Association of genetic polymorphisms in glucocorticoid pathway with dexamethasone treatment in COVID-19 patients

Background/Objectives: Corticosteroids are widely used for the treatment of coronavirus disease (COVID)-19 caused by SARS-CoV- 2 as they attenuate the immune response with their antiinflammatory properties. Genetic polymorphisms of glucocorticoid receptor, metabolizing enzymes or transporters may affect treatment response to dexamethasone. The aim of this study was to evaluate the association of polymorphisms in glucocorticoid pathway with disease severity and duration of dexamethasone treatment in COVID-19 patients. Method(s): Our study included 107 hospitalized COVID-19 patients treated with dexamethasone. We isolated DNA from peripheral blood and genotyped all samples for polymorphisms in NR3C1 (rs6198, rs33388), CYP3A4 (rs35599367), CYP3A5 (rs776746), GSTP1 (rs1695, rs1138272), GSTM1/GSTT1 deletions and ABCB1 (1045642, rs1128503, rs2032582 Fisher's and Mann- Whitney tests were used in statistical analysis. Result(s): The median (min-max) age of the included patients was 62 (26-85) years, 69.2 % were male and 30.8 % female and they had moderate (1.9 %), severe (83 %) or critical (15.1 %) disease. NR3C1 rs6198 polymorphism was associated with more severe disease in additive genetic model (P = 0.022). NR3C1 rs6198, ABCB1 rs1045642 and ABCB1 rs1128503 polymorphisms were associated with a shorter duration of dexamethasone treatment in additive (P = 0.048, P = 0.047 and P = 0.024, respectively) and dominant genetic models (P = 0.015, P = 0.048 and P = 0.020, respectively), while carriers of the polymorphic CYP3A4 rs35599367 allele required longer treatment with dexamethasone (P = 0.033). Other polymorphisms were not associated with disease severity or dexamethasone treatment duration. Conclusion(s): Genetic variability of glucocorticoid pathway genes was associated with the duration of dexamethasone treatment of COVID-19 patients.

Pancreatitis Secondary to Paxlovid-Induced Tacrolimus Toxicity

Introduction: Pancreatitis is a very common gastrointestinal disease that results in hospital admission. Early detection and treatment leads to better outcomes. This is the first reported case of pancreatitis secondary to elevated tacrolimus in a patient with prior renal transplantation after receiving Paxlovid for a COVID-19 infection. Case Description/Methods: A 57-year-old male with past medical history of 4 renal transplants secondary to posterior urethral valves who presented to the emergency room with acute onset epigastric pain for 24 hours. He was on tacrolimus 5 mg every 48 hours monotherapy for his immunosuppression. 10 days prior to his presentation he had developed chills and anxiety. He tested positive for COVID-19 at that time on a home rapid test. His symptoms had not significantly improved and given his immunosuppressed state he was given Paxlovid (Nirmatrelvir/ritonavir). He took 2 days of Paxlovid, however after his second day of treatment he developed severe epigastric pain requiring him to go to the emergency room. On admission his labs were notable for a lipase of 150 U/L (ULN 63 U/L). He underwent a CT scan was notable for an enlarged pancreatic head and neck with peripancreatic fat stranding (Figure). He also had a right upper quadrant ultrasound without any cholelithiasis and only trace sludge noted. His creatinine was noted to be 1.81 mg/dl which was above his baseline of 1.2 mg/dl. His tacrolimus trough level resulted at a level 45.6 ng/ml and later peaked at 82.2 ng/ml. His liver enzymes were normal. He was treated as acute pancreatitis with hydration and his tacrolimus was held with overall clinical improvement. Discussion(s): Tacrolimus is one of the most common medications used in solid organ transplantation. It is a calcineurin inhibitor that inhibits both T-lymphocyte signal transduction and IL-2 transcription. It is metabolized by the protein CYP3A and levels are monitored closely. Paxlovid is currently prescribed as an antiviral therapy for COVID-19 infection. The ritonavir compound in Paxlovid is potent inhibitor of CYP3A. Currently the guidelines do not recommend Paxlvoid as a therapeutic in patients taking tacrolimus as there is concern about increased drug levels. There have been several case reports of pancreatitis in setting of tacrolimus. This case report helps to demonstrate the need for close monitoring of therapeutics levels, especially in medications with high risk of drug to drug interaction to help prevent serious side effects such as tacrolimus induced pancreatitis.

