Aim: To determine whether the known single nucleotide polymorphisms in adrenoreceptor associated genes affect the hemodynamic response to dobutamine in critically ill neonates. Methods: Alleles in the known genetic single nucleotide polymorphisms in β1 and β2 adrenoceptor (AR) genes and Gs protein α-subunit gene (GNAS) possibly affecting inotropic effect were identified in patients of neonatal dobutamine pharmacokinetic-pharmacodynamic study. Linear mixed-effect models were used to describe the effect of genetic polymorphisms to heart rate (HR), left ventricular output (LVO) and right ventricular output (RVO) during dobutamine treatment. Results: 26 neonates (5 term, 21 preterm) were studied. Dobutamine plasma concentration and exposure time respective HR (adjusted to gestational age) is dependent on β1-AR Arg389Gly polymorphism so that in G/G (Gly) homozygotes and G/C heterozygotes dobutamine increases HR more than in C/C (Arg) homozygotes, with parameter estimate (95% CI) of 38.3 (15.8 – 60.7) bpm per AUC of 100 mg·h, p=0.0005. LVO (adjusted to antenatal glucocorticoid administration and illness severity) and RVO (adjusted to gestational age and illness severity) is dependent on GNAS c.393C>T polymorphism so that in T/T homozygotes and C/T heterozygotes but not in C/C homozygotes LVO and RVO increase with dobutamine treatment, 24.5 (6.2 – 42.9) mL kg-1 min-1 per AUC of 100 mg·h, p=0.0116 and 33.2 (12.1 – 54.3) mL kg-1 min-1 per AUC of 100 mg·h, p=0.0025, respectively. Conclusion: In critically ill neonates, β1-AR Arg389Gly and GNAS c.393C>T polymorphisms may play a role in the haemodynamic response to dobutamine during the first hours and days of life.

AIM: To improve the tolerability and therapeutic application of histone deacetylase inhibitors (HDACi), by application of an esterase-sensitive motif (ESM), to target pharmacological activity directly to mononuclear myeloid cells expressing the processing enzyme carboxylesterase-1 (CES1). METHODS. This first-in-human study comprised of single and multiple ascending dose cohorts to determine safety and tolerability. Pharmacodynamic parameters included acetylation, cytokine inhibition and intracellular concentrations of processed acid metabolite in isolated monocytes. Mechanistic work was conducted in vitro and in a CES1/Es1elo mouse strain. RESULTS. ESM-HDAC391 was well tolerated whilst showing robust targeted mechanistic engagement, as demonstrated by selective retention of compound and increased acetylation in monocytes plus inhibition of ex vivo stimulated cytokine production. Importantly, common clinical HDACi toxicities were not observed. ESM-HDAC391 treatment was accompanied by the novel finding of a dose-dependent monocyte depletion that was transient and reversible. In-depth characterisation of monocyte depletion in a transgenic mouse model (CES1/Es1elo) suggested that CSF1R loss on circulating cells contributes to ESM-HDAC-mediated depletion. Further mechanistic investigations using human monocytes in vitro demonstrated HDACi-mediated change in myeloid fate through modulation of CSF1R and downstream effects on cell differentiation. CONCLUSION. These findings demonstrate selective targeting of monocytes in humans using the ESM approach and identify monocytopaenia as a novel outcome of ESM-HDACi treatment, with implications for the potential benefit of these molecules in myeloid-driven diseases.

