Aim To describe the antiepileptic drug (AED) prescription pattern in pregnant women and women of childbearing age in the 2010-2019 period in the Lombardy region, Italy. Methods The Lombardy region administrative healthcare databases (2010-2019) were analysed. AEDs were classified as drugs belonging to the N03A subgroup of the Anatomical Therapeutic Chemical Classification System. Women 15-49 years old were considered as women of childbearing age, while exposure during pregnancy was estimated taking into account the 12 months before delivery (International Classification of Diseases, Ninth Revision, Clinical Modification, ICD-9-CM codes in the diagnosis record from 650 to 659). Results During 2019, 16,605 women of childbearing age (prevalence: 14.8‰) received at least one AED prescription. Pregabalin was the most widely used antiepileptic in women of childbearing age (22.3%), followed by valproic acid (20.0%). The prevalence of AED prescription in pregnant women was 3.8‰, and levetiracetam and lamotrigine (16.6%) were the most commonly prescribed drugs. The prevalence of AED prescription did not change from 2010 to 2019 in women of childbearing age or in pregnant women. Valproic acid was one of the most used AEDs in pregnancy until 2016, after which its prescription declined from 19% to 14% of AED users. Conclusions Despite the decrease in valproic acid prescription over time, this drug is still among the most used AEDs, in particular in women of childbearing age. Educational interventions for healthcare professionals and women are needed in order to reduce the risk of unplanned pregnancy.

Aims:Filgotinib is a potent, oral, JAK1-preferential inhibitor for the treatment of rheumatoid arthritis (RA). This report describes exposure-response (ER) analyses of filgotinib for dose confirmation based on three Phase 3 and two Phase 2 studies in moderate to severe RA patients. Methods:The PK exposures used in ER analyses were derived from population pharmacokinetic analysis. The relationship between filgotinib exposures and various efficacy endpoints (ACR20/50/70 and DAS28) was assessed over octile groups of exposures by using combined exposures of filgotinib and GS-829845 (major, active metabolite). For the ER analyses of safety, exposures were examined between subjects who experienced and who did not experience the evaluated safety events, which was conducted separately for filgotinib and GS-829845. Results:Exposure efficacy relationships consistently revealed high response rates across the exposure range for filgotinib 200 mg once daily dose. A trend of increasing response with increasing exposure was observed over the exposure range for the primary and multiple secondary efficacy endpoints, with exposures associated with the 200 mg dose primarily residing on the curve plateau. For exposure-safety analyses, filgotinib and GS-829845 exposures were similar irrespective of presence/absence of the evaluated safety endpoints, indicating no exposure-safety relationship for common TEAEs, common laboratory abnormalities, serious TEAEs, or serious infections. Conclusions:ER analyses confirmed that filgotinib produced more robust therapeutic effects across the exposure range observed at 200 mg once daily compared to lower doses. The positive exposure-efficacy relationship and a lack of exposure-safety relationship on the evaluated safety endpoints supported the 200 mg once daily dose for commercialization.

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.

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.

COVID-19 has spread globally, affecting almost 160 million individuals. Elderly and pre-existing patients (such as diabetes, heart disease and asthma), seems more susceptible to serious illness with COVID-19. Roflumilast was licensed for usage in the European Union in July 2010 as a phosphodiesterase-4 (PDE4) inhibitor. Roflumilast has been shown to decrease bleomycin-induced lung fibrosis, lung hydroxyproline, right heart thickning in animal prophylactic. The current study reviewed existing data that the PDE-4 inhibitor protects not just renal tissues but also other major organ systems after COVID-19 infection by decreasing immune cell infiltration. These immune-balancing effects of roflumilast were related with a decrease in oxidative and inflammatory burden, caspase-3 suppression, and increased PKA/cAMP levels in renal and other organ tissue.

Aim: The placebo effect and the specific effect are often thought to add up (additive model). Whether this is true or whether there is an interaction between the two, can modify the external validity of a trial. This assumption of additivity was tested by Kleijnen et al. in 1994 but the data produced since then has not been synthetized. In this review, we aimed to systematically review the literature to determine whether additivity held. Methods: We searched Medline and Psychinfo up to 10/01/2019. Studies using the balanced placebo design (BPD), testing two different strengths of placebos, were included. The presence of interaction was evaluated by comparing each group in BPD with analysis of variance or covariance. Results: 30 studies were included and the overall risk of bias was high: four found evidence of additivity and 16 studies found evidence of interaction (seven had evidence of positive additivity). Conclusion: Evidence of additivity between placebo and specific features of treatments was rare in our sample. For ailments that are placebo-responsive, pragmatic trials should be preferred to increase their external validity.