No Dose Adjustments for Cyp3a4 Substrates When Coadministered with Bemnifosbuvir

Background: Bemnifosbuvir (BEM, AT-527) is a guanosine nucleotide prodrug in development for the treatment of COVID-19 and chronic HCV. BEM was identified in vitro as an inhibitor [competitive and time-dependent inhibition (TDI)] and inducer of CYP3A4, prompting evaluation of the clinical relevance of these results in a Ph 1 drug-drug interaction (DDI) study in healthy participants using midazolam (MDZ), a sensitive CYP3A4 substrate as an index drug. Method(s): Two groups of 12 healthy participants were enrolled and received a single dose of 2mg MDZ alone on Day 1. Between Days 3 and 7 inclusive, all participants received oral BEM 550mg twice daily (BID). On day 3 and day 7, Group A received a single dose of 2mg MDZ simultaneously with BEM;Group B on these two days received 2mg MDZ 2h after BEM. Serial plasma samples were obtained and measured for MDZ and 1-OH-MDZ levels. Result(s): A single dose (simultaneous or staggered) of BEM slightly increased the plasma exposure of MDZ (14%-26%). Staggered BEM had less impact (8%-17%) on 1-OH-MDZ than simultaneous dosing (22%-31%). Inhibitory effect of BEM was more pronounced with repeat dosing, consistent with in vitro data showing TDI on CYP3A4. After repeat dosing, simultaneously administered BEM increased plasma MDZ exposure by 83%-98%, without affecting the exposure of 1-OH-MDZ. With repeat dosing, staggered BEM showed less effect on both MDZ and 1-OH-MDZ. There was no effect on vital signs, ECG, and no SAEs or drug discontinuations. Conclusion(s): BEM is a weak inhibitor (ratio between 1.25 and 2) of CYP3A4. No dose adjustment is needed for drugs that are substrates of CYP3A4 when co-administered with BEM.

Drug Interaction between Paxlovid and Tacrolimus in an Adolescent with Inflammatory Bowel Disease

The coronavirus disease of 2019 (COVID-19) caused by SARS-CoV-2 virus led to a worldwide pandemic. Emergency use of an investigational medication, Paxlovid, was approved for patient 12 and older who tested positive for COVID-19 and at high risk for severe infection. Inflammatory Bowel Disease (IBD) is a chronic condition causing inflammation in the gastrointestinal tract. Ulcerative Colitis (UC) is a type of IBD centralized in colon and commonly treated with Immunosuppressive drugs. We present an adolescent with UC treated with paxlovid due to being on tacrolimus who developed with suspected tacrolimus toxicity. CASE REPORT: A 13-year-old female with UC presented to the ED with vomiting and fatigue after paxlovid ttreatment for COVID. The patient's UC treatment included tacrolimus along with ustekinumab. She had been diagnosed with SARS-CoV-2 and prescribed Paxlovid bid x 5 days due to immunosuppressive status. Tacrolimus was held during treatment. Once paxlovid completed, tacrolimus was restarted. Two days later, patient presented to ER for vomiting, fatigue, headaches and myalgia. Labs revealed a tacrolimus level of >60 ng/ml. Electrolytes and Creatinine were normal. Toxicology felt this was due to interaction between paxlovid and tacrolimus. Patient advised to hold tacrolimus for 48 hours and repeat levels were 15.8 ng/mL. Symptoms resolved and level repeated three days later and was 2.9 ng/mL. DISCUSSION: Tacrolimus is an immunosuppressant, commonly used for management of organ transplants but also been found effective in treatment of IBD. Tacrolimus requires close monitoring as toxicity may lead to acute or chronic kidney disease. The normal concentration is between 5-15 ng/mL. Due to rapid escalation of the COVID-19 pandemic, Paxlovid was approved for emergency use for treatment of high-risk patients. It is administered as a 5-day oral course consisting of nirmatrelvir and ritonavir. Our patient was prescribed Paxlovid due to risk secondary to immunosuppression. She was appropriately instructed to stop tacrolimus. Ritonavir is a cytochrome P450 3A inhibitor and can increase plasma concentration of tacrolimus. She restarted tacrolimus treatment 12 hours after her last dose of Paxlovid and presented with symptoms and a level consistent with toxicity. This level was concluded to be due to drug interaction between tacrolimus and Paxlovid. After further withholding of tacrolimus, symptoms improved, and levels normalized. Previous reports in transplant population stress importance of decreasing the dose of tacrolimus or withholding during the course of paxlovid treatment. This case demonstrates the importance of not only ceasing tacrolimus when administering paxlovid, but continuing discontinuation for longer period post completion of therapy to minimize interactions.Copyright © 2023

The Concept of Repurposing in COVID-19 Infection

The strategy of drug repurposing has been proved successful in response to the current corona-virus pandemic, with remdesivir becoming the first drug of choice, an antiviral drug approved for the treatment of COVID-19. In parallel to this, several drugs, such as antimalarial, corticosteroids, and antibi-otics, like azithromycin, are used to treat the severe condition of hospitalized COVID-19 patients, while clinical testing of additional therapeutic drugs, including vaccines, is going on. It is reasonably expected that this review article will deliver optimized and specific curative tools that will increase the attentive-ness of health systems to the probable outlook of epidemics in the future. This review focuses on the ap-plication of repurposed drugs by studying their structure, pharmacokinetic study, different mechanisms of action, and Covid-19 guidelines, which can potentially influence SARS-CoV-2. For most of the drugs, direct clinical evidence regarding their effectiveness in the treatment of COVID-19 is missing. Future clinical trial studies may conclude that one of these can be more potential to inhibit the progression of COVID-19.Copyright © 2022 Bentham Science Publishers.

