Drugs in Research & Development最新文献

{"title":"Effect of Daridorexant on the Pharmacokinetics of Midazolam, and on the Pharmacokinetics and Pharmacodynamics of Warfarin in Healthy Male Subjects.","authors":"Isabelle Zenklusen, Jasper Dingemanse, Christian Reh, Martine Gehin, Priska Kaufmann","doi":"10.1007/s40268-024-00456-8","DOIUrl":"10.1007/s40268-024-00456-8","url":null,"abstract":"<p><strong>Background and objectives: </strong>Daridorexant, a dual orexin receptor antagonist was recently approved for the treatment of insomnia at doses up to 50 mg once per night. This study investigated the effect of single-dose and multiple-dose daridorexant 50 mg at steady state on the pharmacokinetics (PK) of the cytochrome P450 (CYP) 3A4-sensitive substrate midazolam, and the effect of single-dose daridorexant 50 mg on the PK and pharmacodynamics (PD) of the CYP2C9-sensitive substrate warfarin.</p><p><strong>Methods: </strong>In this prospective, single-center, open-label, fixed-sequence, phase I, drug-drug interaction study, 18 healthy male subjects sequentially received Treatment A, B, and C in three periods. Treatment A consisted of a single oral concomitant administration of midazolam 2 mg and warfarin 25 mg on day 1 of the first period. Treatment B consisted of one oral administration of daridorexant 50 mg followed 1 h later by a single oral dose of midazolam 2 mg concomitantly with a single oral dose of warfarin 25 mg on day 1 and a once-daily oral administration of daridorexant 50 mg for 6 days of the second period. Treatment C consisted of a single oral administration of daridorexant 50 mg at steady state followed 1 h later by a single oral administration of midazolam 2 mg on day 1 of the third period. Blood samples were assessed for midazolam and S-warfarin PK, and PD (international normalized ratio and factor VII). Noncompartmental  PK parameters and PD variables were evaluated with geometric mean ratios and 90% confidence intervals of Treatment B/A versus C/A for midazolam, and treatment B/A for warfarin. Safety and tolerability of each treatment were also assessed.</p><p><strong>Results: </strong>Midazolam maximum plasma concentration (C_max) and area under the plasma concentration-time curve from 0 to 24 h (AUC_0-24) were 1.13- and 1.42-fold higher, respectively, after single-dose administration of daridorexant 50 mg compared to administration of midazolam alone, while C_max and AUC_0-24 were 1.12- and 1.35-fold higher, respectively, after administration of daridorexant 50 mg once daily at steady state. Terminal half-life and time to maximum plasma concentration were comparable between treatments. Daridorexant had no influence on the PK and PD of warfarin. All treatments were safe and well tolerated.</p><p><strong>Conclusions: </strong>Daridorexant at 50 mg is classified as a weak CYP3A4 inhibitor after single- and multiple-dose administration once daily at steady state. Daridorexant 50 mg did not induce CYP3A4 activity or inhibit CYP2C9 activity.</p><p><strong>Clinical trial registration: </strong>This trial (NCT05480488) was registered on 29 July, 2022.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":" ","pages":"97-108"},"PeriodicalIF":3.0,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11035509/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140111947","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Drug-Drug Interaction Studies of Esmethadone (REL-1017) Involving CYP3A4- and CYP2D6-Mediated Metabolism.","authors":"Nicola Ferri, Sara De Martin, James Stuart, Sergio Traversa, Franco Folli, Marco Pappagallo, Cedric O'Gorman, Clotilde Guidetti, Andrea Mattarei, Charles E Inturrisi, Paolo L Manfredi","doi":"10.1007/s40268-023-00450-6","DOIUrl":"10.1007/s40268-023-00450-6","url":null,"abstract":"<p><strong>Background and objective: </strong>Esmethadone (dextromethadone; d-methadone; S-methadone (+)-methadone; REL-1017) is the opioid inactive dextro-isomer of racemic methadone. Esmethadone is a low potency N-methyl-D-aspartate (NMDA) receptor channel blocker with higher affinity for GluN2D subtypes. Esmethadone showed robust, rapid, and sustained antidepressant effects in patients with major depressive disorder (MDD) with inadequate response to ongoing serotonergic antidepressant treatment.</p><p><strong>Methods: </strong>Here we described the results of in vitro and phase 1 clinical trials aimed at investigating the esmethadone metabolism and possible drug-drug interactions.