This study was designed to assess the quantitative performance of endogenous drug-drug interaction (DDI) biomarkers (N1-methylnicotinamide (1-NMN), N1-methyladenosine (m1A), and creatinine) for the organic cation transporters, OCT2 and MATE1/2K in the kidney. Ten healthy volunteers received cimetidine (400 and 800 mg, single dose) or dolutegravir (50 mg, twice a day) together with metformin (500 mg). Cimetidine and dolutegravir were considered to act mainly as MATE1/2K and OCT2 inhibitors, respectively. The renal clearance (CLr) of metformin was decreased by 15.5% and 42.5% by cimetidine 400 and 800 mg, and by 26.8% and 56.9% by dolutegravir first and fifth doses, respectively. CLr ratio (CLrR) of 1-NMN were 0.93 and 0.64 for cimetidine 400 and 800 mg, and 0.87 and 0.47 for dolutegravir first and fifth doses, respectively. CLrR of m1A was less than that of 1-NMN: 1.0 and 0.80 for cimetidine 400 and 800 mg, and 0.77 and 0.71 for dolutegravir first and fifth doses, respectively. CLr of creatinine was significantly decreased only by cimetidine 800 mg. Individual CLrR of 1-NMN and m1A showed a positive correlation with the corresponding CLrR of metformin with r2 of 0.58 and 0.55, respectively. When evaluated individually, m1A showed a better correlation during cimetidine periods (r2 0.64) than 1-NMN (r2 0.36), but vice versa during dolutegravir periods (r2 1-NMN, 0.80; m1A, 0.32). These results suggest that 1-NMN and m1A might be more promising than creatinine as endogenous biomarkers for quantitatively assessing the DDI potential of investigational drugs for OCT2 and MATE1/2K based on their CLrR change.
{"title":"Effects of Cimetidine and Dolutegravir on the Endogenous Drug-Drug Interaction Biomarkers for Organic Cation Transporter 2 and Multidrug and Toxin Extrusion Protein 1 in Healthy Volunteers.","authors":"Tomoki Koishikawa, Kaku Fujiwara, Kunal Taskar, Maciej J Zamek-Gliszczynski, Kenta Yoshida, Xiaoyan Chu, Hideki Hirabayashi, Jialin Mao, Kevin Rockich, Tadayuki Takashima, Yoshiyuki Yamaura, Yurong Lai, Yukana Tomoda, Tomoko Kito, Kazuya Maeda, Kenichi Furihata, Yuichi Sugiyama, Hiroyuki Kusuhara","doi":"10.1002/cpt.3482","DOIUrl":"https://doi.org/10.1002/cpt.3482","url":null,"abstract":"<p><p>This study was designed to assess the quantitative performance of endogenous drug-drug interaction (DDI) biomarkers (N1-methylnicotinamide (1-NMN), N1-methyladenosine (m<sup>1</sup>A), and creatinine) for the organic cation transporters, OCT2 and MATE1/2K in the kidney. Ten healthy volunteers received cimetidine (400 and 800 mg, single dose) or dolutegravir (50 mg, twice a day) together with metformin (500 mg). Cimetidine and dolutegravir were considered to act mainly as MATE1/2K and OCT2 inhibitors, respectively. The renal clearance (CL<sub>r</sub>) of metformin was decreased by 15.5% and 42.5% by cimetidine 400 and 800 mg, and by 26.8% and 56.9% by dolutegravir first and fifth doses, respectively. CL<sub>r</sub> ratio (CL<sub>r</sub>R) of 1-NMN were 0.93 and 0.64 for cimetidine 400 and 800 mg, and 0.87 and 0.47 for dolutegravir first and fifth doses, respectively. CL<sub>r</sub>R of m<sup>1</sup>A was less than that of 1-NMN: 1.0 and 0.80 for cimetidine 400 and 800 mg, and 0.77 and 0.71 for dolutegravir first and fifth doses, respectively. CL<sub>r</sub> of creatinine was significantly decreased only by cimetidine 800 mg. Individual CL<sub>r</sub>R of 1-NMN and m<sup>1</sup>A showed a positive correlation with the corresponding CL<sub>r</sub>R of metformin with r<sup>2</sup> of 0.58 and 0.55, respectively. When evaluated individually, m<sup>1</sup>A showed a better correlation during cimetidine periods (r<sup>2</sup> 0.64) than 1-NMN (r<sup>2</sup> 0.36), but vice versa during dolutegravir periods (r<sup>2</sup> 1-NMN, 0.80; m<sup>1</sup>A, 0.32). These results suggest that 1-NMN and m<sup>1</sup>A might be more promising than creatinine as endogenous biomarkers for quantitatively assessing the DDI potential of investigational drugs for OCT2 and MATE1/2K based on their CL<sub>r</sub>R change.