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

Aims: Given the complexity of antithrombotic therapy guidelines especially in patients with combined antithrombotic therapy, there is a risk of inappropriate prescribing and medication errors. In order to prevent this, a multidisciplinary antithrombotic stewardship (ASP) is implemented in our hospital. The primary aim of this study is to determine the efficacy of this ASP by assessing the number of patients on combined antithrombotic therapy for whom one or more interventions are needed. Methods: A prospective cohort study in a large teaching hospital is conducted. Hospitalized patients who received combined antithrombotic therapy in which an oral anticoagulant was combined with one (double therapy) or two (triple therapy) platelet aggregation inhibitors were included. The ASP proactively evaluated the appropriateness of this combined antithrombotic therapy. If needed, ASP improved the concerned therapy. Each improvement measurement by ASP was counted as one intervention. Results: A total of 460 patients were included over a period of 12 months. 251 (54.6%) patients required at least one intervention from the ASP. The most common intervention was to define and document a maximum duration of the combined antithrombotic therapy (65.5%) instead of lifetime use of the combination, to discontinue antithrombotic therapy (19.4%) as the proper indication was lacking and to adjust the dosage (8.1%). Conclusion: As intervention was needed in more than half of the patients on combined antithrombotic therapy, it seems essential to implement an ASP that dedicated evaluates antithrombotic therapy to improve and ensure optimal use and medication safety.

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

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

Benzalkonium chloride (BAC) is a quaternary ammonium compound commonly employed as a preservative in several multidose eye drops. Its use is associated with several adverse events, particularly when used chronically. Topically instilled BAC acts not only on superficial structures but also reaches deeper tissues (trabecular meshwork, optic nerve) and can be deleterious in patient under chronic treatment. In glaucomatous patients, BAC is the primary cause of ocular surface disease (OSD), and it can lead to significant morbidity, influence treatment compliance, quality of life, and surgical outcomes. Clinical and experimental evidence demonstrates that BAC causes instability of the tear layer, loss of goblet cells, apoptosis, subclinical neuroinflammation, and antibiotic resistance. Considering the validity of the alternative formulations (alternative preservatives or preservative-free formulations) it is unreasonable to persist in using such toxic compounds and, perhaps it is time for a moratorium on the use of BAC in eye drops.

Background: 64 million pharmacy filled multicompartment medication compliance aids (MCAs) are dispensed by pharmacies in England each year as a method to improve medication adherence. Despite the widespread use of MCAs and evidence that their use may be associated with harm there is no national consensus regarding MCA provision by acute hospital Trusts in England. Aim: To determine current practice for initiation and supply of MCAs in acute hospital Trusts in England and the potential consequences for patients and hospitals. Methods: A 26 item survey was distributed to all acute hospital Trusts in England. The questionnaire covered policy, initiation, supply and review of MCAs; alternatives offered; and pharmacy staffing and capacity related to MCAs. Results: 72 out of 138 (52%) Trusts responded to the survey. 60/70 (86%) had a policy for the provision of MCAs. 33/55 (60%) that supplied MCAs on discharge supplied a different prescription length for MCA vs. non-MCA prescriptions. 49/55 (89%) Trusts provided only one brand of MCA. 47/55 (85%) MCA-supplying Trusts identified frequent difficulties with MCAs and 13/55 (24%) reported employing staff specifically to complete MCAs. 30/35 (86%) MCA-initiating Trusts had an assessment process for initiation, with care agency request as the most common reason. Conclusion: There is a lack of a national approach to MCA provision and initiation by acute hospital Trusts in England. This leads to significant variation in care and has the potential to put MCA users at an increased risk of medication related harm.

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

In this special issue of the British Journal of Clinical Pharmacology, we highlight innovative methodologies in pediatric drug development.

There is a growing interest in the psychiatric properties of the dissociative anesthetic ketamine, as single doses have been shown to have fast-acting mood-enhancing and anxiolytic effects, which persist for up to a week after the main psychoactive symptoms have diminished. Therefore, ketamine poses potential beneficial effects in patients with refractory anxiety disorders, where other conventional anxiolytics have been ineffective. Ketamine is a non-competitive antagonist of the N-methyl-D-aspartate (NMDA) glutamate receptor, which underlies its induction of pain relief and anaesthesia. However, the role of NMDA receptors in anxiety reduction is still relatively unknown. To fill this paucity in the literature, this systematic review assesses the evidence that ketamine significantly reduces refractory anxiety and discusses to what extent this may be mediated by NMDA receptor antagonism. We highlight the temporary nature of the anxiolytic effects and discuss the high discrepancy among the study designs regarding many fundamental factors such as administration routes, complementary treatments, and other treatments.