Erythema nodosum (EN), the most form of panniculitis, is mainly caused by numerous infective (especially Beta-hemolytic streptococcal infections) and non-infective (especially sarcoidosis) diseases and drugs. EN associated with vaccines has been rarely reported. We describe herein, an original clinical observation of EN induced by BNT162b2, an mRNA vaccine. A 75-year-old woman presented with diffuse erythematous painful rounded nodular lesions, located symmetrically over her legs. Six days before, she had received the second dose of Covid-19 vaccine (BNT162b2 (Pfizer–BioNTech)), followed by a sudden asthenia, polyarthralgia, throbbing and edema over her lower limbs. She had been given the first dose of the same Covid-19 vaccine 29 days prior to the second without incident. General physical examination was normal. Skin examination showed multiple, erythematous tender, nodules, 10–30 mm in diameter, over the tibial area. Complete blood count, renal and hepatic tests, antistreptolysin O titer, antinuclear antibody, thyroid test and chest radiograph and PCR, were carried out, and found to be normal. Histopathology revealed infiltration of deep dermal vessels and subcutaneous fat with lymphomononuclear cells and neutrophils, consistent with erythema nodosum. Treatment with analgesics led to complete resolution of the lesion after three months. The patient has shown no relapse after follow-up for three months. In conclusion, to our knowledge, this is the first case of EN induced by the second dose of BNT162b2 (Pfizer–BioNTech) Covid-19 vaccine. It is important for clinicians to be aware of this rare, yet potential, adverse effect to this vaccine.

Several observational studies have examined the potential protective effect of angiotensin-converting enzyme inhibitor (ACE-I) use on the risk of age-related macular degeneration (AMD) and have reported contradictory results owing to confounding and time-related biases. We aimed to assess the risk of AMD in a base cohort of patients aged 40 and above with hypertension among new users of ACE-I compared to an active comparator cohort of new users of calcium channel blockers (CCB) using data obtained from IQVIA Medical Research database, a primary care database in the UK. In this study, 53,832 and 43,106 new users of ACE-I and CCB were included between 1995 and 2019, respectively. In an on-treatment analysis, patients were followed up from the time of index drug initiation to the date of AMD diagnosis, loss to follow-up, discontinuation or switch to the comparator drug. A comprehensive range of covariates were used to estimate propensity scores to weight and match new users of ACE-I and CCB. Standardized mortality ratio (SMR) weighted Cox proportional hazards model was used to estimate hazard ratios (HRs) of developing AMD. During a median follow-up of 2 years (interquartile range 1-5 years), the incidence rate of AMD was 2.4 and 2.2 per 1,000 person-years among the weighted new users of ACE-I and CCB, respectively. There was no association of ACE-I use on the risk of AMD compared to CCB use in either the propensity score weighted or matched, on-treatment analysis (aHR: 1.07 (95% CI 0.90-1.27) and 0.87 (0.71-1.07) respectively).

Background: Antiretroviral therapy reduces systemic inflammation and immune activation, but not to levels like HIV-negative. Limited drug penetration within tissues has been argued as potential mechanism of persistent inflammation. Data on the role of inflammation on plasma/intracellular (IC) pharmacokinetics (PK) of ARV drugs through to downregulation/expression of cytochrome P450 3A/membrane transport proteins are limited. Aim of this study was to investigate the correlation between inflammation markers and plasma/IC PK of different ARVs regimen in HIV-positive patients. Methods: We included in the study ART-treated HIV+ pts switching to 3 different ARV regimens: 1) DTG-based dual-therapy plus boosted-PIs, 2) DTG-based triple-therapy without PIs, 3) DRV/c-based triple-therapy. Plasma and IC ARV drugs concentration means at the end of dosing interval (T0), IM on samples concomitantly with ARV PK determination: sCD14, CRP, IL-6 and LPS were analysed. Results: 60 samples from pts included in the switching study were used for measuring plasma and IC concentrations of HIV drugs. No significative differences between CRP, sCD14, IL-6 and LPS values in 3 arms of therapy were observed. Significant correlation was observed between tenofovir plasma concentrations and sCD14 (p<0.001), DRV plasma concentration and sCD14 (p=0,07) and DRV IC/plasma ratio and Log10 IL-6 concentrations (p=0.04). Furthermore, in 24 pts on DTG-TT, we observed a negative trend between DTG IC concentrations and sCD14 (p=0.09). Conclusions: Our preliminary data support the hypothesis of lower IC concentrations of DRV and DTG in pts with higher plasma IM, suggesting an interplay between HIV drug penetration and persistent inflammation in cART-treated HIV-positive patients.