</p><p><strong>Results: </strong>Esmethadone is primarily metabolized to EDDP (2-ethylene-1,5-dimethyl-3,3-diphenylpyrrolidine) by multiple enzymes, including CYP3A4/5 and CYP2B6. In vitro studies showed that esmethadone inhibits CYP2D6 with IC₅₀ of 9.6 μM and is an inducer of CYP3A4/5. The clinical relevance of the inhibition of CYP2D6 and the induction of CYP3A4 were investigated by co-administering esmethadone and dextromethorphan (a substrate for CYP2D6) or midazolam (a substrate for CYP3A4) in healthy volunteers. The administration of esmethadone at the dosage of 75 mg (which is the loading dose administered to patients in MDD clinical trials) significantly increased the exposure (AUC) of both dextromethorphan and its metabolite dextrorphan by 2.71 and 3.11-fold, respectively. Esmethadone did not modify the pharmacokinetic profile of midazolam, while it increased C_max and AUC of its metabolite 1'-hydroxymidazolam by 2.4- and 3.8-fold, respectively. A second study evaluated the effect of the CYP3A4 inhibitor cobicistat on the pharmacokinetics of esmethadone. Cobicistat slightly increase (+32%) the total exposure (AUC_0-inf) of esmethadone.</p><p><strong>Conclusions: </strong>In summary, esmethadone demonstrated a negligible effect on CYP3A4 induction and its metabolism was not meaningfully affected by strong CYP3A4 inhibitors while it increased exposure of CYP2D6-metabolized drugs.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":" ","pages":"51-68"},"PeriodicalIF":3.0,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11035515/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138446762","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Efficacy and Safety of Methylphenidate and Atomoxetine in Medication-Naive Children with Attention-Deficit Hyperactivity Disorder in a Real-World Setting.","authors":"Ying Zhang, Li Yin, Cun You, Chunxue Liu, Ping Dong, Xiu Xu, Kaifeng Zhang","doi":"10.1007/s40268-023-00445-3","DOIUrl":"10.1007/s40268-023-00445-3","url":null,"abstract":"<p><strong>Background and objective: </strong>Methylphenidate (MPH) and atomoxetine (ATX) are the most common medications used to treat attention-deficit hyperactivity disorder (ADHD) in China; however, despite this, there is still a paucity of studies comparing their efficacy and safety, particularly for different characteristics. To address the lack of research, a real-world prospective cohort study was conducted to examine these properties of MPH and ATX, and to analyze correlations associated with age, sex, and different ADHD presentation.</p><p><strong>Methods: </strong>Children with ADHD meeting the eligibility criteria were recruited from January 2016 to July 2021. Study participants were treated with either MPH or ATX prescribed in the real-world setting, and were followed up for 26 weeks. Clinical efficacy response and adverse events (AEs) were recorded and measured. Subgroup analysis was performed to examine the efficacy response and AEs associated with age, sex, and different ADHD presentation.</p><p><strong>Results: </strong>A total of 1050 children were recruited and 29 children were lost to follow-up. Of the 1021 children remaining, 533 were treated with MPH and 488 were treated with ATX. No significant differences were found in intelligence quotient, age, sex, or ADHD presentation between the MPH- and ATX-treated groups (p > 0.05). The response rates were 84.6% in the MPH-treated group and 63.3% in the ATX-treated group. Subgroup analysis of response rate demonstrated that the treatment effect of MPH over ATX was consistent across subgroups except in the girls (odds ratio [OR] 2.09, 95% confidence interval [CI] 0.97-4.7) and the hyperactive/impulsive presentation group (OR 2.88, 95% CI 0.77-12.76). A total of 47.8% of children experienced AEs during MPH treatment, significantly lower than the rate of 56.8% during ATX treatment (p < 0.05). The incidence of AEs in the MPH-treated group was higher in young children (<8 years: 56.8%; 8-10 years: 47.2%) and lower in children over 10 years of age (29.0%).</p><p><strong>Conclusions: </strong>Overall, MPH was more effective and better tolerated than ATX. The incidence of AEs in children treated with MPH varied with age, and was higher in young children and lower in children over 10 years of age.