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An introduction is presented which discusses articles within the issue on clinical pharmacology topics including distortion of risk-benefit analysis; application of simulation and pharmacometric modelling in clinical practice; and a pharmacovigilance programme to detect eosinophilic drug reactions.

The explosive growth in medical devices, imaging and diagnostics, computing, and communication and information technologies in drug development and healthcare has created an ever-expanding data landscape that the pharmacometrics (PMX) research community must now traverse. The tools of machine learning (ML) have emerged as a powerful computational approach in other data-rich disciplines but its effective utilization in the pharmaceutical sciences and PMX modelling is in its infancy. ML-based methods can complement PMX modelling by enabling the information in diverse sources of big data, e.g. population-based public databases and disease-specific clinical registries, to be harnessed because they are capable of efficiently identifying salient variables associated with outcomes and delineating their interdependencies. ML algorithms are computationally efficient, have strong predictive capabilities and can enable learning in the big data setting. ML algorithms can be viewed as providing a computational bridge from big data to complement PMX modelling. This review provides an overview of the strengths and weaknesses of ML approaches vis-à-vis population methods, assesses current research into ML applications in the pharmaceutical sciences and provides perspective for potential opportunities and strategies for the successful integration and utilization of ML in PMX., (© 2021 British Pharmacological Society.)

Aims: Drug tolerability refers to the degree to which drugs' overt adverse effects can be tolerated by patients. The tolerability profile is of comparative importance to its efficacy and safety, as it largely determines adherence to treatment and ultimately treatment success or failure. However, the term is frequently used imprecisely, and it is unclear if tolerability is limited to subjective patient-reported symptoms or also covers certain objective signs and findings. The aim of this systematic review was to assess how clinical studies define, evaluate and present drug tolerability., Methods: The study consisted of a systematic review of clinical studies in PubMed® reporting the term "tolerability"., Results: Eighty clinical studies were screened and 56 studies reporting drug tolerability were retained. None of the retained studies defined events encompassed by the term tolerability by making a distinction between safety and tolerability. Twenty-five studies claimed to evaluate tolerability, but none of them described how to evaluate tolerability from the patient perspective. Most studies (54 out of 56) concluded that the treatment was well tolerated, apparently implying favourable safety. However, none of them actually presented tolerability in terms of a contrast between safety and tolerability., Conclusions: Tolerability is used frequently, albeit incorrectly, to refer to a drug's favourable safety profile. Focused evaluation of drug tolerability (i.e., the patient perspective of adverse drug reactions) should become routine. Presentation in regulatory documents, such as risk management plan summaries, product information and patient leaflets should be a continuation of the process of patient-centred healthcare., (© 2021 British Pharmacological Society.)

Patients and Methods: An allergy work-up was performed on adult patients with a history of a penicillin allergy seen by primary medical care in Monastir (Tunisia) between July 2016 and February 2018. Patients with negative skin tests were challenged with amoxicillin. Patients who were delabelled were contacted by phone after 6 months to determine outcomes after any therapeutic penicillin-class antibiotic intake., Results: A total of 39 patients were evaluated and 33 (84.6%) were delabelled. Five patients were penicillin skin-test positive and one was oral challenge positive. We succeeded in contacting 33 delabelled patients at 6 months. Twenty-two patients tolerated a subsequent therapeutic course of amoxicillin, eight patients did not retake penicillin due to a lack of therapeutic indication, and three patients refused an indicated penicillin use fearful of another reaction., Conclusion: This study highlights the importance of allergy work-up in the diagnosis of beta-lactam hypersensitivity. Most patients were excessively labelled as beta-lactam allergic and this mislabelling could increase healthcare costs and lead to the development of drug resistance by the use of wide-spectrum antibiotics., (© 2021 British Pharmacological Society.)

Likely due to specific regulatory requirements in the United States, physicians sometimes interpret interchangeability as the potential for a biologic to be substituted by a biosimilar at the pharmacy level, without the involvement of a physician. However, interchangeability between a biological reference medicine and a corresponding biosimilar medicine should not be defined by its practical application; whether physician-driven switch or pharmacist-driven substitution. Despite the strength of the science supporting interchangeability, when two medicines are deemed to be interchangeable, physicians should be relevant players in any switching decision. A science-based understanding of interchangeability may raise confidence among physicians that currently prescribe biosimilars only in naïve patients, and may make them more comfortable switching from the reference medicine to a biosimilar, to further foster the positive impact of biosimilars. [Extracted from the article]

Aims: While a plethora of systematic reviews have provided evidence of efficacy, effectiveness and safety of direct‐acting oral anticoagulants (DOACs) in the management of nonvalvular atrial fibrillation, there has been little emphasis on clinicians' perspectives. This systematic review aimed to critically appraise, synthesize and present the available evidence of clinicians' views and experiences. Methods: Studies published in English from January 2006 to July 2017 reporting the views and/or experiences of doctors, nurses or pharmacists on any individual DOAC or as a pharmacological group were included. Studies were assessed for quality by two researchers, data extracted and findings synthesized using a narrative approach. Results: Following exclusion of duplicates, 777 titles, 394 abstracts and 196 studies were screened. Ten studies were included in the review, nine of which were quantitative (cross‐sectional surveys) and one qualitative (semistructured interviews), with marked heterogeneity in outcomes reported. Studies were conducted exclusively in Europe and the USA. In those studies reporting clinician preference, DOACs were first choice over warfarin in naïve patients, based on perceptions of evidence of effectiveness equivalent or superior to warfarin and superior safety. Other advantageous factors were in those with an unstable International Normalized Ratio and likely to miss appointments. There were, however, concerns relating to management of over‐anticoagulation and experiences of observed bleeding rates. Conclusion: There is a limited evidence base of clinicians' perspectives of DOACs, necessitating further research, particularly given the trajectory of increased use worldwide. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented regarding a study which examined whether late medicine development industry-funded research are more cited compared with one year after publication and their relation to drug approval by the U.S. Food and Drug Administration (FDA).

If the ACE2-dependent mechanism were to be confirmed as the explanation for chemosensory disorders in COVID-19 patients, it is conceivable that these drugs could modulate the clinical manifestations of taste and smell impairments associated with SARS-CoV-2 infection. In the case of the pandemic overlapping with the seasonal flu epidemic, alteration of taste and smell are specific symptoms of COVID-19 that can be exploited to identify COVID-19 patients and prevent the spread of the infection. Keywords: adverse drug reactions; ageusia; anosmia; cacosmia; COVID-19; dysgeusia; SARS-CoV-2 EN adverse drug reactions ageusia anosmia cacosmia COVID-19 dysgeusia SARS-CoV-2 2186 2188 3 04/30/21 20210501 NES 210501 The COVID-19 pandemic spread worldwide with over 38 million confirmed cases and more than 1 million deaths as of October 15, 2020. [Extracted from the article]

MRGPRX2, a novel Gaq‐coupled human mast cell receptor, mediates non‐immune adverse reactions without the involvement of antibody priming. Constitutively expressed by human skin mast cells, MRGPRX2 modulates cell degranulation producing pseudoallergies manifesting as itch, inflammation and pain. The term pseudoallergy is defined in relation to adverse drug reactions in general and immune/non‐immune‐mediated reactions in particular. A list of drugs with MRGPRX2 activity is presented, including a detailed examination of three important and widely used approved therapies: neuromuscular blockers, quinolones and opioids. For the clinician, the significance of MRGPRX2 is considered as an aid in distinguishing and ultimately identifying specific immune and non‐immune inflammatory reactions. Anaphylactoid/anaphylactic reactions, neurogenic inflammation and inflammatory diseases with a clear or strongly suspected association with MRGPRX2 activation are examined. Inflammatory diseases include chronic urticaria, rosacea, atopic dermatitis, allergic contact dermatitis, mastocytosis, allergic asthma, ulcerative colitis and rheumatoid arthritis. MRGPRX2‐ and allergic IgE/FcεRI‐mediated reactions may be clinically similar. Importantly, the usual testing procedures do not distinguish the two mechanisms. Currently, identification of MRGPRX2 activation and diagnosis of pseudoallergic reactions is generally viewed as a process of exclusion once other non‐immune and immune processes, particularly IgE/FcεRI‐mediated degranulation of mast cells, are ruled out. This does not take into account that MRGPRX2 signals via β‐arrestin, which can be utilized to detect MRGPRX2 activation by employing MRGPRX2 transfected cells to assess MRGPRX2 activation via two pathways, the G‐protein‐independent β‐arrestin pathway and the G‐protein‐dependent Ca2+ pathway. Testing procedures, interpretations for distinguishing mechanisms, patient diagnosis, agonist identification and drug safety evaluations are addressed. [ABSTRACT FROM AUTHOR]

