Model informed dosing of hydroxycholoroquine in COVID-19 patients: Learnings from the recent experience, remaining uncertainties and gaps.

AIMS: In the absence of a commonly agreed dosing protocol based on pharmacokinetic (PK) considerations, the dose and treatment duration for hydroxychloroquine (HCQ) in COVID-19 disease currently vary across national guidelines and clinical study protocols. We have used a model-based approach to explore the relative impact of alternative dosing regimens proposed in different dosing protocols for hydroxychloroquine in COVID-19. METHODS: We compared different PK exposures using Monte Carlo simulations based on a previously published population pharmacokinetic model in patients with rheumatoid arthritis, externally validated using both independent data in lupus erythematous patients and recent data in French COVID-19 patients. Clinical efficacy and safety information from COVID-19 patients treated with HCQ were used to contextualize and assess the actual clinical value of the model predictions. RESULTS: Literature and observed clinical data confirm the variability in clinical responses in COVID-19 when treated with the same fixed doses. Confounding factors were identified that should be taken into account for dose recommendation. For 80% of patients, doses higher than 800 mg day on day 1 followed by 600 mg daily on following days might not be needed for being cured. Limited adverse drug reactions have been reported so far for this dosing regimen, most often confounded by co-medications, comorbidities or underlying COVID-19 disease effects. CONCLUSION: Our results were clear, indicating the unmet need for characterization of target PK exposures to inform HCQ dosing optimization in COVID-19. Dosing optimization for HCQ in COVID-19 is still an unmet need. Efforts in this sense are a prerequisite for best benefit/risk balance.

Evaluation of compliance with isotretinoin PPP recommendations and exploration of reasons for non-compliance: Survey among French-speaking health care professionals and patients in Belgium.

PURPOSE: To evaluate awareness of and compliance in Belgium by French-speaking health care professionals and patients with the isotretinoin safety recommendations regarding its teratogenic risk. METHOD: Survey using online questionnaires, delivered from December 2014 to March 2015 for patients, pharmacists, dermatologists, and GPs and delivered again from September 2015 to October 2015 for GPs. RESULTS: Questionnaires were completed by 24 dermatologists, 24 GPs, 58 pharmacists, and 33 female patients. The pregnancy prevention programme was poorly known by health care professionals (23.6%) and patients (15.2%). Health care professionals informed women of childbearing age in depth about the teratogenic risk (98.3% of pharmacists and 100.0% of GPs and dermatologists) and the importance of an effective contraceptive method (87.9% and 100.0%, respectively). Patients were less informed about the pregnancy test (25.9% and 14.6%) and the need to use a second contraceptive method (29.3% and 27.1%). The low compliance with the last 2 recommendations was due to a lack of adoption by health care professionals regarding the need for these recommendations if female patients have an effective contraceptive method and the pregnancy risk is discussed in detail with them. CONCLUSION: The effectiveness of the pregnancy prevention programme recommendations should be reconsidered by an expert committee. Justifications should be added to effective recommendations to increase their adoption by health care professionals and patients.

Use of paracetamol during pregnancy and child neurological development.

Paracetamol (acetaminophen) remains the first line for the treatment of pain and fever in pregnancy. Recently published epidemiological studies suggested a possible association between paracetamol exposure in utero and attention-deficit-hyperactivity disorder/hyperkinetic disorder (ADHD/HKD) or adverse development issues in children. However, the effects observed are in the weak to moderate range, and limitations in the studies' design prevent inference on a causal association with ADHD/HKD or child neurological development. In parallel, recent animal data showed that cognition and behaviour may be altered following exposure to therapeutic doses of paracetamol during early development. These effects may be mediated by interference of paracetamol with brain-derived neurotrophic factor, neurotransmitter systems (including serotonergic, dopaminergic, adrenergic, as well as the endogenous endocannabinoid systems), or cyclooxygenase-2. However, no firm conclusion can be made on the relevance of these observations to humans. We conclude that additional well-designed cohort studies are necessary to confirm or disprove the association. In the context of current knowledge, paracetamol is still to be considered safe in pregnancy and should remain the first-line treatment for pain and fever.

Challenges in Assessing COVID-19 Vaccines Safety Signals-The Case of ChAdOx1 nCoV-19 Vaccine and Corneal Graft Rejection.

