Aim: A better knowledge of opioid prescribing patterns would help to identify areas of potential improvement in cancer pain management. This study aimed to identify potential inappropriate use (PIU) of strong opioid analgesics in cancer outpatients in their last year of life. Methods: A retrospective cohort of cancer patients dead between 2011 and 2014 and who were exposed as outpatient to a strong opioid analgesic in the last year of life was identified in the “Echantillon Généraliste de Bénéficiaires” (a 1/97th random sample of the French general population). Prescribing patterns of strong opioids were analyzed and PIU was defined by at least one of these criteria: overlapping prescriptions; contraindicated prescriptions; lack of laxatives; potential drug interactions; prescription in patients hospitalized for opioid-related disorders. Factors associated with PIU were investigated through a multiple logistic regression model. Results: One third of the 2,236 patients (median age 72 years (IQR: 61-82), 44.1% of women) presented a PIU (insufficient laxative prescription (19.6% of patients), insufficient background treatment with transmucosal fentanyl (14.8%), overlapping prescriptions (2.6%)). The rate of PIU significantly decreased from 37.6% (2011) to 29.8% (2014). For patients with a duration of opioid use  3 months, factors associated with PIU were fentanyl prescription (aOR=2.36; 95% CI [1.86-3.00]) and previous use of strong opioid (aOR=1.88; [1.50-2.36]) Conclusion: In France, one third of cancer patients exposed to strong opioids experienced PIU and this proportion tended to decrease over time. There is still room for progress in cancer pain management at the end of life.

AIM: Influenza infection poses a severe threat to pregnant mothers, and antiviral treatment is recommended. However, the safety of neuraminidase-inhibitor antiviral medications during pregnancy has not been well described. METHODS: A systematic review and meta-analysis were performed to evaluate the adverse neonatal outcomes associated with exposure to neuraminidase inhibitors during pregnancy. The PubMed, Embase, and Cochrane Library databases were searched to identify potential studies for inclusion. RESULTS: Nine cohort studies that estimated adverse neonatal outcomes associated with exposure to neuraminidase-inhibitor medication during pregnancy were included. Exposure to a neuraminidase inhibitor during pregnancy was not associated with an increased risk of congenital malformation (odds ratio [OR] 0.9, 95% confidence interval [CI] 0.72–1.12, P = 0.341), low Apgar score (OR 0.96, 95% CI 0.77–1.2, P = 0.733), or preterm birth (OR 0.99, 95% CI 0.89–1.09, P = 0.771) compared with no exposure. However, exposure to a neuraminidase inhibitor was associated with a reduced risk of low birth weight (OR 0.79, 95% CI 0.68–0.92, P = 0.002) and giving birth to a small-for-gestational-age infant (OR 0.78, 95% CI 0.69–0.88, P < 0.001). Further analyses limited to oseltamivir exposure were consistent with the overall results. CONCLUSION: Exposure to neuraminidase-inhibitor medication during pregnancy does not appear to be associated with adverse neonatal outcomes. We recommend further studies to investigate this association, which will help clinicians determine whether to prescribe a neuraminidase inhibitor during pregnancy.

Identifying the optimal treatment based on specific aetiology of each patient is the main promise of precision medicine. In order to realize this promise researches and physicians must first identify the underlying cause; over the last 10 years, advances in genetics have made this possible for several monogenic epilepsies. At present through next generation techniques we can reach the precise genetic aetiology in 30 to 50% of genetic epilepsies beginning in the paediatric age. While committed in such gene hunting, progresses in the study of experimental models of epilepsy have also provided a better understanding of the mechanisms underlying the condition. Such impressive advances is already being translated into improving care, management and treatment of some patients. Identification of a precise genetic etiology can already direct physicians to prescribe treatments correcting specific metabolic defects avoid antiseizure medicines that can aggravate the pathogenic defect or select the drug that counteract the functional disturbance caused by the gene mutation. Personalized, tailored treatments should not just focus on how to stop seizures but possibly preventing their onset and cure the disorder often consisting of epilepsy and its comorbidities including cognitive, motor and behavior deficiencies. This review discusses the therapeutic implications following a specific genetic diagnosis and the correlation between genetic findings, pathophysiological mechanism and tailored seizure treatment emphasizing the impact on current clinical practice.