Dapsone is employed for both non‐dermatological and dermatological indications but with non‐existent population pharmacokinetics (popPK) data in Nigerians. This study was therefore designed to develop a popPK model in Nigerians. Non‐compartmental analysis and nonlinear mixed effects modelling were utilized for data analysis. Eleven participants administered 50 mg dapsone tablet were included in the analysis. Derived pharmacokinetic parameters were: Cmax = 1.16 ± 0.32 μg/mL, Tmax = 3.77 ± 2.40 h, and t1/2z = 30.23 ± 11.76 h. PopPK model parameter estimates with inter‐individual variability were Tlag = 0.40 h (10.0%, fixed); ka = 1.78 h−1 (75.9%); V/F = 89.25 L (21.6%); and Cl/F = 1.32 Lh−1 (27.7%). Sex was significantly associated with Cl/F, and body weight with V/F. Best popPK model was one‐compartment with lag time, and first‐order absorption and elimination. Sex and body weight significantly influenced the clearance and distribution volume of dapsone respectively. [ABSTRACT FROM AUTHOR]

Aims: Advanced age is an important risk factor for adverse events during procedural sedation. Remimazolam is safe and effective in gastroscopic sedation. However, the ideal dose and application for older patients are not well known. We aim to investigate its 95% effective dose (ED95) for older patients undergoing gastroscopy and to assess its safety and efficacy, with propofol as the comparison. Methods: The trial consists of 2 parts, patients aged >65 years and scheduled for outpatient painless gastroscopy were enrolled. In the first part, Dixon's up‐and‐down methodology was used to determine the ED95 of remimazolam besylate and propofol for gastroscopic insertion, in combination with 0.2 μg/kg remifentanil. In the second part, patients in each group received 0.2 μg/kg remifentanil and ED95 dose of the study drugs for sedation induction, supplemental doses were added to maintain sedation depth when necessary. The primary outcome was the incidence of adverse events. The secondary outcome was the recovery time. Results: The ED95 of remimazolam besylate and propofol induction were 0.2039 (95% confidence interval 0.1753–0.3896) mg/kg and 1.9733 (95% confidence interval 1.7346–3.7021) mg/kg respectively. Adverse events were reported in 26 (40.6%) patients in the remimazolam group and 54 (83.1%) in the propofol group (P <.0001), whereas the remimazolam group presented a higher incidence of hiccups (P =.0169). Besides, the median time to awakening was approximately 1 min shorter with remimazolam than with propofol (P <.05). Conclusion: For older patients undergoing gastroscopy, the ED95 dose of remimazolam is a safer alternative than propofol when inducing the same sedation depth. [ABSTRACT FROM AUTHOR]

Aims: Patients with epilepsy often require long‐term use of antiseizure medications (ASMs) to control their seizures. However, movement disorders (MDs) related to ASMs can significantly impact their quality of life. This study aims to analyse MDs related to ASMs in the Food and Drug Administration Adverse Event Reporting System database to provide recommendations for safe medication. Methods: All adverse drug reactions associated with 26 marketed ASMs in Food and Drug Administration Adverse Event Reporting System were extracted for analysis. Disproportionality analyses were used to assess the association between ASMs and MDs, and signal colour scale maps were created to identify potential ASM–MD safety signals. Results: A total of 1921 cases experienced MDs while taking ASMs were included. A higher prevalence of MDs was observed in females compared to males. The association between specific MDs with ASMs was revealed, including known and unknown MDs such as tremors, Parkinson and paralysis. Lamotrigine and carbamazepine exhibited multiple significant MDs, while levetiracetam and pregabalin were linked to the earlier onset of MDs. Generally, higher doses were linked to a higher incidence of MDs. Conclusion: MDs were the most obvious adverse drug reactions in the nervous system triggered by using ASMs. Fourteen drugs exhibited positive signals for MDs, including some not previously reported. Conversely, 12 ASMs were deemed to have a lower possibility of inducing MDs. The incidence of MDs can be mitigated by selecting appropriate ASMs for epileptic patients. These findings enhance our understanding of the relationship between ASMs and MDs. [ABSTRACT FROM AUTHOR]

Aims: Pharmacokinetic/pharmacodynamic target attainment of ceftriaxone is compromised in intensive care unit (ICU) patients and non‐ICU hospitalized patients in Beira, Mozambique. Whether this also accounts for non‐ICU patients in a high‐income setting is unknown. We therefore assessed the probability of target attainment (PTA) of the currently recommended dosing regimen of 2 g every 24 h (q24h) in this patient group. Methods: We performed a multicentre population pharmacokinetic study in hospitalized non‐ICU adult patients empirically treated with intravenous ceftriaxone. During both the acute phase of infection (i.e. first 24 h of treatment) and convalescence, a maximum of 4 random blood samples were obtained per patient for ceftriaxone total and unbound concentration measurements. PTA was calculated using NONMEM and was defined as the percentage of patients of which the unbound ceftriaxone concentration exceeded the minimum inhibitory concentration (MIC) for >50% of the first dosing interval of 24 h. Monte Carlo simulations were performed to determine PTA for different estimated glomerular filtration rates (eGFR; CKD‐EPI) and MICs. PTA >90% was considered adequate. Results: Forty‐one patients provided 252 ceftriaxone total and 253 unbound concentrations. The median eGFR was 65 mL/min/1.73 m2 (5th to 95th percentile 36–122). With the recommended dose of 2 g q24h, PTA >90% was achieved for bacteria with an MIC ≤2 mg/L. Simulations showed that PTA was insufficient for an MIC of 4 mg/L in case the eGFR was 122 mL/min/1.73 m2 (PTA 56.9%) and for an MIC of 8 mg/L regardless of eGFR. Conclusion: The PTA of 2 g q24h ceftriaxone dosing is adequate for common pathogens during the acute phase of infection in non‐ICU patients. [ABSTRACT FROM AUTHOR]

Aims: Nalbuphine is a synthetic opioid with comparable analgesic activity to morphine but with a better safety profile. Nalbuphine is only available in injectable form due to low oral bioavailability. Nasal nalbuphine spray provides advantages in drug safety, avoids hepatic first‐pass metabolism, is non‐invasive and is convenient for patient‐controlled analgesia by self‐administration. This study aimed to evaluate the safety and pharmacokinetics (PK) of the newly developed nalbuphine nasal spray in comparison with a solution for injections. Methods: Twenty‐four healthy Caucasian volunteers were enrolled in this randomized, open‐label, cross‐over study. Subjects were administered one of the drugs: nasal spray 7.0 mg/dose, nalbuphine hydrochloride solution for injection 10 mg/dose intravenously (IV) or intramuscularly (IM). High‐performance liquid chromatography–tandem mass spectrometry was used to determine nalbuphine concentrations. Results: A comparison of PK profiles for IV, IM and intranasal (IN) routes of nalbuphine administration revealed a close similarity of absorption phases for nasal spray and IM injection. Differences between the mean Tmax and dose‐adjusted Cmax values for nasal spray and IM injection were statistically insignificant. The median values of the elimination rate constants and the terminal elimination half‐life following IV, IM and IN nalbuphine administration were similar. The mean absolute bioavailability of the nasal spray equalled 65.04%. Conclusions: The similarity of PK parameters of IM‐injected nalbuphine solution and the nasal spray allows us to assume the latter is a feasible alternative to intramuscular nalbuphine injections appropriate for self‐administration and field environments for managing moderate and severe pain of various aetiologies. [ABSTRACT FROM AUTHOR]