The rapid and large-scale roll-out of new COVID-19 vaccines has led to unprecedented challenges in assessing vaccine safety. In 2021, the European Medicines Agency (EMA) processed about 1.7 million safety reports related to COVID-19 vaccines in the EudraVigilance (EV) database and identified more than 900 potential signals. Beyond the large amount of information to be processed, the evaluation of safety signals has faced several difficulties and limitations, both in the assessment of case reports and in the investigation of databases. The evaluation of a signal of corneal graft rejection (CGR) with Vaxzevria® was no exception to this. In this commentary, we present the challenges encountered in making regulatory decisions in the context of evolving evidence and knowledge. The pandemic crisis emphasised the importance of quick and proactive communication to address the many questions and, above all, to ensure the transparency of safety data.

Herb-anticancer drug interactions in real life based on VigiBase, the WHO global database.

Cancer patients could combine herbal treatments with their chemotherapy. We consulted VigiBase, a WHO database of individual case safety reports (ICSRs) which archives reports of suspected Adverse Drug Reactions (ADRs) when herbal products are used in conjunction with anti-cancer treatment. We focused on the possible interactions between antineoplastic (L01 ATC class) or hormone antagonists (L02B ATC class) with 10 commonly used herbs (pineapple, green tea, cannabis, black cohosh, turmeric, echinacea, St John's wort, milk thistle and ginger) to compare ADRs described in ICSRs with the literature. A total of 1057 ICSRs were extracted from the database but only 134 were complete enough (or did not concern too many therapeutic lines) to keep them for analysis. Finally, 51 rationalizable ICSRs could be explained, which led us to propose a pharmacokinetic or pharmacodynamic interaction mechanism. Reports concerned more frequently women and half of the rationalizable ICSRs involved Viscum album and Silybum marianum. 5% of the ADRs described could have been avoided if clinicians had had access to the published information. It is also important to note that in 8% of the cases, the ADRs observed were life threatening. Phytovigilance should thus be considered more by health care professionals to best treat cancer patients and for better integrative care.

Use and misuse of prescription stimulants by university students: a cross-sectional survey in the french-speaking community of Belgium, 2018.

BACKGROUND: Misuse of prescription stimulants (PS) has been reported among students to enhance academic performance in Flanders (Belgium). However, PS misuse among students in the French-speaking community is unknown. The main purpose of the study was to estimate the prevalence of medical use and misuse of PS by university students in the French-speaking community (Belgium), and to investigate the reasons and sources associated with PS misuse. METHODS: A cross-sectional online survey was performed in 2018. All university students 18 years and older were invited to participate and asked about PS use, including medical (i.e., used for therapeutic purposes) and nonmedical reasons and sources of PS. RESULTS: In total, 12 144 students participated in the survey (median age = 21 years, 65.5% female). The estimated prevalence of PS use was 6.9% (ever use) and 5.5% (past-year). Among ever users, 34.7% were classified as medical users and 65.3% as misusers. Lifetime prevalence of misuse was estimated at 4.5%. The most common reason for medical use was treatment of attention disorder (85.9%). Reasons for misuse were mainly to improve concentration (76.1%) or to stay awake and study longer (50.7%). Friends or acquaintances inside the student community and general practitioners were the main sources of PS for misuse (41.5% and 23.5%, respectively). CONCLUSIONS: This study found that rates of misuse of PS in French-speaking universities in Belgium were in line with studies conducted in Flanders and Europe. Academic institutions can use these results to tailor their drug prevention campaigns.

Population Pharmacokinetics of Hydroxychloroquine in COVID-19 Patients: Implications for Dose Optimization.

