Hayley L Letson, Jodie L Morris, Geoffrey P Dobson
Introduction: The binding of drugs to plasma proteins is an important consideration in drug development. We have reported that the dose of adenosine, lidocaine, and magnesium (ALM) fluid therapy for resuscitation from hemorrhagic shock is nearly 3-times higher for pigs than rats. Since lidocaine strongly binds to serum alpha-1-acid glycoprotein (AGP), the aim of the study was to investigate the effect of hemorrhagic shock on levels of AGP in rats and pigs.
Materials and methods: Healthy adult male Sprague-Dawley rats and female crossbred pigs (n = 33 each) underwent tail vein and peripheral ear vein blood sampling, respectively, to collect plasma for AGP measurements. Rats (n = 17) and pigs (n = 16) underwent surgical instrumentation and uncontrolled hemorrhage via liver resection, and were treated with 3% NaCl ± ALM IV bolus followed 60 min later by 4 h 0.9% NaCl ± ALM IV drip. Rats were monitored for 72 h with blood samples taken post-surgery, and at 5.25, 24, and 72 h. Pigs were monitored for 6 h with blood samples taken post-surgery, and at 60 min and 6 h. Plasma AGP was measured with rat- and pig-specific enzyme-linked immunosorbent assay kits.
Results: Baseline AGP levels in rats were 3.91 μg/mL and significantly 83-fold lower than in pigs (325 μg/mL). Surgical instrumentation was associated with ~10-fold increases in AGP in rats and a 21% fall in pigs. AGP levels remained elevated in rats after hemorrhage and resuscitation (28-29 μg/mL). In contrast, no significant differences in plasma AGP were found in ALM- or Saline-treated pigs over the monitoring period.
Conclusions: We conclude that the trauma of surgery alone was associated with significant increases in AGP in rats, compared to a contrasting decrease in pigs. Higher levels of plasma AGP in pigs prior to hemorrhagic shock is consistent with the higher ALM doses required to resuscitate pigs compared with rats.
{"title":"Changes in plasma alpha-1 acid glycoprotein following hemorrhagic trauma: Possible role in dose differences of ALM drug therapy in rat and pig resuscitation.","authors":"Hayley L Letson, Jodie L Morris, Geoffrey P Dobson","doi":"10.1002/prp2.1133","DOIUrl":"10.1002/prp2.1133","url":null,"abstract":"<p><strong>Introduction: </strong>The binding of drugs to plasma proteins is an important consideration in drug development. We have reported that the dose of adenosine, lidocaine, and magnesium (ALM) fluid therapy for resuscitation from hemorrhagic shock is nearly 3-times higher for pigs than rats. Since lidocaine strongly binds to serum alpha-1-acid glycoprotein (AGP), the aim of the study was to investigate the effect of hemorrhagic shock on levels of AGP in rats and pigs.</p><p><strong>Materials and methods: </strong>Healthy adult male Sprague-Dawley rats and female crossbred pigs (n = 33 each) underwent tail vein and peripheral ear vein blood sampling, respectively, to collect plasma for AGP measurements. Rats (n = 17) and pigs (n = 16) underwent surgical instrumentation and uncontrolled hemorrhage via liver resection, and were treated with 3% NaCl ± ALM IV bolus followed 60 min later by 4 h 0.9% NaCl ± ALM IV drip. Rats were monitored for 72 h with blood samples taken post-surgery, and at 5.25, 24, and 72 h. Pigs were monitored for 6 h with blood samples taken post-surgery, and at 60 min and 6 h. Plasma AGP was measured with rat- and pig-specific enzyme-linked immunosorbent assay kits.</p><p><strong>Results: </strong>Baseline AGP levels in rats were 3.91 μg/mL and significantly 83-fold lower than in pigs (325 μg/mL). Surgical instrumentation was associated with ~10-fold increases in AGP in rats and a 21% fall in pigs. AGP levels remained elevated in rats after hemorrhage and resuscitation (28-29 μg/mL). In contrast, no significant differences in plasma AGP were found in ALM- or Saline-treated pigs over the monitoring period.</p><p><strong>Conclusions: </strong>We conclude that the trauma of surgery alone was associated with significant increases in AGP in rats, compared to a contrasting decrease in pigs. Higher levels of plasma AGP in pigs prior to hemorrhagic shock is consistent with the higher ALM doses required to resuscitate pigs compared with rats.</p>","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"11 5","pages":"e01133"},"PeriodicalIF":2.6,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/b8/0b/PRP2-11-e01133.PMC10465298.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10206095","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}
Sabrina Robert, Marc-Olivier Pilon, Essaïd Oussaïd, Maxime Meloche, Grégoire Leclair, Martin Jutras, Marie-Josée Gaulin, Ian Mongrain, David Busseuil, Jean-Claude Tardif, Marie-Pierre Dubé, Simon de Denus
Small studies suggest that amiodarone is a weak inhibitor of cytochrome P450 (CYP) 2D6. Inhibition of CYP2D6 leads to increases in concentrations of drugs metabolized by the enzyme, such as metoprolol. Considering that both metoprolol and amiodarone have β-adrenergic blocking properties and that the modest interaction between the two drugs would result in increased metoprolol concentrations, this could lead to a higher risk of bradycardia and atrioventricular block. The primary objective of this study was to evaluate whether metoprolol plasma concentrations collected at random timepoints from patients enrolled in the Montreal Heart Institute Hospital Cohort could be useful in identifying the modest pharmacokinetic interaction between amiodarone and metoprolol. We performed an analysis of a cross-sectional study, conducted as part of the Montreal Heart Institute Hospital Cohort. All participants were self-described "White" adults with metoprolol being a part of their daily pharmacotherapy regimen. Of the 999 patients being treated with metoprolol, 36 were also taking amiodarone. Amiodarone use was associated with higher metoprolol concentrations following adjustment for different covariates (p = .0132). Consistently, the association between amiodarone use and lower heart rate was apparent and significant after adjustment for all covariates under study (p = .0001). Our results highlight that single randomly collected blood samples can be leveraged to detect modest pharmacokinetic interactions.
