Tobramycin a Priori Dosing Regimens Based on PopPK Model Simulations in Critically Ill Patients: Are They Transferable?

BACKGROUND: In recent years, multiple population pharmacokinetic models have been developed for drugs such as tobramycin that need therapeutic drug monitoring. Some of these models have been used to develop a priori dosing regimens for their respective populations. However, these dosing regimens may not apply to other populations. Therefore, this study aimed to evaluate tobramycin population pharmacokinetic models in critically ill patients and establish an adequate dosing regimen. METHODS: Evaluated models were identified from a literature review of aminoglycoside population pharmacokinetic models in critically ill patients. After retrospective data collection in 2 Quebec hospitals, external evaluation and model re-estimation were performed with NONMEM (v7.5) to assess imprecision and bias values. Dosing regimens were simulated and compared between the best-performing model and its re-estimated counterparts. RESULTS: None of the 3 evaluated models showed acceptable imprecision or bias values in the data sets of the 19 patients. Similar percentages of target attainment were obtained for the original and re-estimated models after the dosing regimen simulations. CONCLUSION: Although the predictive performance evaluation criteria were inadequate, the original and re-estimated models yielded similar results. This raises the question of what a priori bias and imprecision thresholds should be defined as acceptable for the external evaluation of models to be applied in clinical practice. Studies evaluating the impact of these thresholds are needed.

Development and Evaluation of a Height-Based Tobramycin Initial Dosing Nomogram for the Treatment of Adult Cystic Fibrosis Pulmonary Exacerbations.

ABSTRACT: Tobramycin is widely used to treat pulmonary exacerbations of cystic fibrosis. Height has been previously found to be significantly more predictive of tobramycin pharmacokinetics than body weight. This study aimed to develop a height-based initial dosing nomogram and evaluate its performance in peak concentration (Cmax) precision relative to standard and fixed dosing. Monte Carlo simulations were performed to develop a nomogram representing the doses required to reach Cmax targets at different heights. Cmax data observed at 2 clinical centers [McGill University Health Centre (MUHC) and Institut universitaire de cardiologie et pneumologie de Québec (IUCPQ-UL)] were compared with population-predicted Cmax using the doses derived from the nomogram alongside a fixed dose. Height-based dosing resulted in significantly less variable-predicted Cmax values [coefficient of variation (CV) MUHC = 15.7% and IUCPQ-UL = 10.8%] than the Cmax values observed in clinical practice (CV MUHC = 30.0% and CV IUCPQ-UL = 26.9%) and predicted Cmax values obtained from a fixed dose (CV MUHC = 21.2% and CV IUCPQ-UL = 16.3%). An initial dosing nomogram was developed to help reduce pharmacokinetic variability in the observed Cmax. More precise dosing would allow for better clinical outcomes in adult patients with cystic fibrosis.

Consideration of height-based tobramycin dosing regimens for the treatment of adult cystic fibrosis pulmonary exacerbations.

AIMS: Some population pharmacokinetic models have been developed using height to explain some of the interindividual variability in tobramycin pharmacokinetics in cystic fibrosis patients. However, their predictive performance when extrapolated to other clinical centres is unclear. Therefore, the aim of this study was to externally evaluate the predictability of tobramycin population pharmacokinetic models with an independent dataset and perform simulations using previously recommended height-based dosing regimens. METHODS: A literature search was conducted through the PubMed database to identify relevant population pharmacokinetic models. Tobramycin plasma concentration data from April 2014 to November 2019 were retrospectively collected from the Institut universitaire de cardiologie et de pneumologie de Québec, Canada. External evaluations were performed using NONMEM® v7.5 and RStudio® v1.3.1073. Monte Carlo simulations were performed to evaluate the probability of target attainment of Cmax /MIC ratios for several dosing regimens. RESULTS: The validation dataset included 27 patients and 143 concentration samples. Three models were evaluated. Only the ones by Crass et al. and Alghanem et al. performed satisfactorily in terms of prediction-based diagnostics with MDPE values of -3.4% and 29.3% and MDAPE values of 19.0 and 29.5%, respectively. In simulation-based evaluations, both pcVPC and NPDE showed no evidence of model misspecification. Our simulations suggest that patients treated with a once-daily dose of 3.4 mg/cm should produce peak and trough levels consistent with current guidelines. CONCLUSION: Our results show that the models by Crass et al. and Alghanem et al. are appropriate for simulation-based applications to aid individualized dosing in our population and that height-based dosing regimens could be considered in cystic fibrosis patients.