Aims: Despite the availability of newer antiseizure medications, carbamazepine (CBZ) remains the gold standard. However, patients of Asian ancestry are susceptible to CBZ‐related severe cutaneous adverse reactions. Universal HLA‐B*15:02 screening is a promising intervention to address this. With the increasing recognition of integrating real‐world evidence in economic evaluations, the cost‐effectiveness of universal HLA‐B*15:02 screening was assessed using available real‐world data in Malaysia. Methods: A hybrid model of a decision tree and Markov model was developed to evaluate 3 strategies for treating newly diagnosed epilepsy among adults: (i) CBZ initiation without HLA‐B*15:02 screening (current practice); (ii) universal HLA‐B*15:02 screening prior to CBZ initiation; and (iii) alternative prescribing without HLA‐B*15:02 screening. The model was populated with real‐world inputs derived from the Malaysian population. From a societal perspective, base‐case analysis and sensitivity analyses estimated the costs and outcomes over a lifetime. Incremental cost‐effectiveness ratios were calculated. Results: In the base‐cases analysis, universal HLA‐B*15:02 screening yielded the lowest total costs and the highest total quality‐adjusted life years (QALYs) gained. Compared with current practice, universal screening was less costly by USD100 and more effective by QALYs increase of 0.1306, while alternative prescribing resulted in 0.1383 QALYs loss at additional costs of USD332. The highest seizure remission rate (56%) was estimated for universal HLA‐B*15:02 screening vs. current practice (54%) and alternative prescribing (48%). Conclusion: Our study suggests that universal HLA‐B*15:02 screening is a cost‐effective intervention in Malaysia. With the demonstrated value of real‐world evidence in economic evaluations, more relevant standardization efforts should be emphasized to better inform decision‐making. [ABSTRACT FROM AUTHOR]

Aims: Pleural mesothelioma (PM) is a highly aggressive thoracic tumour with poor prognosis. Although reduced tissue drug accumulation is one of the key features of platinum (Pt) resistance, little is known about Pt distribution in human PM. Methods: We assessed Pt levels of blood samples and surgically resected specimens from 25 PM patients who had received neoadjuvant Pt‐based chemotherapy (CHT). Pt levels and tissue distributions were measured by laser ablation‐inductively coupled plasma‐mass spectrometry and correlated with clinicopathological features. Results: In surgically resected PM specimens, mean Pt levels of nontumourous (fibrotic) areas were significantly higher (vs tumourous regions, P = 0.0031). No major heterogeneity of Pt distribution was seen within the tumourous areas. Pt levels correlated neither with the microvessel area nor with apoptosis rate in the tumourous or nontumourous regions. A significant positive correlation was found between serum and both full tissue section and tumourous area mean Pt levels (r = 0.532, P = 0.006, 95% confidence interval [95% CI] 0.161‐0.771 and r = 0.415, P = 0.039, 95% CI 0.011‐0.702, respectively). Furthermore, a significant negative correlation was detected between serum Pt concentrations and elapsed time from the last cycle of CHT (r = −0.474, P = 0.017, 95% CI −0.738‐−0.084). Serum Pt levels correlated negatively with overall survival (OS) (P = 0.029). Conclusions: There are major differences in drug distribution between tumourous and nontumourous areas of PM specimens. Serum Pt levels significantly correlate with full section and tumourous area average Pt levels, elapsed time from the last CHT cycle, and OS. Further studies investigating clinicopathological factors that modulate tissue Pt concentration and distribution are warranted. [ABSTRACT FROM AUTHOR]

Over the last three to four decades, Therapeutic Drug Monitoring (TDM) has shaped itself as therapeutic drug management, an integral component of precision medicine. The practice of TDM is not extensive in India, despite being one of the fastest‐growing economies in the world. It is currently limited to a few academic medical centres and teaching hospitals. Apart from the immunosuppressive drugs, several other therapeutic areas, such as anticancer, antifungal, antibiotic and antitubercular, have demonstrated great potential to improve patient outcomes in Indian settings. Factors such as the higher prevalence of nutritional deficiencies, tropical diseases, widespread use of alternative medicines, unalike pharmacogenomics and sparse population‐specific data available on therapeutic ranges of several drugs make the population of this subcontinent unique regarding the relevance of TDM. Despite the impact of TDM in clinical science and its widespread application, TDM has failed to receive the attention it deserves in India. This review intends to bring out a strength, weakness, opportunity and threats (SWOT) analysis for TDM in India so that appropriate steps for fostering the growth of TDM could be envisioned. The need of the hour is the creation of a cooperative group including all the stakeholders, such as TDM professionals, clinicians and the government and devising a National Action Plan to strengthen TDM. Nodal TDM centres should be established, and pilot programmes should be rolled out to identify the thrust areas for TDM in the country, capacity building and creating awareness to integrate TDM into mainstream clinical medicine. [ABSTRACT FROM AUTHOR]

Aims: To provide posthoc analyses of a clinical trial that reported beneficial effects of medication reviews on health‐related quality of life. Specifically, to describe the medication changes with a focus on deprescribing and to explore patient‐ and medication‐related factors that may identify patients most likely to benefit from medication reviews. Methods: Posthoc analyses of data from a pragmatic, nonblinded, randomized clinical trial investigating a medication review intervention (NCT03911934) in 408 geriatric outpatients treated with ≥9 medicines. Results: In the medication review group (n = 196), 26% of the medicines prescribed at baseline were discontinued with 82% still being discontinued after 13 months. The most common reason for discontinuation was lack of indication (72% of discontinuations). The medicines most often discontinued in the medication review group compared with usual care included: metoclopramide (11/15 = 73% discontinued vs. 1/12 = 8% in usual care), acetylsalicylic acid (20/48 = 42% vs. 2/47 = 4%), simvastatin (18/48 = 38% vs. 2/58 = 3%), zopiclone (23/59 = 39% vs. 4/54 = 7%), quinine (9/14 = 64% vs. 6/16 = 38%), citalopram (4/18 = 22% vs. 0/20 = 0%) and tramadol (18/37 = 49% vs. 8/30 = 27%). Factors associated with number of deprescribed medicines included: number of prescribed medicines, Drug Burden Index, patient motivation for medicine changes, and prescriptions of metoclopramide, iron preparations, antidepressants other than selective serotonin reuptake inhibitors, nonsteroidal anti‐inflammatory drugs, or drugs for urinary incontinence. Conclusion: Physician‐led medication reviews resulted in persistent deprescribing of medicines in older polypharmacy patients treated with ≥9 medicines. Motivation for having their medicine changed, treatment with more medicines, and a higher burden of sedative and anticholinergic medicines characterized the patients most likely to benefit from physician‐led medication reviews. [ABSTRACT FROM AUTHOR]

Tamoxifen is the most used hormonal therapy for oestrogen receptor‐positive breast cancer. CYP2D6 is the main enzyme in the metabolic pathway of tamoxifen to endoxifen. Variations in endoxifen plasma concentrations are associated with CYP2D6 polymorphisms. This study aimed to determine the association between the CYP2D6 polymorphisms and endoxifen plasma concentrations in a cohort of Zimbabwean breast cancer patients (n = 40). TaqMan genotyping and copy number assays were done to determine CYP2D6 genotypes. Tamoxifen and metabolites were quantitated using LC‐MS/MS. The population had high frequencies of the CYP2D6 reduced function alleles, *17 (15%) and *29 (18%). The median endoxifen concentration was 4.78 ng/mL, and in 55% of the patients, mostly intermediate metabolizers were below the endoxifen therapeutic threshold of 5.97 ng/mL. The CYP2D6 phenotypes and activity scores were significantly associated with endoxifen plasma concentrations (P = 0.0151) and with endoxifen to N‐desmethyl‐tamoxifen ratios (P = 0.0006). [ABSTRACT FROM AUTHOR]

Amikacin is an aminoglycoside antibiotic that is frequently used for the treatment of neonatal late‐onset sepsis, for which therapeutic drug monitoring (TDM) is advised. In order to decrease the TDM associated burden of plasma sampling, a noninvasive TDM method using saliva samples was investigated. Methods: This was a prospective single‐centre, observational feasibility study with 23 premature and term neonates from whom up to 8 saliva samples were collected, together with residual plasma from clinical routine. Amikacin concentrations in saliva and plasma were quantified with liquid chromatography–tandem mass spectrometry. A population pharmacokinetic analysis was performed to develop an integrated pharmacokinetic model of amikacin in plasma and saliva and for the identification of covariates. TDM performance of different sampling regimens was evaluated using Monte Carlo simulations in a fictional cohort of representative neonates (n = 10 000). Results: Amikacin could be detected in saliva and a saliva compartment was appended to a 2‐compartment plasma model. First‐order absorption (k13) of the saliva compartment was 0.0345 h−1 with an interindividual variability of 45.3%. The rate of first‐order elimination (k30) was 0.176 h−1. Postmenstrual age had a significant negative covariate effect on k13, with an exponent of −4.3. Target attainment increased from 77.6 to 79.2% and from 79.9 to 83.2% using 1–to 5 saliva samples or 1–5 plasma samples, respectively. Conclusion: TDM of amikacin using saliva samples results in target attainment comparable to plasma samples and may be beneficial for (premature) neonates with late‐onset sepsis. [ABSTRACT FROM AUTHOR]