Manuscript title:Sustainable medicines use in clinical practice – it is time to help the teacher

Objective: Our hypothesis was that the intervention would decrease (or at least not increase) the number of potentially inappropriate medications (PIMs) and the number of hospital readmissions within 30 days of discharge per hospital stay. Methods: A cohort of hospitalized older adults enrolled in the PAERPA integrated care pathway (the exposed cohort) was matched retrospectively with hospitalized older adults not enrolled in the pathway (unexposed cohort) between January 1st, 2015, and December 31st, 2018. It was an analysis of French health administrative database. The inclusion criteria for exposed patients were admission to an acute care department in general hospital, age 75 or over, at least three comorbidities or the prescription of diuretics or oral anticoagulants, discharge alive, and performance of a medication review. Results: For the study population (n=582), the mean ± standard deviation age was 82.9 ± 4.9, and 190 (65.3%) were women. Depending on the definition used, the overall median number of PIMs ranged from 2 [0;3] upon admission to 3 [0;3] at discharge. The intervention was not associated with a significant difference in the mean number of PIMs. Patients in the exposed cohort were half as likely to be readmitted to hospital within 30 days of discharge, relative to patients in the unexposed cohort. Conclusion: Our results show that a medication review was not associated with a decrease in the mean number of PIMs. However, the integrated care intervention including the medication review was associated with a reduction in the number of hospital readmissions at 30 days.

Several cases of herpes zoster (HZ) following mRNA COVID-19 vaccination (BNT162b2 and mRNA-1273) have been reported, and first epidemiological evidences suggest an increased risk. We used the worldwide pharmacovigilance database VigiBase to describe HZ cases following mRNA COVID-19 vaccination. We performed disproportionality analyses (case/non-case statistical approach) to assess the relative risk of HZ reporting in mRNA COVID-19 vaccine recipients compared to influenza vaccine recipients and according to patient age. Until 30th June 2021, of 716,928 reports about mRNA COVID-19 vaccines, we found 7,728 HZ cases. When compared to influenza vaccines, mRNA COVID-19 vaccines were associated with a significantly higher reporting of HZ (reporting odds-ratio 1.9, 95%CI [1.8-2.1]). Furthermore, we found a reduced risk of reporting HZ among under 40 year-old persons compared to older persons (reporting odds-ratio 0.39, 95%CI [0.36-0.41]). For the first time, we could assess at a global level the risk of HZ after mRNA COVID-19 vaccination.

Methaemoglobin results from the oxidation of ferrous to ferric iron in the centre of the haem moeity of haemoglobin. The production of dose-dependent methaemoglobinaemia by 8-aminoquinoline antimalarial drugs appears to be associated with, but is not directly linked to therapeutic efficacy against latent vivax and ovale malarias. Iatrogenic methaemoglobinaemia may be a useful pharmacodynamic measure in 8-aminoquinoline drug and dose optimization.

Aim: The effect of the Dutch nationwide adjustment of reduced 6-TGN target values (from 600-1200 pmol/8x108 RBC to 320-630 pmol/8x108 RBC) on toxicity and clinical outcome of thiopurine treatment in patients with inflammatory bowel disease (IBD) has not yet been established. Therefore the authors determined the incidence of toxicity-induced discontinuations and efficacy at both target concentrations. Methods: This retrospective study was performed in IBD patients treated with azathioprine or mercaptopurine. Two groups were defined: the former target (FT) group with target concentrations of 600-1200 pmol/8x10^8 RBC and the adjusted target (AT) group with target concentrations of 320-630 pmol/8x10^8 RBC. Patients were followed for maximum 52 weeks or until discontinuation of thiopurine therapy. Data were collected from the local hospital electronic health software of Rijnstate Hospital. Results: 151 patients were included, 76 in the FT group and 75 in the AT group. At week 52, 100 out of 150 patients (66%) of the total population discontinued thiopurine therapy. Forty-eight of this discontinuations were due toxicity (48%). The estimated cumulative incidence of toxicity was higher in the FT group compared to the AT group (47% and 35% respectively, p=0.25). No loss of efficacy was seen in the AT group. Conclusion: Reduction of the target range may lead to less toxicity induced discontinuations. In addition, this study did not find any indication that the reduction of the target range diminished efficacy.