BACKGROUND AND OBJECTIVE: In the absence of characterization on pharmacokinetics and reference concentrations for hydroxychloroquine in COVID-19 patients, the dose and treatment duration for hydrochloroquine are currently empirical, mainly based on in vitro data, and may vary across national guidelines and clinical study protocols. The aim of this paper is to describe the pharmacokinetics of hydroxychloroquine in COVID-19 patients, considered to be a key step toward its dosing optimization. METHODS: We have developed a population pharmacokinetic model for hydroxychloroquine in COVID-19 patients using prospectively collected pharmacokinetic data from patients either enrolled in a clinical trial or treated with hydroxychloroquine as part of standard of care in two tertiary Belgian hospitals. RESULTS: The final population pharmacokinetic model was a one-compartment model with first-order absorption and elimination. The estimated parameter values were 9.3/h, 860.8 L, and 15.7 L/h for the absorption rate constant, the central compartment volume, and the clearance, respectively. The bioavailability factor was fixed to 0.74 based on previously published models. Model validations by bootstraps, prediction corrected visual predictive checks, and normalized prediction distribution errors gave satisfactory results. Simulations were performed to compare the exposure obtained with alternative dosing regimens. CONCLUSION: The developed models provide useful insight for the dosing optimization of hydroxychloroquine in COVID-19 patients. The present results should be used in conjunction with exposure-efficacy and exposure-safety data to inform optimal dosing of hydroxychloroquine in COVID-19.

Development and in vitro evaluation of a novel floating multiple unit dosage form obtained by melt pelletization.

The feasibility of preparing floating pellets by melt pelletization was investigated. The pellets were prepared in a high shear mixer. Formulations were based on a mixture of Compritol and Precirol as lipidic binders and on sodium bicarbonate as a gas-generating agent. The floating ability of the pellets was evaluated in vitro. Good floating capabilities were obtained for formulations containing the gas-generating agent in both the inner matrix and the outer coating layer of the pellets. As an example, a placebo formulation containing 50% lactose 450 Me, 22% Compritol, 15% Precirol, 8% sodium bicarbonate and 5% Methocel K100 (w/w) in the inner matrix, and 66% Precirol and 34% sodium bicarbonate (w/w) as a coating effervescent layer, showed very good floating capabilities. The percentage of floating placebo pellets was around 80% after 1 h and still above 75% for 23 h. Floating pellet formulations with high drug content, based on the use of tetracycline hydrochloride and theophylline were also evaluated. They showed a comparable floating ability to placebo formulations, combined with sustained release properties thanks to the lipophilic character of the binders used.

Physical and thermal characterisation of Precirol and Compritol as lipophilic glycerides used for the preparation of controlled-release matrix pellets.

Physical and thermal properties of Compritol and Precirol as potential lipophilic binders in melt pelletisation process for the preparation of sustained-release matrix pellets were evaluated in this study. Experimental measurements were carried out using X-ray diffractometry, differential scanning calorimetry (DSC), hot-stage microscopy (HSM) and rheological measurements. These studies have shown that the lipophilic binders may present a relatively complex behaviour depending on the sample treatment (untreated, freshly solidified, aged samples). DSC and HSM methods have shown the presence of polymorphism for Precirol. Moreover, both untreated and fresh solidified Precirol and Compritol samples present partially amorphous layered structure which slowly crystallise in time. The rate of crystallisation was found to be more rapid for Precirol, and highly dependent on the ageing conditions (storage temperature). Finally, the evaluation of the thermal and rheological properties of Precirol and Compritol mixtures have shown that the use of such mixtures, presenting well distinct melting properties, could be a very interesting tool for the preparation of high fatty binder content prolonged-release pellets in high shear mixers if the product temperature is carefully controlled (between 45 and 50 degrees C) during the pelletisation process.

Development and evaluation of prolonged release pellets obtained by the melt pelletization process.

This study was performed in order to evaluate the possibility of obtaining prolonged release matrix pellets by a melt pelletization process in a laboratory high shear mixer (Mi-Pro, Pro-C-epT). Phenylephrine hydrochloride pellet formulations based on lactose 450 mesh and a mixture of Compritol 888 and Precirol ATO 5 as melting binders were evaluated. The fatty binder content of pellets was substantially increased (from 18 to 80% w/w). The effects of jacket temperature, massing time (MT) and impeller speed (IS) on the pellet characteristics were investigated. It was shown that pellets of narrow size distribution can be produced by using an IS of 800 rpm, a chopper speed of 4000 rpm and a MT of 8 min. On the other hand, the applicability of this technique for the production of sustained-release pellets using ciprofloxacin hydrochloride, ketoprofen and theophylline as less water soluble model drugs than phenylephrine hydrochloride was also studied. This study demonstrated that formulations based on an appropriate mixture of Precirol and Compritol can be used to produce in a short time prolonged release pellets for very hydrosoluble drugs like phenylephrine hydrochloride as well as for the other drugs tested.