Background Linezolid is often used for the infections caused by drug-resistant Gram-positive bacteria. Recent studies suggested that large between-subject variability (BSV) and within-subject variability could alter drug pharmacokinetics (PK) during linezolid therapy due to pathophysiological changes. Objective The review synthesized information on linezolid population PK studies and summarized the significant covariates that influence the PKs of linezolid. Methods A literature search was performed from PubMed, Web of Science, and Embase from their inception to 30 September 2021. Published studies were included if they contained data analyzing linezolid PK parameters in humans using a population approach with a nonlinear mixed-effects model. Results Twenty-five studies were included in adults and five studies in pediatric patients. One- and two-compartment models were the commonly used structural models for linezolid. Body size [weight, lean body weight, and body surface area], creatinine clearance (CLcr), and age significantly influenced linezolid PK. The median clearance (CL) values (range) in infants [0.128 L/h/kg (0.121-0.135)] and children [0.107 L/h/kg (0.088-0.151)] were higher than in adults [0.098 L/h/kg (0.044-0.237)]. For patients with severe renal impairment (CLcr ≤ 30 mL/min), the CL was 37.2% (15.2-55.3%) lower than in patients with normal renal function. Conclusion Linezolid’s optimal dosage could be adjusted based on the patient’s body size, renal function, and age. More studies are needed to explore the exact mechanism of elimination of linezolid and evaluate PK characteristics in pediatric patients.

Background: Mycophenolate mofetil (MMF) is the most widely used second-line agent in auto-immune hepatitis (AIH). It is generally titrated up to patient response and continued for at least two years following complete liver enzyme normalization. However, in this maintenance phase individual dose adjustment to reach mycophenolic acid (MPA) exposure with the best benefit-risk probability may avoid adverse outcomes. The aim of the present study was to develop population pharmacokinetic (popPK) models and Maximum A-Posteriori Bayesian estimators (MAP-BEs) to estimate MPA inter-dose area under the curve (AUC0-12h) in AIH patients administered MMF using nonlinear mixed effect modelling. Methods: We analysed 50 MPA PK profiles from 34 different patients, together with some demographic, clinical, and laboratory test data. The median number of samples per profile, immediately preceding and following the morning MMF dose, was 7 [4 – 10]. PopPK modeling was performed using parametric, top-down, nonlinear mixed effect modelling with NONMEM 7.3. MAP-BEs were developed based on the the best popPK model and the best limited sampling strategy (LSS) selected among several. Results: The pharmacokinetic data were best described by a 2-compartment model, Erlang distribution to describe the absorption phase, and a proportional error. The best MAP-BE relied on the LSS at 0.33, 1 and 3 hours after mycophenolate mofetil dose administration and was very accurate (bias=5.6%) and precise (RMSE<20%). Conclusion: The precise and accurate Bayesian estimator developed in this study for AIH patients on MMF can be used to improve the therapeutic management of these patients.

Aims: Voriconazole is the mainstay for the treatment for invasive fungal infections in heart transplant patients and significantly increase tacrolimus exposure because of drug-drug interaction (DDI). However, the magnitude of this DDI is highly variable and hard to predicted. The purpose of this study was to present the characteristics of DDI between tacrolimus and voriconazole, and further identify the predictors of tacrolimus dose modification. Methods: We retrospectively enrolled 69 heart transplant recipients without using voriconazole as the control and 68 patients received voriconazole treatment in voriconazole group. CYP3A4*1G, CYP3A5*3 and CYP2C19*2 or *3 were genotyped by Sanger sequencing. The requirement of tacrolimus dose for therapeutic concentrations and tacrolimus dose-corrected trough concentration (C0/D) before and after VRC administration were evaluated. Results: The DDI between tacrolimus and voriconazole was in a large inter-individual variability with more than ten-fold changes in tacrolimus dose (range 1.28–13.00) and C0/D (range 1.43–13.75). Besides, the fold changes of tacrolimus dose were associated with CYP2C19 genotype, which was significantly lower in CYP2C19 extensive metabolizers than that in CYP2C19 intermediate metabolizers or poor metabolizers (4.06±1.85 vs 5.49±2.47, p=0.0031). While no significant difference was found in both CYP3A4 and CYP3A5 genotypes. Moreover, CYP2C19 genotype and hematocrit were independent predicting factors for tacrolimus dose modification after voriconazole co-therapy. Conclusions: This study provided a potential basis for comprehensive factors to adjust tacrolimus dosage when co-administrated with voriconazole in individual patients. CYP2C19 genotype and hematocrit should be considered in tailoring tacrolimus dose.