Remdesivir (VEKLURY) for Treating COVID-19: Guinea Pig Ex Vivo and In Vivo Cardiac Electrophysiological Effects.

ABSTRACT: Bradycardia and QTc interval prolongation on the ECG have been reported with remdesivir (Veklury), an antiviral drug recently approved for treating severely ill patients with COVID-19. The objective was to evaluate the effects of remdesivir on cardiac electrophysiology ex vivo and in vivo. Ex vivo: Langendorff retroperfusion experiments were performed on isolated hearts from male Hartley guinea pigs (n = 23, total) exposed to either remdesivir 3, 10, or 30 µmol/L to assess drug-induced prolongation of the monophasic action potential duration measured at 90% repolarization (MAPD 90 ). In vivo: ECG recordings using wireless cardiac telemetry were performed in guinea pigs (n = 6) treated with daily i.p. doses of remdesivir 5 mg/kg on day 1 and 2.5 mg/kg on days 2-10. Ex vivo remdesivir (3, 10, and 30 µmol/L) had no statistically significant effect on MAPD 90 , while pacing the hearts at basic stimulation cycle lengths of 200 or 250 milliseconds, or when the hearts were not paced and beating at their intrinsic heart rate. In a second set of similar ex vivo experiments, remdesivir 10 µmol/L did not potentiate the MAPD 90 -prolonging effects of dofetilide 20 nmol/L (n = 4) hearts. In vivo remdesivir caused small but statistically significant prolongations of the RR and QTc F intervals at day 1 (5 mg/kg) and at day 10 (2.5 mg/kg). No ventricular arrhythmias were ever observed under the effect of remdesivir. Remdesivir causes bradycardia, and mild QTc prolongation, which nonetheless, could be of clinical relevance in many hospitalized patients with COVID-19 concomitantly treated with multiple drugs.

Women with breast cancer's perceptions of nurse-led telephone-based motivational interviewing consultations to enhance adherence to adjuvant endocrine therapy: a qualitative study.

BACKGROUND: Daily adjuvant endocrine therapy (AET) for 5 or 10 years is the standard of care for women diagnosed with non-metastatic hormone receptor-positive breast cancer. However, many women experience AET-related issues that may hamper quality of life and adherence. Here, we aimed to describe women's perceptions of motivational interviewing (MI)-guided consultations delivered by a trained nurse navigator over the telephone to enhance AET adherence. METHODS: Eighteen women who were first prescribed AET for non-metastatic breast cancer in the last 5 years, who self-reported AET-related issues, and who participated in at least two MI-guided consultations over a year were interviewed about their perceptions of the intervention, using a semi-structured interview guide. Audio recordings were transcribed verbatim and analyzed using a thematic analysis approach. RESULTS: Three main themes emerged from the data about women's perceptions on MI-guided consultations. These consultations were described as (1) a person-centred experience, (2) providing key information about AET, and (3) supportive of present and future AET experience, by contributing to AET side-effect management, motivation, adherence, calming negative emotions, improving well-being and self-esteem, and making women to feel empowered. CONCLUSIONS: Nurse-led telephone-based MI-guided consultations about AET were found to respond to participants' needs and to enhance participants' perceptions of being informed and being supported in experiencing various facets of AET. Telephone-based consultations for AET are perceived as a promising strategy in an increasing virtual care world.

SCN5A-C683R exhibits combined gain-of-function and loss-of-function properties related to adrenaline-triggered ventricular arrhythmia.