{"title":"Impact of amiodarone use on metoprolol concentrations, α-OH-metoprolol concentrations, metoprolol dosing and heart rate: A cross-sectional study.","authors":"Sabrina Robert, Marc-Olivier Pilon, Essaïd Oussaïd, Maxime Meloche, Grégoire Leclair, Martin Jutras, Marie-Josée Gaulin, Ian Mongrain, David Busseuil, Jean-Claude Tardif, Marie-Pierre Dubé, Simon de Denus","doi":"10.1002/prp2.1137","DOIUrl":"10.1002/prp2.1137","url":null,"abstract":"<p><p>Small studies suggest that amiodarone is a weak inhibitor of cytochrome P450 (CYP) 2D6. Inhibition of CYP2D6 leads to increases in concentrations of drugs metabolized by the enzyme, such as metoprolol. Considering that both metoprolol and amiodarone have β-adrenergic blocking properties and that the modest interaction between the two drugs would result in increased metoprolol concentrations, this could lead to a higher risk of bradycardia and atrioventricular block. The primary objective of this study was to evaluate whether metoprolol plasma concentrations collected at random timepoints from patients enrolled in the Montreal Heart Institute Hospital Cohort could be useful in identifying the modest pharmacokinetic interaction between amiodarone and metoprolol. We performed an analysis of a cross-sectional study, conducted as part of the Montreal Heart Institute Hospital Cohort. All participants were self-described \"White\" adults with metoprolol being a part of their daily pharmacotherapy regimen. Of the 999 patients being treated with metoprolol, 36 were also taking amiodarone. Amiodarone use was associated with higher metoprolol concentrations following adjustment for different covariates (p = .0132). Consistently, the association between amiodarone use and lower heart rate was apparent and significant after adjustment for all covariates under study (p = .0001). Our results highlight that single randomly collected blood samples can be leveraged to detect modest pharmacokinetic interactions.</p>","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"11 5","pages":"e01137"},"PeriodicalIF":2.6,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/64/dd/PRP2-11-e01137.PMC10512912.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41148366","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}
Lance Wollenberg, Erik Hahn, Jason Williams, Kevin Litwiler
Encorafenib is a novel kinase inhibitor of BRAF V600E as well as wild-type BRAF and CRAF and has received approval, in combination with binimetinib, to treat BRAF V600E or V600K mutation-positive unresectable or metastatic melanoma or in combination with cetuximab to treat BRAF V600E mutation-positive colorectal cancer. The absorption, distribution, metabolism and excretion (ADME) of encorafenib was studied by administering [14 C] encorafenib (100 mg containing 90 μCi of radiolabeled material) to 4 healthy male subjects (NCT01436656). Following a single oral 100-mg dose of [14 C] encorafenib to healthy male subjects, the overall recovery of radioactivity in the excreta was ≥93.9% in all four subjects, indicating that good mass balance was achieved. An equal mean of 47.2% for the radioactivity dose was eliminated in the feces and urine. The percentage of the dose eliminated in the feces (5.0%) and urine (1.8%) as unchanged encorafenib was minor. Metabolism was found to be the major clearance pathway (~88% of the recovered radioactive dose) for encorafenib in humans and is predominantly mediated through N-dealkylation of the isopropyl carbamic acid methyl ester to form the primary phase 1 direct metabolite M42.5 (LHY746). Oral absorption was estimated from the radioactive dose recovered in the urine (47.2%) and the total radioactive dose recovered in the feces as metabolites (39%). Based on these values and the assumptions that encorafenib and its metabolites are stable in feces, the fraction of oral absorption was estimated to be at least ~86%.
