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

Introduction: In critically ill patients, Transfusion Related Acute Lung Injury (TRALI) remains the leading cause of transfusion-related fatalities in critical care setting and associated with inflammation and oxidative stress state. Recent research raised the potential efficacy of high dose intravenous ascorbic acid in critically ill patients. Objective: The aim of this trial was to investigate the effect of high dose intravenous ascorbic acid (VC) as a targeted therapy for TRALI in terms of serum proinflammatory (interleukin-8, interleukin-1β, C-reactive protein), anti-inflammatory (interleukin-10), oxidative stress (superoxide dismutase, malondialdehyde) markers, and plasma VC levels. Secondary outcomes were oxygenation (PaO2/FiO2 ratio), vasopressor use, duration of mechanical ventilation, ICU length of stay, 7-days mortality and 28-days mortality. Methods: Eighty critically ill patients with TRALI (n=80) were randomized to receive 2.5gm/6hr intravenous vitamin C for 96 hours (ASTRALI group) or placebo. Patients were followed-up to measure the outcomes initially (T0) and at the end of treatment (T96). Results: When compared to control group, ASTRALI group at T96, showed significantly higher median of interleukin-10 (31.6 ± 25.8 Vs. 17.7 ± 12.0 pg/mL, p<0.0001) levels and superoxide dismutase (12876 ± 4627 U/L Vs. 5895 ± 6632 U/L, p<0.0001) activities, lower median C-reactive protein (76 ± 50 Vs. 89 ± 56 mg/L, p=0.033), interleukin-8 (11.8 ± 7.3, 35.5 ± 19.8 pg/mL, p<0.0001), and malondialdehyde (0.197 ± 0.034 Vs. 0.234 ± 0.074 µM/L, p=0.002) levels. Conclusion: High dose ascorbic acid was associated with significantly reduced oxidative stress, reduced pro-inflammatory markers except IL-1β, elevated anti-inflammatory marker, and elevated plasma VC levels

Brigatinib was recently approved for the treatment of anaplastic lymphoma kinase-positive non-small cell lung cancer and is dosed according to a one-dose-fits-all paradigm. We aimed to identify a pharmacokinetically-guided precision dosing strategy to improve treatment response with brigatinib through simulations using a previously published pharmacokinetic-pharmacodynamic model. Dosing strategies explored were the approved 180mg QD, the highest tolerable dose tested in clinical trials: 240mg QD, and two precision dosing strategies targeting the median trough concentrations following 180mg QD, and 240mg QD. We investigated the impact of alternative dosing regimens on progression-free survival (PFS), overall survival (OS), and the probability of developing a grade ≥2 rash or grade ≥2 amylase increase. Median PFS and OS increased by 1.6 and 7.8 months, respectively between the currently approved dosing strategy and precision dosing to the median trough concentration of the 240mg dosing strategy, with only a minor increase in the probability of developing toxicity.

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

“Pharmacovigilance is the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other medication-related problem”, according to the WHO. With the increasing volume of legislation, pharmacovigilance systems have shifted from reactive (responding to emerging risks), to planned, active, risk-proportionate approaches operating throughout the lifecycle of medicines. Whilst medicines are beneficial to society, adverse reactions represent a significant cause of concern. They are a major cause of failed regulatory authorizations, and withdrawal from the marketplace post-approval. Evaluation of real-world data plays an increasingly important role in pharmacovigilance. There is great interest on the part of the regulators, MAHs, academia and patients in optimizing the use of safety data. Innovative approaches, including pharmacogenetics and passive measures (sensors), will lead to increased complexity in data collation and evaluation, and inevitably to an increase in the volume of case reports. There is a multiplicity of regulations and guidelines on how to manage these data, with an inherent lack of harmonization. We summarize the current characterization of safety data types, sources, and the classification of these data. Using this benchmark, we discuss the future requirements of an effective pharmacovigilance ecosystem, keeping the principle of parsimony in mind.

Aim: Two recommendations for hemodialysis in lithium poisoning, one from the Extracorporeal TReatments in Poisoning (EXTRIP) workgroup and a single center retrospective one (Paris), differ. We compared outcomes in lithium poisoning based on these criteria with a primary outcome of worsening neurological symptoms in patients where EXTRIP and Paris criteria were discordant. Methods: Poison center data were queried for lithium poisoned patients for whom hemodialysis was either recommended or performed. Patients were categorized according to EXTRIP and Paris criteria and excluded if the peak lithium concentration was <1.2 mmol/L or if neurological follow-up was unavailable. Comparative analyses were only performed when both criteria could be assessed. Results: 219 patients were analyzed. Paris criteria were applied in 70 and EXTRIP criteria in 178. 42 patients were excluded because Paris criteria could not be applied. When Paris and EXTRIP both supported hemodialysis, 50/57 (88%) of patients who received hemodialysis improved, as did all 3 who did not receive hemodialysis. When Paris and EXTRIP opposed hemodialysis, all non-dialyzed patients did well. Among the 86 patients for whom EXTRIP supported hemodialysis but Paris did not, 4/19 (21%) patients not dialyzed deteriorated (p=0.02; OR=8.7, 95%CI=1.5-51.8), one of whom died. All 8 patients for whom Paris criteria supported hemodialysis but EXTRIP did not were dialyzed and improved. Conclusion: When the EXTRIP and Paris criteria are discordant, EXTRIP criteria outperforms the Paris criteria at identifying potentially ill patients who might benefit from hemodialysis.