NEW FINDINGS: What is the role of SCN5A-C683R? SCN5A-C683R is a novel variant associated with an uncommon phenotype of adrenaline-triggered ventricular arrhythmia in the absence of a distinct ECG phenotype. What is the main finding and its importance? Functional studies demonstrated that NaV 1.5/C683R results in a mixed electrophysiological phenotype with gain-of-function (GOF) and loss-of-function (LOF) properties compared with NaV 1.5/wild type. Gain-of-function properties are characterized by a significant increase of the maximal current density and a hyperpolarizing shift of the steady-state activation. The LOF effect of NaV 1.5/C683R is characterized by increased closed-state inactivation. Electrophysiological properties and clinical manifestation of SCN5A-C683R are different from long-QT-3 or Brugada syndrome and might represent a distinct inherited arrhythmia syndrome. ABSTRACT: Mutations of SCN5Ahave been identified as the genetic substrate of various inherited arrhythmia syndromes, including long-QT-3 and Brugada syndrome. We recently identified a novel SCN5A variant (C683R) in two genetically unrelated families. The index patients of both families experienced adrenaline-triggered ventricular arrhythmia with cardiac arrest but did not show a specific ECG phenotype, raising the hypothesis that SCN5A-C683R might be a susceptibility variant and the genetic substrate of distinct inherited arrhythmia. We conducted functional cellular studies to characterize the electrophysiological properties of NaV 1.5/C683R in order to explore the potential pathogenicity of this novel variant. The C683R variant was engineered by site-directed mutagenesis. NaV 1.5/wild type (WT) and NaV 1.5/C683R were expressed in tsA201 cells. Electrophysiological characterization of C683R was performed using the whole-cell patch-clamp technique. Adrenergic stimulation was mimicked by exposure to the protein kinase A activator 8-CPT-cAMP. The impact of ß-blockers was tested by exposing NaV 1.5/WT and NaV 1.5/C683R currents to propranolol and nadolol. C683R resulted in a co-association of gain-of-function and loss-of-function properties of NaV 1.5. Gain-of-function properties were characterized by a significant increase of the maximal NaV 1.5 current density compared with NaV 1.5/WT (861 ± 309 vs. 627 ± 489 pA/pF; P < 0.05, n ≥ 9) that was potentiated in NaV 1.5/C683R with 8-CPT-cAMP stimulation (869 ± 287 vs. 607 ± 320 pA/pF; P < 0.05, n ≥ 12). C683R also resulted in a significant hyperpolarizing shift in the voltage of steady-state activation (-65.4 ± 3.0 vs. -57.2 ± 4.8 mV; P < 0.001), resulting in an increased window current compared with WT. The loss-of-function effect of NaV 1.5/C683R was characterized by significantly increased closed-state inactivation compared with NaV 1.5/WT (P < 0.05). C683R is a novel SCN5A variant resulting in a co-association of gain-of-function and loss-of-function properties of the cardiac sodium channel NaV 1.5. The phenotype is characterized by adrenaline-triggered ventricular arrhythmias. Electrophysiological properties and clinical manifestations are different from long-QT-3 or Brugada syndrome and might represent a distinct inherited arrhythmia syndrome.

The guinea-pig expresses functional CYP2C and P-glycoprotein: further validation of its usefulness in drug biotransformation/transport studies.

BACKGROUND: The guinea-pig is an excellent animal model for studying cardiopulmonary physiology/pharmacology. Interestingly, it also possesses a number of drug-metabolizing enzymes found in humans, such as CYP1A, CYP2D and CYP3A. OBJECTIVE: To evaluate the hypothesis that the guinea-pig also expresses a functional CYP2C drug-metabolizing enzyme and the P-glycoprotein (P-gp) drug transporter in various tissues. METHODS: cDNAs encoding CYP2C and P-gp were obtained from guinea-pig liver or small intestine and sequenced. Western blotting was performed to confirm the expression of CYP2C and P-gp. The functional enzymatic activity of guinea-pig CYP2C was evaluated with microsomal preparations using diclofenac and tolbutamide as specific drug substrates in HPLC analyses. To further study both P-gp and CYP2C functional activities, the guinea-pig ABCB1/MDR1 and CYP2C genes were cloned. The recombinant plasmids were then transfected in HEK293 (human embryonic kidney) cells and either calcein-acetoxymethyl ester (AM) accumulation assays or 14,15-EET/DHET formation experiments were performed to evaluate either P-gp transport activity or CYP2C epoxygenase activity, respectively. The guinea-pig tissue distribution of P-gp was studied by Western blotting. RESULTS: Functional expression of CYP2C was demonstrated in guinea-pig liver microsomal preparations. CYP2C-mediated biotransformation of diclofenac and tolbutamide were shown. Expression of P-gp protein was detected in guinea-pig liver and small intestine. Functional activity of guinea-pig P-gp was demonstrated in ABCB1/MDR1-transfected cells. GP-CYP2C-transfected cells also showed functional epoxygenase activity. CONCLUSION: The guinea-pig expresses functional CYP2C and P-gp, thus suggesting its usefulness for further validating data obtained with other animal models in drug biotransformation/transport studies.

Scoping Review on Transitions in the Context of Pediatric Palliative Care.