Since the beginning of the COVID-19 pandemic, industry and healthcare providers have investigated methodologies to manage infection of SARS-CoV-2. One treatment breakthrough has been the introduction of monoclonal antibodies to prevent worsening SARS-CoV-2 infection in non-hospitalized patients diagnosed with COVID-19. These monoclonal antibodies, like bamlanivimab, bind to the SARS-CoV-2 spike protein and prevent its ability to binding to human ACE2 receptors. This is a case of a 91 year-old man with no prior seizure history who developed new-onset seizures after bamlanivimab infusion.

Aim Antimicrobial resistance is an evolving phenomenon with alarming public health consequences. Antibiotic cycling is a widely known antimicrobial stewardship initiative which encompasses periodical shifts in empirical treatment protocols with the aim to limit selective pressures on bacterial populations. Nonetheless, mathematical models have challenged its presumable efficacy by favouring a higher heterogeneity in antibiotic administration. We present a review of the evidence regarding the actual impact of antimicrobial cycling on bacterial resistance control within hospitals. Methods A systematic literature review was conducted using the PubMed/MedLine, Embase, CINAHL Plus and Global Health databases. Results A systematic search process retrieved a sole randomised study, and so we broadened inclusion criteria to encompass quasi-experimental designs. Fifteen studies formed our dataset including seven prospective trials and eight before-and-after studies. Nine studies evaluated cycling versus a control group and produced conflicting results whilst three studies compared cycling with antibiotic mixing, with none of the strategies appearing superior. The rest evaluated resistance dynamics of each of the on-cycle antibiotics with contradictory findings. Research protocols differed in parameters such as the cycle length, the choice of antibiotics, the opportunity to de-escalate to narrow-spectrum agents and the measurement of indicators of collateral damage. This limited our ability to evaluate the replicability of findings and the overall policy effects. Conclusions Dearth of robust designs and standardised protocols limits our ability to reach safe conclusions. Nonetheless, in view of the available data we find no reason to believe that cycling should be expected to improve antibiotic resistance rates within hospitals.

A document by Teun van Gelder. Click on the document to view its contents.

Pregnant, or potentially pregnant women have historically been excluded from clinical trials of new medications. However, it is increasingly recognised that it is imperative to generate evidence from the population in whom the drugs are likely to be used in order to inform safe, evidence-based shared clinical decision making. Reluctance by researchers and regulators to perform such studies often relates to concerns about risk, particularly to the fetus. However, this must be offset against the risk of untreated disease or using a drug in pregnancy where safety, efficacy and dosing information are not known. This review summarises the historical perspective, the ethical and legal frameworks which inform the conduct of such research, then highlights examples of innovative practice which have enabled high quality, ethical research to proceed to inform the evidence-based use of medication in pregnancy.

Aims: No study has evaluated the BET pharmacokinetics in twin pregnancies separated by chorionicity. The aim this study is to describe and compare the BET pharmacokinetic parameters in singleton, dichorionic (DC) and monochorionic (MC) twin pregnancies in the third trimester of pregnancy. Methods: Twenty-six pregnant women received an intramuscular dose of 6 mg of BET sodium phosphate plus 6 mg BET acetate. Serial blood samples were collected for 24 hours after the first intramuscular BET esters dose. BET plasma concentrations were quantified using a validated HPLC analytical method. BET pharmacokinetic parameters were obtained employing a non-compartment model, and were compared using ANOVA’s test with Tukey’s multiple comparisons test. Correlations between clinical features and pharmacokinetic parameters were analyzed using Pearson’s correlation. Preliminary data on the BET placental transfer were also presented. Results: The geometric mean (IC 95%) of AUC0-∞ 670.0 (504.3-805.2) vs 434.9 (311.2-539.6) ng.h/mL and the CL/F 18.38 (13.84-22.65) vs 29.40 (21.17-36.69) were significantly lower and higher, respectively, in DC twin pregnancies compared to singleton. Others pharmacokinetic parameters did not differ among the groups. Conclusions: Data from this study suggest that the presence of two fetoplacental units may increase the BET metabolism by CYP3A4 enzyme and increase its elimination. Pharmacokinetic-pharmacodynamic clinical studies are needed to investigate whether this BET pharmacokinetic changes have clinical repercussions for the newborns and require dose adjustment in DC twin pregnancies.