Tocilizumab for reduction of mortality in severe COVID-19 patients: how should we GRADE it?Vladimir TrkuljaVladimir Trkulja, MD, PhDDepartment of PharmacologyZagreb University School of MedicineŠalata 1110000 Zagreb, Croatiae-mail: vladimir.trkulja@mef.hrNumber of words: 799Number of figures/tables: 1To the Editor,A recent systematic review/meta-analysis 1 of randomized trials (RCTs) of tocilizumab (plus standard of care [SoC] vs. SoC w/wo placebo) in severe COVID-19 patients was a pleasure to read owing to a clear presentation of a thorough approach to data (e.g., sensitivity analyses, accounting for corticosteroid use, need for mechanical ventilation [MV] at baseline). Authors assigned high quality (certainty) GRADE levels to the evidence of efficacy in reduction of mortality overall (10 RCTs) and in patients without MV at baseline (data from 9 RCTs), and reduction of incident MV (10 RCTs). The grading was based on fixed-effect pooling, likely owing to low inconsistency index (I2) and closely similar fixed-effect and random-effects estimates1. It is this point that deserves a few comments. Conceptually, fixed-effect meta-analysis of RCTs in medicine is rarely justified, since the underlying assumption is practically inevitably violated due to variety of elements contributing to clinical heterogeneity2. The authors1 presented a range of differences in trial designs (e.g., one or repeated tocilizumab dose, more or less use of concomitant corticosteroids, differences in proportion of subjects on MV). When variance across trials is low, fixed and random-effects estimates are numerically close/identical, but the conceptual differences remain. Again, conceptually, the random-effects method is a preferred approach2 (regardless of numerical closeness of fixed/random estimates) and the choice (fixed/random) should not be based on the heterogeneity estimates2. At this point, the issue of the choice of the variance (τ2) estimator should be mentioned. A number of estimators have been explored: performance depends on the nature of the outcome, may vary across trial sizes, depends on the differences in size of included trials, and is problematic when the number of studies is lowe.g.,2-5. Variance reflects on the assigned trial weights and measures of uncertainty about the pooled estimate. While no τ2 estimator is ideal 2-5, it has been suggested that the Paule-Mandel (PM) estimator performs better than the common DerSimonian-Laird estimator for binary outcomes3.Another point to consider is the method to calculate confidence intervals (CIs) around the pooled estimate. While not without certain limitations 6, the Hartung-Knapp-Sidik-Jonkman (HKSJ) method has been repeatedly shown (under variety of scenarios) to result in more adequate coverage probability than the standard method4,7. Figure 1A re-creates meta-analysis (data presented by the authors1) on mortality across the 10 RCTs (all subjects) – it is only that it uses PM variance estimator and HKSJ correction: random-effects estimate suggests that the mean of the distribution of the effects is 0.88 (as reported1), but the CIs extend to 1.04, suggesting that it includes also effects that are somewhat above unity. It also provides prediction intervals (wider) - the best illustration of heterogeneity2,8. When viewed from the present standpoint, data indicate a non-trivial level of imprecision and heterogeneity. The authors themselves reported apparent differences (mortality reduction vs. no reduction) between estimates based on RCTs with a high proportion vs. low proportion of patients concomitantly treated with corticosteroids 1(or those generated accounting only for corticosteroid-treated vs. not treated patients, but such data were very scarce1): so, there is apparent inconsistency of the estimates across clinical settings. As re-created in Figure 1B-C, there was a tendency of reduced mortality in trials with a high proportion of patients co-treated with corticosteroids (corticosteroid treatment regimen likely variable), but with quite some imprecision and heterogeneity; and no such tendency with “low corticosteroid use”. Similarly, in patients not on MV at baseline, there was a consistent reduction in mortality risk across trials with a high proportion of steroid co-treated patients, but not in trials with a low proportion of co-treated patients (Figure 1D-E). There was also a consistent reduction of risk of incident MV in trials with a high proportion of corticosteroid co-treated patients (Figure 1F), whereas the estimate in trials with “low steroid use” is burdened with heterogeneity and imprecision (Figure 1G).Considering the above, if one were to assign a GRADE level9 to evidence of benefit of tocilizumab in severe COVID-19 patients based on the 10 RCTs addressed in the published meta-analysis1, then the following seems reasonable: a) considering (indiscriminately) all 10 RCTs (and all patients), certainty about reduced mortality is closer to “low/moderate” then to “high” due to imprecision (CIs 0.75-1.04) and heterogeneity/inconsistency; b) data on the effect of tocilizumab+corticosteroid combination that could be extracted from the 10 RCTs are scarce. Trials with high vs. low concomitant use of corticosteroids could be perceived as a proxy, but this is indirect, suggestive and not conclusive evidence. Therefore, while the effects of tocilizumab on the risk of incident MV and mortality in patients not on MV at baseline in trials with a high proportion of corticosteroid co-treated patients were consistent and reasonably precisely estimated, certainty about the benefit of tocilizumab (on top of corticosteroids; regimen?) in this setting is at best moderate/low.ReferencesVela D, Vela-Gaxha Z, Rexhepi M, Olloni R, Hyseni V, nallbani R. Efficacy and safety of tocilizumab versus standard of care/placebo in patients with COVID-19; a systematic review and meta-analysis of randomized controlled trials. Br J Clin Pharmacol . 2021; doi: 10.1111/bcp.15124.Higgins JPT, Thomson SG, Spiegelhalter DJ. A re-evaluation of random-effects meta-analysis. J R Statist Soc A . 2009; 172(Pt1):137-159.Veroniki AA, Jackson D, Viechtbauer W, Bender R, Bowden J, Knapp G, Kuss O, Higgins JPT, Langan D, Salanti G. Methods to estimate the between-study variance and its uncertainty in meta-analysis. Res Synth Methods . 2016;7(1): 55-79.Langan D, Higgins JPT, Jakson D, Bowden J. Veroniki AA, Kontopantelis E, Viechtbauer W, Simmonds M. A comparison of heterogeneity variance estimators in simulated random-effects meta-analyses. Res Synth Methods. 2019; 10(1):83-98.IntHout J, Ioannidis JPA, Borm GF, Goeman JJ. Small studies are more heterogeneous than large ones: a meta-meta-analysis. J Clin Epidemiol . 2015; 68(8):860-869.Jakson D, Law M, Rucker G, Schwarzer G. The Hartung-Knapp modification for random-effects meta-analysis: a useful refinement but are there any residual concerns? Stat Med . 2017; 36(25):3923-3934.IntHout J, Ioannidis JPA, Borm GF. The Hartung-Knapp-Sidik-Jonkman method for random effects meta-analysis is straightforward and considerably outperforms the standard DerSimonian-Laird method.BMC Med Res Methodol . 2014; 14:25 doi:10.1186/1471-2288-14-25.IntHout J, Ioannidis JPA, Rovers MM, Goeman JJ. Plea for routinely presenting prediction intervals in meta-analysis. BMJ Open . 2016; 6:e010247 doi: 10.1136/bmjopen-2015-010247Guyatt GH, Oxman, AD, Vist GE, Kurz R, Falck-Ytter Y, Schunemann HJ. GRADE: what is “quality of evidence” and why is it important to clinicians. BMJ . 2008;336(7651):995-998.Balduzzi S, Rucker G, Schwarzer G. How to perform a meta-analysis with R: a practical tutorial. Evid Based Ment Health . 2019; 22(4):153-160.Figure 1 . Re-creation of the published meta-analysis1 using data provided in the published figures: the difference is in that the present estimates are generated using the Paule-Mandel variance estimator (Q-profile method for variance estimate confidence intervals) instead of the DerSimonian-Laired method available in the RevMan software used by the authors1, and Hartung Knapp Sidik Jonkman correction for random effects (see text for explanation). Panel A corresponds to published1Figure 1, panels B and C correspond to published1supplemental Figure S4. Published meta-analysis1 does not include figures that would correspond to panels D-G. Panels E and G are reduced to summaries for brevity. Note that in all meta-analyses point-estimates of I2 and τ2 were low, but the upper limits of their confidence intervals were rather high, particularly when only 4 RCTs were included (except in panel F with highly consistent results across trials). “High%” or “low %” steroid use refers to trials (as presented in the published meta-analysis1) in which >50% or <50% of the patients were co-treated with corticosteroids. Meta-analyses were performed using packagemeta 10 in R.MV – mechanical ventilation; RCT – randomized controlled trial; SoC – standard of care