Background: Children with complex and chronic conditions receiving palliative care will likely experience many transitions during their life and their treatments. Transition periods for children with life-limiting conditions and their families can be bewildering and highly anxiety-inducing. However, clinical observations seem to point to a more heterogenous care offer, including a lack or discontinuity of services, at the expense of their quality of life. Objective: This paper aims to establish a portrait of the existing literature and identify research gaps on the multiple transitions experienced by this population. Design: A scoping review is provided, following a PRISMA protocol. MEDLINE, PubMed and CINAHL were consulted. The search strategy is based on three key concepts: (1) palliative care/complex condition, (2) child/adolescent, and (3) transition. Articles were screened with the help of Covidence. Results: A total of 72 articles are included for analysis. The aimed population is either identified by age group or by medical status. Respondents are most often parents rather than the children themselves. Transitions include: reaching adulthood, changes in care environment, changes in medical status, and school integration. Conclusion: The discussion notices a definitional murkiness about transitions and highlights the fact that the multifaceted and complex nature of transition over time is largely ignored. New research should involve a diversity of participants and include children's voices. Recommendations include clearer concept definitions, health care policies that adopt an ecosystemic approach, and professional training in the systemic family approach in palliative care.

Designing a resilience-based intervention program for children with cancer and their families: a study protocol.

Background: Advances in pediatric oncology have significantly increased survival rates, yet have introduced challenges in managing long-term treatment side effects. This study process introduces an interdisciplinary clinical intervention program rooted in the family resilience framework, aimed at improving well-being across the cancer trajectory for children and their families, especially those in Canadian communities far from specialized oncology centers with limited access to resources. Methods: Employing an intervention mapping approach, this program collaboratively involves patients, families, professionals, and researchers. It aims to identify vulnerability factors, establish a logic model of change, and devise comprehensive strategies that include professional interventions alongside self-management tools. These strategies, tailored to address biopsychosocial and spiritual challenges, are adapted to the unique contexts of communities distant from specialized cancer treatment centers. A mixed-methods approach will evaluate program effectiveness. Expected results: Anticipated outcomes include the empowerment of families with self-management tools and professional support, designed to mitigate biopsychosocial and spiritual complications. By addressing the specific needs and limitations of these communities, the program strives to improve the overall health and well-being of both undergoing treatment and survivorship phases. Discussion: By focusing on comprehensive care that includes both professional interventions and self-management, this initiative marks a significant shift toward a holistic, family-centered approach in pediatric oncology care for remote communities. It underlines the necessity of accessible interventions that confront immediate and long-term challenges, aiming to elevate the standard of care by emphasizing resilience, professional support, and family empowerment in underserved areas.

Decreased CYP3A expression and activity in guinea pig models of diet-induced metabolic syndrome: is fatty liver infiltration involved?

BACKGROUND: In humans, CYP3A drug-metabolizing enzyme subfamily is the most important. Numerous pathophysiological factors, such as diabetes and obesity, were shown to affect CYP3A activity. Often considered a precursor state for type II diabetes, metabolic syndrome exerts a modulating role on CYP3A, in our hypothesis. OBJECTIVE: To evaluate the effect of metabolic syndrome on CYP3A drug-metabolizing activity/expression in guinea pigs. METHODS: Hepatic microsomes were prepared from male Hartley guinea pigs fed with a control, a high-fat high sucrose (HFHS) or a high-fat high fructose diet (HFHF). Domperidone was selected as a probe substrate of CYP3A and formation of four of its metabolites was evaluated using high-performance liquid chromatography. CYP3A protein and mRNA expression were assessed by Western blot and reverse-transcription quantitative polymerase chain reaction, respectively. Hepatic fatty infiltration was evaluated using standard Oil Red O staining. Triglyceride and free fatty acid liver content were also quantified. RESULTS: Microsomal CYP3A activity was significantly decreased in both HFHS and HFHF diet groups versus the control diet group. Significant decreases of CYP3A mRNA and protein expression were observed in both HFHS and HFHF diet groups. Oil Red O staining showed a massive liver fatty infiltration in the HFHS and HFHF diet groups, which was not observed in the control diet group. Both triglyceride and free fatty acid liver content were significantly increased in the HFHS and HFHF diet groups. CONCLUSION: Diet-induced metabolic syndrome decreases CYP3A expression/activity in guinea pigs. This may ultimately lead to variability in drug response, ranging from lack of effect to life-threatening toxicity.

Overview of Cardiac Arrhythmias and Treatment Strategies.