{"title":"A phase I, single-center, open-label study to investigate the absorption, distribution, metabolism and excretion of encorafenib following a single oral dose of 100 mg [<sup>14</sup> C] encorafenib in healthy male subjects.","authors":"Lance Wollenberg, Erik Hahn, Jason Williams, Kevin Litwiler","doi":"10.1002/prp2.1140","DOIUrl":"10.1002/prp2.1140","url":null,"abstract":"<p><p>Encorafenib is a novel kinase inhibitor of BRAF V600E as well as wild-type BRAF and CRAF and has received approval, in combination with binimetinib, to treat BRAF V600E or V600K mutation-positive unresectable or metastatic melanoma or in combination with cetuximab to treat BRAF V600E mutation-positive colorectal cancer. The absorption, distribution, metabolism and excretion (ADME) of encorafenib was studied by administering [<sup>14</sup> C] encorafenib (100 mg containing 90 μCi of radiolabeled material) to 4 healthy male subjects (NCT01436656). Following a single oral 100-mg dose of [<sup>14</sup> C] encorafenib to healthy male subjects, the overall recovery of radioactivity in the excreta was ≥93.9% in all four subjects, indicating that good mass balance was achieved. An equal mean of 47.2% for the radioactivity dose was eliminated in the feces and urine. The percentage of the dose eliminated in the feces (5.0%) and urine (1.8%) as unchanged encorafenib was minor. Metabolism was found to be the major clearance pathway (~88% of the recovered radioactive dose) for encorafenib in humans and is predominantly mediated through N-dealkylation of the isopropyl carbamic acid methyl ester to form the primary phase 1 direct metabolite M42.5 (LHY746). Oral absorption was estimated from the radioactive dose recovered in the urine (47.2%) and the total radioactive dose recovered in the feces as metabolites (39%). Based on these values and the assumptions that encorafenib and its metabolites are stable in feces, the fraction of oral absorption was estimated to be at least ~86%.</p>","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"11 5","pages":"e01140"},"PeriodicalIF":2.6,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10541456/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41168723","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}
Over a decade's experience of post-stroke rehabilitation by administering the specific anti-TNF biological, etanercept, by the novel perispinal route, is consistent with a wide range of chronically diminished neurological function having been caused by persistent excessive cerebral levels of TNF. We propose that this TNF persistence, and cerebral disease chronicity, largely arises from a positive autocrine feedback loop of this cytokine, allowing the persistence of microglial activation caused by the excess TNF that these cells produce. It appears that many of these observations have never been exploited to construct a broad understanding and treatment of certain chronic, yet reversible, neurological illnesses. We propose that this treatment allows these chronically activated microglia to revert to their normal quiescent state, rather than simply neutralizing the direct harmful effects of this cytokine after its release from microglia. Logically, this also applies to the chronic cerebral aspects of various other neurological conditions characterized by activated microglia. These include long COVID, Lyme disease, post-stroke syndromes, traumatic brain injury, chronic traumatic encephalopathy, post-chemotherapy, post-irradiation cerebral dysfunction, cerebral palsy, fetal alcohol syndrome, hepatic encephalopathy, the antinociceptive state of morphine tolerance, and neurogenic pain. In addition, certain psychiatric states, in isolation or as sequelae of infectious diseases such as Lyme disease and long COVID, are candidates for being understood through this approach and treated accordingly. Perispinal etanercept provides the prospect of being able to treat various chronic central nervous system illnesses, whether they are of infectious or non-infectious origin, through reversing excess TNF generation by microglia.
{"title":"Autocrine positive feedback of tumor necrosis factor from activated microglia proposed to be of widespread relevance in chronic neurological disease.","authors":"Ian A Clark, Bryce Vissel","doi":"10.1002/prp2.1136","DOIUrl":"10.1002/prp2.1136","url":null,"abstract":"<p><p>Over a decade's experience of post-stroke rehabilitation by administering the specific anti-TNF biological, etanercept, by the novel perispinal route, is consistent with a wide range of chronically diminished neurological function having been caused by persistent excessive cerebral levels of TNF. We propose that this TNF persistence, and cerebral disease chronicity, largely arises from a positive autocrine feedback loop of this cytokine, allowing the persistence of microglial activation caused by the excess TNF that these cells produce. It appears that many of these observations have never been exploited to construct a broad understanding and treatment of certain chronic, yet reversible, neurological illnesses. We propose that this treatment allows these chronically activated microglia to revert to their normal quiescent state, rather than simply neutralizing the direct harmful effects of this cytokine after its release from microglia. Logically, this also applies to the chronic cerebral aspects of various other neurological conditions characterized by activated microglia. These include long COVID, Lyme disease, post-stroke syndromes, traumatic brain injury, chronic traumatic encephalopathy, post-chemotherapy, post-irradiation cerebral dysfunction, cerebral palsy, fetal alcohol syndrome, hepatic encephalopathy, the antinociceptive state of morphine tolerance, and neurogenic pain. In addition, certain psychiatric states, in isolation or as sequelae of infectious diseases such as Lyme disease and long COVID, are candidates for being understood through this approach and treated accordingly. Perispinal etanercept provides the prospect of being able to treat various chronic central nervous system illnesses, whether they are of infectious or non-infectious origin, through reversing excess TNF generation by microglia.</p>","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"11 5","pages":"e01136"},"PeriodicalIF":2.6,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/29/3a/PRP2-11-e01136.PMC10520644.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41130046","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}
Tacrolimus interacts with letermovir and azole antifungals, whereas letermovir has nonuniform effects on the pharmacokinetics of azole antifungals. We retrospectively investigated the interaction of tacrolimus (continuous infusion) with letermovir considering co-administered azole antifungals in adult hematopoietic stem cell transplantation patients. The extent of intraindividual variation in the ratio of tacrolimus concentration to dose normalized by body weight (C/D ratio) was investigated. The correlation between the C/D ratio and estimated glomerular filtration rate (eGFR) was analyzed. In 35 patients (795 points), the C/D ratio was higher in the tacrolimus plus letermovir period than in the tacrolimus alone period (1234.7 [566.2-2721.0] ng/mL/mg/kg vs. 564.4 [245.3-1861.3] ng/mL/mg/kg, p < .001). This trend was observed when co-administered with azole antifungals (n = 30, 1285.5 [662.7-2506.7] ng/mL/mg/kg vs. 547.1 [245.3-1861.3] ng/mL/mg/kg, p < .001), but not without azole antifungals (n = 5, 809.9 [566.2-1573.3] ng/mL/mg/kg vs. 616.1 [350.6-979.8] ng/mL/mg/kg, p = .125). For patients co-administered fluconazole, the tacrolimus C/D ratio increased in patients with letermovir than those without letermovir (n = 28, 1215.0 [662.7-2506.7] ng/mL/mg/kg vs. 529.9 [245.3-1654.4] ng/mL/mg/kg, p < .001). Tacrolimus C/D ratio did not correlate with eGFR under letermovir and fluconazole administrations (y = 0.1x + 1307.1, r = .008, p = .968). Close blood concentration monitoring of intravenous tacrolimus is required when patients administered letermovir and azole antifungals.