This realist enquiry applying behavioural theory aimed to identify behavioural mechanisms and contexts that facilitate prescribers tapering opioids. We identified relevant opioid tapering interventions and services from a 2018 international systematic review and a 2019 England-wide survey, respectively. Interventions and services were eligible if they provided information about contexts and/or behavioural mechanisms influencing opioid tapering success. A stakeholder group (n=23) generated draft programme theories based around the 14 domains of the theoretical domains framework. We refined these using the trial and service data. From 71 articles and 21 survey responses, 56 and 16 respectively were included, representing primary care, hospital, specialist pain facilities and prison services. We identified six programme theories that included five behavioural mechanisms: prescribers’ knowledge about how to taper; build prescribers’ beliefs about capabilities to initiate tapering discussions and manage psychological consequences of tapering; perceived professional role in tapering; the environmental context enabling referral to specialists; and facilitating positive social influence by aligning patient: prescriber expectations of tapering. No interventions are addressing all six mechanisms supportive of tapering. Work is required to operationalise programme theories according to organisational structures and resources. An example operationalisation is combining tapering guidelines with information about local excess opioid problems and endorsing these with organisational branding. Prescribers being given the skills and confidence to initiate tapering discussions by training them in cognitive-based interventions and incorporating access to psychological and physical support in the patient pathway. Patients being provided with leaflets about the tapering process and informed about the patient pathway.