Maintenance of normal cardiac rhythm requires coordinated activity of ion channels and transporters that allow well-ordered propagation of electrical impulses across the myocardium. Disruptions in this orderly process provoke cardiac arrhythmias that may be lethal in some patients. Risk of common acquired arrhythmias is increased markedly when structural heart disease caused by myocardial infarction (due to fibrotic scar formation) or left ventricular dysfunction is present. Genetic polymorphisms influence structure or excitability of the myocardial substrate, which increases vulnerability or risk of arrhythmias in patients. Similarly, genetic polymorphisms of drug-metabolizing enzymes give rise to distinct subgroups within the population that affect specific drug biotransformation reactions. Nonetheless, identification of triggers involved in initiation or maintenance of cardiac arrhythmias remains a major challenge. Herein, we provide an overview of knowledge regarding physiopathology of inherited and acquired cardiac arrhythmias along with a summary of treatments (pharmacologic or non-pharmacologic) used to limit their effect on morbidity and potential mortality. Improved understanding of molecular and cellular aspects of arrhythmogenesis and more epidemiologic studies (for a more accurate portrait of incidence and prevalence) are crucial for development of novel treatments and for management of cardiac arrhythmias and their consequences in patients, as their incidence is increasing worldwide.

[End-of-life support experiences at home during the Covid-19 pandemic: Issues and challenges]. / Expériences d'accompagnement en fin de vie à domicile durant la pandémie de COVID-19 : enjeux et défis.

Objective The aim of this text is to describe the challenges and issues associated with family caregivers during the experience of caring for a person at the end of life at home, in the context of a pandemic. This support situation, already normally demanding, turned out to be more difficult and complicated than usual due to the many challenges and issues associated, in particular, with the health restrictions imposed at the time. Here, we present an analysis of comments gathered from family caregivers during the pandemic. Method Testimonials from caregivers were drawn from a research study entitled COVIDEUIL. The qualitative component of this study included many rich comments drawn from the voices of PPA and collected by questionnaire. For the present article, the focus was on qualitative data relating to the end-of-life situation at home of a loved one. This theme was documented by analyzing the responses of 71 caregivers. These people described, sometimes in detail, the particular circumstances surrounding their loved one's final days and death. Results PPAs report various issues in end-of-life care at home during the pandemic. Some results are similar to studies already carried out, including fatigue and the benefits of outside help, while others are perhaps more amplified, including the lack of support from caregivers, isolation, and the absence of continuity in services, due to the pandemic context. Testimonies show that home care requires physical and mental availability on the part of PPAs; the burden is imposing. In some cases, financial resources have been invested to pay for home care services. Moreover, formal and informal help remains an important element in maintaining home care until the end, otherwise it is compromised and institutional care becomes necessary. Conclusion For PPAs who were able to provide end-of-life care at home for their loved one at the end of life, various challenges were reported. In short, if end-of-life care at home is to be a safe and satisfying experience, PPAs must receive adequate support, and care must be tailored to the needs of the person being cared for. Support at the end of life at home is part of a long process of assistance and care provided by PPAs. The formal assistance offered should follow the evolution of the dyad's journey-PPA and cared-for person. End-of-life care at home is likely to increase as the population ages. As such, care and services must be orchestrated and adapted from the moment the diagnosis is announced. The Observatoire québécois de la proche aidance will certainly be able to assess the impact of the national policy on PPAs and measure the effects on their health, well-being and quality of life (art. 40) (ministère de la Santé et des Services sociaux, 2021a).

Stability of Opened Durvalumab (IMFINZI) Vials. The Beginning of the End of Costly Product Wastage?

Durvalumab is a monoclonal antibody approved for the treatment of lung, urothelial and biliary tract cancers. Durvalumab is supplied in vials as a solution containing no preservatives. Monographs recommend single use of durvalumab vials, and that any leftovers be discarded within 24 h. Thus, significant portions of unused product from opened vials are wasted on a daily basis, generating considerable financial losses. The objective of the present study was to assess the physicochemical and microbiological stability of durvalumab vials kept at 4 °C or room temperature, at 7 and 14 days after opening. Following pH and osmolality measurements, turbidity and submicronic aggregation of durvalumab solution were evaluated by spectrophotometry and dynamic light scattering, respectively. Moreover, steric exclusion high performance liquid chromatography (SE-HPLC), ion exchange HPLC (IEX-HPLC) and peptide mapping HPLC were used to respectively assess aggregation/fragmentation, charge distribution and primary structure of durvalumab. Microbiological stability of durvalumab was evaluated by incubation of vial leftovers on blood agar. All experiments showed physicochemical and microbiological stability of durvalumab vial leftovers for at least 14 days when aseptically handled and kept at either 4 °C or at room temperature. These results suggest the possible extension of utilization of durvalumab vial leftovers well beyond 24 h.