It is unclear whether polypharmacy is associated with difficulty taking medications amongst people aged ≥85 living at home. This is despite the projected decline in availability of family carers, who may support independent living. Using Newcastle 85+ Study data and mixed‐effects modelling, we investigated the association between polypharmacy and difficulty taking medications amongst 85‐year‐olds living at home, over a 10‐year time period. Polypharmacy was not associated with difficulty taking medications as either a continuous (OR = 0.99 [0.91–1.08]) or categorical variable (5–9 medications, OR = 0.69 [0.34–1.41]; ≥10 medications, OR = 0.85 [0.34–2.07]). The significant predictors included disability, visual impairment and cognitive impairment. Our results suggest that people aged ≥85 living at home with disability, visual impairment and/or cognitive impairment will have difficulty taking their medications, regardless of how many they are prescribed. Therefore, healthcare professionals should routinely ask about, assess and address problems that these patient groups may have with taking their medicines, independent of the number of drugs taken. [ABSTRACT FROM AUTHOR]

Drug shortages make it difficult or impossible to meet the therapeutic needs of individual patients or populations. In the first part of this review we proposed an operational definition that incorporates the processes by which products are manufactured, the causes of shortages and stock‐outs (local shortages), and the contributory factors. Here we discuss causes and possible solutions. Drug shortages have complex causes, and a single cause cannot always be identified. Reasons include lack or shortage of raw materials, manufacturing difficulties, regulatory and political actions, voluntary recalls, just‐in‐time inventory systems, halts in production for financial or other business reasons, low demand (eg, orphan products, reduced usage), mergers, market shifts (eg, diversion to home markets) and unexpected increases in demand (eg, improved diagnosis, new trial information, epidemics and pandemics, inappropriate use, off‐label use). Potential solutions are as diverse as the potential causes. Prevention is hard, because shortages are not easily predicted. Everyone in the supply chain is involved in anticipating and managing shortages, with responsibilities for preventing them or at least trying to mitigate their effects. This includes manufacturers and suppliers, particularly of generic formulations, pharmacists, prescribers, patients and governments. Solutions can therefore be linked to the causes and classified according to where the responsibility for implementing them lies. [ABSTRACT FROM AUTHOR]

Aim: To investigate whether it is feasible to perform pharmacogenetic testing and implement the test results as part of medication reviews during hospitalization of multimorbid patients. Methods: Patients with ≥2 chronic conditions and ≥5 regular drugs with at least one potential gene‐drug interaction (GDI) were included from one geriatric and one cardiology ward for pharmacogenetic testing. After inclusion by the study pharmacist, blood samples were collected and shipped to the laboratory for analysis. For patients still hospitalized at the time when the pharmacogenetic test results were available, the information was used in medication reviews. Recommendations from the pharmacist on actionable GDIs were communicated to the hospital physicians, who subsequently decided on potential immediate changes or forwarded suggestions in referrals to general practitioners. Results: The pharmacogenetic test results were available for medication review in 18 of the 46 patients (39.1%), where median length of hospital stay was 4.7 days (1.6‐18.3). The pharmacist recommended medication changes for 21 of 49 detected GDIs (42.9%). The hospital physicians accepted 19 (90.5%) of the recommendations. The most commonly detected GDIs involved metoprolol (CYP2D6 genotype), clopidogrel (CYP2C19 genotype) and atorvastatin (CYP3A4/5 and SLCOB1B1 genotype). Conclusions: The study shows that implementation of pharmacogenetic testing for medication review of hospitalized patients has the potential to improve drug treatment before being transferred to primary care. However, the logistics workflow needs to be further optimized, as test results were available during hospitalization for less than half of the patients included in the study. [ABSTRACT FROM AUTHOR]

Aims: The aim of this study was to quantify identifiable sources of variability, including key pharmacogenetic variants in oxypurinol pharmacokinetics and their pharmacodynamic effect on serum urate (SU). Methods: Hmong participants (n = 34) received 100 mg allopurinol twice daily for 7 days followed by 150 mg allopurinol twice daily for 7 days. A sequential population pharmacokinetic pharmacodynamics (PKPD) analysis with non‐linear mixed effects modelling was performed. 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. Inhibition 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 (0.32 per T allele, 95% CI 0.13, 0.55) were found to predict differences in oxypurinol clearance. Oxypurinol concentration required to inhibit 50% of xanthine dehydrogenase activity was affected by PDZK1 rs12129861 genotype (−0.27 per A allele, 95% CI −0.38, −0.13). Most individuals with both PDZK1 rs12129861 AA and SLC22A12 rs505802 CC genotypes achieve target SU (with at least 75% success rate) 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 requiring selection of alternative medications. Conclusions: The proposed allopurinol dosing guide uses individuals' fat‐free mass, renal function and SLC22A12 rs505802 and PDZK1 rs12129861 genotypes to achieve target SU. [ABSTRACT FROM AUTHOR]

Aims: To investigate the drug‐drug interaction (DDI) of ciprofol injectable emulsion and mefenamic acid capsules in healthy subjects. Methods: Twenty healthy subjects were enrolled in this single‐centre, open‐label, two‐period DDI study. Ciprofol (0.4 mg kg−1) was administered as a single dose on days 1 and 5. A 500‐mg oral loading dose of mefenamic acid was given on day 4 followed by a 250‐mg maintenance dose every 6 h (a total of eight doses). Blood samples for pharmacokinetic analyses were collected. Depth of anaesthesia was monitored using the Modified Observer's Assessment of Alertness and Sedation (MOAA/S) scale and Bispectral Index scores (BISs). Results: Compared with administration of ciprofol alone, administration with mefenamic acid showed no significant difference in exposure. The geometric mean ratios (GMRs) and their 90% confidence intervals (CIs) for maximum plasma concentration (Cmax), area under the plasma concentration‐time curve calculated from 0 to the last measurement point (AUC0‐last) and AUC to infinity (AUC0‐inf) were 91.6% (86.5‐96.9%), 103.3% (100.3‐106.4%) and 107.0% (101.2‐113.2%), respectively. The MOAA/S and BIS curves for the two treatment periods essentially coincided, indicating that the anaesthesia effect of ciprofol was not affected by mefenamic acid. Seven subjects (35%) reported eight adverse events (AEs) when ciprorol was administered alone and 12 subjects (60%) reported 18 AEs when ciprofol was administered in combination with mefenamic acid. All AEs were mild. Conclusions: Mefenamic acid, a UGT1A9 inhibitor, had no significant effect on the pharmacokinetics and pharmacodynamics of ciprofol in healthy subjects. Ciprofol was safe and well tolerated when administered with mefenamic acid. [ABSTRACT FROM AUTHOR]

Aims: To evaluate and compare the relative performance of the tree‐based scan statistic (TreeScan) with the crude cohort study, Bayesian confidence propagation neural network (BCPNN) and Gamma Poisson Shrinker (GPS) in detecting statin‐related adverse events (AEs) in an electronic healthcare database. Methods: Data from a Chinese healthcare database from 2010 to 2016 were evaluated. We identified statin users based on prescription information in their out‐/in‐patient records, and AEs were defined according to the ICD‐10 codes in patients' diagnosis records. TreeScan was applied to detect AE signals related to statin use and was compared with 3 other methods based on sensitivity, specificity, positive predictive value, negative predictive value, accuracy, the Youden index, area under the precision–recall curve and the area under the receiver operating characteristic curve. Results: A total of 224 187 patients were enrolled and divided into 85 758 statin users and 138 429 nonusers. TreeScan generated 29 positive signals, of which 9 were known AEs. The sensitivities of TreeScan, BCPNN and GPS were all 69.2%, which was higher than that of the crude cohort study (46%). The specificity (82.3%), positive predictive value (31.0%), negative predictive value (95.9%), accuracy (81.0%), Youden index (51.5%) and area under the receiver operating characteristic curve (75.8%) of TreeScan were the highest among the 4 methods. Conclusion: TreeScan outperformed the crude cohort, BCPNN and GPS in detecting statin‐related AEs in an electronic healthcare database. Therefore, it can be used as a complementary tool for other signal detection methods in drug safety surveillance. [ABSTRACT FROM AUTHOR]

