British journal of clinical pharmacology最新文献

Severe valproic acid (VPA) overdose is characterized by coma (sometimes with cerebral oedema), respiratory depression, hypotension and metabolic abnormalities. Traditional management of VPA poisoning has been limited to gastrointestinal decontamination, L-carnitine supplementation and, in severe cases, haemodialysis. Recently, interest has developed in the use of carbapenem antibiotics as an adjunctive therapy in patients with severe VPA poisoning. Carbapenems inhibit acylpeptide hydrolase, the enzyme responsible for reconstituting VPA from VPA-glucuronide, and transiently promote distribution of VPA into erythrocytes. In patients receiving VPA therapeutically, carbapenems lower VPA concentrations abruptly, dramatically, and for a sustained period. This article discusses the possibility of exploiting this pharmacokinetic drug–drug interaction in patients with or at risk of severe VPA poisoning.

Aims: Research on hydroxychloroquine (HCQ) for children with chronic immune thrombocytopenia (ITP) is limited. The association between antinuclear antibody (ANA) positivity and its efficacy remains unclear.

Methods: This retrospective cohort study compared the clinical characteristics of children with chronic ITP who received HCQ with those who did not, as well as patients who responded to HCQ at 3 months with those who did not. Mixed-effects models were performed to assess the effect of HCQ on platelet counts and the association between ANA and its efficacy. Records of HCQ-related side effects were reviewed.

Results: A total of 191 children with chronic ITP were included in this study, including 42 patients who received HCQ. At the last follow-up, 69.0% of patients treated with HCQ achieved complete response or response, with a median follow-up time of 56 months (range: 17-146 months), a higher frequency compared to 48.3% of patients who were not treated with HCQ (odds ratio [OR], 2.39; 95% confidence interval [CI], 1.15-4.95). The overall response rates to HCQ were 56.8% (21/37) at 3 months and 40.5% (15/37) at 1 year. HCQ was effective for increasing platelet counts (mean difference: 23.82 × 10⁹/L; 95% CI: 7.44-40.21), but the association between ANA positivity and its efficacy was not found. Side effects were recorded in six patients (14.3%).

Conclusions: HCQ was associated with increased platelet counts in chronic ITP children. The baseline ANA level was not found to be associated with the efficacy of HCQ. Side effects of HCQ warrant consideration.

Aims: In Europe, the European Medicines Agency (EMA) has an accelerated pathway to prioritize approval of medicines. Approved drugs are then assessed by Health Technology Assessment (HTA) bodies before being made available to patients. The aim of the study was to evaluate the characteristics of the drugs admitted to the EMA accelerated assessment (AA) and scrutinize the downstream HTA procedures regarding these medicines and the final assessment regarding added therapeutic value (ATV).

Methods: Regulatory publicly available documents were scrutinized for all medicines authorized by the EMA between 2019 and 2021 to create a regulatory database. A second database was created by extracting data of the medicines that had requested the EMA accelerated pathway from three national HTA bodies (AIFA, HAS and G-BA).

Results: Standard assessments by the EMA had a median of 364 days while AAs were significantly shorter (189 days). Only 12 out of 164 authorized medicines were assessed in this manner. Small chemical entities had a significantly lower chance of being assessed under the AA, while biological and PRIME scheme medicines had a higher chance; AA had a higher chance of leading to authorizations under exceptional circumstances. These 12 products were assessed more quickly compared to other products by HTA bodies, although this did not always lead to decisions of major ATV over alternatives.

Conclusions: A minority of medicinal products are assessed under the accelerated pathway. HTA bodies also assess these products more quickly, but do not always perceive an important clinical advantage over alternatives.

Early approval mechanisms, such as conditional approval in the EU, have been used extensively to provide timely access to therapeutic innovations to cancer patients with unmet medical needs.

While based on promising early evidence, such approvals are challenging from many perspectives due to the lack of comprehensive data. The limitation typically relates to data that demonstrates clinical benefit via early endpoints and is only acceptable when the early evidence is particularly convincing to assume that the benefits of early access are greater than the potential harms.

This paper describes the requirements for conditional approval and presents common pitfalls in oncology, such as misunderstandings about the strength of evidence from exploratory trials and secondary analyses, lack of planning and opportunities to improve communication. Thereafter, we present a framework (‘EDGE’) on how to improve the submission and evaluation of drug applications for conditional approval in the EU.

Aims: Residual neuromuscular blockade (RNB) commonly occurs when using neuromuscular blockers and increases the risk for pulmonary complications, such as airway obstruction and severe hypoxemia, in extubated patients. Rocuronium exhibits a high variability in recovery time, contributing to an increased risk for RNB. This study aimed to identify and characterize the sources of variability in rocuronium exposure and response via a population pharmacokinetic/pharmacodynamic (PK/PD) analysis and to apply the developed PK/PD model to investigate clinical implications.

Methods: A nonlinear mixed-effect model was developed for rocuronium in patients undergoing general anaesthesia, using doses of 0.3-1.2 mg/kg. Plasma concentrations and the neuromuscular block (train of four ratio) were assessed up to 6 h after dosing. The influence of age, body mass index, renal function and sex on PK and PD was explored. Simulations were performed to predict the recovery time.

