A document by Christopher Threapleton. Click on the document to view its contents.

Aim: The risk-benefit profile of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) in coronavirus disease 2019 (Covid-19) is still a matter of debate. With growing evidence on the protective effect of this group of commonly used antihypertensives in Covid-19, we aimed to thoroughly investigate the association between the use of major classes of antihypertensive medications and Covid-19 outcomes in comparison with the use of ACEIs and ARBs. Methods: We conducted a population-based study in patients with pre-existing hypertension in the UK Biobank. Multivariable logistic regression analysis was performed adjusting for a wide range of confounders. Results: The use of either beta-blockers (BBs), calcium-channel blockers (CCBs), or diuretics was associated with a higher risk of Covid-19 hospitalization compared to ACEI use (adjusted OR, 1.63; 95% CI, 1.40 to 1.90) and ARB use (adjusted OR, 1.50; 95% CI, 1.27 to 1.77). The risk of 28-day mortality among Covid-19 patients was also increased among users of BBs, CCBs or diuretics when compared to ACEI users (adjusted OR, 1.64; 95% CI, 1.23 to 2.19) but not when compared to ARB users (adjusted OR, 1.18; 95% CI, 0.87 to 1.59). However, no associations were observed when the same analysis was conducted among hospitalized Covid-19 patients only. Conclusion: Our results suggest protective effects of blocking of the renin-angiotensin-aldosterone system on Covid-19 hospitalization and mortality among patients with pharmaceutically treated hypertension, which should be addressed by randomized controlled trials. If confirmed, this finding could have high clinical relevance for treating hypertension during the SARS-CoV-2 pandemic.

There is paucity of evidence to support clinical decision making and counseling related to medication use in pregnancy. Despite multiple efforts from legislative bodies and advocacy groups, the inclusion of pregnant women in clinical drug trials assessing efficacy and safety remains scarce. Pregnancy can be complicated by multiple co-morbidities that require pharmacological intervention; these interventions primarily target the pregnant women but also sometimes have secondary effects for the fetus. The U.S. Food and Drug Administration has issued multiple guidance documents on incorporating pregnant women in clinical trials to aid pharmaceutical companies in designing a protocol to ensure safety and adherence to ethical standards. Advances in pediatric pharmacology studies provide lessons for researchers on the best practice of designing clinical trials with inclusion of patients from special populations. In this review, we present the status of pregnant women in clinical trials, highlighting the ethical stigma and possible future directives.

AIM Ropeginterferon alfa-2b is a new site-specific conjugated 40 kDa branched polyethylene-glycol recombinant interferon (IFN). The aim of the study was to determine its safety, pharmacokinetics (PK) and pharmacodynamic (PD). METHODS Ropeginterferon alfa-2b was evaluated first in human in 48 healthy male volunteers after a single dose subcutaneous injection by either 24, 48, 90, 180, 225, 270mcg of the product or 180mcg of marketed pegylated (peg)-IFN alfa-2a. Within each dosing group, 6 subjects received ropeginterferon alfa-2b and 2 subjects received peg-IFN alfa-2a. RESULTS Dose-related increases in ropeginterferon alfa-2b PK parameters (Cmax, AUC, and AUC0-t) were observed over the dose range 24 to 270mcg. The geometric mean values for these PK parameters of ropeginterferon alfa-2b were higher than that of peg-IFN alfa-2a at the 180mcg dose level of 176%, 166%, and 182%, respectively. Mean PD parameters (Emax, Tmax, and AUC0-t) for ropeginterferon alfa-2b increased with dose for both biomarkers neopterin and 2’, 5’-OAS. Ropeginterferon alfa-2b has similar PD profiles as peg-IFN alfa-2a. The treatment related adverse events are similar between the two study drugs, but the overall incidence was numerically lower for ropeginterferon alfa-2b (83%) than peg-IFN alfa-2a (100%) at the 180mcg dose level. CONCLUSIONS Single subcutaneous dose of Ropeginterferon alfa-2b of up to 270mcg is safe and well tolerated. It displays dose related increase in PK and PD parameters, potentially less frequent injection, and better safety profiles. Ropeginterferon alfa-2b is being developed for diseases in which previous peg-IFN use has been limited by side effects.