Aims: The UK Prescribing Safety Assessment was modified for use in Australia and New Zealand (ANZ) as the Prescribing Skills Assessment (PSA). We investigated the implementation, student performance and acceptability of the ANZ PSA for final‐year medical students. Methods: This study used a mixed‐method approach involving student data (n = 6440) for 2017–2019 (PSA overall score and 8 domain subscores). Data were also aggregated by medical school and included student evaluation survey results. Quantitative data were analysed using descriptive and multivariate analyses. The pass rate was established by a modified Angoff method. Thematic analyses of open‐ended survey comments were conducted. Results: The average pass rate was slightly higher in 2017 (89%) which used a different examination to 2018 (85%) and 2019 (86%). Little difference was identified between schools for the PSA overall performance or domain subscores. There was low intercorrelation between subscores. Most students provided positive feedback about the PSA regarding the interface and clarity of questions, but an average of 35% reported insufficient time for completion. Further, 70% on average felt unprepared by their school curricula for the PSA, which is in part explained by the low prescribing experience; 69% reported completing ≤10 prescriptions during training. Conclusion: The ANZ PSA was associated with high pass rates and acceptability, although student preparedness was highlighted as a concern for further investigation. We demonstrate how a collaboration of medical schools can adapt a medical education assessment resource (UK PSA) as a means for fulfilling an unmet need. [ABSTRACT FROM AUTHOR]

Aims: RO7049389 (linvencorvir) is a developmental oral treatment for chronic hepatitis B virus infection. The aim of this work was to conduct mass balance (MB) and absolute bioavailability (BA) analyses in healthy volunteers, alongside in vitro evaluations of the metabolism of RO7049389 and a major circulating active metabolite M5 in human hepatocytes, and physiologically based pharmacokinetic (PBPK) modelling to refine the underlying drug disposition paradigm. Methods: Participants in the clinical study (MB: Caucasian, male, n = 6; BA: Caucasian and Asian, male and female, n = 16, 8 in each ethnic groups) received oral [14C] or unlabelled RO7049389 (600/1000 mg) followed by 100 μg intravenous [13C]RO7049389. Metabolic pathways with fractions metabolized—obtained from the in vitro incubation results of 10 μM [14C]RO7049389 and 1 μM M5 with (long‐term cocultured) human hepatocytes in the absence and presence of the cytochrome P450 3A4 (CYP3A4) inhibitor itraconazole—were used to complement the PBPK models, alongside the clinical MB and BA data. Results: The model performance in predicting the pharmacokinetic profiles of RO7049389 and M5 aligned with clinical observations in Caucasians and was also successfully applied to Asians. Accordingly, the drug disposition pathways for RO7049389 were postulated with newly characterized estimates of the fractions: biliary excretion by P‐glycoprotein (~41%), direct glucuronidation via uridine 5′‐diphosphoglucuronosyltransferase 1A3 (~11%), hexose conjugation (~6%), oxidation by CYP3A4 (~28%) and other oxidation reactions (~9%). Conclusion: These results support the ongoing clinical development program for RO7049389 and highlight the broader value of PBPK and MB analyses in drug development. [ABSTRACT FROM AUTHOR]

Aims: To evaluate predictors for successful biologic tapering among patients with inflammatory arthritis using baseline characteristics from the BIODOPT trial. Methods: Adult patients with rheumatoid arthritis, psoriatic arthritis or axial spondyloarthritis on stable biologic dose and in low disease activity ≥12 months were enrolled. Participants were randomized (2:1) to disease activity‐guided biologic tapering or continuation of baseline biologic. Patients achieving successful tapering reduced their biologic dose by ≥50%, had no protocol deviations and were in low disease activity at 18 months. Modified Poisson regression with robust variance estimator was applied. Results: In total, 142 patients were randomized to tapering (n = 95) or control (n = 47). Successful tapering was achieved by 32 and 2%, respectively. Tapering group was the only statistically significant independent predictor for successful tapering, risk ratio (RR): 14.0 (95% confidence interval [CI]: 1.9 to 101.3, P =.009). However, higher Short Form Health Survey 36 mental component summary (SF‐36 MCS) was observed to be a predictor of potential importance, RR: 1.06 (95% CI: 0.99 to 1.13, P =.097). When limiting the analyses to the tapering group only, none of the baseline variables were statistically significant independent predictors but SF‐36 MCS was still considered to be of potential importance, RR: 1.05 (95% CI: 0.99 to 1.12, P =.098). Conclusion: Successful tapering is a reachable target for 1 in 3 patients with inflammatory arthritis who are interested in reducing their biological therapy. No statistically significant predictors (besides allocation to tapering) were identified. Future research on mental health and tapering is encouraged. [ABSTRACT FROM AUTHOR]

Aims: Lipid‐lowering medications are widely used to control blood cholesterol levels and manage a range of cardiovascular and lipid disorders. We aimed to explore the possible associations between LDL lowering and multiple disease outcomes or biomarkers. Methods: We performed a Mendelian randomization phenome‐wide association study (MR‐PheWAS) in 337 475 UK Biobank participants to test for associations between four proposed LDL‐C‐lowering genetic risk scores (PCSK9, HMGCR, NPC1L1 and LDLR) and 1135 disease outcomes, with follow‐up MR analyses in 52 serum, urine, imaging and clinical biomarkers. We used inverse‐variance weighted MR in the main analyses and complementary MR methods (weighted median, weighted mode, MR‐Egger and MR‐PRESSO) as sensitivity analyses. We accounted for multiple testing with false discovery rate correction (P < 2.0 × 10−4 for phecodes, P < 1.3 × 10−2 for biomarkers). Results: We found evidence for an association between genetically instrumented LDL lowering and 10 distinct disease outcomes, suggesting potential causality. All genetic instruments were associated with hyperlipidaemias and cardiovascular diseases in the expected directions. Biomarker analyses supported an effect of LDL‐C lowering through PCSK9 on lung function (FEV [beta per 1 mg/dL lower LDL‐C −1.49, 95% CI −2.21, −0.78]; FVC [−1.42, 95% CI −2.29, −0.54]) and through HMGCR on hippocampal volume (beta per 1 mg/dL lower LDL‐C 6.09, 95% CI 1.74, 10.44). Conclusions: We found genetic evidence to support both positive and negative effects of LDL‐C lowering through all four LDL‐C‐lowering pathways. Future studies should further explore the effects of LDL‐C lowering on lung function and changes in brain volume. [ABSTRACT FROM AUTHOR]

Aims: Clinically significant interactions with food occur for more than half of antiretroviral drugs. Different physiochemical properties deriving from the chemical structures of antiretroviral drugs may contribute to the variable food effect. Chemometric methods allow analysing a large number of interrelated variables concomitantly and visualizing correlations between them. We used a chemometric approach to determine the types of correlations among different features of antiretroviral drugs and food that may influence interactions. Methods: Thirty‐three antiretroviral drugs were analysed: ten nucleoside reverse transcriptase inhibitors, six non‐nucleoside reverse transcriptase inhibitors, five integrase strand transfer inhibitors, ten protease inhibitors, one fusion inhibitor and one HIV maturation inhibitor. Input data for the analysis were collected from already published clinical studies, chemical records and calculations. We constructed a hierarchical partial least squares (PLS) model with three response parameters: postprandial change of time to reach maximum drug concentration (ΔTmax), albumin binding (%) and logarithm of partition coefficient (logP). Predictor parameters were the first two principal components of principal component analysis (PCA) models for six groups of molecular descriptors. Results: PCA models explained 64.4% to 83.4% of the variance of the original parameters (average: 76.9%), whereas the PLS model had four significant components and explained 86.2% and 71.4% of the variance in the sets of predictor and response parameters, respectively. We observed 58 significant correlations between ΔTmax, albumin binding (%), logP and constitutional, topological, hydrogen bonding and charge‐based molecular descriptors. Conclusions: Chemometrics is a useful and valuable tool for analysing interactions between antiretroviral drugs and food. [ABSTRACT FROM AUTHOR]