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":" ","pages":"29-39"},"PeriodicalIF":3.0,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11035522/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138048223","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Future Perspectives of Pulmonary Arterial Hypertension: A Review of Novel Pipeline Treatments and Indications.","authors":"Maria Eugenia Novara, Enrica Di Martino, Brandon Stephens, Mary Nayrouz, Patrizio Vitulo, Anna Carollo, Alessio Provenzani","doi":"10.1007/s40268-024-00453-x","DOIUrl":"10.1007/s40268-024-00453-x","url":null,"abstract":"<p><p>Pulmonary arterial hypertension is characterized by elevated blood pressure and pathological changes in the pulmonary arterioles, leading to the development of right-heart failure and potentially fatal outcomes if left untreated. This review aims to provide an overview of novel drugs or formulations and new drug indications for pulmonary arterial hypertension that are currently in phases II-III of randomized controlled trials, and describe the rationale for the use of these targeted therapies, as well as their efficacy, safety profile, and impact on quality of life and survival. The literature research was conducted using data from ClinicalTrials.gov for the period between 1 January 2016 up to 31 December 2022. The population of interest includes individuals aged ≥ 18 years who have been diagnosed with pulmonary arterial hypertension. The review selection criteria included trials with recruiting, enrolling by invitation, active, terminated or completed status in 2022 and 2023. A total of 24 studies were selected for evaluation based on the inclusion and exclusion criteria. This review summarizes the updated information from randomized clinical trials involving novel therapies for pulmonary arterial hypertension. However, larger clinical trials are required to validate their clinical safety and effects. In the future, clinicians should choose therapies based on the patient's individual situation and requirements when developing treatment strategies.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":" ","pages":"13-28"},"PeriodicalIF":3.0,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11035521/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140186128","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Real-World Experience of Carglumic Acid for Methylmalonic and Propionic Acidurias: An Interim Analysis of the Multicentre Observational PROTECT Study.","authors":"Sufin Yap, Delphine Lamireau, Francois Feillet, Angeles Ruiz Gomez, James Davison, Trine Tangeraas, Vincenzo Giordano","doi":"10.1007/s40268-023-00449-z","DOIUrl":"10.1007/s40268-023-00449-z","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background and objective: &lt;/strong&gt;Methylmalonic aciduria (MMA) and propionic aciduria (PA) are organic acidurias characterised by the accumulation of toxic metabolites and hyperammonaemia related to secondary N-acetylglutamate deficiency. Carglumic acid, a synthetic analogue of N-acetylglutamate, decreases ammonia levels by restoring the functioning of the urea cycle. However, there are limited data available on the long-term safety and effectiveness of carglumic acid. Here, we present an interim analysis of the ongoing, long-term, prospective, observational PROTECT study (NCT04176523), which is investigating the long-term use of carglumic acid in children and adults with MMA and PA.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Individuals with MMA or PA from France, Germany, Italy, Norway, Spain, Sweden and the UK who have received at least 1 year of carglumic acid treatment as part of their usual care are eligible for inclusion. The primary objective is the number and duration of acute metabolic decompensation events with hyperammonaemia (ammonia level &gt;159 µmol/L during a patient's first month of life or &gt;60 µmol/L thereafter, with an increased lactate level [&gt; 1.8 mmol/L] and/or acidosis [pH &lt; 7.35]) before and after treatment with carglumic acid. Peak plasma ammonia levels during the last decompensation event before and the first decompensation event after carglumic acid initiation, and the annualised rate of decompensation events before and after treatment initiation are also being assessed. Secondary objectives include the duration of hospital stay associated with decompensation events. Data are being collected at approximately 12 months' and 18 months' follow-up.