Aims: To investigate the effects of ABCB1 DNA methylation in donors on individual differences in tacrolimus blood concentrations following liver transplantation. Methods: Twenty-three donor liver samples carrying the CYP3A5*3/*3 genotype were classified into two groups based on the initial tacrolimus concentration/dose (C0/D) ratio following liver transplantation. ABCB1 mRNA levels in liver tissues and HepG2 cells were determined by qRT-PCR. DNA methylation status in liver tissues and HepG2 cells was determined using Illumina 850 methylation chip sequencing technology and pyrosequencing. 5-Aza-2dC was used to reverse methylation in HepG2 cells. Intracellular tacrolimus concentrations were determined by liquid mass spectrometry. Results: Genome-wide methylation sequencing and pyrosequencing analyses showed that the methylation levels of three ABCB1 CpG sites (cg12501229, cg00634941, and cg05496710) were significantly different between groups with different tacrolimus C0/D ratios. ABCB1 mRNA expression in donor livers was found to be positively correlated with tacrolimus C0/D ratio (r = 0.458, P < 0.05). After treatment with 5-Aza-2-Dc, the methylation levels of the ABCB1 CpG sites in HepG2 cells significantly decreased, and this was confirmed by pyrosequencing; there was also a significant increase in ABCB1 transcription, and this most likely induced a decrease in intracellular tacrolimus concentrations. Conclusions: ABCB1 CpG site methylation affects tacrolimus metabolism in humans by regulating ABCB1 expression. Therefore, ABCB1 DNA methylation in donor livers might be an important epigenetic factor that affects tacrolimus blood concentrations following liver transplantation.