他克莫司与莱特莫韦和唑类抗真菌药物相互作用,而莱特莫韦对唑类抗真菌药物的药代动力学影响不均匀。我们回顾性地研究了他克莫司(持续输注)与利特莫韦在成人造血干细胞移植患者中联合使用唑类抗真菌药物的相互作用。研究了他克莫司浓度与体重归一化剂量之比(C/D比)的个体变异程度。分析C/D比值与肾小球滤过率(eGFR)的相关性。35例患者(795分)中,他克莫司联合莱特莫韦组C/D比值高于单用他克莫司组(1234.7 [566.2-2721.0]ng/mL/mg/kg vs. 564.4 [245.3-1861.3] ng/mL/mg/kg, p
{"title":"Drug interactions of tacrolimus with letermovir and azole antifungals following hematopoietic stem cell transplantation: A retrospective observational analysis.","authors":"Yuri Shinogi, Toshinori Hirai, Miki Ishibashi, Kazuko Ino, Isao Tawara, Takuya Iwamoto","doi":"10.1002/prp2.1120","DOIUrl":"https://doi.org/10.1002/prp2.1120","url":null,"abstract":"<p><p>Tacrolimus interacts with letermovir and azole antifungals, whereas letermovir has nonuniform effects on the pharmacokinetics of azole antifungals. We retrospectively investigated the interaction of tacrolimus (continuous infusion) with letermovir considering co-administered azole antifungals in adult hematopoietic stem cell transplantation patients. The extent of intraindividual variation in the ratio of tacrolimus concentration to dose normalized by body weight (C/D ratio) was investigated. The correlation between the C/D ratio and estimated glomerular filtration rate (eGFR) was analyzed. In 35 patients (795 points), the C/D ratio was higher in the tacrolimus plus letermovir period than in the tacrolimus alone period (1234.7 [566.2-2721.0] ng/mL/mg/kg vs. 564.4 [245.3-1861.3] ng/mL/mg/kg, p < .001). This trend was observed when co-administered with azole antifungals (n = 30, 1285.5 [662.7-2506.7] ng/mL/mg/kg vs. 547.1 [245.3-1861.3] ng/mL/mg/kg, p < .001), but not without azole antifungals (n = 5, 809.9 [566.2-1573.3] ng/mL/mg/kg vs. 616.1 [350.6-979.8] ng/mL/mg/kg, p = .125). For patients co-administered fluconazole, the tacrolimus C/D ratio increased in patients with letermovir than those without letermovir (n = 28, 1215.0 [662.7-2506.7] ng/mL/mg/kg vs. 529.9 [245.3-1654.4] ng/mL/mg/kg, p < .001). Tacrolimus C/D ratio did not correlate with eGFR under letermovir and fluconazole administrations (y = 0.1x + 1307.1, r = .008, p = .968). Close blood concentration monitoring of intravenous tacrolimus is required when patients administered letermovir and azole antifungals.</p>","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"11 4","pages":"e01120"},"PeriodicalIF":2.6,"publicationDate":"2023-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/e7/e0/PRP2-11-e01120.PMC10395274.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9933206","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}
Josephine A Adattini, Jeffry Adiwidjaja, Annette S Gross, Andrew J McLachlan
We aimed to use physiologically based pharmacokinetic (PBPK) modeling and simulation to predict imatinib steady-state plasma exposure in patients with chronic myeloid leukemia (CML) to investigate variability in outcomes. A validated imatinib PBPK model (Simcyp Simulator) was used to predict imatinib AUCss , Css,min and Css,max for patients with CML (n = 68) from a real-world retrospective observational study. Differences in imatinib exposure were evaluated based on clinical outcomes, (a) Early Molecular Response (EMR) achievement and (b) occurrence of grade ≥3 adverse drug reactions (ADRs), using the Kruskal-Wallis rank sum test. Sensitivity analyses explored the influence of patient characteristics and drug interactions on imatinib exposure. Simulated imatinib exposure was significantly higher in patients who achieved EMR compared to patients who did not (geometric mean AUC0-24,ss 51.2 vs. 42.7 μg h mL-1 , p < 0.05; Css,min 1.1 vs. 0.9 μg mL-1 , p < 0.05; Css,max 3.4 vs. 2.8 μg mL-1 , p < 0.05). Patients who experienced grade ≥3 ADRs had a significantly higher simulated imatinib exposure compared to patients who did not (AUC0-24,ss 56.1 vs. 45.9 μg h mL-1 , p < 0.05; Css,min 1.2 vs. 1.0 μg mL-1 , p < 0.05; Css,max 3.7 vs. 3.0 μg mL-1 , p < 0.05). Simulations identified a range of patient (sex, age, weight, abundance of hepatic CYP2C8 and CYP3A4, α1 -acid glycoprotein concentrations, liver and kidney function) and medication-related factors (dose, concomitant CYP2C8 modulators) contributing to the inter-individual variability in imatinib exposure. Relationships between imatinib plasma exposure, EMR achievement and ADRs support the rationale for therapeutic drug monitoring to guide imatinib dosing to achieve optimal outcomes in CML.