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.

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.

A document by Emma Magavern. Click on the document to view its contents.

Aim: Quantify identifiable sources of variability, including key pharmacogenetic variants in oxypurinol pharmacokinetics and their pharmacodynamic effect on serum urate. Methods: Hmong participants (n=34) received 100 mg allopurinol twice daily for 7 days followed by 150 mg allopurinol twice daily for 7 days. Serum urates (SU) were obtained pre- and post-allopurinol. Serum oxypurinol concentrations were obtained at times 0, 2, 4, and 6 hours after the last dose. A sequential population pharmacokinetic pharmacodynamics (PKPD) analysis with non-linear mixed-effects modeling evaluated the impact of anthropometrics, concomitant medications, and genetic variants on oxypurinol PKPD parameters. Allopurinol maintenance dose to achieve target SU was simulated based on the final PKPD model. Results: A one-compartment model with first order absorption and elimination best described the oxypurinol concentration-time data. Inhibitory of SU by oxypurinol was described with a direct inhibitory Emax model using steady-state oxypurinol concentrations. Fat-free body mass, estimated creatinine clearance and SLC22A12 rs505802 genotype were found to predict differences in oxypurinol clearance. Oxypurinol concentration required to inhibit 50% of xanthine dehydrogenase activity was affected by PDZK1 rs12129861 genotype. Most individuals with both PDZK1 rs12129861 AA and SLC22A12 rs505802 CC genotypes achieve target SU with allopurinol below the maximum dose, regardless of renal function and body mass. In contrast, individuals with both PDZK1 rs12129861 GG and SLC22A12 rs505802 TT genotypes would require more than the maximum dose, thus alternative medications. Conclusion: The proposed allopurinol dosing guide uses individuals’ fat-free mass, renal function, and SLC22A12 rs505802 and PDZK1 rs12129861 genotypes to achieve target SU.

Tyrosine kinase inhibitors (TKIs) have revolutionized the management of chronic myeloid leukemia (CML), and currently in patients with CML in chronic phase (CML-CP) the first-line treatment is based on BCR-ABL targeted therapy with TKIs [1]. Although generally well tolerated, all BCR-ABL TKIs can be associated with hematologic and non-hematologic toxicities [2]. Most of the patients with CML-CP continue receiving TKIs, unless there is lack of optimal response and/or serious toxicities.

The deployment of artesunate for severe malaria and the artemisinin combination therapies (ACTs) for uncomplicated malaria has been a major advance in antimalarial therapeutics. These drugs have reduced treated mortality, accelerated recovery, and reduced treatment failure rates and transmission from the treated infection. These drugs remain highly effective against falciparum malaria in most malaria endemic areas but significant resistance has emerged in the Greater Mekong subregion of Southeast Asia. Resistance to artemisinin was followed by resistance in the ACT partner drugs, and fit multidrug resistant parasite lineages have now spread widely across the region. ACTs are highly effective against P. vivax and the other malaria species. Recent studies show that radical curative regimens of primaquine (to prevent relapse) can be shortened to seven days, and that the newly introduced single dose tafenoquine is an alternative, although the currently recommended dose is insufficient in Southeast Asia and Oceania. Targeted malaria elimination using focal mass treatments with dihydroartemisinin-piperaquine have proved safe and effective malaria elimination accelerators, but progress overall towards malaria elimination is very slow. Indeed since 2015 overall malaria case numbers globally have risen.