Aims: Brepocitinib is a tyrosine kinase 2/Janus kinase 1 inhibitor being investigated for the treatment of several autoimmune diseases. This study assessed the absorption, distribution, metabolism and excretion of oral brepocitinib, and the absolute oral bioavailability (F) and fraction absorbed (Fa) using a 14C microtracer approach. Methods: This was a phase 1 open‐label, nonrandomized, fixed sequence, two‐period, single‐dose study of brepocitinib in healthy male participants. Participants received a single oral 60 mg dose of 14C brepocitinib (~300 nCi) in Period A, then an unlabelled oral 60 mg dose followed by an intravenous (IV) 30 μg dose of 14C labelled brepocitinib (~300 nCi) in Period B. Mass balance, pharmacokinetic parameters and safety were assessed. Results: Six participants were enrolled. Brepocitinib was absorbed rapidly following oral administration. In Period A, total recovery of the oral dose was 96.7% ± 6.3% (88.0% ± 8.0% in urine, 8.7% ± 2.1% in faeces). In Period B, a small fraction (6.0% of the oral dose) was recovered unchanged in urine. F and Fa were 74.6% (90% confidence interval 67.3%, 82.8%) and 106.9%, respectively. Brepocitinib demonstrated an acceptable safety profile and was well tolerated following oral or oral then IV administrations. No deaths, serious adverse events or discontinuations were reported. Conclusion: Intestinal absorption of brepocitinib was essentially complete after oral administration, with F ~75%. Drug‐related material recovery was high, with the majority excreted in urine. The major route of elimination of brepocitinib was renal excretion as metabolites, whereas urinary elimination of unchanged brepocitinib was minor. NCT: NCT03770039. [ABSTRACT FROM AUTHOR]

Aims: Pharmacogenomic testing has the potential to target medicines more effectively towards those who will benefit and avoid use in individuals at risk of harm. Health economies are actively considering how pharmacogenomic tests can be integrated into health care systems to improve use of medicines. However, one of the barriers to effective implementation is evaluation of the evidence including clinical usefulness, cost‐effectiveness, and operational requirements. We sought to develop a framework that could aid the implementation of pharmacogenomic testing. We take the view from the National Health Service (NHS) in England. Methods: We used a literature review using EMBASE and Medline databases to identify prospective studies of pharmacogenomic testing, focusing on clinical outcomes and implementation of pharmacogenomics. Using this search, we identified key themes relating to the implementation of pharmacogenomic tests. We used a clinical advisory group with expertise in pharmacology, pharmacogenomics, formulary evaluation, and policy implementation to review data from our literature review and the interpretation of these data. With the clinical advisory group, we prioritized themes and developed a framework to evaluate proposals to implement pharmacogenomics tests. Results: Themes that emerged from review of the literature and subsequent discussion were distilled into a 10‐point checklist that is proposed as a tool to aid evidence‐based implementation of pharmacogenomic testing into routine clinical care within the NHS. Conclusion: Our 10‐point checklist outlines a standardized approach that could be used to evaluate proposals to implement pharmacogenomic tests. We propose a national approach, taking the view of the NHS in England. Using this approach could centralize commissioning of appropriate pharmacogenomic tests, reduce inequity and duplication using regional approaches, and provide a robust and evidence‐based framework for adoption. Such an approach could also be applied to other health systems. [ABSTRACT FROM AUTHOR]

Aims: The objective of this study was to evaluate the effects of a strong cytochrome P450 family (CYP) 3A4 inhibitor (itraconazole) and inducer (carbamazepine) on the pharmacokinetics and safety of nirmatrelvir/ritonavir. Methods: Pharmacokinetics were measured in two phase 1, open‐label, fixed‐sequence studies in healthy adults. During Period 1, oral nirmatrelvir/ritonavir 300 mg/100 mg twice daily was administered alone; during Period 2, it was administered with itraconazole or carbamazepine. Nirmatrelvir/ritonavir was administered as repeated doses or one dose in the itraconazole and carbamazepine studies, respectively. Nirmatrelvir and ritonavir plasma concentrations and adverse event (AE) rates in both periods were analysed. Results: Each study included 12 participants. Following administration of nirmatrelvir/ritonavir with itraconazole (Test) or alone (Reference), test/reference ratios of the adjusted geometric means (90% CIs) for nirmatrelvir AUCtau and Cmax were 138.82% (129.25%, 149.11%) and 118.57% (112.50%, 124.97%), respectively. After administration of nirmatrelvir/ritonavir with carbamazepine (Test) or alone (Reference), test/reference ratios (90% CIs) of the adjusted geometric means for nirmatrelvir AUCinf and Cmax were 44.50% (33.77%, 58.65%) and 56.82% (47.04%, 68.62%), respectively. Nirmatrelvir/ritonavir was generally safe when administered with or without itraconazole or carbamazepine. No serious or severe AEs were reported. Conclusions: Coadministration of a strong CYP3A4 inhibitor with a strong CYP3A inhibitor used for pharmacokinetic enhancement (i.e., ritonavir) resulted in small increases in plasma nirmatrelvir exposure, whereas coadministration of a strong inducer substantially decreased systemic nirmatrelvir and ritonavir exposures suggesting a contraindication in the label with CYP3A4 strong inducers. Administration of nirmatrelvir/ritonavir alone or with itraconazole or carbamazepine was generally safe. [ABSTRACT FROM AUTHOR]

Aims: The new modified‐release formulation of tegoprazan, a novel potassium‐competitive acid blocker, is expected to improve the management of acid‐related disease, including nocturnal acid breakthrough, by prolonging the duration of acid suppression. This study aimed to explore the pharmacokinetics (PK) and pharmacodynamics (PD) of various combinations of tegoprazan with immediate‐release (IR) and delayed‐release (DR) formulations. Methods: A three‐cohort, open‐label, randomized, single‐dose, three‐treatment, six‐sequence, three‐period crossover study was conducted. Various combinations of tegoprazan IR and DR formulations (50, 75 or 100 mg) were administered orally once per period. The 24‐h intragastric pH was monitored before and after each administration. PK blood samples were collected for up to 48 h. PK and PD were compared among treatments. Results: Eighteen healthy Korean subjects completed the study. All treatment groups showed intragastric pH above 4 approximately 1 h following tegoprazan administration. Among the various combinations, the IR and DR combination at a 1:1 ratio induced greater gastric acid suppression (%Time pH ≥ 4) than IR alone in each dose group, both for 24 h (50 mg; 59% vs. 52%, P =.2188, 95% confidence interval [CI] −6.92–22.27, 100 mg; 85% vs. 70%, P <.05, 95% CI 8.92–22.19) and at night (50 mg; 27% vs. 16%, P =.1563, 95% CI −11.79–37.71, 100 mg; 77% vs. 49%, P <.05, 95% CI 16.14–42.98), with similar systemic exposure. Conclusions: The combinatorial tegoprazan in the IR and DR 1:1 ratio formulation was found to induce stronger gastric acid suppression throughout the day and at night, compared to the conventional IR formulation. [ABSTRACT FROM AUTHOR]

Aims: Several cases of ertapenem‐related neurotoxicity have been published in the current literature. However, studies evaluating the ertapenem blood concentration (EBC) as a risk of these adverse events are scarce. We aimed to evaluate the relationship between the trough EBC and the risk of neurological toxicity. Methods: This was a retrospective study, including patients who underwent ertapenem treatment between October 2019 and February 2021. We excluded patients in the critical care unit and those whose blood samples were not properly taken in order to analyse ertapenem trough concentration. We also excluded patients whose clinical follow‐up was not properly realized for the entire period of ertapenem treatment. The main outcome was the presence of any suspicious neurological side effect owing to ertapenem administration and its relationship with the plasma concentration. Secondary outcomes were to identify clinical and analytical data contributing to a higher risk of neurotoxicity. Results: The initial cohort comprised 158 individuals. For the final analysis we evaluated 102 patients, reporting a neurological alteration in 13/102 (12.7%). Mean trough EBC was significantly higher in patients showing neurotoxicity in comparison with those who did not (37.8 mcg mL−1, standard deviation [SD] ± 35.7 vs. 14.6 mcg mL−1, SD ± 15.2; P =.002). In multivariable logistic regression analysis, EBC (odds ratio [OR] = 1.07; P =.006), a moderate renal insufficiency (OR = 9.2; P =.02) and a history of previous neurologic disease (OR = 9.9; P =.02) were identified as risk factors of neurological alteration during ertapenem treatment. Conclusions: In patients at risk, determining the ertapenem plasma concentration may help to minimize the risk of neurotoxicity. [ABSTRACT FROM AUTHOR]