Background: For diseases with a genetic cause genomics can deliver improved diagnostics and facilitate access to targeted treatments. Drug pharmacodynamics and pharmacokinetics are often dependent on genetic variation underlying these processes. As pharmacogenomics comes of age it may be the first way in which genomics is utilised at a population level. Still required is guidance and standards of how genomic information can be communicated within the health record, and how clinicians should be alerted to variation impacting the use of medicines. Methods: The Professional Record Standards Body commissioned by National Health Service England developed guidance on using pharmacogenomics information in clinical practice. We conducted research with those implementing pharmacogenomics in England and internationally to produce guidance and recommendations for a systems-based approach. Results: A consensus viewpoint is that systems need to be in place to ensure the safe provision of pharmacogenomics information that is curated, actionable and up-to-date. Standards should be established with respect to notification and information exchange, which could impact new or existing prescribing and these must be in keeping with routine practice. Alerting systems should contribute to safer practices. Conclusion: Ensuring pharmacogenetics information is available to make use of medicines safer will require major effort of which this guidance is a beginning. Standards are required to ensure useful genomic information within the health record can be communicated to clinicians in the right format and times to be actioned successfully. A multidisciplinary group of stakeholders must be engaged in developing pharmacogenomic standards to support the most appropriate prescribing.

Aims Theophylline clearance in patients with chronic liver diseases (CLDs), chronic hepatitis (CH) and liver cirrhosis (LC), was evaluated by population pharmacokinetic (PPK) analysis. Methods PPK analysis included 433 minimum steady-state concentrations from 192 Japanese bronchial asthma patients and was performed using NONMEM. The severity of LC was assessed by the Child-Pugh (CP) class and model for end-stage liver disease (MELD) score. Results Two final models (CP and MELD models) were obtained, and described apparent theophylline clearance (CL/F) as follows: CP model: CL/F=0.0473×0.874CH×0.697CPA×0.592CPB×0.441CPC, MELD model: CL/F=0.0472×0.876CH×0.687MELD < 10×0.568MELD 10-14×0.487MELD 15-19×0.417MELD 20-24×0.328MELD ≥ 25. The CP model showed that mean CL/F in patients without CLDs, and with CH, and LC with CP class A, B, and C was 0.0473, 0.0413, 0.0330, 0.0280, and 0.0209 L/h kg-1, respectively. The MELD model predicted that CL/F in patients without CLDs, and with CH, and LC with a MELD score of < 10, 10-14, 15-19, 20-24, and ≥ 25 was 0.0472, 0.0413, 0.0324, 0.0268, 0.0230, 0.0197, and 0.0155 L/h kg-1, respectively. Conclusions CL/F in various stages of LC was evaluated and a change in CL/F was highly dependent on the severity of CLDs in both models. The MELD model classified LC into 5 categories, and subdivided CP class C patients into 3 further categories. The MELD model provided a more accurate and precise description of CL/F than the CP model, particularly in high-severity LC patients.

Aspirin has known effects beyond inhibiting platelet cyclooxygenase-1 (COX1) that have been incompletely characterized. Transcriptomics can comprehensively characterize the on- and off-target effects of medications. We used a systems pharmacogenomics approach of aspirin exposure in volunteers coupled with serial platelet function and purified platelet mRNA sequencing to test the hypothesis that aspirin’s effects on the platelet transcriptome are associated with platelet function. We prospectively recruited 74 adult volunteers for a randomized cross over study of 81- vs. 325 mg/day, each for 4 weeks. Using mRNA sequencing of purified platelets collected before and after each 4-week exposure, we identified 208 aspirin-responsive genes with no evidence for dosage effects. In independent cohorts of healthy volunteers and patients with diabetes we validated aspirin’s effects on five genes: EIF2S3, CHRNB1, EPAS1, SLC9A3R2, and HLA-DRA. Functional characterization of the effects of aspirin on mRNA as well as platelet ribosomal RNA demonstrated that aspirin may act as an inhibitor of protein synthesis. Database searches for small molecules that mimicked the effects of aspirin on platelet gene expression in vitro identified aspirin but no other molecules that share aspirin’s known mechanisms of action. The effects of aspirin on platelet mRNA were correlated with higher levels of platelet function both at baseline and after aspirin exposure – an effect that counteracts aspirin’s known antiplatelet effect. In summary, this work collectively demonstrates a dose-independent effect of aspirin on the platelet transcriptome that counteracts the well-known antiplatelet effects of aspirin.