Homologation of the Alkyl Side Chain of Antimitotic Phenyl 4-(2-Oxo-3-alkylimidazolidin-1-yl)benzenesulfonate Prodrugs Selectively Targeting CYP1A1-Expressing Breast Cancers Improves Their Stability in Rodent Liver Microsomes.

Phenyl 4-(2-oxo-3-alkylimidazolidin-1-yl)benzenesulfonates (PAIB-SOs) are a new family of antimitotic prodrugs bioactivated in breast cancer cells expressing CYP1A1. In this study, we report that the 14C-labeled prototypical PAIB-SO [14C]CEU-818 and its antimitotic counterpart [14C]CEU-602 are distributed in whole mouse body and they show a short half-life in mice. To circumvent this limitation, we evaluated the effect of the homologation of the alkyl side chain of the imidazolidin-2-one moiety of PAIB-SOs. Our studies evidence that PAIB-SOs bearing an n-pentyl side chain exhibit antiproliferative activity in the nanomolar-to-low-micromolar range and a high selectivity toward CYP1A1-positive breast cancer cells. Moreover, the most potent n-pentyl PAIB-SOs were significantly more stable toward rodent liver microsomes. In addition, PAIB-SOs 10 and 14 show significant antitumor activity and low toxicity in chorioallantoic membrane (CAM) assay. Our study confirms that homologation is a suitable approach to improve the rodent hepatic stability of PAIB-SOs.

ATP acts as a survival signal and prevents the mineralization of aortic valve.

Calcific aortic valve disease (CAVD) is a disorder related to progressive mineralization of valvular tissue that is a leading cause of heart disease. Thus far, there is no medical treatment to prevent the mineralization of aortic valves. It is generally thought that pathologic mineralization is linked to apoptosis of vascular cells. However, the role of apoptosis during mineralization as well as the survival signals for valvular interstitial cells (VICs), the main cellular component of aortic valves, remains to be identified. Here, through several lines of evidence, we show that bioavailability of extracellular ATP is a signal which determines survival or apoptosis of VICs and, in doing so, plays a major role in the development of CAVD. Specifically, in CAVD and in VIC cultures undergoing mineralization, we found a high level of the ectonucleotidase ENPP1. In addition, a genetic polymorphism in the intron 9 of the ENPP1 gene was associated with CAVD in a case-control cohort as well as with mRNA expression levels of ENPP1 in aortic valves. A high level of ENPP1 in CAVD promoted apoptosis-mediated mineralization of VICs by depleting the extracellular pool of ATP. We then documented that release of ATP by VICs promoted cell survival via the P2Y(2) receptor and the PI3K/Akt signaling pathway. Hence, our results show that level of ENPP1 modulates extracellular concentration of ATP, which is an important survival signal for VICs. These findings may help to develop novel pharmacological treatment for CAVD.

Iloperidone (Fanapt®), a novel atypical antipsychotic, is a potent HERG blocker and delays cardiac ventricular repolarization at clinically relevant concentration.

QT interval prolongation on the electrocardiogram (ECG) has extensively been reported with iloperidone, a novel antipsychotic drug. The objective of the present study was to evaluate the effects of iloperidone on cardiac ventricular repolarization at three different levels; in vitro, ex vivo and in vivo. (1) In vitro level: whole-cell patch-clamp experiments were performed on HERG-transfected HEK293 cells exposed to iloperidone 0.01-1 µmol/L (n = 35 cells, total) to assess drug effect on HERG current. (2) Ex vivo level: Langendorff retroperfusion experiments were performed on isolated hearts from male Hartley guinea pigs (n = 7) exposed to iloperidone 100 nmol/L with/without chromanol 293B 10 µmol/L to assess drug-induced prolongation of monophasic action potential duration measured at 90% repolarization (MAPD(90)). (3) In vivo level: ECG recordings using wireless cardiac telemetry were performed in guinea pigs (n = 5) implanted with radio transmitters and treated with a single oral gavage dose of iloperidone 3 mg/kg. (1) Patch-clamp experiments revealed an estimated IC50 for iloperidone on HERG current of 161 ± 20 nmol/L. (2) While pacing the hearts at stimulation cycle lengths of 200 or 250 ms, or during natural sinus rhythm (no external pacing), iloperidone 100 nmol/L prolonged MAPD(90) by respectively 9.2 ± 0.9, 11.2 ± 1.6 and 21.4 ± 2.3 ms. After adding chromanol 293B, MAPD(90) was further prolonged by 7.3 ± 3.3, 11.5 ± 2.3 and 29.2 ± 6.7 ms, respectively. (3) Iloperidone 3mg/kg p.o. caused a maximal 42.7 ± 10.2 ms prolongation of corrected QT interval (QTc(F)), 40 min after administration. Iloperidone prolongs the QT interval, the cardiac action potentials and is a potent HERG blocker. Patients are at increased risk of cardiac proarrhythmia during iloperidone treatment, as this drug possesses significant cardiac repolarization-delaying properties at clinically relevant concentration.