Using Real World Evidence (Rwe) to Assess Drug-Drug Interaction (Ddi) between Paxlovid and the Top 100 Prescribed Drugs in the Us

BACKGROUND: Paxlovid (nirmatrelvir/ritonavir) has received a US Emergency Use Authorization for patients >=12 years with mild-to- moderate COVID-19 at high-risk of progression to severe disease. DDI studies conducted with Paxlovid implicate the PK enhancer ritonavir as the main perpetrator of DDIs. Ritonavir is a potent inhibitor of CYP3A4, CYP2D6, and P-gp. The Paxlovid Fact Sheet1 identifies contraindicated drugs and those with a potentially important interaction. METHOD(S): A retrospective analysis was conducted using RWE from the Optum Clinformatics Data Mart. Patients were identified based on CDC criteria for high-risk COVID-19 and confirmed continuous insurance enrollment from Jan 1 to Dec 31, 2019 with >=1 prescription claim. Excluding non-drug claims (e.g., vaccines), the top 100 drugs were selected and ranked based on total patient counts. DDI potential with Paxlovid was evaluated using US Prescribing and DailyMed Information or relevant literature for each drug. RESULT(S): Of the top 100, 70 drugs are not expected to have a DDI with Paxlovid. These drugs are eliminated unchanged in urine, cleared by enzymes other than CYP3A4 or CYP2D6, are not P-gp substrates, or are cleared by multiple pathways. The remaining 30 drugs expected to have a DDI are represented in the Paxlovid Fact Sheet. The top four drug classes expected to interact with Paxlovid include corticosteroids, narcotic analgesics, anticoagulants, and statins. One drug, simvastatin, is contraindicated. The mechanism of interaction with Paxlovid, or lack thereof, will be presented in detail for each drug. CONCLUSION(S): Paxlovid DDI management is important to ensure the right patients receive this antiviral. This analysis provides an understanding of Paxlovid interactions with the top 100 drugs likely to be used in high-risk COVID-19 patients and serves as an additional DDI management resource.

Alternative Management of Cushing's Syndrome During Covid-19 Pandemic

Cushing's syndrome results from prolonged exposure to glucocorticoids. Surgery is often the first-line treatment for this condition, regardless of etiology. However, the COVID-19 pandemic caused a decrease in surgical procedures due to the risk of infection transmission. There are still emergency cases of Cushing's syndrome that are admitted to the hospital and require urgent management. The current treatment should be focused on medical management and endovascular embolization in selective cases. Embolization can be performed in facilities where there aretrained personnel with experience in adrenal embolization. Surgery, which traditionally is a first-line therapy, can increase the risk of infection, therefore, it should be avoided. The current review provides a brief description of the possible options for the management of adrenal Cushing's syndrome during the COVID-19 pandemic.Copyright © 2022 Bentham Science Publishers.

Drug Interaction between Paxlovid and Tacrolimus in an Adolescent with Inflammatory Bowel Disease

The coronavirus disease of 2019 (COVID-19) caused by SARS-CoV-2 virus led to a worldwide pandemic. Emergency use of an investigational medication, Paxlovid, was approved for patient 12 and older who tested positive for COVID-19 and at high risk for severe infection. Inflammatory Bowel Disease (IBD) is a chronic condition causing inflammation in the gastrointestinal tract. Ulcerative Colitis (UC) is a type of IBD centralized in colon and commonly treated with Immunosuppressive drugs. We present an adolescent with UC treated with paxlovid due to being on tacrolimus who developed with suspected tacrolimus toxicity. CASE REPORT: A 13-year-old female with UC presented to the ED with vomiting and fatigue after paxlovid ttreatment for COVID. The patient's UC treatment included tacrolimus along with ustekinumab. She had been diagnosed with SARS-CoV-2 and prescribed Paxlovid bid x 5 days due to immunosuppressive status. Tacrolimus was held during treatment. Once paxlovid completed, tacrolimus was restarted. Two days later, patient presented to ER for vomiting, fatigue, headaches and myalgia. Labs revealed a tacrolimus level of >60 ng/ml . Electrolytes and Creatinine were normal. Toxicology felt this was due to interaction between paxlovid and tacrolimus. Patient advised to hold tacrolimus for 48 hours and repeat levels were 15.8 ng/ mL. Symptoms resolved and level repeated three days later and was 2.9 ng/mL DISCUSSION: Tacrolimus is an immunosuppressant, commonly used for management of organ transplants but also been found effective in treatment of IBD. Tacrolimus requires close monitoring as toxicity may lead to acute or chronic kidney disease. The normal concentration is between 5-15 ng/mL. Due to rapid escalation of the COVID-19 pandemic, Paxlovid was approved for emergency use for treatment of high-risk patients. It is administered as a 5-day oral course consisting of nirmatrelvir and ritonavir. Our patient was prescribed Paxlovid due to risk secondary to immunosuppression. She was appropriately instructed to stop tacrolimus. Ritonavir is a cytochrome P450 3A inhibitor and can increase plasma concentration of tacrolimus. She restarted tacrolimus treatment 12 hours after her last dose of Paxlovid and presented with symptoms and a level consistent with toxicity. This level was concluded to be due to drug interaction between tacrolimus and Paxlovid. After further withholding of tacrolimus, symptoms improved, and levels normalized. Previous reports in transplant population stress importance of decreasing the dose of tacrolimus or withholding during the course of paxlovid treatment. This case demonstrates the importance of not only ceasing tacrolimus when administering paxlovid, but continuing discontinuation for longer period post completion of therapy to minimize interactions.