DWP16001 is a novel sodium-glucose cotransporter-2 (SGLT2) inhibitor under development for the treatment of type 2 diabetes mellitus. This study was conducted to evaluate the pharmacokinetics (PK), pharmacodynamics (PD), and safety of DWP16001 after single and multiple doses in healthy subjects. A randomized, double-blind, placebo- and active-controlled, single- and multiple-dose study was conducted. Twelve subjects in each dose group received a single dose (0.2, 0.5, 1.0, 2.0, or 5.0 mg) or multiple doses (0.1, 0.3, 0.5, 1.0, or 2.0 mg once daily for 15 consecutive days) of DWP16001, dapagliflozin 10 mg, or placebo, in a ratio of 8:2:2. Serial blood samples and interval urine samples were collected for PK and PD analyses. Safety and tolerability were assessed throughout the study period. A dose-dependent increase in urinary glucose excretion (UGE) was observed after a single dose, and the steady-state UGE was 50–60 g/day after multiple doses in the dose range of 0.3 – 2.0 mg. DWP16001 was rapidly absorbed with the time to peak plasma concentration of 1.0 – 3.0 hours, and eliminated with a mean elimination half-life of 13 - 29 hours. The systemic exposure of DWP16001 increased proportionally with the dose after multiple administrations in the range of 0.1 – 2.0 mg. DWP16001 was well tolerated in all dose groups. DWP16001 caused glucosuria in a dose-dependent manner, and systemic exposure was observed after multiple doses. DWP16001 was well tolerated up to 5.0 mg after a single oral dose and up to 2.0 mg after multiple oral administration

Aim: Edoxaban is a non-vitamin K antagonist oral anticoagulant (NOAC) widely used for long-term stroke prevention in patients with non-valvular atrial fibrillation (NVAF). Adherence to NOACs is unsatisfactory and decreases over time. The aim of this study was to explore appropriated remedial dosing regimens for non-adherent edoxaban-treated NVAF patients through the Monte Carlo simulation. Methods: Six proposed regimens were compared with the recommendations in the European Heart Rhythm Association (EHRA) guide regarding the trough total deviation time considering both edoxaban plasma concentration and inactive factor Xa activity. Monte Carlo simulations were performed using RxODE based on the published population pharmacokinetics/pharmacodynamics model. Results: The proposed remedial strategies were different from EHRA recommendations and were related to delay duration. The missed dose can be taken immediately if the delay time is within 11 h. When the delay period is between 12 and 19 h, a half dose followed by a regular dosing schedule is recommended. When the delay time exceeds 19 h, a full dose followed by a half dose is preferred compared to that recommended in the EHRA guide. Our proposed strategies resulted in a shorter total deviation time than EHRA guide. Conclusion: PK/PD modelling and simulation are effective in developing and evaluating the remedial strategies of edoxaban, which could help maximize its therapeutic effect.