Metabolic syndrome potentiates the cardiac action potential-prolonging action of drugs: a possible 'anti-proarrhythmic' role for amlodipine.

Type II diabetes was shown to prolong the QT interval on the ECG and to promote cardiac arrhythmias. This is not so clear for metabolic syndrome, a precursor state of type II diabetes. The objectives of the present study were to generate a guinea pig model of metabolic syndrome by long-term exposure to diabetogenic diets, and to evaluate the monophasic action potential duration (MAPD)-modulating effects of drugs in these animals. Male Hartley guinea pigs were fed with either the control, the High Fat High Sucrose (HFHS) or the High Fat High Fructose (HFHF) diet for 150 days. Evolution of weight, blood cholesterol, triglycerides, urea and glucose tolerance were regularly monitored. Histopathological evolution was also evaluated in target organs such as pancreas, heart, liver and kidneys. Ex vivo experiments using the Langendorff retroperfusion technique, isolated hearts from guinea pigs either fed with the control, the HFHS or the HFHF diet were exposed to dofetilide 20 nM (D), chromanol 293B 10 µM (C) and amlodipine 100 nM (A) in different drug combinations and monophasic action potential duration was measured at 90% repolarization (MAPD90). Our data show that it is possible to generate a guinea pig model of metabolic syndrome by chronic exposure to diabetogenic diets. Minor histopathological abnormalities were observed, mainly in the pancreas and the liver. Metabolic syndrome potentiates the MAPD-prolonging actions of I(Kr)-blocking (dofetilide) and I(Ks)-blocking (chromanol 293B) drugs, an effect that is reversible upon administration of the calcium channel blocker amlodipine.

Model Re-Estimation: An Alternative for Poor Predictive Performance during External Evaluations? Example of Gentamicin in Critically Ill Patients.

BACKGROUND: An external evaluation is crucial before clinical applications; however, only a few gentamicin population pharmacokinetic (PopPK) models for critically ill patients included it in the model development. In this study, we aimed to evaluate gentamicin PopPK models developed for critically ill patients. METHODS: The evaluated models were selected following a literature review on aminoglycoside PopPK models for critically ill patients. The data of patients were retrospectively collected from two Quebec hospitals, the external evaluation and model re-estimation were performed with NONMEM® (v7.5) and the population bias and imprecisions were estimated. Dosing regimens were simulated using the best performing model. RESULTS: From the datasets of 39 and 48 patients from the two Quebec hospitals, none of the evaluated models presented acceptable values for bias and imprecision. Following model re-estimations, all models showed an acceptable predictive performance. An a priori dosing nomogram was developed with the best performing re-estimated model and was consistent based on recommended dosing regimens. CONCLUSION: Due to the poor predictive performance during the external evaluations, the latter must be prioritized during model development. Model re-estimation may be an alternative to developing a new model, especially when most known models display similar covariates.

Methods of Therapeutic Drug Monitoring to Guide Vancomycin Dosing Regimens: Trough Concentration versus Ratio of Area Under the Curve to Minimum Inhibitory Concentration.