Objectives: To assess the effectiveness of dimethyl fumarate (DMF) on annual rate of relapse (ARR) and disability progression in multiple sclerosis (MS) compared to injectable immunomodulators (IMM), teriflunomide (TERI) and fingolimob (FTY), in real life setting. Methods: A population-based cohort study was conducted using data of the French nationwide claims database, SNDS. All patients initiating IMM, TERI, FTY or DMF between July 1, 2015 and December 12, 2017, with 4.5 years of database history and 1 to 3.5 years of follow-up were included in this study. DMF patients were 1:1 matched to IMM, TERI or FTY using a high dimensional Propensity Score. Negative binomial regression and a logistic regression models were used to estimate the relative risk (RR ± [95% CI]) of ARR and the Odds Ratio (OR ± [95% CI]) of disability progression, respectively. Results: Overall, 9 304 subjects were identified: 29.0% initiated DMF, 33.2% TERI, 5.6% FTY and 32.2% an IMM. The matched cohorts consisted of 1779 DMF- IMM, patients, 1679 DMF-TERI patients, and 376 DMF-FTY patients. DMF significantly reduced ARR compared to IMM (RR 0.72 [0.61 - 0.86]) and TERI (0.81 [0.68 - 0.96]) and did not show any significant difference when compared with FTY The risk of the progression of MS specific disability was not significantly different for any matched cohorts. Interpretation: DMF is associated with lower risk of relapse for patients with RRMS than other first-line RRMS agents (TERI and IIM).

Aim: The Norwegian Association for Clinical Pharmacology in their National Guidelines decreased therapeutic range (TR) of topiramate (TPM) from 5-20 mg/L to 2-10 mg/L. The objective of this study is to ascertain which TR produces better clinical outcomes. Methods: Data source were request forms for routine therapeutic drug monitoring of TPM. Concentration dependent adverse drug reactions (ADRs) were evaluated in 1,721 samples taken pre-dose. Seizure frequency analysis was performed in 294 samples of monotherapy. Statistics: Prism 5.0, GraphPad Instatt: Mann–Whitney U test for median plasma level (PL). χ2-test for seizure frequency and for distribution of PL according to TR 5-20 mg/L and intervals <2, 2-5, 5-10, 10-20, >20 mg/L. Results: Better seizure control was found in children both in whole cohort (without seizure 49% vs 37% adults), as well as in monotherapy (56% vs 44%), in children with PL 5-20 mg/L vs 5 mg/L (65% vs 44%) and in children with PL 5-10 mg/L vs <2 mg/L. Seizure-free children had higher PL than those with seizure yearly: median (lower, upper quartile) [mg/L]: 5.5 (3.4-6.5) vs 4.7 (4.3-7.95). No difference was found in adults. Seizure control was poorer in all patients with PL <2 mg/L compared to 5-10 mg/L; and 10-20 mg/L; further in PL within 5-10 mg/L vs 10-20 mg/L; and in the period 2003-2005. ADRs reported in 38 samples (2.8%) were without relation to PL. Conclusions: Change of TR is not recommended.

Pharmaceutical industry and drugs advertisement is sometimes accused of “creating diseases”. This article assesses and describes the role of that industry in fostering medicalization. First, the notions of medicalization and pharmaceuticalization are defined. Then, the problem of distinguishing between harmful overmedicalization and well-founded medicalization is presented. Next, the phenomenon of disease mongering is explained and illustrated by the case analysis of medicalizing pain and suffering in three contexts: 1) the general idea of medicalizing physical pain, 2) the medicalization of grief, and 3) disease mongering of pseudoaddiction - a condition promoted in order to increase the demand for opioid pain relievers.

Aims: The objective of this retrospective cohort study was to provide an overview of the utilization of originator and biosimilar infliximab in the Netherlands. Methods: All infliximab dispensings were selected from the PHARMO In-patient Pharmacy Database from 2002-2018. Descriptive analyses were performed in order to characterise initiators and to describe switching patterns over time. Results: Overall, 3,840 patients with 61,274 infliximab dispensings were identified. 2,496 patients initiated an originator infliximab and 777 patients initiated a biosimilar infliximab. Overall, 57% of the patients was female and mean age was 43.2 years. Both originators and biosimilars were mostly prescribed by gastroenterologists, followed by internists and rheumatologists. After market authorization of the first biosimilar the proportion of new patients initiating the biosimilar increased from 39% in 2015 to 91% in 2018. Out of 704 patients eligible for switching 34% switched. Among switchers, the proportion of females was 60% and mean age at index was 45.1 years. Among non-switchers, 55% was female and mean age was 39.8 years. The median time to switch was 1.7 years and switchers were most frequently initiated on infliximab by a rheumatologist (42%), while non-switchers were most frequently initiated by a gastroenterologist (42%). Conclusions: The results of this large population-based cohort show an increase in biosimilar initiation in daily clinical practice. The number of switchers remains relatively low as non-medical switch is not encouraged in the Netherlands.