我们的目的是使用基于生理的药代动力学(PBPK)建模和模拟来预测慢性髓性白血病(CML)患者的伊马替尼稳态血浆暴露,以研究结果的变异性。通过验证的伊马替尼PBPK模型(Simcyp Simulator)来预测CML患者(n = 68)的伊马替尼AUCss、Css、min和Css、max。使用Kruskal-Wallis秩和检验,根据临床结果(a)早期分子反应(EMR)的实现和(b)≥3级药物不良反应(adr)的发生来评估伊马替尼暴露的差异。敏感性分析探讨了患者特征和药物相互作用对伊马替尼暴露的影响。模拟伊马替尼暴露在患者明显高于EMR相比,患者没有(几何平均数AUC0-24,党卫军51.2 vs 42.7μg h mL-1 p党卫军,最小1.1 vs 0.9μg mL-1 p党卫军,最大3.4 vs 2.8μg mL-1 p 0-24,党卫军56.1 vs 45.9μg h mL-1 p党卫军,最小1.2 vs 1.0μg mL-1 p党卫军,最大3.7 vs 3.0μg mL-1 p浓度1酸性糖蛋白,肝脏和肾脏功能)和与药物因素(剂量,伴随CYP2C8调节剂)导致伊马替尼暴露的个体间变异性。伊马替尼血浆暴露、EMR实现和不良反应之间的关系支持治疗药物监测的基本原理,以指导伊马替尼给药,以实现CML的最佳结果。
{"title":"Application of physiologically based pharmacokinetic modeling to understand real-world outcomes in patients receiving imatinib for chronic myeloid leukemia.","authors":"Josephine A Adattini, Jeffry Adiwidjaja, Annette S Gross, Andrew J McLachlan","doi":"10.1002/prp2.1082","DOIUrl":"https://doi.org/10.1002/prp2.1082","url":null,"abstract":"<p><p>We aimed to use physiologically based pharmacokinetic (PBPK) modeling and simulation to predict imatinib steady-state plasma exposure in patients with chronic myeloid leukemia (CML) to investigate variability in outcomes. A validated imatinib PBPK model (Simcyp Simulator) was used to predict imatinib AUC<sub>ss</sub> , C<sub>ss,min</sub> and C<sub>ss,max</sub> for patients with CML (n = 68) from a real-world retrospective observational study. Differences in imatinib exposure were evaluated based on clinical outcomes, (a) Early Molecular Response (EMR) achievement and (b) occurrence of grade ≥3 adverse drug reactions (ADRs), using the Kruskal-Wallis rank sum test. Sensitivity analyses explored the influence of patient characteristics and drug interactions on imatinib exposure. Simulated imatinib exposure was significantly higher in patients who achieved EMR compared to patients who did not (geometric mean AUC<sub>0-24,ss</sub> 51.2 vs. 42.7 μg h mL<sup>-1</sup> , p < 0.05; C<sub>ss,min</sub> 1.1 vs. 0.9 μg mL<sup>-1</sup> , p < 0.05; C<sub>ss,max</sub> 3.4 vs. 2.8 μg mL<sup>-1</sup> , p < 0.05). Patients who experienced grade ≥3 ADRs had a significantly higher simulated imatinib exposure compared to patients who did not (AUC<sub>0-24,ss</sub> 56.1 vs. 45.9 μg h mL<sup>-1</sup> , p < 0.05; C<sub>ss,min</sub> 1.2 vs. 1.0 μg mL<sup>-1</sup> , p < 0.05; C<sub>ss,max</sub> 3.7 vs. 3.0 μg mL<sup>-1</sup> , p < 0.05). Simulations identified a range of patient (sex, age, weight, abundance of hepatic CYP2C8 and CYP3A4, α<sub>1</sub> -acid glycoprotein concentrations, liver and kidney function) and medication-related factors (dose, concomitant CYP2C8 modulators) contributing to the inter-individual variability in imatinib exposure. Relationships between imatinib plasma exposure, EMR achievement and ADRs support the rationale for therapeutic drug monitoring to guide imatinib dosing to achieve optimal outcomes in CML.</p>","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"11 4","pages":"e01082"},"PeriodicalIF":2.6,"publicationDate":"2023-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10326685/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9807933","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}
Lucia Ferrazzano, Alessandra Tolomelli, Ivan Guryanov, Marco Macis, Ulrich Abel, Antonio Ricci, Walter Cabri
One of the main objectives of peptide drug design is the improvement of peptide pharmacokinetics with maintaining biological activity, which can be achieved by the complex modifications of the primary structure of the peptides. However, these changes often lead to the formation of peculiar impurities in the peptide drugs and their metabolites, which require the development of advanced analytical methods to properly assess their content. Here, we investigated the degradation of the potent long-acting GnRH antagonist degarelix in various biologic media by the tailor-made HPLC method, which allows precise determination of 5-Aph(Hyd)-degarelix isomer, an impurity found in the degarelix active pharmaceutical ingredient (API) during its manufacturing. Unexpectedly, we discovered a rapid and irreversible conversion of degarelix API into the corresponding hydantoin isomer in serum, suggesting that this impurity can be also a potential drug metabolite in vivo. This finding underlines the importance of the development of more accurate and performing analytical techniques to correctly characterize the chemical composition of the manufactured drugs and their behavior under physiological conditions.