Fomepizole is a promising new treatment for preventing liver injury following paracetamol (acetaminophen) overdose. However, we need robust clinical trials to be performed to demonstrate its effect on clinical outcomes that are important to our patients and important to healthcare providers. Until such trials are performed, the toxicology community should learn the lessons from the COVID pandemic – potential novel therapeutic options may be theoretically appealing, but their effectiveness needs to be assessed in robust clinical trials before they are used in clinical practice.

Aims Protein kinase inhibitors (PKI) have revolutionized the prognosis of several types of cancer, justifying the acceleration of their clinical evaluation before they obtain marketing authorization. Pharmacovigilance signals of heart failure (HF) following exposure to PKIs have been detected in recent years. Our objective was to identify the PKIs most frequently associated with the development of HF. Methods Using the French National Healthcare Database, all patients newly exposed to a PKI between January 2011 and June 2014 were followed up for 18 months. Specific hospitalisation diagnosis and long-term disease codes related to HF were used to identify HF patients. HF Incidence Rate Ratios (IRR) were measured and adjusted Hazard Ratios (aHR) were estimated using a Cox model. Results Thirteen PKIs were studied. Among the 49,714 new PKI users during the study period, the mean IRR of HF was 3.38 per 100 person-years, with a median time to onset of 155 days. We found a significant increase in the incidence of HF for 6 drugs: pazopanib (aHR= 2.42, 95% CI: 1.67-3.52), dasatinib (aHR= 2.22, 95% CI: 1.42-3.44), ruxolitinib (aHR= 2.11, 95% CI: 1.69-2.64), crizotinib (aHR= 1.71, 95% CI: 1.07-2.72), everolimus (aHR= 1.45, 95% CI: 1.26-1.67) and vemurafenib (aHR= 1.37, 95% CI: 1.01-1.86). Conclusions Our study provides knowledge on HF following exposure to a PKI. Additional studies could confirm these results for dasatinib, everolimus, pazopanib and ruxolitinib, and particularly for the two drugs with results slightly above the significance threshold, crizotinib and vemurafenib in our sensitivity analyses.

Cholinesterase inhibitors have been shown to improve cognitive functioning in patients with Alzheimer’s Disease (AD), but are associated with side effects and only 20-40% of the patients clinically improve. In this study, we aimed to investigate the acute pharmacodynamic (PD) effects of a single dose of galantamine on CNS functioning in mild to moderate AD patients and its potential to predict long-term treatment response. This study consisted of a challenge phase, in which a single dose of 16 mg galantamine was administered to 50 mild to moderate AD patients in a double-blind, placebo-controlled cross-over fashion. Acute PD effects were monitored with use of a CNS test battery. In the subsequent treatment phase of the study, patients were treated with open-label galantamine according to regular care. After 6 months of galantamine treatment, patients were categorized as either responder or as non-responder based on their MMSE, NPI and DAD scores. An analysis of covariance was performed to study the difference in acute PD effects between responders and non-responders. Acute decreases of absolute frontal alpha (-20.4; 95%CI=-31.6,-7.47; p=.0046), beta (-15.7; 95% CI=-28.3,-0.93; p=.0390) and theta (-25.9; 95%CI=-38.4,-10.9; p=.0024) EEG parameters and of relative frontal theta power (-3.27%; 95%CI=-5.96,-0.58; p=.0187) on EEG after a single dose administration of galantamine significantly distinguished long-term treatment responders (n=11) from non-responders (n=32) after 6 months. This study demonstrates that patients who demonstrate a reduction in EEG power in the alpha and theta frequency after a single administration of galantamine 16 mg will most likely respond to treatment.

X-linked adrenoleukodystrophy (X-ALD) is an inherited, neurodegenerative rare disease that can result in devastating symptoms of blindness, gait disturbances, and spastic quadriparesis due to progressive demyelination. Typically, the disease progresses rapidly, causing death within the first decade of life. With limited treatments available, efforts to determine an effective therapy that can alter disease progression or mitigate symptoms have been undertaken for many years, particularly through drug repurposing. Repurposing has generally been guided through clinical experience and small trials. At this time, none of the drug candidates have been approved for use, which may be due, in part, to the lack of pharmacokinetic/pharmacodynamic (PK/PD) information on the repurposed medications in the target patient population. Greater consideration for the disease pathophysiology, drug pharmacology, and potential drug-target interactions, specifically at the site of action, would improve drug repurposing and facilitate development. Although there is a good understanding of X-ALD pathophysiology, the absence of information on drug targets, pharmacokinetics, and pharmacodynamics hinders the repurposing of drugs for this condition. Incorporating advanced translational and clinical pharmacological approaches in preclinical studies and early stages clinical trials will improve the success of repurposed drugs for X-ALD as well as other rare diseases.