Introduction: Off‐label drug use in the paediatric population is common, and the lack of high‐quality efficacy studies poses patients at risk for failing pharmacotherapy. Next to efficacy studies, pharmacokinetic (PK) studies are increasingly used to inform paediatric dose selection. As resources for paediatric trials are limited, we aimed to summarize existing PK and efficacy studies to identify knowledge gaps in available evidence supporting paediatric dosing recommendations, thereby taking paediatric cardiovascular drugs as proof of concept. Methods: For each cardiovascular drug, paediatric indication and prespecified age group, together comprising one record, the authorized state was assessed. Next, for off‐label records, the highest level of evidence was scored. High‐quality efficacy studies were defined as meta‐analysis or randomized controlled trials. Other comparative research, noncomparative research or consensus‐based expert opinions were considered low quality. The level of evidence for PK studies was scored per drug and per age group, but regardless of indication. Results: A total of 58 drugs included 417 records, of which 279 (67%) were off‐label. Of all off‐label records, the majority (81%) were not supported by high‐quality efficacy studies, but for 140 of these records (62%) high‐quality PK studies were available. Conclusion: We demonstrated that for the majority of off‐label cardiovascular drugs, only low‐quality efficacy studies were available. However, high‐quality PK studies were frequently available. Combining these PK data with extrapolation of efficacy data from adults may help to close the current information gap and prioritize the drugs for which clinical studies and safety data are urgently needed. [ABSTRACT FROM AUTHOR]

Aim: To evaluate the impact of the COVID‐19 pandemic on the patterns of antimicrobial use and the incidence of pathogens in primary and secondary healthcare settings in Northern Ireland. Methods: Data were collected on antibiotic use and Gram‐positive and Gram‐negative pathogens from primary and secondary healthcare settings in Northern Ireland for the period before (January 2015‐March 2020) and during (April 2020‐December 2021) the pandemic. Time series intervention analysis methods were utilized. Results: In the hospital setting, the mean total hospital antibiotic consumption during the pandemic was 1864.5 defined daily doses (DDDs) per 1000 occupied‐bed days (OBD), showing no significant change from pre‐pandemic (P =.7365). During the pandemic, the use of second‐generation cephalosporins, third‐generation cephalosporins, co‐amoxiclav and levofloxacin increased, there was a decrease in the percentage use of the hospital Access group (P =.0083) and an increase in the percentage use of Watch group (P =.0040), and the number of hospital Klebsiella oxytoca and methicillin‐susceptible Staphylococcus aureus cases increased. In primary care, the mean total antibiotic consumption during the COVID‐19 pandemic was 20.53 DDDs per 1000 inhabitants per day (DID), compared to 25.56 DID before the COVID‐19 pandemic (P =.0071). During the pandemic, there was a decrease in the use of several antibiotic classes, an increase in the percentage use of the Reserve group (P =.0032) and an increase in the number of community‐onset Pseudomonas aeruginosa cases. Conclusion: This study provides details of both changes in antibiotic consumption and the prevalence of infections in hospitals and primary care before and during the COVID‐19 pandemic that emphasize the importance of antimicrobial stewardship in pandemic situations. [ABSTRACT FROM AUTHOR]

Patients with chronic psychosis on prolonged antipsychotic therapy may present with paroxysmal dystonia along with an exacerbation of their psychotic symptoms: paroxysmal dystonia and psychotic exacerbations (PDPE). The interindividual variability in the clinical presentations of PDPE can pose challenges in its diagnosis and treatment. The objectives of this work are to (i) discuss this rare phenomenon through a series of 10 patients and a relevant literature review, (ii) conceptualize its neurobiological underpinnings, and (iii) explore the preliminary treatment approaches for its management. Acute stress and/or a dysfunctional gamma‐aminobutyric acid (GABA) ergic or dopaminergic system may be implicated in the pathogenesis of PDPE. The episodes respond acutely to parenteral benzodiazepines, while long‐term management can be achieved by reducing antipsychotic doses, switching to clozapine or using central GABA enhancers. This article is the first attempt at conceptualizing and exploring treatment options for the rare condition PDPE and intends to guide future research in this regard. [ABSTRACT FROM AUTHOR]

Aims: The aim of this study was to determine whether the testing strategy for clopidogrel and/or aspirin resistance using CYP2C19 genotyping or urinary 11‐dhTxB2 testing has an impact on clinical outcomes. Methods: A multicentre, randomized, controlled trial was conducted at 14 centres in China from 2019 to 2021. For the intervention group, a specific antiplatelet strategy was assigned based on the CYP2C19 genotype and 11‐dhTxB2, a urinary metabolite of aspirin, and the control group received nonguided (ie, standard of care) treatment. 11‐dhTXB2 is a thromboxane A2 metabolite that can help quantify the effects of resistance to aspirin in individuals after ingestion. The primary efficacy outcome was new stroke, the secondary efficacy outcome was a poor functional prognosis (a modified Rankin scale score ≥3), and the primary safety outcome was bleeding, all within the 90‐day follow‐up period. Results: A total of 2815 patients were screened and 2663 patients were enrolled in the trial, with 1344 subjects assigned to the intervention group and 1319 subjects assigned to the control group. A total of 60.1% were carriers of the CYP2C19 loss‐of‐function allele (*2, *3) and 8.71% tested positive for urinary 11‐dhTxB2‐ indicating aspirin resistance in the intervention group. The primary outcome was not different between the intervention and control groups (P =.842). A total of 200 patients (14.88%) in the intervention group and 240 patients (18.20%) in the control group had a poor functional prognosis (hazard ratio 0.77, 95% confidence interval [CI] 0.63 to 0.95, P =.012). Bleeding events occurred in 49 patients (3.65%) in the intervention group and 72 patients (5.46%) in the control group (hazard ratio 0.66, 95% CI 0.45 to 0.95, P =.025). Conclusions: Personalized antiplatelet therapy based on the CYP2C19 genotype and 11‐dhTxB2 levels was associated with favourable neurological function and reduced bleeding risk in acute ischaemic stroke and transient ischaemic attack patients. The results may help support the role of CYP2C19 genotyping and urinary 11‐dhTxB2 testing in the provision of precise clinical treatment. [ABSTRACT FROM AUTHOR]

Aims: To mediate its pharmacodynamic effects, glyceryl trinitrate (GTN) requires bioactivation, by which it releases nitric oxide or a nitric oxide moiety. The exact mechanism of GTN bioactivation remains uncertain. Mitochondrial aldehyde dehydrogenase (ALDH‐2) has been proposed as the primary enzyme responsible for this bioactivation process. Evidence for the importance of ALDH‐2 in GTN bioactivation has been inconsistent, particularly in human models. An alternative hypothesis suggests that decreased ALDH‐2 activity leads to accumulation of reactive cytotoxic aldehydes, which either inhibit the vasoactive product(s) of GTN or impair other enzymatic pathways involved in the bioactivation of GTN. We investigated the effect of supplemental vitamin C on vascular responses to GTN in healthy volunteers of East Asian descent, of whom 12 with and 12 without the ALDH‐2 polymorphism participated. Methods: Subjects underwent 2 sequential brachial artery infusions of GTN at rates of 5, 11 and 22 nmol/min, separated by a 30‐min washout period. The GTN infusions were carried out in the presence and absence of vitamin C using a randomized, crossover design. Venous occlusion plethysmography was used to measure forearm blood flow responses to GTN. Results: Compared to subjects with functional ALDH‐2, the variant group exhibited blunted hemodynamic responses to intra‐arterial GTN infusions, although this reduction in response was not statically significant. Contrary to our hypothesis, vitamin C had an inhibitory effect on GTN mediated vasodilation as compared to GTN during saline in both groups. Conclusion: We conclude that vitamin C did not augment the acute vascular response to GTN in those with the ALDH‐2 polymorphism. [ABSTRACT FROM AUTHOR]