{"title":"Investigation of the GnRH antagonist degarelix isomerization in biological matrices.","authors":"Lucia Ferrazzano, Alessandra Tolomelli, Ivan Guryanov, Marco Macis, Ulrich Abel, Antonio Ricci, Walter Cabri","doi":"10.1002/prp2.1117","DOIUrl":"https://doi.org/10.1002/prp2.1117","url":null,"abstract":"<p><p>One of the main objectives of peptide drug design is the improvement of peptide pharmacokinetics with maintaining biological activity, which can be achieved by the complex modifications of the primary structure of the peptides. However, these changes often lead to the formation of peculiar impurities in the peptide drugs and their metabolites, which require the development of advanced analytical methods to properly assess their content. Here, we investigated the degradation of the potent long-acting GnRH antagonist degarelix in various biologic media by the tailor-made HPLC method, which allows precise determination of 5-Aph(Hyd)-degarelix isomer, an impurity found in the degarelix active pharmaceutical ingredient (API) during its manufacturing. Unexpectedly, we discovered a rapid and irreversible conversion of degarelix API into the corresponding hydantoin isomer in serum, suggesting that this impurity can be also a potential drug metabolite in vivo. This finding underlines the importance of the development of more accurate and performing analytical techniques to correctly characterize the chemical composition of the manufactured drugs and their behavior under physiological conditions.</p>","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"11 4","pages":"e01117"},"PeriodicalIF":2.6,"publicationDate":"2023-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10350552/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9891068","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}
Ethnopharmacology seeks to investigate humankind's use of natural materials, such as plants, fungi, microorganisms, animals, and minerals, for medicinal purposes. In this highly interdisciplinary field, which can be described as a bridge between the natural/medical and socio-cultural sciences, pharmacological, anthropological, and socio-cultural research methods are often applied, along with methods from other branches of science. When entering the field of ethnopharmacology as a newcomer, student, or early career researcher today, the tremendous amount of scientific publications, and even classical books from this field and related scientific disciplines, can be overwhelming. Ethnopharmacology has evolved over the past decades, and new key topics, such as the decolonization of the field, issues on intellectual property and benefit-sharing, species conservation, the preservation of traditional knowledge, the protection of indigenous communities, science outreach, and climate change, have become important and urgent aspects of the field that must not be disregarded by today's ethnopharmacologists. One of the questions of newcomers will be, "Where to begin?" This review article offers a brief (and certainly not comprehensive) introduction to the science of ethnopharmacology, highlighting some of its past most notable achievements and future prospects. In addition, this article provides an example for newcomers to the field of how to address different stages that may be involved in conducting ethnopharmacological field and lab studies, including early-stage drug discovery and community work. The example presented summarizes a series of studies conducted in the remote Greater Mpigi region of Uganda, located in East Africa. Stages of ethnopharmacological research described include ethnobotanical surveying and fieldwork, the pharmacological assessment of activity with diverse targets in the laboratory, and the transfer of results back to indigenous communities, that is, non-financial benefit sharing as a potential best practice example. As a result of this research example, a total of six original research articles have been published on the medicinal application and ethnopharmacology of 16 plant species from the Ugandan study site, offering a large quantity of results. These six publications reflect the multifaceted nature of the interdisciplinary science of ethnopharmacology, which may serve as a reference point and inspiration for newcomers to design and conduct their own independent ethnopharmacological research endeavors at other study sites. Major bottlenecks and solutions are provided, and the current social media channels with educational ethnopharmacological content are briefly introduced.