Drug disposition in children is impacted by developmental changes in drug absorption, distribution, metabolism and excretion. This mandates the need for dosing regimens specifically tailored to children. Yet, there are gaps in the knowledge on these developmental changes, for example regarding hepatic and renal drug transport and drug metabolism, putting children at risk for subtherapeutic or toxic drug exposure. Pediatric drug research is faced with ethical and analytical challenges. This review addresses how these knowledge gaps can be filled and challenges can be overcome by using innovative study designs.

The poly lactate co-glycolic acid (PLGA) nanoparticles of tubercular drugs have been demonstrated to have sustained release profile over seven days. There is no information on the location or mode of release of these nanoparticles in living system. Therefore, we have planned the study to explore the pharmacokinetics and biodistribution of PLGA rifampicin nanoparticles in healthy human volunteers. Rifampicin was labeled with 99mTc by indirect method and nanoparticles were prepared by a single emulsion evaporation method. To investigate the pharmacokinetics and biodistribution of nanoparticles, a single dose of 450 mg of rifampicin was administered orally to healthy human volunteers divided into two different groups. Following a single oral dosage of the rifampicin nanoformulation, the PK parameters were significantly different between the nanoparticle and conventional groups AUC (113.8 vs 58.6), MRT (16.2 vs 5.8) and Ke (0.04 vs 0.10). Also SPECT/CT images revealed bio-distrubution of nanoparticles in the distal portions of the intestine, which is consistent with our dosimetry analysis Significant difference in PK parameters and bio-distribution of nanoparticles in spleen and lymph nodes with maximum deposition were observed in large intestine. Nanoparticle distribution pattern may be advantageous for the treatment of intestinal or lymph node TB and has the potential to result in a lower dose of rifampicin nanoformulation for the treatment of pulmonary TB.

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

Aim: To conduct the first systematic synthesis of existing evidence reviews on interventions to enhance medication safety in RACS, to establish and compare their effectiveness. Method: This umbrella review included examination of meta-analyses, scoping and systematic reviews. Four electronic databases (MEDLINE, EMBASE, CINAHL, and The Cochrane library database of Systematic Reviews) were explored for eligible reviews. Those meeting the inclusion criteria were critically appraised using the JBI Critical Appraisal Instrument for Systematic reviews and Research Syntheses by two authors. Results: Fourteen reviews covering 166 unique, primary studies were included. Interventions were grouped according to type: medication review (n= 12); staff education (n= 8); multidisciplinary team meetings (n= 6); computerised clinical decision support systems (n= 5); and transferring medicines information between health care settings (n= 1). Most reviews showed mixed evidence to support interventions’ effectiveness, due to the significant heterogeneity between original research studies in respect to sites, samples sizes and intervention periods. However, in all intervention categories, pharmacists’ collaboration with other health care professionals was most beneficial, showing definitive evidence for improving medication safety and quality of prescribing in RACS. The evidence suggests that combining two or more interventions is the most promising approach, despite this presenting implementation barriers in the resource-limited environments of many RACS, and methodological challenges in identifying the precise contribution of individual interventions, when implemented concurrently. Conclusion: Health stakeholders should explore a combination of at least two interventions, such as medication review and staff education, to improve medication safety in RACS.

Re letter to British Journal of Clinical Pharmacology

A document by Thomas Svare Ehlers. Click on the document to view its contents.

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

Aims To evaluate the effect of severe chronic obstructive pulmonary disease (COPD) on drug metabolism by comparing the pharmacokinetics of patients with severe COPD with healthy volunteers and using the modified ‘Inje’ drug cocktail. Methods This was a single-centre pharmacokinetic study with 12 healthy participants and 7 participants with GOLD D COPD. Midazolam 1 mg, dextromethorphan 30 mg, losartan 25 mg, omeprazole 20 mg, caffeine 130 mg, and paracetamol 1000 mg were simultaneously administered and intensive pharmacokinetic sampling was conducted over 8 hours. Drug metabolism by CYP3A4, CYP2D6, CYP2C9, CYP2C19, CYP1A2, UGT1A6 and UGT1A9 in participants with COPD were compared with phenotypes in healthy controls. Results The oral clearance (95% CI) in participants with COPD relative to controls was: midazolam 63% (60-67%), dextromethorphan 72% (40-103%), losartan 53% (52-55%), omeprazole 35% (31-39%), caffeine 52% (50-53%), and paracetamol 73% (72-74%). There was a five-fold increase in AUC for omeprazole and approximately two-fold increases for caffeine, losartan, dextromethorphan, and midazolam. The AUC of paracetamol, which is mostly glucuronidated, was increased by about 60%. Conclusion Severe COPD is associated with a clinically significant reduction in drug clearance. This may be greater for cytochrome P450 substrates than for glucuronidated drugs. This supports reduced starting doses when prescribing for patients with severe COPD.