Aims: To determine if the combination of exercise and statin could normalize postprandial triglyceridemia (PPTG) in hypercholesteraemic individuals. Mehods: Eight hypercholesteraemic (blood cholesterol 182±38 mg·dL-1; LDL-c 102±32 mg·dL-1) overweight (BMI 30±4 kg·m-2) individuals with metabolic syndrome (i.e., Met Synd) were compared to a group of eight metabolically healthy controls (i.e., MetH, blood cholesterol 149±23 mg·dL-1; LDL-c 77±23 mg·dL-1, and BMI 23±2 kg·m-2). Each group underwent two PPTG tests, either 14-h after a bout of intense exercise (EXER) or without previous exercise (REST). Additionally, Met Synd individuals were tested 96 h after withdrawal of their habitual statin medication (PLAC trials) to study medication effects. Results: A bout of exercise before the test meal did not reduce PPTG in Met Synd (P=0.347), but reduced PPTG by 46% in MetH (224±142 to 413±267 mg·dL-1·for 5 h iAUC; P=0.02). In both trials (i.e., REST and EXER) statin withdrawal in Met Synd greatly increased PPTG (average 65%; P<0.01), mean LDL-c (average 25%; P<0.01), total cholesterol (average 16%; P<0.01) and Apo B48 (24%; P<0.01), without interference from exercise. However, Apo B100 was not affected by statin withdrawal. Conclusions: Hypercholesteraemic Met Synd individuals (compared to metabolically healthy controls) are resistant to the effects of exercise on reducing PPTG. However, chronic statin medication blunts the elevations in TG after a fat meal (i.e., iAUC of PPTG) reducing their cardiovascular risk associated to their atherogenic dyslipidemia. Statin decreases PPTG by reducing the secretion or accelerating the catabolism of intestinal Apo B48.

Personalization of oral small molecule anticancer drug doses based on individual patient blood drug levels, also known as therapeutic drug monitoring or TDM, has the potential to significantly improve the effectiveness of treatment by maximizing drug efficacy and minimize toxicity. However, this option has not yet been widely embraced by the oncology community. Some reasons for this include increased logistical complexity of dose individualization, the lack of clinical laboratories that measure small molecule drug concentrations in support of patient care, and the lack of reimbursement of costs. However, the main obstacle may be the lack of studies clearly demonstrating that monitoring of oral small molecule anticancer drug levels actually improves clinical outcomes. Without unequivocal evidence in support of TDM-guided dose individualization, especially demonstration of improved survival with TDM in randomized controlled trials, wide acceptance of this approach by oncologists and reimbursement by insurance companies is unlikely, and patients may continue to suffer as a result of receiving incorrect drug doses. This article reviews the current status of therapeutic drug monitoring of oral small molecule drugs in oncology and intends to provide strategic insights into the design of studies for evaluating the utility of TDM in this clinical context.

Background: In Italy both the consumption of antibiotics and the prevalence of bacterial resistance are higher than in other European countries. In 2017, the first National Action Plan on Antimicrobial Resistance (PNCAR) was adopted in Italy. In response to the PNCAR two National Reports on Antibiotics’ use in the human setting have been published. The article’s aim is to describe the pattern of antibiotics consumption in the community setting in Italy from 2013 to 2018. Methods: In order to analyse the consumption for reimbursed antibiotics dispensed by community pharmacies different data sources were used. Consumption was measured in terms of Defined Daily Dose (DDD), prescriptions or prevalence of use. Results: In 2018, the consumption of antibiotics in Italy amounted to 16.1 DDD per 1,000 inhabitants per day. The rates of consumption by geographical area were: 12.7 DDD in the North, 16.9 in the Centre and 20.4 in the South. The use was greater in the extreme age groups than in the population aged from 20 to 64 years. The consumption was higher in winter season with high peaks in the incidence of flu syndromes. In the paediatric population, a utilization rate of 1,010 prescriptions per 1,000 children, with a prevalence of use of 40.8%, was found. Conclusion: The study provides useful information on geographical variability of antibiotics’ use in Italy to guide decision makers in the introduction of tailored interventions, as suggested by PNCAR, aimed at promoting a more rational use of antibiotics for humans and reducing antimicrobial resistance.