Figures from the Editors selected issue highlights will be displayed each month in the journal image carousel on the BJCP homepage http://bpspubs.onlinelibrary.wiley.com/hub/journal/10.1111/(ISSN)1365-2125/. Treatment regimens for tuberculosis are lengthy and require a high number of combination drugs and unfortunately antitubercular drug development to date has not been very successful. In their paper, Morris Muliaditan M. and Oscar della Pasqua (London, UK), showed that drug-disease modelling may provide rationale for dose selection and companion drugs to treat tuberculosis. [Extracted from the article]

Aims: To review the medicines optimisation activities of the All Wales Medicines Strategy Group (AWMSG), a committee established in 2002 to advise the Welsh Government on "all matters related to prescribing". Although AWMSG conducts other activities (e.g., health technology appraisal for medicines), we focus here on its role in advising on medicines optimisation., Methods: Prescribing indicators have been used in Wales to measure change, together with data on volumes and costs of medicines dispensed. A range of improvement strategies have been categorised under the "four Es", namely educational initiatives, economic incentives, "engineering" and "enforcement"., Results: AWMSG has helped health professionals in NHS Wales to reduce harm and waste, and to reduce inappropriate local or regional duplication and variation. Specific initiatives include the achievement of major cost savings by supporting increased generic prescribing and an "invest to save" approach related to prescribing of hypnotics and tranquillisers, non-steroidal anti-inflammatory drugs (NSAIDs) and proton pump inhibitors. AWMSG also successfully commissioned the introduction of a single national in-patient medication chart for Wales in 2004. Ongoing priorities include a focus on reducing prescribing of certain medicines deemed "low value for prescribing" and on optimising the use of biosimilar medicines., Conclusions: Since 2002, AWMSG has acted as a national medicines optimisation committee in Wales. From the outset, pharmacists and clinical pharmacologists have collaborated closely and shared their complementary expertise to make a much greater contribution to the safe, effective and cost-effective use of medicines than either group could have achieved by working separately., (© 2021 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

A letter to the editor is presented regarding the implication of the use of opioids in people with chronic obstructive pulmonary disease (COPD) for symptom relief.

Aims: Population pharmacokinetics (PK) models may be effective in improving antibiotic exposure with individualized dosing. The aim of the study is to assess cefazolin exposure using a population PK model in critically ill children., Methods: We conducted a single-centre observational study including children under 18 years old who had cefazolin plasma monitoring before and after a cefazolin model implementation. The first concentration at steady state of each cefazolin course was analysed. The optimal exposure was defined by concentration values ranging from free concentration over four times the minimal inhibitory concentration (MIC) for 100% of the dosing interval to total trough or plateau concentration under 100 mg. L -1 ., Results: A total of 58 patients were included, of whom 39 and 19 children received conventional dosing or model-informed dosing, respectively. Median [range] age was 2.3 [0.1-17] years old, and median weight was 14.2 [2.9-72] kg. There were more continuous infusions (CI) in the model group than in the conventional group (n = 19/19 [100%] vs. n = 23/39 [59%]). Compared to conventional dosing, model-informed dosing provided more optimal exposure (n = 17/39 [44%] vs. n = 15/19 [79%], P = .01) and less underexposure (n = 18/39 [46%] vs. n = 2/19 [10%], P = .008), without increasing overexposure (n = 4/39 [10%] vs. n = 2/19 [11%], P = 1). Moreover, the time to C-reactive protein decrease by 50% was significantly shorter in the model group than the conventional group (3 [0.5-13] vs. 4 [1-34]; P = .045)., Conclusions: Use of individualized cefazolin model-informed dosing improves critically ill children's exposure. Further studies are needed to assess the clinical benefit of cefazolin PK model application., (© 2024 British Pharmacological Society.)

Aims: To investigate plasma apixaban concentrations and thrombin generation assay (TGA) parameters across different apixaban doses in atrial fibrillation patients who had dose-reduction criteria for apixaban., Methods: This observational study included 374 patients (mean age 75.6 ± 7.7 years, 54.8% female) with dose-reduction criteria for apixaban. The patients were divided into 3 groups: (i) on-label standard dose (5 mg twice daily, n = 166); (ii) on-label reduced dose (2.5 mg twice daily, n = 55); and (iii) off-label underdose (2.5 mg twice daily, n = 153). Apixaban concentrations determined via the anti-Xa assay and TGA parameters were compared at trough levels., Results: The off-label underdose group exhibited significantly lower apixaban trough concentrations than the on-label reduced-dose and standard-dose groups (56.7 ± 42.9 vs. 83.7 ± 70.4 vs. 129.9 ± 101.8 ng/mL, all P < .001). Less than 70% of all patients fell within the expected range of apixaban concentrations. Proportions exceeding the upper limit of the expected range were significantly lower in the off-label underdose group (1.3%) than in the on-label reduced-dose (9.1%, P = .005) and standard-dose (12.7%, P < .001) groups. The TGA parameters showed the on-label standard-dose group displaying the lowest thrombogenic profiles. Lower creatinine clearance was the most significant predictor of higher apixaban concentrations., Conclusion: Off-label underdosed apixaban resulted in lower apixaban concentrations than both on-label standard and reduced-dose regimens. A considerable proportion of the patients exhibited apixaban concentrations outside the expected range, suggesting the potential benefits of plasma concentration monitoring. Further studies are needed to compare dosages directly, investigate the impact of plasma apixaban concentration monitoring and validate the current dose-reduction criteria., (© 2024 British Pharmacological Society.)

In this systematic review, we report on the effects of diuretic deprescribing compared to continued diuretic use. We included clinical studies reporting on outcomes such as mortality, heart failure recurrence, tolerability and feasibility. We assessed risk of bias and certainty of the evidence using the GRADE framework. We included 25 publications from 22 primary studies (15 randomized controlled trials; 7 nonrandomized studies). The mean number of participants in the deprescribing groups was 35, and median/mean age 64 years. In patients with heart failure, there was no clear evidence that diuretic deprescribing was associated with increased mortality compared to diuretic continuation (low certainty evidence). The risk of cardiovascular composite outcomes associated with diuretic deprescribing was inconsistent (studies showing lower risk for diuretic deprescribing, or comparable risk with diuretic continuation; very low certainty evidence). The effect on heart failure recurrence after diuretic deprescribing in patients with diuretics for heart failure, and of hypertension in patients with diuretics for hypertension was inconsistent across the included studies (low certainty evidence). In patients with diuretics for hypertension, diuretic deprescribing was well tolerated (moderate certainty evidence), while in patients with diuretics for heart failure, deprescribing diuretics can result in complaints of peripheral oedema (very low certainty evidence). The overall risk of bias was generally high. In summary, this systematic review suggests that diuretic discontinuation could be a safe and feasible treatment option for carefully selected patients. However, there isa lack of high-quality evidence on its feasibility, safety and tolerability of diuretic deprescribing, warranting further research., (© 2024 The Author(s). British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Drug-induced skin disease or cutaneous adverse drug reactions (CADRs) are terms that encompass the clinical manifestations of the skin, mucosae and adnexa induced by a drug or its metabolites. The skin is the organ most frequently affected by drug reactions, which may affect up to 10% of hospitalized patients and occur in 1-3% of multimedicated patients. Most CADRs are mild or self-resolving conditions; however, 2-6.7% of could develop into potentially life-threatening conditions. CADRs represent a heterogeneous field and can be diagnostically challenging as they may potentially mimic any dermatosis. Currently, there are between 29-35 different cutaneous drug-reaction patterns reported ranging from mild dermatitis to an extensively burnt patient. The most frequently reported are maculopapular rash, urticaria/angioedema, fixed drug eruption and erythema multiforme. Less common but more severe patterns include erythroderma, drug reaction with eosinophilia and systemic symptoms, and Stevens-Johnson syndrome/toxic epidermal necrolysis spectrum. Almost any drug can induce a CADR, but antibiotics, nonsteroidal anti-inflammatory drugs and antiepileptics are the most frequently involved. Different mechanisms are involved in the pathogenesis of CADRs, although in some cases, these remain still unknown. CADRs could be classified in different ways: (i) type A (augmented) or type B (bizarre); (ii) immediate or delayed; (iii) immune-mediated or nonimmune-mediated; (iv) nonsevere or life-threatening; and (v) by their phenotype, including exanthematous, urticarial, pustular and blistering morphology. Recognizing a specific CADR will mostly depend on the ability of the physician to perform a detailed clinical examination, the proper description of the morphology of the skin lesions and supporting laboratory and/or skin biopsy findings., (© 2022 British Pharmacological Society.)