Concern about potential deleterious effects of pharmaceuticals in the environment is growing fast. From wiping out vulture populations in Asia, to feminization of fish, pharmaceuticals have shown to provoke important consequences albeit at very low concentrations. A recent article addresses the environmental impact of metered-dose inhalers for asthma in the United Kingdom due to the greenhouse effects hydrofluorocarbons they contain. Since 2005, it is mandatory for all new drugs in Europe to be assessed for their environmental impact. Crucially, this regulation solely refers to the active pharmaceutical ingredient, not the “whole medicine” or finished medical product. This can sometimes lead to incongruences. For instance, it does not consider the environmental impact of the hydrofluorocarbons contained in MDIs. Another example is Adasuve®, an antipsychotic (loxapine) aimed at the rapid control of agitation in patients suffering from psychotic disorders. The device was developed as a rapid systemic delivery of loxapine by inhalation of a thermally generated aerosol for single use. Apart from the active substance it holds a medical-grade plastic housing and a lithium battery. Therefore, after every single use, a lithium battery waste is produced. We envision that we are on a brink of a new era in pharmacotherapy, in which environmental aspects of drugs are taken into account. In definitive, we agree with Wilkinson & Woodcock. When considering the environmental impact of pharmaceuticals, we need to take into account the whole package.

AIM: To explore the level of agreement on drug-drug interaction (DDI) information listed in three major online drug information resources (DIRs) in terms of: (1) interacting drug pairs; (2) severity rating; (3) evidence rating and (4) clinical management recommendations. METHODS: We extracted DDI information from the British National Formulary (BNF), Thesaurus, and Micromedex. Following drug name normalisation, we estimated the overlap of the DIRs. We annotated clinical management recommendations either manually, where possible, or through application of a machine learning algorithm. RESULTS: The DIRs contained 51,481 (BNF), 38,037 (Thesaurus), and 65,446 (Micromedex) drug pairs involved in DDIs. The number of common DDIs across the three DIRs was 6,970 (13.54% of BNF, 18.32% of Thesaurus, and 10.65% of Micromedex). Micromedex and Thesaurus overall showed higher levels of similarity in their severity ratings, while the BNF agreed more with Micromedex on the critical severity ratings and with Thesaurus on the least significant ones. Evidence rating agreement between BNF and Micromedex was generally poor. Variation in clinical management recommendations was also identified, with some categories (i.e. Monitor and Adjust dose) showing higher levels of agreement compared to others (i.e. Use with caution, Wash-out, Modify administration). CONCLUSIONS: There is considerable variation in the DDIs included in the examined DIRs, together with variability in categorisation of severity and clinical advice given. DDIs labelled as critical are more likely to appear in multiple DIRs. Such variability in information could have deleterious consequences for patient safety, and there is a need for harmonisation and standardisation.

Aim We aimed to explore the effect of pregnancy on bedaquiline pharmacokinetics and describe bedaquiline exposure in the human milk of mothers treated for rifampicin-resistant TB, where there is no human data available. Methods We performed a longitudinal pharmacokinetic study in pregnant women treated for rifampicin-resistant TB to explore the effect of pregnancy on bedaquiline exposure. Pharmacokinetic sampling was performed at four time-points over six hours in the third trimester, and again at approximately six weeks postpartum. We obtained serial human milk samples from breastfeeding mothers, and a single plasma sample taken from breastfed and non-breastfed infants to assess bedaquiline exposure. We used liquid chromatography-tandem mass spectrometry to perform the human milk and plasma bedaquiline assays, and population pharmacokinetic modelling to interpret the bedaquiline concentrations. Results We recruited 13 women, six of whom completed the ante- and post-partum PK sampling. All participants were HIV-positive on antiretroviral therapy. We observed lower ante- and post-partum bedaquiline exposures than reported in non-pregnant controls. Bedaquiline concentrations in human milk were higher than maternal plasma (milk to maternal plasma ratio: 24:1). A single random plasma bedaquiline and M2 concentration was available in four infants (median age: 6.5 weeks): concentrations in the one breastfed infant were similar to maternal plasma concentrations; concentrations in the three non-breastfed infants were detectable but lower than maternal plasma concentrations. Conclusion We report low exposure of bedaquiline in pregnant women treated for rifampicin-resistant TB. Bedaquiline significantly accumulates in human milk; breastfed infants receive mg/kg doses of bedaquiline equivalent to maternal doses.