Aim: To analyze the appropriateness of DOAC dosing and determinants for under-and overdosing as well as acceptance and implementation rates of interventions by clinical pharmacists. Methods: Cross-sectional study from January 2019-December 2019 in a tertiary hospital in hospitalized patients with atrial fibrillation on DOACs (n=1688). Primary outcome was the proportion of patients with inappropriate DOAC prescribing with identification of determinants for under-and overdosing. Secondary outcomes included acceptance and implementation rates of pharmacists’ advices and determination of reasons for non-acceptance/non-implementation. Results: In 16.9% of patients, inappropriate prescribing was observed. For all DOACs considered together, body weight<60 kg(OR 0.46 [0.27-0.77]), edoxaban use(OR 0.42 [0.24-0.74]), undergoing surgery(OR 0.57 [0.37-0.87]) and being DOAC naïve(OR 0.45 [0.29-0.71]) were associated with a significantly lower odds of underdosing. Bleeding history(OR 1.86 [1.24-2.80]) and narcotic use(OR 1.67 [1.13-2.46]) were associated with a significantly higher odds for underdosing. Determinants with a significantly higher odds of overdosing were renal impairment(OR 11.29 [6.23-20.45]) and body weight<60 kg(OR 2.34 [1.42-3.85]), whereas the use of dabigatran(OR 0.24 [0.08-0.71]) and apixaban(OR 0.18 [0.10-0.32]) were associated with a significantly lower odds of overdosing compared to rivaroxaban. Physicians accepted the pharmacists’ advice in 179 cases (79.2%) consisting of 92 (51.4%) advices for underdosing, 82 (45.8%) for overdosing and 5 (2.8%) for contraindications. The advices were effectively implemented for 75 (81.5%) underdosed, 69 (84.1%) overdosed and 4 (80.0%) contraindicated cases. Conclusion: Inappropriate DOAC prescribing remains common. Clinical services led by pharmacists helps physicians to reduce the number of inadequate prescriptions for high risk medications such as DOACs.

Aims: To continually evaluate the role of cardiovascular drugs in COVID-19 clinical outcomes. Methods: Eligible publications were identified from >500 databases on 1-Nov-2020. One reviewer extracted data with 20% of the records independently extracted/evaluated by a second reviewer. Results: Of 52,735 screened records, 429 and 390 studies were included in the qualitative and quantitative syntheses, respectively. The most-reported drugs were angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs) with ACEI/ARB exposure having borderline association with positive COVID-19 status (OR 1.14, 95% CI 1.00–1.31). Among COVID-19 patients, unadjusted estimates showed that ACEI/ARB exposure was associated with hospitalization (OR 1.76, 1.34–2.32), disease severity (OR 1.41, 1.27–1.56) and all-cause mortality (OR 1.22, 1.12–1.33) but not hospitalization length (mean difference -0.27, -1.36; 0.82 days). After adjustment, ACEI/ARB exposure was not associated with positive COVID-19 status (OR 0.92, 0.71–1.19), hospitalization (OR 0.93, 0.70–1.24), disease severity (OR 1.05, 0.81–1.38), or all-cause mortality (OR 0.85, 0.71–1.01). Similarly, subgroup analyses involving only hypertensive patients revealed that ACEI/ARB exposure was not associated with positive COVID-19 status (OR 0.93, 0.79–1.09), hospitalization (OR 0.84, 0.58–1.22), hospitalization length (mean difference -0.14, -1.65; 1.36 days), disease severity (OR 0.92, 0.76–1.11) while it decreased the odds of dying (OR 0.76, 0.65–0.88). A similar trend was observed for other cardiovascular drugs. However, the validity of these findings is limited by a high level of heterogeneity and serious risk of bias. Conclusion: Cardiovascular drugs are not associated with poor COVID-19 outcomes in adjusted analyses. Patients should continue taking these drugs as prescribed.

There is a critical skills gap on the African continent in regulatory sciences, and an acknowledged need to develop a long-term strategy for training and professional development of African regulatory personnel. Capacity building programs for African regulators should link education, training and research with career development in an approach that combines an academic base and experiential learning aligned within a competency framework. A regulatory ecosystem that engages with a broad range of stakeholders will mean that expertise in the ever-expanding field of regulatory science filters into teaching and research in a symbiotic way. In this way capacity development interventions will be a collaborative approach between the learning context (academic and training institutions) and the performance context (regulatory agencies and industry), which will ultimately best serve the patients. Monitoring and evaluation of capacity development interventions will be essential to show value of investments and ultimately guide continued funding and sustainability. This paper reviews the skills and human capacity gap and outlines a staged tactical approach for Africa that builds on previous efforts to strengthen African regulatory ecosystems.