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

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

Esomeprazole is a proton pump inhibitor being investigated for treatment of preeclampsia. Esomeprazole pharmacokinetics during pregnancy is unknown. We used data from 10 pregnant patients with preterm preeclampsia, and 49 non-pregnant individuals to develop a population pharmacokinetic model of esomeprazole. A two-compartment model described the data well. In pregnant patients after single dose, clearance was 42.2% (14.9%– 61.6%) lower compared to non-pregnant, most likely due to downregulation of CYP2C19. In non-pregnant after repeated dosing, clearance was 54.9% (48.2% – 63.5%) lower in extensive metabolizers and bioavailability was 33% (10.0% – 52.0%) higher compared to single dosing, which could be due to autoinhibition of CYP2C19. Esomeprazole pharmacokinetics during pregnancy appears to be more dependent on CYP3A4.

Aim: Residual neuromuscular blockade is a common complication after general anaesthesia. Sugammadex can reverse the action of aminosteroid neuromuscular blockers. Our study aimed to explore sugammadex safety issues in the real world and determine the spectrum of adverse reactions. Methods: All sugammadex-related adverse events reported in VigiBase between 2010 and 2019 were classified by group queries according to the Medical Dictionary for Regulatory Activities. A disproportionality analysis of data was performed using the information component (IC); positive IC values were deemed significant. Results: Overall, 16,219,410 adverse events were reported, and 2032 were associated with sugammadex. The most frequent reactions were recurrence of neuromuscular blockade (n = 54, IC: 6.74, 95% credibility interval [CI]: 6.33–7.10), laryngospasm (n = 53, IC: 6.05, IC025:5.64), bronchospasm (n = 119, IC: 5.63 , IC025:5.36), and bradycardia (n = 169, IC: 5.13, IC025:4.90). Fatal cases were more likely with cardiac disorders, especially in patients over 65 years. In addition, the common adverse drug reactions (ADRs) differed between different age groups (P < 0.01). The ADRs were higher between 0–17 years than in other age groups. The onset time of common ADRs was typically within one day, and 68.9% occurred within half an hour after sugammadex administration. Conclusions: Anaesthesiologists should carefully monitor the anaesthesia recovery period to correct the adverse drug reactions caused by sugammadex and recommend monitoring neuromuscular function throughout the anaesthesia process. Sugammadex should be used carefully in patients with cardiovascular diseases, and ECG and hemodynamic changes monitored after medication.

The incidence of new-onset seizures, which we defined as de novo seizures occurring within four weeks of receiving any of the FDA-approved Covid 19 vaccinations as reported in patient-reported data compiled in the US Centers for Disease Control and Prevention Vaccine Adverse Events Reporting System Data (CDC VAERS) has not been explored. The VAERS database contains de-identified patient-reported adverse events following vaccinations and represents post-marketing surveillance and analysis of vaccine safety. After adjusting for time at risk, this resulted in estimated incidence rates of 3.19 seizures per 100,000 persons per year for either Pfizer, Moderna or Janssen vaccines and 0.090 seizures per 100,000 persons per year for the influenza vaccine. A data-driven, individualized dataset that is comprehensive and coupled with a longitudinal follow-up in larger numbers of vaccinated individuals is needed to expand on our preliminary findings of vaccine-related seizures. The VAERS database helps in the identification of a safety signal detection and is fundamentally a hypothesis-generating system; the data or results cannot be used to analyze cause and effect.

Aim: This systematic review aims to assess the safety profile of oxcarbazepine during pregnancy. Methods: Observational studies that included women who took oxcarbazepine anytime during pregnancy were included in our systematic review. The review did not include non-English articles, reviews, meta-analyses, case reports, and animal studies. Different online sources such as MEDLINE, Cochrane library, Virtual Health Library, etc. were searched for published and unpublished literature. Assessment of the risk of bias in observational studies was done using the Newcastle-Ottawa Scale. The meta-analyses were performed using a random-effect model. GRADE was used for the evaluation of the quality of evidence for the primary outcomes. Results: We included 19 cohort studies with a total number of 5,071,137 patients, of which 2,450 were exposed to oxcarbazepine either as monotherapy or polytherapy. The summary odds ratio (OR) was 1.69 (95% CI, 0.95-2.98) for congenital malformations following in-utero exposure to oxcarbazepine as compared to the control group of unexposed patients [seven studies (n=625)], and was 1.19 (95% CI, 0.67-2.12) when compared to those following lamotrigine (LTG) exposure during pregnancy [3 studies (n=591)]. In total, three studies (n=770) reported the association between in-utero oxcarbazepine exposure and fetal/perinatal deaths. The meta-analysis yielded a summary OR of 3.33 (95% CI, 1.70-6.51). Significance: Our systematic review will help healthcare providers and guideline developers regarding the treatment of epilepsy and other neurological disorders during pregnancy. More cohort studies with a higher sample size concerning oxcarbazepine use in pregnant patients are required to truly assess the in-utero safety profile of the drug.