Paxlovid ( Nirmatrelvir/Ritonavir ) and Cyclosporin in a Kidney Transplant Patient with Covid-19 Infection

Introduction: COVID-19 infection causes high morbidity,mortality and burden to the healthcare system.Solid organ transplant patients with COVID-19 have been reported to have between 13-30% rate of mortality.Over the past 2 years,treatment of COVID-19 has evolved with new drugs being introduce such as Molnupiravir which reported to reduce death and hospitalization up to 50%.Recently a new novel drug Paxlovid (Nirmatrelvir/Ritonavir) develop by Pfizer has shed much hope in terms of managing COVID-19 patient especially in those with solid organ transplant.However,there is not much data in using Paxlovid for kidney transplant with COVID-19.Paxlovid is known to have drug-drug interaction with medication that is highly dependent on CYP3A4 which is a member of Cytochrome P450 enzyme for clearance.It is advice to withhold certain calcineurin inhibitor drugs if on Paxlovid.However,there was no mention on withholding cyclosporin which is one of the drugs in in kidney transplant patient.We've reported the first case in literature of a kidney transplant patient on cyclosporin diagnose with COVID 19 on Paxlovid. Method(s): Our patient is a End Stage Renal Disease on regular hemodialysis for a year.He subsequently had a living related renal transplant.He was vaccinated and boosted with SARS-CoV-2 Vaccine from Pfizer BioNTech.Baseline creatinine level was 126 umol/L.Immunosuppressants are Cyclosporin 50mg BD,Prednisolone 7.5mg OD and Azathioprine 50mg OD.Baseline cyclosporin trough level was 113ng/ml.He was well until SARS-CoV-2 Rapid Test Kit was positive on day four of illness.Serum Creatinine level was 137 umol/L.His estimated Glomerular Filtration Rate was 53 ml/min/1.73m2.Chest Radiograph shows ground glass opacity on both lower zone.Patient was treated for COVID-19 Pneumonia Category 3A.In view eGFR was 53 ml/min/1.73m2,Paxlovid was started at adjusted dose (Nirmatrelvir 150mg/Ritonavir 100mg BD).Patient had four doses of Paxlovid before we were able to send cyclosporin level on day three of his admission due to logistic problem.Cyclosporin trough level was 737 ng/ml and we withheld his cyclosporin.Paxlovid was continued and there was improvement in terms of his symptoms.Serial chest radiographs showed improvement as in Figure 1.We were able to monitor his cyclosporin trough level and serum creatinine on daily basis as shown in Figure 2 and Figure 3 respectively.He completed five days of Paxlovid.On day seven of admission,cyclosporin was restarted back at 25mg BD. [Formula presented] [Formula presented] [Formula presented] Results: He was discharged well with cyclosporin dose being adjusted back to his old dose.We followed him up as outpatient and monitor his cyclosporin level which was stable and continued on his old immunosuppressant regime. Conclusion(s): This case highlights the potential treatment with Paxlovid in patients with kidney transplant on cyclosporin diagnosed to have COVID-19 infection.Drug-drug interaction between cyclosporin and Paxlovid needs to be taken into account.Moving forward in the endemic era,there will be increase usage of Paxlovid that can help to reduce severity,hospital admission and mortality in solid organ transplant with COVID-19 infection.Close monitoring of cyclosporin level,proper mitigation strategy,adjustment of immunosuppressants and safe prescription of Paxlovid will be beneficial for kidney transplant patient infected with COVID-19.This can help in reducing morbidity and mortality in our kidney transplant patients. No conflict of interestCopyright © 2023

The Effect of Carriage of CYP3A5*3 and CYP3A4*22 Polymorphic Variants on the Safety of Remdesivir Therapy in Patients with COVID-19.

The aim of the study was to assess the association of polymorphic variants CYP3A5*3 6986 A>G rs776746 and CYP3A4*22 rs35599367 C>T with the safety parameters of remdesivir therapy in patients with COVID-19. Material and methods. The study included 156 patients admitted to the City Clinical Hospital No. 15 of the Moscow Health Department with COVID-19 diagnosis, who received remdesivir as an antiviral drug. The frequency of adverse reactions (bradycardia, dyspeptic disorders), as well as various laboratory parameters (ALT, AST, creatinine, ferritin, interleukin-6, and d-dimer levels) were compared between the carriers of wild-type and polymorphic variants of the studied genes. Results. Carriers of CYP3A5*3 polymorphic variants (GA+AA) had higher ALT levels after the treatment with remdesivir than carriers of the wild variant (GG). When comparing the level of interleukin-6 after therapy with remdesivir, carriers of the polymorphic variant of the CYP3A4*22 (CT) gene had a significantly higher level of this cytokine. Conclusion. An association between the carriage of polymorphic variants of CYP3A5*3 and an increase in the level of liver enzymes was found. Polymorphic variants of CYP3A4*22 were associated with higher levels of interleukin-6. Additional pharmacogenetic studies are required to assess the possibilities of personalizing antiviral therapy for COVID-19.Copyright © Team of Authors, 2022.