Aims: In order to better predict the pharmacokinetics (PK) of antibodies in children, and to facilitate dose optimization of antibodies in pediatric patients, there is a need to develop systems PK models that integrate ontogeny related changes in human physiological parameters. Methods: A population-based physiological-based PK (PBPK) model to characterize antibody PK in pediatrics has been developed, by incorporating age-related changes in body weight, organ weight, organ blood flow rate, and interstitial volumes in a previously published platform model. The model was further used to perform Monte Carlo simulations to investigate clearance vs. age and dose-exposure relationship for infliximab. Results: By estimating only one parameter and associated interindividual variability, the model was able to characterize clinical PK of infliximab from two pediatric cohorts (n=141, 4-19 years) reasonably well. Model simulations demonstrated that only 50% of children reached desired trough concentrations when receiving FDA-labelled dosing regimen for infliximab, suggesting that higher doses and/or more frequent dosing are needed to achieve target trough concentrations of this antibody. Conclusion: The pediatric PBPK model presented here can serve as a framework to characterize the PK of antibodies in pediatric patients. The model can also be applied to other protein therapeutics to advance precision medicine paradigm and optimize antibody dosing regimens in children.

There is a need for anti-diabetic agents successfully targeting insulin sensitivity and treating obesity control at the same time. The aim of this first-in-human study was 1) to evaluate safety and tolerability; 2) to evaluate pharmacokinetics and 3) to assess indications of receptor engagement of single ascending doses of KBP-042, a Dual Amylin and Calcitonin Receptor Agonists (DACRA) that has shown promising preclinical data, with superior activity in terms of typical amylin-induced responses including reduction of food intake, weight loss and gluco-regulatory capacities. A randomised double-blind placebo-controlled single ascending dose study was performed with six dose levels of KBP-042 (5, 7.5, 10, 20, 20 evening and 40µg) in healthy male adults. KBP-042 or placebo was administered as a single dose after an overnight fast, followed by a standardized lunch after four hours. KBP-042 was associated with dose-dependent complaints of nausea and vomiting, with a lack of tolerability at doses of 20µg and above. Doses of 5 to 40 μg KBP-042 were behaved according to a linear pharmacokinetic profile. Indications of target receptor engagement were observed at the level of glucose control and lowering of bone resorption, compared to placebo. The results of this study showed that doses up to 40 μg were safe, although tolerability was not present at the highest doses. The study confirmed target receptor engagement at the studied doses.

Aims: To optimize the dosing regimen in patients with severe renal impairment based on population pharmacokinetic/pharmacodynamic (PPK/PD) analysis. Methods: The pharmacokinetics and safety of nemonoxacin was evaluated in a single-dose, open-label, nonrandomized, parallel-group study after single oral dose of 0.5 g nemonoxacin capsule in 10 patients with severe renal impairment and 10 healthy controls. Both blood and urine samples were collected within 48 hours after admission and determined the concentrations. A PPK model was built using nonlinear mixed effects modelling. The probability of target attainment (PTA) and the cumulative fraction of response (CFR) against S. Pneumoniae and S. aureus was calculated by Monte Carlo simulation. Results: The data best fitted to a two-compartment model, from which the PPK parameters were estimated, including clearance (8.55 L/h), central compartment volume (80.8 L), and peripheral compartment volume (50.6 L). The accumulative urinary excretion was 23.4±6.5% in severe renal impairment patients and 66.1±16.8% in healthy controls. PPK/PD modeling and simulation of 4 dosage regimens found that nemonoxacin 0.5 g q48h was the optimal dosing regimen in severe renal impairment patients, evidenced by higher PTA (92.7%) and CFR (>99%) at nemonoxacin MIC ≤ 1 mg/L against S. pneumoniae and S. aureus. The alternative regimens (0.25 g q24h; loading dose 0.5 g on Day 1 followed by 0.25 g q24h) were insufficient to cover the pathogens even if MIC ≤ 0.5 mg/L. Conclusion: An extended dosing interval (0.5 g q48h) may be appropriate for optimal efficacy of nemonoxacin in case of severe renal impairment.