Paracetamol poisoning continues to be a worldwide problem and despite the availability of an affective antidote, N-acetylcysteine (NAC), the optimal way to use this antidote, particularly following very large doses of paracetamol, has not been established. Recent case series have shown an increased toxicity from paracetamol, even in those receiving prompt NAC therapy, at high doses of paracetamol, particularly in patients above the 300 mg/L nomogram treatment line. Clinical trial evidence supporting shorter NAC dosing now allows the possibility for intensifying treatment without the risk of very high rates of ADRs. New biomarkers also show the possibility of early identification of patients at risk of liver injury who might also benefit from increased intensity treatment. This article discusses these data and proposes a logical therapy for increasing NAC dosing which now requires clinical trial testing.

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.

Introduction: Free-of-charge (FoC) medicine schemes are increasingly available and allow access to investigational treatments outside clinical trials or in advance of licensing or NHS commissioning. Methods: We retrospectively reviewed FoC medicine schemes evaluated between 2013 and 2019 by a single NHS trust and a regional drug and therapeutics committee (DTC). The details of each locally reviewed FoC scheme, and any nationally available MHRA Early Access to Medicines Scheme (MHRA EAMS) in the same period, were recorded and categorised. Results: Most FoC schemes (95%) allowed access to medicines intended to address an unmet clinical need. Over 7 years, 90% were company-FoC schemes and 10% were MHRA EAMS that were locally reviewed. Phase 3 clinical trial data were available for 44% of FoC schemes; 37% had phase 2 data; and 19% were supported only by phase 1, retrospective observational studies, or pre-clinical data. Utilisation of company-FoC schemes increased on average by 50% per year, while MHRA EAMS showed little growth. Conclusion: Company-FoC medicine schemes are increasingly common. This may indicate a preference for pharmaceutical companies to independently co-ordinate schemes. Motivations for company-FoC schemes remain unclear and many provide access to treatments that are yet to be evaluated in appropriately conducted clinical trials, and whose efficacy and risk of harm remain uncertain. There is no standardisation of this practice and there is no regulatory oversight. Moreover, no standardised data collection framework is in place that could demonstrate the utility of such programmes in addressing unmet clinical need or allow generation of further evidence.

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.

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.

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.

Aim: Metamizole (dipyrone) is a prodrug not detectable in serum or urine after oral ingestion. The primary metabolite is 4-methylaminoantipyrine (4-MAA), which can be N-demethylated to 4-aminoantipyrine (4-AA) or oxidized to 4-formylaminoantipyrine (4-FAA) by cytochrome P450 (CYP)-dependent reactions. Our aim was to identify the CYPs involved. Methods: We investigated the metabolism of 4-MAA in vitro using CYP expressing supersomes and the pharmacokinetics of metamizole in the presence of CYP inhibitors in healthy volunteers. Results: The experiments in supersomes revealed CYP1A2 as the major CYP for 4-MAA N-demethylation and 4-FAA formation. CYP2C19 and CYP2D6 contributed to N-demethylation but not to FAA formation. In the subsequent clinical study, we investigated the influence of ciprofloxacin (strong CYP1A2 inhibitor), fluconazole (strong CYP2C19 inhibitor) and the combination ciprofloxacin/fluconazole on the pharmacokinetics of a single dose of metamizole in n=12 healthy volunteers in a randomized, placebo-controlled, double-blind study. Both ciprofloxacin and fluconazole inhibited the metabolism of 4-MAA, confirming the in vitro results. Ciprofloxacin, fluconazole and ciprofloxacin/fluconazole increased the AUC0-12h of 4-MAA by 51%, 17% and 92%, respectively. Ciprofloxacin, fluconazole and ciprofloxacin/fluconazole decreased the AUC0-12h of 4-AA by 27%, 12% and 24%, respectively, and of 4-FAA by 33%, 9% and 51%, respectively. Ciprofloxacin, fluconazole and ciprofloxacin/fluconazole increased the half-life of 4-MAA from 3.22 h (placebo) to 3.91, 3.69 and 6.07 h, respectively. Conclusion: CYP1A2 is the major CYP for the conversion of 4-MAA to 4-AA and 4-FAA. CYP1A2 inhibition increases the 4-MAA exposure by a factor of approximately 1.5, which could be relevant for dose-dependent adverse reactions.