Safety and efficacy of apremilast in adults hospitalized with COVID-19

Introduction: Apremilast, a nonbiologic oral phosphodiesterase 4 (PDE4) inhibitor, was evaluated as a treatment for the hyperinflammatory response in patients (pts) hospitalized with severe COVID-19. Aims and Objectives: To assess the safety and effectiveness of apremilast plus standard of care (SoC) in pts hospitalized with severe COVID-19. Method(s): COMMUNITY (EudraCT 2020-002594-10) was a phase 3, double-blind, randomized, multinational, platform trial in adult pts hospitalized with COVID-19. Pts received apremilast 30 mg BID (APR) or placebo (PBO) for 14 days or until hospital discharge, whichever occurred first. Supportive care (per study center practices) was allowed except for CYP3A inducers and concurrent PDE4 antagonists. Result(s): From November 24, 2020 to June 4, 2021, 384 pts were enrolled (APR+SoC: n=194;PBO+SoC: n=190);enrollment halted early due to futility. Mean age was 56.5 years;59% were men. Most pts had a COVID-19 clinical severity score of 4 (48%) or 3 (29%) (range: 1-8, 1=death). Median (95% CI) time to confirmed clinical recovery through Day 29 (primary endpoint) was 14 (11-15) days for both groups (P=0.8779). All-cause mortality incidence rates through Day 29 (key secondary endpoint) were 18% (APR+SoC) and 17% (PBO+SoC) (P=0.9665). Treatmentemergent adverse event (TEAE) rates were similar between APR+SoC (54%;n=189) and PBO+SoC (55%;n=187) groups. TEAEs Common Terminology Criteria AE grade >=3 occurred in 25% of APR+SoC pts and 30% of PBO+SoC pts. Serious TEAE rates were 27% (APR+SoC) and 30% (PBO+SoC). Conclusion(s): Although APR+SoC did not improve survival in pts hospitalized with severe COVID-19, APR was well tolerated with a safety profile consistent with the established safety profile.

The Effect of Carriage of CYP3A5*3 and CYP3A4*22 Polymorphic Variants on the Safety of Remdesivir Therapy in Patients with COVID-19

The aim of the study was to assess the association of polymorphic variants CYP3A5*3 6986 A>G rs776746 and CYP3A4*22 rs35599367 C>T with the safety parameters of remdesivir therapy in patients with COVID-19. Material and methods. The study included 156 patients admitted to the City Clinical Hospital No. 15 of the Moscow Health Department with COVID-19 diagnosis, who received remdesivir as an antiviral drug. The frequency of adverse reactions (bradycardia, dyspeptic disorders), as well as various laboratory parameters (ALT, AST, creatinine, ferritin, interleukin-6, and d-dimer levels) were compared between the carriers of wild-type and polymorphic variants of the studied genes. Results. Carriers of CYP3A5*3 polymorphic variants (GA+AA) had higher ALT levels after the treatment with remdesivir than carriers of the wild variant (GG). When comparing the level of interleukin-6 after therapy with remdesivir, carriers of the polymorphic variant of the CYP3A4*22 (CT) gene had a significantly higher level of this cytokine. Conclusion. An association between the carriage of polymorphic variants of CYP3A5*3 and an increase in the level of liver enzymes was found. Polymorphic variants of CYP3A4*22 were associated with higher levels of interleukin-6. Additional pharmacogenetic studies are required to assess the possibilities of personalizing antiviral therapy for COVID-19.

Evaluation of drug-drug interaction potential of ensitrelvir for CYP3A by clinical studies and physiologically-based pharmacokinetic model

Background. Ensitrelvir is a new drug candidate to treat COVID-19 disease. According to the in vitro drug-drug interaction (DDI) study, time-dependent inhibition by ensitrelvir was observed on cytochrome P450 3A (CYP3A). The purpose of this study was to evaluate the effect of ensitrelvir on the pharmacokinetics (PK) of CYP3A substrates by clinial DDI studies and physiologically-based pharmacokinetic (PBPK) analyses. Methods. Clinical studies: The effect of once daily multiple-doses of ensitrelvir with the loading dose on Day 1/ maintenance dose (750/250 mg) for 6 days on the PK of midazolam (MDZ) was assessed. MDZ was administered on Days -2 and 6. The effects of once daily multiple-doses of ensitrelvir with 750/250 mg for 5 days on the PK of dexamethasone (DXS) and prednisolone (PLS) were also assessed because these corticosteroids were also CYP3A substrates. DXS and PLS were administered on Days -2, 5 (co-administration with ensitrelvir), 9 and 14 to evaluate the effects after the last dose of ensitrelvir. PBPK analyses: The effects of once daily multiple-doses of ensitrelvir with another dose regimen (the loading dose/mentenance dose [375/125 mg] for 5 days) on the PK of CYP3A substrates were predicted using Simcyp PBPK Simulator (Version 20, Certara UK Limited, UK). Results. The AUC0-inf of MDZ co-administered with ensitrelvir was increased by 8.80-fold compared to those of MDZ alone, indicating that ensitrelvir is a strong CYP3A inhibitor with 750/250 mg for 6 days. The AUC0-inf of DXS on Day 5 was increased 3.47-fold and the effect of ensitrelvir on the PK of DXS was diminished over time after the last dose of ensitrelvir. The AUC0-inf of PLS on Day 5 was increased 1.25-fold and no clinically meaningful effect of ensitrelvir on the PK of PLS was observed. The PBPK analyses predicted that the co-administration of ensitrelvir increased the AUC of MDZ by 3.83-fold and the AUC of DXS by 2.49-fold following ensitrelvir at 375/125 mg for 5 days. A clinical study with MDZ under the analyses conditions is underway to confirm the PBPK results. Conclusion. The clinical study revealed that ensitrelvir affects the PK of CYP3A substrates with 750/250 mg for 5 or 6 days. The PBPK analyses suggests that ensitrelvir is expected to a moderate inhibitor of CYP3A with 375/125 mg for 5 days.