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Of the patients currently enrolled in the PROTECT study, data from ten available patients with MMA (n = 4) and PA (n = 6) were analysed. The patients had received carglumic acid for 14-77 (mean 36) months. Carglumic acid reduced the median peak ammonia level of the total patient population from 250 µmol/L (range 97-2569) before treatment to 103 µmol/L (range 97-171) after treatment. The annualised rate of acute metabolic decompensations with hyperammonaemia was reduced by a median of - 41% (range - 100% to + 60%) after treatment with carglumic acid. Of the five patients who experienced a decompensation event before treatment and for whom a post-treatment rate could be calculated, the annualised decompensation event rate was lower after carglumic acid treatment in four patients. The mean duration of hospital inpatient stay during decompensation events was shorter after than before carglumic acid treatment initiation in four of five patients for whom length of stay could be calculated.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;In this group of patients with MMA and PA, treatment with carglumic acid for at least 1 year reduced peak plasma ammonia levels in the total patient population and reduced the frequency of metabolic decompensation events, as well as t","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":" ","pages":"69-80"},"PeriodicalIF":3.0,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11035519/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139404930","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Case Report: Life-Threatening Fluoxetine-Linked Postoperative Bleeding Informed by Pharmacogenetic Evaluation.","authors":"Sara Rogers, Patrick J Silva, George Udeani, Monica Deleon, Sriarchala Mutyala, Ladan Panahi, Asim Abu-Baker, Gabriel Neal, Kenneth S Ramos","doi":"10.1007/s40268-023-00451-5","DOIUrl":"10.1007/s40268-023-00451-5","url":null,"abstract":"<p><strong>Background: </strong>Selective serotonin reuptake inhibitors (SSRI) are commonly used for the treatment of depression and anxiety. Inhibition of serotonin reuptake in platelets increases bleeding risk in patients taking SSRIs.</p><p><strong>Case: </strong>Here, we present the case of a 52-year-old patient who developed severe postsurgical bleeding requiring blood transfusion following panniculectomy.</p><p><strong>Conclusion: </strong>SSRI-induced bleeding is dose-related and strongly influenced by individual variations in drug metabolizing enzymes and transporters. Supplementary file1 (MP4 8441 KB).</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":" ","pages":"117-121"},"PeriodicalIF":3.0,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11035520/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139984292","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bioequivalence Study of Tebipenem Pivoxil in Healthy Chinese Adults.","authors":"Rui Hao, Yiming Shao, Sisi Lin, Yi Wu, Li Bian, Yiwen Zhang","doi":"10.1007/s40268-024-00454-w","DOIUrl":"10.1007/s40268-024-00454-w","url":null,"abstract":"<p><strong>Background and objective: </strong>Tebipenem pivoxil (TP) is a carbapenem and is applied against pneumonia, otitis media, and sinusitis. This study compared the pharmacokinetics (PK) and safety of a test (T) preparation and reference (R) preparation of TP in healthy Chinese adults.</p><p><strong>Methods: </strong>This study was a single-center, randomized, open, single-dose (fasting/postprandial) oral administration, two-agent, two-sequence, two-cycle, crossover bioequivalence trial. A total of 60 participants were enrolled (24 fasting and 36 postprandial). All participants were randomly assigned to the TR sequence and RT sequence. Subsequently, they switched T sequences or R sequences 7 days later. PK blood samples were collected according to the protocol, plasma TP concentration was determined by liquid chromatography-mass spectrometry, main PK parameters were calculated based on a non-compartment model, and adverse events were recorded during the test.</p><p><strong>Results: </strong>In the feeding arm, the geometric mean ratio of maximum concentration (C_max) was 89.84% (90% confidence interval 84.33-95.70), the geometric mean ratio of area under the plasma concentration-time curve from time 0 to last time of quantifiable concentration (AUC_0-t) was 86.80% (83.62-90.10), and the geometric mean ratio of area under the plasma concentration-time curve from time 0 to infinity time of quantifiable concentration (AUC_0-∞) was 86.90% (83.73-90.20), which were within the acceptable range of bioequivalence (80-125%). In the fasting arm, the geometric mean ratio of C_max was 96.07% (89.62-102.99), the geometric mean ratio of AUC_0-t was 93.09% (90.47-95.78), and the geometric mean ratio of AUC_0-∞ was 93.09% (90.48-95.77), which was within the acceptable range of bioequivalence (80-125%). Hence, the T preparation and R preparation of TP had bioequivalence in the fasting arm and feeding arm of the clinical trial. In addition, all adverse events were mild, and no severe adverse events were noted.