Aims: The investigation regarding the clinical significance of programmed cell death protein-1 (PD-1)-targeted immunotherapy in Chinese patients is rare. This study evaluated safety and efficacy of PD-1 with Toripalimab, Camrelizumab or Sintilimab for Chinese Hepatocellular carcinoma (HCC) patients in a real-life cohort. Methods: We retrospectively analyzed HBV associated HCC patients treated with Toripalimab, Camrelizumab or Sintilimab in a retrospective cohort from Nov 2018 to Dec 2019. Efficacy was evaluated with objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), time to tumor progression (TTP) and overall survival (OS). Results: Seventy eight patients were finally included in the analysis: 26 for Toripalimab, 36 for Camrelizumab, and 16 for Sintilimab. Mean duration of follow-up was 22.7 ± 12.6 weeks and the mean Cycles of PD-1 at cut-off were 4.8 ± 2.7 for all patients. The ORR and DCR for the whole cohort were 17.9% and 73.1%, respectively. Overall, 21 (26.9%) patients had radiological disease progression and 6 (7.7%) patients died during follow-up. Median PFS was 40.7 (95% CI, 34.7-46.7) weeks, median TTP was 45.7 (95% CI, 40.5-60.0) weeks, and median OS was 51.1 (95% CI, 46.4-55.9) weeks. Most frequent drug-related AEs were Rash (19.2%), Hypertension (15.4%), Fatigue (12.8%), Paraesthesia (12.8%), and Diarrhoea (10.3%). Conclusions: Our findings suggest that: 1. PD-1-targeted immunotherapy with Toripalimab, Camrelizumab or Sintilimab yielded a promising outcome in Chinese HBV patients with HCC; 2. Immunotherapy was well tolerated generally and had manageable side effects, which is worth of popularization and application in clinical practice.

AIM: The main objective was to determine the prevalence of prescribing issues in HIV-infected subjects ≥65 years according to the Beers and STOPP/START criteria and drug-drug interactions (Liverpool website). Secondary objectives were to assess the concordance between Beers and STOPP/START criteria in our population, and to identify the drugs most frequently involved in the prescribing issues. METHODS: Cross-sectional cohort study based on a systematic review of the electronic drug prescriptions of 91 HIV-infected patients aged ≥65 years. Discrepancies between prescription criteria were assessed using crosstabs and compared using the Chi-square test or Fisher exact test. RESULTS: The mean age was 72.1 (5.6) years, 75.8% had ≥3 comorbidities, and 59.3% polypharmacy. Prescribing issues were identified in 87.9%; 71.4% by STOPP/START and 45.1% by Beers. Comparing both criteria, 56.9% of prescribing issues by STOPP/START were detected by Beers, while 92.5% of those detected by the Beers criteria were detected by STOPP/START (p<0.001). Orange/red flag interactions were found in 45.1%: 3 severe (red) in 2 patients (2.2%). The most frequent drugs involved in prescribing issues were benzodiazepines (>30%). Cobicistat was the drug most frequently involved in interactions (42.9%). CONCLUSIONS: The prevalence of prescribing issues among older HIV-infected persons gives cause for concern, as it is almost 90%. Optimization strategies, including a critical review of the treatment plan, should be implemented in clinical routine by a multidisciplinary team, in particular in patients with multiple comorbidities and polypharmacy. The STOPP/START criteria should be recommended for European populations, since they seem to better detect prescribing issues.

Aims The field of cell-based therapies for human diseases is currently evolving from promising treatment options to established therapeutic concepts. The design of the non-clinical development program for cell-based products, intended to provide a rationale for treatment and to gain insight into the safety profile, is challenging because of limitations caused by species-specificity. The elements of the non-clinical package for cell-based products were evaluated using advice reports from the European Medicines Agency database from 2013-2018 to identify the approach followed for non-clinical development of these products. Methods The purpose of the in vivo studies was designated to be (a combination of) pharmacology/proof-of-concept, safety, biodistribution and/or tumourigenicity. For biodistribution and tumourigenicity also the need for, type and design of in vitro and in vivo studies were recorded. Results In vivo studies for cell-based therapies were primarily aimed at proof-of-concept (75/86), followed by addressing safety (64/86), biodistribution (49/86) or tumourigenicity (46/86). No animal studies were performed or proposed by sponsors or regulators for six (out of 86) products, which contained cell types that have been studied in humans for a relatively long time. For one-third of the products in vivo biodistribution and/or tumourigenicity studies were not considered necessary. In vivo tumourigenicity studies were regarded of limited value. Conclusions Compared to more conventional medicinal products, the non-clinical development program for cell-based products was more tailored and focussing on proof-of-concept. For tumourigenicity an in vitro approach may suffice. Total omission of in vivo studies appears to be possible for products with sufficient clinical experience.