Results: A two-compartment model with linear elimination and an indirect sigmoid I-max model was used to describe PK and PD. The transfer rate into the periphery increases with age. The predicted recovery time was significantly longer in older subjects aged 85 years (median: 2.8 h; interquartile range [IQR]: 2.18-4.0) compared to young adults aged 25 years (median: 2.5 h; IQR: 2.0-3.1) following single bolus administrations of doses ≥ 0.7 mg/kg.

Conclusions: Our findings suggest that older patients take slightly longer to recover than younger adults due to an age-dependent increase in tissue uptake. However, a priori dose adjustments for rocuronium in older patients are not feasible, since age contribution is overshadowed by the overall variability in the recovery time.

Symmetrical drug-related intertriginous and flexural exanthema (SDRIFE) is a rare, symmetrical skin eruption triggered by various medications, predominantly beta-lactam antibiotics. We report the case of a 69-year-old male with moderate-to-severe ulcerative colitis who developed SDRIFE following the seventh intravenous administration of infliximab. The patient presented with symmetrical, pruritic erythema in the cubital and popliteal fossae, groins, gluteal and retroauricular regions without systemic involvement. Skin biopsy showed mild exocytosis of T lymphocytes in the epidermis and dense superficial perivascular CD3+ and CD4+ infiltration, consistent with a type IVa hypersensitivity reaction. The patient responded well to a regimen of systemic antihistamines, topical corticosteroids and tacrolimus ointment, with complete regression of lesions within one week. Despite mild recurrences of SDRIFE after each infliximab administration, the therapy was not discontinued due to the mild nature of the reaction and favourable prognosis. The authors are not aware of previously published cases of type IVa SDRIFE induced by infliximab. Unlike previous reports of severe type IVc SDRIFE reactions requiring discontinuation of infliximab, our case highlights the predominance of CD4+ cells, which may explain the mild clinical course. Understanding the underlying immunologic mechanisms of infliximab-induced SDRIFE could affect treatment decisions and prevent unnecessary discontinuation of effective therapies.

We thank Lindeman et al.¹ for their response to our review on the management of serotonin toxicity and providing their opinion on the potential role of olanzapine as an antidote. We wish to clarify that our position is not one of pessimism but rather an emphasis on the critical importance of early resuscitative and supportive care as the cornerstone of management of severe serotonin toxicity, and the requirement for a clinically evidence-based approach to the use of antidotes.²

The pharmacodynamic arguments presented for olanzapine's receptor-binding properties are of interest but without robust clinical evidence beyond anecdotal reports, only provide the basis for clinical studies. While receptor occupancy studies of olanzapine suggest binding and high occupancy at 5-HT2 receptors, this is not evidence that it will decrease high concentrations of serotonin in the central nervous system or decrease the resultant clinical effects. Further, the study by Kapur et al. only examined 17 people receiving varying doses of olanzapine (5–60 mg/day) after treatment for at least 5 days,³ which cannot be translated to the single administration of olanzapine to treat serotonin toxicity. In fact, the data presented in your table would suggest that risperidone is a better agent.

Before an antidote is recommended, it is essential to assess the risk of adverse effects, compared to supportive care alone. A major drawback with chlorpromazine is the high risk of hypotension, particularly in a critically unwell patient with severe serotonin toxicity requiring intubation. A similar risk assessment would be required for olanzapine in serotonin toxicity. Numerous studies have demonstrated that olanzapine is often associated with anticholinergic effects and delirium.⁴

With the limited clinical reports of olanzapine use in serotonin toxicity, we encourage the authors to publish their experience. Interestingly, a study in overdose patients demonstrated that olanzapine and risperidone co-ingestion with a serotonergic agent reduced the risk of serotonin toxicity, with the lowest risk observed with risperidone.⁵ Even better would be to undertake a controlled trial of olanzapine versus placebo in serotonin toxicity to avoid the low-level evidence available for other antidotes. Until more evidence is available, we maintain that early recognition, withdrawal of serotonergic agents, and effective resuscitative and supportive measures remain the foundation of serotonin toxicity management.

Sincerely,

The authors have no conflicts of interest to declare.

Aims: The aim of this study was to compare the final approval decision and time from submission to final decision for new drug applications and applications for extension of indications to the EMA and the FDA within cancer drugs.

Methods: We performed a retrospective analysis on antineoplastic drug applications with a final decision in both the EMA and the FDA from January 1, 2018, to December 31, 2022. For each included drug application, we collected data from the EMA website and the Drugs@FDA database.

Results: A total of 48 new drug applications and 94 applications for extension were included. Agreement in the final decision between the EMA and the FDA was found in 94% of new drug applications and 96% of applications for extension. For new drug applications, the time from submission to approval in the EMA and the FDA were median (interquartile range, IQR) 424 (394-481) days and 216 (169-243) days, respectively. For extensions, the median time from submission to approval in the EMA and the FDA were 295 (245-348) days and 176 (140-183) days, respectively.

Conclusions: We found a high agreement in final approval decisions for cancer drug applications between the EMA and the FDA both for new drug applications and applications for extension. The time from submission to the final decision was markedly shorter in the FDA than in the EMA, albeit the difference was smaller for extensions than for new drug applications. The results indicate that the longer time from submission to decision in the EMA than in the FDA has limited influence on the final approval decisions.