Background: The most recent vancomycin monitoring guideline recommends targeting a value for area under the curve (AUC) of 400 to 600 mg*h/L, with an assumed minimum inhibitory concentration (MIC) of 1 mg/L. Few studies have investigated the effect of this method on vancomycin dosing regimens, relative to a target trough concentration of 15 to 20 mg/L. Objective: To compare vancomycin dosing regimens generated with the 2 monitoring methods. Methods: This retrospective chart review included hospitalized patients who received vancomycin between May 2019 and April 2020. The dosing regimens were compared, with the paired Student t test, in terms of unit dose, daily dose, and dosing interval. Variables of interest were collected from electronic medical charts. A pharmacy resident used first-order pharmacokinetic equations to determine dosing regimens based on AUC monitoring. Local pharmacists retrospectively determined dosing regimens for trough-based monitoring. Results: Of 100 courses of treatment initially identified, 66 were included in the analysis. The unit dose was similar with the 2 methods (1086 mg with AUC-based monitoring versus 1100 mg with trough-based monitoring; p = 0.62). AUC monitoring was associated with a 12.8% lower daily dose (2294 mg versus 2630 mg; p < 0.001) and a 13.5% longer dosing interval (13.24 h versus 11.67 h; p < 0.001) relative to trough-based monitoring. AUC monitoring also generated a lower extrapolated trough concentration (12.90 mg/L versus 16.22 mg/L; p < 0.001). Conclusions: A target trough concentration of 15 to 20 mg/L was confirmed as being unnecessarily high. AUC monitoring could allow a reduction in daily vancomycin dose and an extension of the dosing interval relative to trough-based monitoring.

Contexte: La plus récente directive en matière de surveillance de la vancomycine recommande de cibler une valeur de surface sous la courbe (en anglais, AUC) de 400 à 600 mg*h/L, avec une concentration minimale inhibitrice (CMI) supposée de 1 mg/L. Peu d'études ont étudié l'effet de cette méthode sur les schémas posologiques de la vancomycine, par rapport à une concentration minimale cible de 15 à 20 mg/L. Objectif: Comparer les schémas posologiques de la vancomycine générés avec les 2 méthodes de surveillance. Méthodes: Cette revue rétrospective des dossiers comprenait des patients hospitalisés ayant reçu de la vancomycine entre mai 2019 et avril 2020. Un test de Student pour données appariées a été réalisé afin de comparer les schémas posologiques sur le plan de la dose unitaire, de la dose quotidienne et de l'intervalle de dosage. Les variables d'intérêt ont été recueillies à partir de dossiers médicaux électroniques. Un résident en pharmacie a utilisé des équations pharmacocinétiques de premier ordre pour déterminer les schémas posologiques en fonction de la surveillance de l'AUC. Les pharmaciens locaux ont déterminé rétrospectivement les schémas posologiques pour la surveillance basée sur la concentration résiduelle. Résultats: Sur 100 cours de traitement initialement identifiés, 66 ont été inclus dans l'analyse. La dose unitaire était similaire avec les 2 méthodes (1086 mg avec surveillance basée sur l'AUC contre 1100 mg avec surveillance basée sur la concentration résiduelle; p = 0,62). La surveillance de l'AUC était associée à une dose quotidienne inférieure de 12,8 % (2294 mg contre 2630 mg; p < 0,001) et à un intervalle de dosage plus long de 13,5 % (13,24 h contre 11,67 h; p < 0,001) par rapport à la surveillance basée sur la concentration résiduelle. La surveillance de l'AUC a également généré une concentration minimale extrapolée plus faible (12,90 mg/L contre 16,22 mg/L; p < 0,001). Conclusions: Une concentration résiduelle cible de 15 à 20 mg/L a été confirmée comme étant inutilement élevée. La surveillance de l'AUC pourrait permettre une réduction de la dose quotidienne de vancomycine et un allongement de l'intervalle de dosage par rapport à la surveillance basée sur la concentration résiduelle.

Aminoglycosides' dosing and monitoring practices in critically ill patients in Quebec hospitals.

Considering the aminoglycosides' characteristics in terms of efficacy and toxicity, multiple dosing recommendations and nomograms have been suggested over several decades. The objective is to describe the dosing and monitoring practices of amikacin, gentamicin, and tobramycin in critically ill patients across health care institutions in the province of Quebec.This survey was developed with multiple-choices and short answers and targeted the lead pharmacist responsible of antimicrobial stewardship in each health care institution.Gentamicin and tobramycin dosing regimens were in-line with guidelines from different countries. Amikacin was not commonly used in Quebec. Therapeutic targets were generally consistent with the literature.Dosing adaptation were mostly done based on clinician judgment or with homemade software. Given the variability seen across practices in Quebec institutions, standardization and optimization of aminoglycosides therapeutic drug monitoring may be considered.