</p><p><strong>Conclusion: </strong>Preparations T and R of TP were bioequivalent in the fasting and postprandial groups in clinical trials, and TP was safe.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":" ","pages":"89-96"},"PeriodicalIF":3.0,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11035523/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140050731","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Human Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of ASC42, a Novel Farnesoid X Receptor Agonist.","authors":"Handan He, Jinzi J Wu","doi":"10.1007/s40268-023-00444-4","DOIUrl":"10.1007/s40268-023-00444-4","url":null,"abstract":"<p><strong>Background: </strong>ASC42 is a non-steroidal farnesoid X receptor agonist currently in clinical development for chronic liver diseases, such as nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (NAFLD/NASH) and primary biliary cirrhosis (PBC).</p><p><strong>Objective: </strong>The objective of this study was to assess the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of ASC42 in healthy subjects.</p><p><strong>Methods: </strong>We conducted the first-in-human study of ASC42 following single and multiple ascending doses (SAD/MAD) and food effect in healthy subjects. The SAD study included five cohorts receiving 5-200 mg ASC42 or placebo and one cohort that was given 15 mg ASC42 with a high-fat meal. The MAD study included three cohorts receiving 5-50 mg ASC42 or placebo once-daily (QD) for 14 days.</p><p><strong>Results: </strong>A total of 65 healthy subjects were enrolled and one subject in the MAD study (cohort 8, ASC42 50 mg) withdrew from the study due to an unrelated serious adverse event (SAE) of atrial fibrillation. Pruritus was observed at the highest doses (200 mg cohort in SAD and 50 mg cohort in MAD). Most AEs were mild or moderate. No life-threatening or fatal AEs occurred. ASC42 showed a proportional increase in exposure and elimination half-life following both single and multiple dosing. There was a 21% and 37% decrease in area under the curve (AUC) and maximum plasma concentration (C_max) when ASC42 was coadministered with food. The steady state was reached on day 4 with a mild accumulation (1.02-1.74-fold). ASC42 showed dose-dependent increases in fibroblast growth factor 19 and decreases in 7α-hydroxy-4-cholesten-3-one. Cholesterol remained within normal limits during study.</p><p><strong>Conclusion: </strong>ASC42 was well tolerated with a pharmacokinetic profile suitable for QD dosing, and demonstrated dose-dependent targets engagement without altering plasma cholesterol in healthy subjects.</p><p><strong>Trial registration number: </strong>NCT04679129.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":" ","pages":"453-464"},"PeriodicalIF":3.0,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10676321/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71428340","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tremor Induced by Cyclosporine, Tacrolimus, Sirolimus, or Everolimus: A Review of the Literature.","authors":"Aparna Wagle Shukla, Caroline Lunny, Omar Mahboob, Uzair Khalid, Malea Joyce, Nivedita Jha, Nandakumar Nagaraja, Ashutosh M Shukla","doi":"10.1007/s40268-023-00428-4","DOIUrl":"10.1007/s40268-023-00428-4","url":null,"abstract":"<p><p>Calcineurin inhibitors such as cyclosporine and tacrolimus are immunosuppressant drugs that are known to induce tremors. Non-calcineurin inhibitors such as sirolimus and everolimus have also reportedly been accompanied by tremors, albeit less likely. However, the prevalence rates reported in the literature are notably wide, and the risk profiles for these drug-induced tremors are less understood. We searched PubMed to extract data on the risk of tremors with these drugs when prescribed for various transplant and non-transplant indications. We ascertained whether the risk of drug-induced tremor is influenced by the underlying diagnosis, dosing formulations, drug concentrations, and blood monitoring. We extracted data on treatment strategies and outcomes for tremors. Articles were primarily screened based on English language publications, abstracts, and studies with n ≥ 5, which included case series, retrospective studies, case-controlled studies, and prospective studies. We found 81 eligible studies comprising 33 cyclosporine, 43 tacrolimus, 6 sirolimus, and 1 everolimus