Phenytoin to Expedite Sirolimus & Tacrolimus Elimination: A Case Report

Purpose: Sirolimus (SIR), a mammalian target of rapamycin inhibitor (mTORi), may be used with or without a calcineurin inhibitor after heart transplant (HT). The antiproliferative properties & 72-hour half-life (T1/2) that make SIR desirable to provide uniform drug exposure & attenuate cardiac allograft vasculopathy add complications when surgical needs or toxicities arise.1,2 SIR-related wound healing impairment necessitates cessation before invasive procedures, yet managing long-acting SIR in these settings is complex due a large volume of distribution & vulnerability to interactions with CYP3A4 inhibitors, prolonging T1/2.2 Phenytoin (PHY), a potent inducer of CYP3A4, has been used to speed tacrolimus (FK) clearance.3 Interaction between PHY & SIR is reported.4 Strategic use of PHY to clear SIR is not described. Method(s): Case review leveraging PHY-inducing effects to expedite SIR & FK elimination while awaiting urgent thoracotomy for mucormycosis. Result(s): The patient developed invasive pulmonary mucormycosis 3 years post-HT. Supratherapeutic levels on admission were SIR 20 ng/mL & FK 15 ng/mL with mycophenolate 500 mg twice daily & prednisone 5 mg twice daily. Treatment was initiated with CYP3A4-inhibiting isavuconazonium sulfate (ISU) & amphotericin B irrigation. Infected lung segment resection was delayed for wound healing risks of SIR. To hasten SIR elimination via CYP3A4 induction, fosPHY load then PHY 100 mg orally thrice daily was initiated on day 5. To maintain infection treatment while inducing metabolism, ISU was converted to systemic amphotericin B. Figure 1 describes SIR, FK, ISU & PHY courses. The calculated T1/2 was shorted from 440 hours on ISU days 3-5 to 32 hours days 7-10 (allowing time for induction). On day 14 thoracotomy & left upper lobectomy were successfully performed with FK & SIR unquantifiable. Conclusion(s): This case illustrates effective induction SIR & FK metabolism using PHY. In the era of CYP 3A4-inhibiting nirmatrelvir-ritonavir availability for COVID-19, strategies to address inadvertent calcineurin inhibitor or mTORi toxicity are paramount. Employing this approach when needing to clear drugs quickly may be beneficial.