Aim To describe the antiepileptic drug (AED) prescription pattern in pregnant women and women of childbearing age in the 2010-2019 period in the Lombardy region, Italy. Methods The Lombardy region administrative healthcare databases (2010-2019) were analysed. AEDs were classified as drugs belonging to the N03A subgroup of the Anatomical Therapeutic Chemical Classification System. Women 15-49 years old were considered as women of childbearing age, while exposure during pregnancy was estimated taking into account the 12 months before delivery (International Classification of Diseases, Ninth Revision, Clinical Modification, ICD-9-CM codes in the diagnosis record from 650 to 659). Results During 2019, 16,605 women of childbearing age (prevalence: 14.8‰) received at least one AED prescription. Pregabalin was the most widely used antiepileptic in women of childbearing age (22.3%), followed by valproic acid (20.0%). The prevalence of AED prescription in pregnant women was 3.8‰, and levetiracetam and lamotrigine (16.6%) were the most commonly prescribed drugs. The prevalence of AED prescription did not change from 2010 to 2019 in women of childbearing age or in pregnant women. Valproic acid was one of the most used AEDs in pregnancy until 2016, after which its prescription declined from 19% to 14% of AED users. Conclusions Despite the decrease in valproic acid prescription over time, this drug is still among the most used AEDs, in particular in women of childbearing age. Educational interventions for healthcare professionals and women are needed in order to reduce the risk of unplanned pregnancy.

Favipiravir is one of the repurposed antiviral medications for the treatment of SARS-CoV-2 infection. Since the dosing regimen is a prominent factor for the success of the antiviral therapy, this prospective observational study aimed to characterize the pharmacokinetic characteristics of favipiravir in COVID-19 patients. Adult patients (n=21) hospitalized for mild to moderate COVID-19 with a positive RT-PCR test, and assigned for favipiravir treatment were included. Favipiravir was administered for 5 days, with a loading dose of 3200 mg and a 1200 mg/day maintenance dose. Serial blood samples were collected on Day-2 and Day-4 of the therapy. Laboratory findings of the patients and in-hospital mortality were assessed. Favipiravir concentrations exhibited high variations and a significant decrease during the treatment of COVID-19. The median favipiravir trough concentration (C0-trough) on Day-2 was 21.26 µg/mL whereas it decreased significantly to 1.61 µg/mL on Day-4, the area under the concentration versus time curve decreased from 345.6 µg.h/mL to 108.6 µg.h/mL, respectively. Gender seems significant to affect favipiravir concentrations. Day-2-C0-trough of female patients was significantly higher than male patients. Of the 5 patients that died, 4 were male with a significant increase in ferritin levels from Day-0 to Day-5 compared to surviving patients. In addition, there was a significant decrease in D-dimer and CRP levels in the surviving patients. Our findings indicate that favipiravir concentrations show significant changes during the treatment of COVID-19. Therapeutic drug monitoring may best guide dose adjustments in patients that do not respond to treatment with favipiravir.

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.