that discussed tremor as an adverse event. In the pooled analysis of studies with n > 100, the incidence of tremor was 17% with cyclosporine, 21.5% with tacrolimus, and 7.8% with sirolimus and everolimus together. Regarding the underlying diagnosis, tremor was more frequently reported in kidney transplant (cyclosporine 28%, tacrolimus 30.1%) and bone marrow transplant (cyclosporine 40%, tacrolimus 41.9%) patients compared with liver transplant (cyclosporine 9%, tacrolimus 11.5%) and nontransplant indications (cyclosporine 21.5%, tacrolimus 11.3%). Most studies did not report whether the risk of tremors correlated with drug concentrations in the blood. The prevalence of tremors when using the twice-daily formulation of tacrolimus was nearly the same as the once-daily formulation (17% vs 18%). Data on individual-level risk factors for tremors were lacking. Except for three studies that found some benefit to maintaining magnesium levels, there were minimal data on treatments and outcomes. A large body of data supports a substantive and wide prevalence of tremor resulting from tacrolimus use followed by cyclosporine, especially in patients receiving a kidney transplant. However, there is little reporting on the patient-related risk factors for tremor, risk relationship with drug concentrations, treatment strategies, and outcomes.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":" ","pages":"301-329"},"PeriodicalIF":3.0,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10676343/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10097358","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacovigilance Study of Infigratinib: A Safety Analysis of the FDA Adverse Event Reporting System.","authors":"Dehua Zhao, Xiaoqing Long, Jiping Zhou, Jisheng Wang","doi":"10.1007/s40268-023-00439-1","DOIUrl":"10.1007/s40268-023-00439-1","url":null,"abstract":"<p><strong>Background: </strong>Infigratinib is a fibroblast growth factor receptor (FGFR)-specifc tyrosine kinase inhibitor indicated for the treatment of patients with previously treated, unresectable, locally advanced or metastatic cholangiocarcinoma. However, few studies have been conducted to evaluated the safety of infigratinib in the real world. In this study, we conducted a pharmacovigilance study to evaluate the adverse events (AEs) of infigratinib by using the Food and Drug Administration Adverse Event Reporting System (FAERS) database.</p><p><strong>Methods: </strong>OpenVigil 2.1 was employed to extract the FAERS database. Descriptive analysis was used to describe the characteristics of infigratinib-associated AE reports. Disproportionality analysis was performed by calculating the proportional reporting ratio (PRR), reporting odds ratios (ROR), and Bayesian analysis confidence propagation neural network (BCPNN) to detect positive signals.</p><p><strong>Results: </strong>Our findings revealed 149 AE reports, among which 36 significant signals were identified. These significant AE signals were mainly observed in gastrointestinal disorders (N = 26, ROR = 26.03, PRR = 8.44, information component [IC] = 3.08) and skin and subcutaneous tissue disorders (N = 21, ROR = 92.13, PRR = 40.41, IC = 5.34). Notably, dehydration and skin exfoliation were unexpected AEs, but had relatively high signal intensities (ROR = 29.75, PRR = 26.64, IC = 4.74; ROR = 50.61, PRR = 45.24, IC = 5.50, respectively) despite not being listed on the drug label. Furthermore, our analysis showed that infigratinib dose differed statistically between severe and non-severe reports (113.82 ± 16.13 mg vs 125 ± 0.00 mg, t = - 4.28; p < 0.001). However, there were no significant differences in sex, age, and types of AEs between the two groups (p  = 0.06, p  = 0.86, and p = 0.93, respectively).</p><p><strong>Conclusions: </strong>These findings suggest that gastrointestinal and skin toxicities are the most common adverse reactions for infigratinib. It is important to recognize skin exfoliation and dehydration in clinical practice, as they are unexpected AEs. Additionally, our study indicates that infigratinib dose may correlate with an increased risk of AE severity, highlighting the need for dose adjustment of infigratinib when exposure to the drug is increased due to internal or external factors.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":" ","pages":"403-409"},"PeriodicalIF":3.0,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10676333/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10223275","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}