oncology are based on a single treatment schedule only. More recently, however, multiple schedules are more frequently investigated in the same trial. Methods Here, we consider sequential phase I trials, where the trial proceeds with a new schedule (e.g. daily or weekly dosing) once the dose escalation with another schedule has been completed. The aim is to utilize the information from both the completed and the ongoing schedules to inform decisions on the dose level for the next dose cohort. For this purpose, we adapted the time-to-event pharmacokinetics (TITE-PK) model, which were originally developed for simultaneous investigation of multiple schedules. TITE-PK integrates information from multiple schedules using a pharmacokinetics (PK) model. Results In a simulation study, the developed approach is compared to the bridging continual reassessment method and the Bayesian logistic regression model using a meta-analytic-predictive prior. TITE-PK results in better performance than comparators in terms of recommending acceptable dose and avoiding overly toxic doses for sequential phase I trials in most of the scenarios considered. Furthermore, better performance of TITE-PK is achieved while requiring similar number of patients in the simulated trials. For the scenarios involving one schedule, TITE-PK displays similar performance with alternatives in terms of acceptable dose recommendations. The and code for the implementation of an illustrative sequential phase I trial example in oncology is publicly available (https://github.com/gunhanb/TITEPK_sequential). Conclusion In phase I oncology trials with sequential multiple schedules, the use of all relevant information is of great importance. For these trials, the adapted TITE-PK which combines information using PK principles is recommended.