{"title":"How to approach a study in ethnopharmacology? Providing an example of the different research stages for newcomers to the field today.","authors":"Fabien Schultz, Leif-Alexander Garbe","doi":"10.1002/prp2.1109","DOIUrl":"https://doi.org/10.1002/prp2.1109","url":null,"abstract":"<p><p>Ethnopharmacology seeks to investigate humankind's use of natural materials, such as plants, fungi, microorganisms, animals, and minerals, for medicinal purposes. In this highly interdisciplinary field, which can be described as a bridge between the natural/medical and socio-cultural sciences, pharmacological, anthropological, and socio-cultural research methods are often applied, along with methods from other branches of science. When entering the field of ethnopharmacology as a newcomer, student, or early career researcher today, the tremendous amount of scientific publications, and even classical books from this field and related scientific disciplines, can be overwhelming. Ethnopharmacology has evolved over the past decades, and new key topics, such as the decolonization of the field, issues on intellectual property and benefit-sharing, species conservation, the preservation of traditional knowledge, the protection of indigenous communities, science outreach, and climate change, have become important and urgent aspects of the field that must not be disregarded by today's ethnopharmacologists. One of the questions of newcomers will be, \"Where to begin?\" This review article offers a brief (and certainly not comprehensive) introduction to the science of ethnopharmacology, highlighting some of its past most notable achievements and future prospects. In addition, this article provides an example for newcomers to the field of how to address different stages that may be involved in conducting ethnopharmacological field and lab studies, including early-stage drug discovery and community work. The example presented summarizes a series of studies conducted in the remote Greater Mpigi region of Uganda, located in East Africa. Stages of ethnopharmacological research described include ethnobotanical surveying and fieldwork, the pharmacological assessment of activity with diverse targets in the laboratory, and the transfer of results back to indigenous communities, that is, non-financial benefit sharing as a potential best practice example. As a result of this research example, a total of six original research articles have been published on the medicinal application and ethnopharmacology of 16 plant species from the Ugandan study site, offering a large quantity of results. These six publications reflect the multifaceted nature of the interdisciplinary science of ethnopharmacology, which may serve as a reference point and inspiration for newcomers to design and conduct their own independent ethnopharmacological research endeavors at other study sites. Major bottlenecks and solutions are provided, and the current social media channels with educational ethnopharmacological content are briefly introduced.</p>","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"11 4","pages":"e01109"},"PeriodicalIF":2.6,"publicationDate":"2023-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/b9/c6/PRP2-11-e01109.PMC10375576.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9895647","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}
Pengxiang Zhou, Lu Chen, Ente Wang, Lanzhi He, Shuxia Tian, Suodi Zhai
This study aims to evaluate the efficacy and safety of multiple or single-dosage intravenous ibuprofen (IVIB) in managing postoperative pain and fever in adults who are unable to take oral medications. A systematic review and meta-analysis was conducted based on randomized controlled trials (RCTs) comparing IVIB with placebo or other analgesic and antipyretic medications for postoperative pain and fever management. Data were collected from 8 main databases from the inception to June 2022. Risk of bias assessment was performed, and the GRADE methodology was used to assess the certainty of pooled evidence. Primary outcomes included visual analogue scale (VAS) scores within 24 h postoperative and reduction of temperature. Meta-analyses were conducted to calculate the mean difference (MD) or risk ratios (RR) and 95% CIs. As a result, a total of twenty-three RCTs with 3716 participants were included. For postoperative pain, with moderate-to-low certainty evidence, IVIB was associated with lower postoperative VAS scores than placebo, with MD ranging from -3.53 (95% CI, -4.32 to -2.75) at 0 min to -0.96 (95% CI, -1.35 to -0.57) at 24 h. Compared with intravenous acetaminophen, IVIB demonstrated lower VAS scores (MD, -1.54 at 0 min; -0.36 at 24 h). For fever, IVIB showed satisfactory antipyretic efficiency in a short period of time, but no difference was observed between IVIB and intravenous acetaminophen. IVIB was well-tolerated for both pain and fever management. In conclusion, moderate-to-low certainty evidence supports the use of IVIB for adults with postoperative pain and fever who are unable to take oral medications.