A CASE OF COVID-19-ASSOCIATED PULMONARY ASPERGILLOSIS

SESSION TITLE: COVID-19 Case Report Posters 1 SESSION TYPE: Case Report Posters PRESENTED ON: 10/17/2022 12:15 pm - 01:15 pm INTRODUCTION: COVID-19 patients requiring admission to an ICU have a higher risk of invasive pulmonary aspergillosis (IPA) with a reported incidence of 19.6%-33.3%. CASE PRESENTATION: A 63-year-old male presented with progressively worsening dyspnea for one week. He has a past medical history of atrial fibrillation, hypertension, and obesity. He was tested positive for COVID about two weeks prior. He did receive a single dose of Moderna vaccine. Initial chest x-ray(CXR) showed diffuse ground-glass opacities. He was initiated on Remdesivir and decadron, and later received a dose of tocilizumab. He was intubated on hospital day 3 for worsened hypoxemia. Repeat CXR suggested some improvement but a new left lower lobe airspace haziness. He also had new-onset leukocytosis with elevated procalcitonin level. He was started on cefepime for concern of superimposed hospital-acquired pneumonia. A second dose of tocilizumab was administered. No clinical improvement was seen, and additional workups were obtained. Serial CXRs revealed increasing diffuse airspace opacities concerning for ARDS. Tracheal aspirate culture grew coagulase-negative staphylococcus and Aspergillosis Fumigatus. Cefepime was changed to vancomycin, and voriconazole and caspofungin were added. Unfortunately, the patient's respiratory status worsened with increasing ventilation requirement. He also developed septic shock and acute renal failure requiring CVVH. He became even more hypotensive after CVVH initiation, and multiple vasopressors were required to maintain his hemodynamics. Unfortunately, he continued to deteriorate and he also developed profound respiratory acidosis. He died shortly afterwards after family decided to withdraw care. DISCUSSION: In this case, in addition to superimposed bacterial pneumonia, pulmonary aspergillosis likely also contributed to his clinical deterioration. The mechanism by which fungal infections develop in COVID-19 infection is not well-understood. Severe COVID-related immune dysregulation, ARDS, and high-dose steroids use are potential culprits for the increased risk of IPA. Tocilizumab, an IL-6 receptor monoclonal antibody used in patients with severe COVID-19 infection, may also predispose the patient to IPA according to post-marketing data. The mortality rate from current case reports is as high as 64.7%. Diagnosis and treatment in such a scenario remain a challenge. Sputum culture, serum Beta-galactomannan, Beta-D glucan, and aspergillosis PCR have low sensitivity. Tissue biopsy and CT scan in critically ill patients are often not feasible. Voriconazole is usually considered the first-line treatment in IPA. CYP3A4-mediated drug interactions between azoles and antiviral agents require further investigation. CONCLUSIONS: Clinicians should be aware that severe COVID-19 patients are at higher risk of IPA. The prognosis is poor. Early detection and treatment in clinically deteriorated patients are warranted. Reference #1: Borman, A.M., Palmer, M.D., Fraser, M., Patterson, Z., Mann, C., Oliver, D., Linton, C.J., Gough, M., Brown, P., Dzietczyk, A. and Hedley, M., 2020. COVID-19-associated invasive aspergillosis: data from the UK National Mycology Reference Laboratory. Journal of clinical microbiology, 59(1), pp.e02136-20. Reference #2: Lai CC, Yu WL. COVID-19 associated with pulmonary aspergillosis: A literature review. J Microbiol Immunol Infect. 2021;54(1):46-53. doi:10.1016/j.jmii.2020.09.004 Reference #3: Thompson Iii GR, Cornely OA, Pappas PG, et al. Invasive Aspergillosis as an Under-recognized Superinfection in COVID-19. Open Forum Infect Dis. 2020;7(7):ofaa242. Published 2020 Jun 19. doi:10.1093/ofid/ofaa242 DISCLOSURES: No relevant relationships by Jason Chang No relevant relationships by Jason Chang No relevant relationships by kaiqing Lin No relevant relationships by Guangchen Zou

Tirzepatide (Mounjaro) for Type 2 Diabetes

The FDA has approved tirzepatide (Mounjaro - Lilly), a peptide hormone with activity at both glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors, to improve glycemic control in adults with type 2 diabetes. Tirzepatide, which is injected subcutaneously once weekly, is the fi rst dual GIP/GLP-1 receptor agonist to become available in the US. Selective GIP receptor agonists are not available in the US;GLP-1 receptor agonists have been available for years. Copyright © 2022, Medical Letter Inc.. All rights reserved.

In Silico Prediction of the Metabolic Resistance of Vitamin D Analogs against CYP3A4 Metabolizing Enzyme.

The microsomal cytochrome P450 3A4 (CYP3A4) and mitochondrial cytochrome P450 24A1 (CYP24A1) hydroxylating enzymes both metabolize vitamin D and its analogs. The three-dimensional (3D) structure of the full-length native human CYP3A4 has been solved, but the respective structure of the main vitamin D hydroxylating CYP24A1 enzyme is unknown. The structures of recombinant CYP24A1 enzymes have been solved; however, from studies of the vitamin D receptor, the use of a truncated protein for docking studies of ligands led to incorrect results. As the structure of the native CYP3A4 protein is known, we performed rigid docking supported by molecular dynamic simulation using CYP3A4 to predict the metabolic conversion of analogs of 1,25-dihydroxyvitamin D2 (1,25D2). This is highly important to the design of novel vitamin D-based drug candidates of reasonable metabolic stability as CYP3A4 metabolizes ca. 50% of the drug substances. The use of the 3D structure data of human CYP3A4 has allowed us to explain the substantial differences in the metabolic conversion of the side-chain geometric analogs of 1,25D2. The calculated free enthalpy of the binding of an analog of 1,25D2 to CYP3A4 agreed with the experimentally observed conversion of the analog by CYP24A1. The metabolic conversion of an analog of 1,25D2 to the main vitamin D hydroxylating enzyme CYP24A1, of unknown 3D structure, can be explained by the binding strength of the analog to the known 3D structure of the CYP3A4 enzyme.