A case of acute necrotising pancreatitis following the second dose of Pfizer-BioNTech COVID-19 mRNA vaccineAs of 22 June 2021, there have been about 400,000,000 doses of the Pfizer-BioNTech COVID-19 mRNA vaccine administered world-wide. At this time, 176 cases of pancreatitis have been reported in pharmacovigilance reports submitted to the WHO.1 No epidemiological link between the Pfizer-BioNTech COVID-19 mRNA vaccine and pancreatitis has been reported. We report a case of acute necrotising pancreatitis following the second dose of the Pfizer-BioNTech COVID-19 mRNA vaccine. This case has been reported to the New Zealand Pharmacovigilance Centre and the patient has consented to publication of the case report.A 43-year-old, NZ European male was diagnosed with acute necrotising pancreatitis 10 hours following the administration of his second Pfizer-BioNTech COVID-19 mRNA vaccine. He has a background of atopy with seasonal rhinitis, eczema and asthma, all of which are ‘mild’. He takes no regular medications and takes as needed melatonin 2 mg nocte, cetirizine 10 mg for hay fever, and betamethasone and emollient cream for dermatitis. He has no family history of note and works in a senior professional role. He drinks six standard units of alcohol per week, has never been a tobacco smoker and does not use recreational drugs – and his employer undertakes regular drug testing.He had a previous episode of pancreatitis in 2011, precipitated by high alcohol intake during a holiday abroad. He is otherwise previously well. There is no family history of note, his father was a smoker and died of lung cancer in his 60s, his mother is well, he has two siblings and three children all of whom are well. He is not aware of any diseases of note in his extended family.In May 2021 he received his second dose of Pfizer-BioNTech COVID-19 mRNA vaccine, he was well at that time. Four hours after the dose he had two 330ml bottles of 5% alcohol beer with his dinner. Six hours after the dose he became unwell with nausea, epigastric pain, and vomiting. Ten hours after the dose blood tests on admission to hospital included: white cell count 18.5 x109/L (4 - 11), neutrophils 15.5 x109/L (1.9 - 7.5), lymphocytes 0.8 x109/L (1.0 - 4.0), CRP <3 mg/L (<5), lipase 23,750 U/L (10 – 70), and triglycerides 3.3 mmol/L. Acute pancreatitis was diagnosed. An ultrasound scan showed pancreatitis without evidence of cholelithiasis. He subsequently deteriorated and a computer tomography (CT) scan on 17 May, day 9 of the illness, showed severe necrotising pancreatitis with collections.During the admission under a specialist hepatobiliary surgical team, known causes of pancreatitis were excluded including: steroid use, trauma, family history of autoimmune conditions, and infection. He did not have the risk factors of obesity, smoking or heavy alcohol consumption. He had the risk factor of a previous episode of acute pancreatitis. The incidence of pancreatitis in New Zealand Europeans in this age group is approximately 50 per 100,000 per year.2 Idiopathic cases represent about 15% of these.Using the Naranjo criteria, the pancreatitis being ’caused’ by the Pfizer-BioNTech COVID-19 mRNA vaccine score was 6 ‘probable’.3 Clinical case discussion (including a hepatobiliary surgeon, gastroenterologist and clinical pharmacologist) concluded that while idiopathic pancreatitis could not be excluded, the onset of symptoms and findings were consistent with an acute precipitating event around the time the second vaccine dose was administered.In addition to the 176 cases reported in VigiBase™, searches of PubMed and Google Scholar™ identified two published case reports of pancreatitis following the Pfizer-BioNTech COVID-19 mRNA vaccine. These were following administration of the first dose of the Pfizer-BioNTech COVID-19 mRNA vaccine. In one case symptoms developed several hours after vaccine administration and the other several days after vaccine administration.4,5Acute pancreatitis is a rare in patients with COVID-19 but characteristic patterns of illness have been reported.6 This raises the possibility that an immune response to either the virus or the vaccine could have common sequalae.This case of acute pancreatitis was temporally associated with the Pfizer-BioNTech COVID-19 mRNA vaccine suggesting a causal link. The characteristics of pancreatitis cases associated with the Pfizer-BioNTech COVID-19 mRNA vaccine should be examined to see if a consistent pattern is present.VigiAccess™ http://www.vigiaccess.org/ - accessed June 24, 2021.Pendharkar SA, Mathew J, Zhao J, Windsor JA, Exeter J, Petrov MS. Ethnic and geographic variations in the incidence of pancreatitis and post- pancreatitis diabetes mellitus in New Zealand: a nationwide population- based study. 2017;130(1450):14.Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther . 1981;30(2):239-245. doi:10.1038/clpt.1981.154Cieślewicz A, Dudek M, Krela-Kaźmierczak I, Jabłecka A, Lesiak M, Korzeniowska K. Pancreatic Injury after COVID-19 Vaccine—A Case Report. Vaccines . 2021;9(6):576. doi:10.3390/vaccines9060576Parkash O, Sharko A, Farooqi A, Ying GW, Sura P. Acute Pancreatitis: A Possible Side Effect of COVID-19 Vaccine. Cureus . Published online April 28, 2021. doi:10.7759/cureus.14741Bircakova B, Bruha R, Lambert L, Grusova G, Michalek P, Burgetova A. A bimodal pattern of the onset of COVID-19 related acute pancreatitis supports both the cytotoxic and immune-related pathogenesis – a systematic review. Scand J Gastroenterol . 2021;56(7):870-873. doi:10.1080/00365521.2021.1922751