{"title":"Intravenous ibuprofen in postoperative pain and fever management in adults: A systematic review and meta-analysis of randomized controlled trials.","authors":"Pengxiang Zhou, Lu Chen, Ente Wang, Lanzhi He, Shuxia Tian, Suodi Zhai","doi":"10.1002/prp2.1123","DOIUrl":"https://doi.org/10.1002/prp2.1123","url":null,"abstract":"<p><p>This study aims to evaluate the efficacy and safety of multiple or single-dosage intravenous ibuprofen (IVIB) in managing postoperative pain and fever in adults who are unable to take oral medications. A systematic review and meta-analysis was conducted based on randomized controlled trials (RCTs) comparing IVIB with placebo or other analgesic and antipyretic medications for postoperative pain and fever management. Data were collected from 8 main databases from the inception to June 2022. Risk of bias assessment was performed, and the GRADE methodology was used to assess the certainty of pooled evidence. Primary outcomes included visual analogue scale (VAS) scores within 24 h postoperative and reduction of temperature. Meta-analyses were conducted to calculate the mean difference (MD) or risk ratios (RR) and 95% CIs. As a result, a total of twenty-three RCTs with 3716 participants were included. For postoperative pain, with moderate-to-low certainty evidence, IVIB was associated with lower postoperative VAS scores than placebo, with MD ranging from -3.53 (95% CI, -4.32 to -2.75) at 0 min to -0.96 (95% CI, -1.35 to -0.57) at 24 h. Compared with intravenous acetaminophen, IVIB demonstrated lower VAS scores (MD, -1.54 at 0 min; -0.36 at 24 h). For fever, IVIB showed satisfactory antipyretic efficiency in a short period of time, but no difference was observed between IVIB and intravenous acetaminophen. IVIB was well-tolerated for both pain and fever management. In conclusion, moderate-to-low certainty evidence supports the use of IVIB for adults with postoperative pain and fever who are unable to take oral medications.</p>","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"11 4","pages":"e01123"},"PeriodicalIF":2.6,"publicationDate":"2023-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/c9/fa/PRP2-11-e01123.PMC10395276.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9933209","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}
Robert Freeze, Kelly W Yang, Timothy Haystead, Philip Hughes, Scott Scarneo
Rheumatoid arthritis (RA) is a complex autoimmune disease characterized by hyperactive immune cells within the joints, which leads to inflammation, bone degeneration, and chronic pain. For several decades, frontline immunomodulators such as the anti-tumor necrosis factor (TNF) biologics adalimumab (Humira), etanercept (Enbrel), and infliximab (Remicade) have successfully managed disease progression for many patients. However, over time, patients become refractory to these treatments requiring chronic disease to be managed with conventional and more problematic disease modifying antirheumatic drugs such as methotrexate and hydroxychloroquine, and corticosteroids. Due to the large proportion of patients who continue to fail on frontline biologic therapies, there remains an unmet need to derive novel alternative targets with improved efficacy and safety profiles to treat RA. Recent advances in the field have defined novel targets that play important roles in RA pathology, including the Janus activated kinase (JAK) and transforming growth factor beta activated kinase-1 (TAK1). Although three inhibitors of the JAK signaling pathway have been approved for the treatment of moderately to severely active RA in patients who failed on one or more anti-TNFs, at present, no FDA approved TAK1 treatments exist. Our recent discovery of a highly potent and selective, orally bioavailable TAK1 inhibitor has provided insight into the therapeutic potential of this protein kinase as a novel target for RA. Here, we show the distinct cytokine signaling of tofacitnib (Xeljanz; JAK1/3 inhibitor) compared to HS-276 (TAK1 inhibitor) in lipopolysaccharide (LPS) challenged THP-1 cells. Furthermore, in the collagen induced arthritis pre-clinical mouse model of RA, both tofacintib and HS-276 attenuated disease activity score and inflammatory cytokines in the serum. Overall, our results delineate the distinct cytokine signaling of JAK1/3 and TAK1 targeted therapies in vitro and in vivo and suggest that selective TAK1 inhibitors may provide superior therapeutic relief in RA with fewer adverse events.
{"title":"Delineation of the distinct inflammatory signaling roles of TAK1 and JAK1/3 in the CIA model of rheumatoid arthritis.","authors":"Robert Freeze, Kelly W Yang, Timothy Haystead, Philip Hughes, Scott Scarneo","doi":"10.1002/prp2.1124","DOIUrl":"10.1002/prp2.1124","url":null,"abstract":"<p><p>Rheumatoid arthritis (RA) is a complex autoimmune disease characterized by hyperactive immune cells within the joints, which leads to inflammation, bone degeneration, and chronic pain. For several decades, frontline immunomodulators such as the anti-tumor necrosis factor (TNF) biologics adalimumab (Humira), etanercept (Enbrel), and infliximab (Remicade) have successfully managed disease progression for many patients. However, over time, patients become refractory to these treatments requiring chronic disease to be managed with conventional and more problematic disease modifying antirheumatic drugs such as methotrexate and hydroxychloroquine, and corticosteroids. Due to the large proportion of patients who continue to fail on frontline biologic therapies, there remains an unmet need to derive novel alternative targets with improved efficacy and safety profiles to treat RA. Recent advances in the field have defined novel targets that play important roles in RA pathology, including the Janus activated kinase (JAK) and transforming growth factor beta activated kinase-1 (TAK1). Although three inhibitors of the JAK signaling pathway have been approved for the treatment of moderately to severely active RA in patients who failed on one or more anti-TNFs, at present, no FDA approved TAK1 treatments exist. Our recent discovery of a highly potent and selective, orally bioavailable TAK1 inhibitor has provided insight into the therapeutic potential of this protein kinase as a novel target for RA. Here, we show the distinct cytokine signaling of tofacitnib (Xeljanz; JAK1/3 inhibitor) compared to HS-276 (TAK1 inhibitor) in lipopolysaccharide (LPS) challenged THP-1 cells. Furthermore, in the collagen induced arthritis pre-clinical mouse model of RA, both tofacintib and HS-276 attenuated disease activity score and inflammatory cytokines in the serum. Overall, our results delineate the distinct cytokine signaling of JAK1/3 and TAK1 targeted therapies in vitro and in vivo and suggest that selective TAK1 inhibitors may provide superior therapeutic relief in RA with fewer adverse events.</p>","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"11 4","pages":"e01124"},"PeriodicalIF":2.6,"publicationDate":"2023-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/9f/9f/PRP2-11-e01124.PMC10415874.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9997425","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}