Hydroxychloroquine is metabolized by CYP2D6, CYP3A4 and CYP2C8, and inhibits CYP2D6, while its metabolites also inhibit CYP3A4 in vitro

Introduction: Hydroxychloroquine is used for the treatment of malaria, rheumatoid arthritis and lupus erythematosus. In 2020, hydroxychloroquine was also repurposed for the treatment of COVID-19. Although current evidence does not encourage the use of hydroxychloroquine to treat COVID-19, its therapeutic and prophylactic use against COVID-19 is still investigated in clinical trials. Despite being in clinical use for more than 60 years, its clinical pharmacology is not well understood. Hydroxychloroquine is metabolized into three active metabolites, but the key metabolizing enzymes have not been unambiguously identified. Moreover, little is known about the inhibitory effects of hydroxychloroquine on cytochrome P450 (CYP) enzymes. Objectives: This study aimed to investigate the CYP metabolic and inhibitory profile of hydroxychloroquine and its three metabolites in vitro. Methods: Hydroxychloroquine metabolism was studied in human liver microsomes (HLM) and recombinant CYP enzymes using substrate depletion and CYP-selective inhibitors. The inhibitory effects of hydroxychloroquine and its metabolites on nine CYP enzymes were also determined in HLM, using automated probe substrate cocktail assays. Results: Based on screening experiments, CYP3A4, CYP2D6 and CYP2C8 were the key enzymes involved in hydroxychloroquine metabolism in vitro. Although the intrinsic clearance (CLint) value of hydroxychloroquine depletion by recombinant CYP2D6 (0.87 μl/min/pmol) was more than 10-fold higher than that by CYP3A4 (0.075 μl/min/pmol), scaling of the recombinant data to HLM level resulted in similar CLint values for CYP2D6 and CYP3A4 (11 and 14 μl/min/mg) because of the much greater abundancy of CYP3A4 than that of CYP2D6. The scaled HLM CLint of CYP2C8 was 5.7 μl/min/mg. Data in HLM with CYPselective inhibitors also suggested relatively equal roles for CYP2D6 and CYP3A4 in hydroxychloroquine metabolism, and a smaller contribution for CYP2C8. In CYP inhibition experiments, hydroxychloroquine and its three metabolites were direct CYP2D6 inhibitors (50% inhibitory concentration IC50 18-135 μM), while all metabolites were CYP3A timedependent inhibitors (IC50 12-117 μM, IC50 shift 2.2-3.4-fold). CYP2D6 inhibition explains the reported clinical drug-drug interaction between hydroxychloroquine and the CYP2D6 substrate metoprolol. The present data, together with the inhibitors' estimated intracellular hepatocyte concentrations, were successfully used in a static model to predict the fold increase in metoprolol AUC (predicted: 2.3- 2.8-fold, observed: 1.65-fold). Conclusion: The present study unambiguously demonstrates that hydroxychloroquine is metabolized mainly by CYP2D6, CYP3A4 and CYP2C8 in vitro. Moreover, hydroxychloroquine and its three metabolites are CYP2D6 reversible inhibitors, and hydroxychloroquine metabolites are CYP3A time-dependent inhibitors. The current data can be used in static and physiologically-based pharmacokinetic models to predict hydroxychloroquine drug-drug interaction potential, as shown with the successful prediction of hydroxychloroquine - metoprolol drug-drug interaction. (Table Presented).

15th Congress of the European Association for Clinical Pharmacology and Therapeutics, EACPT

The proceedings contain 294 papers. The topics discussed include: impact of the genotype and phenotype of CYP3A and P-GP on the apixaban and rivaroxaban blood concentrations in real-world setting;direct oral anticoagulant-related bleeding in atrial fibrillation patients alters DNA methylation of NOS3 and KDR genes;impact of obesity on dexamethasone pharmacokinetic in COVID-19 hospitalized patients: an observational exploratory study;intestinal permeability in transplant patients: are systemic short-chain fatty acids an early biomarker?;immunogenicity 5-months after homologous or heterologous booster vaccination in health care workers primed with Ad26.COV2.S;geographic variation in top-10 prescribed medication and potentially inappropriate prescription in Portugal: an ecological study of 2.2 million older adults;quantitative proteomics of hepatic drug-metabolizing enzymes and transporters in patients with colorectal cancer liver metastasis;pharmacological characterization of a novel lipid-rich breast cancer patient-derived xenograft;and multiple sclerosis drugs and dental and gingival disorders: an observational retrospective study and disproportionality analysis in the world pharmacovigilance database.

Brensocatib: Dipeptidyl peptidase 1 (DPP1) inhibitor Treatment of non-cystic fibrosis bronchiectasis

Neutrophils, which are among the first immune cells to respond to both infection and injury, when activated can release pre-stored serine proteases such as neutrophil elastase, cathepsin G and proteinase 3. An abundant release of these proteolytic enzymes in the alveolar compartment as well as the airways can trigger collateral pulmonary tissue damage. Indeed, much of the tissue destruction that characterizes non-cystic fibrosis bronchiectasis appears to be caused by serine proteases. The transitory pharmacological inhibition of bone marrow dipeptidyl peptidase 1 (DPP1), which converts neutrophil proteolytic enzymes into their mature active form, is a therapeutic possibility to decrease the constitutively produced serine protease pool of neutrophils. Brensocatib (also called INS-1007 or AZD-7986) is a potent reversible DPP1 inhibitor that has been successfully evaluated in a phase II trial as a treatment for non-cystic fibrosis bronchiectasis and, consequently, has been granted breakthrough therapy designation by the U.S. Food and Drug Administration and Priority Medicines (PRIME) designation by the European Medicines Agency.