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":null,"pages":null},"PeriodicalIF":6.3,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142574937","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Correction to Beyond MABEL: An Integrative Approach to First in Human Dose Selection of Immunomodulators by the Health and Environmental Sciences Institute (HESI) Immuno-Safety Technical Committee (ITC).","authors":"","doi":"10.1002/cpt.3489","DOIUrl":"https://doi.org/10.1002/cpt.3489","url":null,"abstract":"","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":null,"pages":null},"PeriodicalIF":6.3,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142566787","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jonas A Blöcher, Marleen J Meyer-Tönnies, Felix Morof, Vincent Rönnpagel, Jonas Bethmann, Marcus Vollmer, Stefan Engeli, Mladen V Tzvetkov
An over-the-counter product berberine (a major alkaloid in goldenseal) is a substrate of the uptake transporter OCT1 and the metabolizing enzyme CYP2D6. The two genes exhibit common functional polymorphisms. Approximately 9% of Europeans and white Americans are either poor CYP2D6 metabolizers or poor OCT1 transporters. In this study, we investigated the effects of OCT1 and CYP2D6 polymorphisms on berberine pharmacokinetics in humans. We confirmed in vitro that berberine is an OCT1 substrate (KM of 7.0 μM, CLint of 306 ± 29 μL/min/mg). Common OCT1 alleles *3 to *6 showed uptake reduced by at least 65% and Oct1/2 knockout mice showed 3.2-fold higher AUCs in liver perfusion experiments. However, in humans, poor OCT1 transporters did not show any differences in berberine pharmacokinetics compared with reference participants. In contrast, CYP2D6 polymorphisms significantly affected berberine metabolism, but exclusively in females. Females who were poor CYP2D6 metabolizers had an 80% lower M1-to-berberine ratio. General linear model analyses suggest strong synergistic, rather than additive, effects between female sex and CYP2D6 genotype. Overall, berberine displayed low oral bioavailability, yet females had a 2.8-fold higher AUC and a 3.6-fold higher Cmax than males (P < 0.001). These effects were only partially attributable to the sex-CYP2D6 genotype interaction. In conclusion, despite berberine being an OCT1 substrate, OCT1 deficiency did not affect berberine pharmacokinetics in humans. In contrast, CYP2D6 emerges as a critical enzyme for berberine metabolism in females, but not in males, highlighting sex-specific differences. We suggest that factors beyond CYP2D6 metabolism are determining berberine's systemic exposure, especially in males (NCT05463003).
{"title":"Sex-Dependent Effects of CYP2D6 on the Pharmacokinetics of Berberine in Humans.","authors":"Jonas A Blöcher, Marleen J Meyer-Tönnies, Felix Morof, Vincent Rönnpagel, Jonas Bethmann, Marcus Vollmer, Stefan Engeli, Mladen V Tzvetkov","doi":"10.1002/cpt.3454","DOIUrl":"https://doi.org/10.1002/cpt.3454","url":null,"abstract":"<p><p>An over-the-counter product berberine (a major alkaloid in goldenseal) is a substrate of the uptake transporter OCT1 and the metabolizing enzyme CYP2D6. The two genes exhibit common functional polymorphisms. Approximately 9% of Europeans and white Americans are either poor CYP2D6 metabolizers or poor OCT1 transporters. In this study, we investigated the effects of OCT1 and CYP2D6 polymorphisms on berberine pharmacokinetics in humans. We confirmed in vitro that berberine is an OCT1 substrate (K<sub>M</sub> of 7.0 μM, CL<sub>int</sub> of 306 ± 29 μL/min/mg). Common OCT1 alleles *3 to *6 showed uptake reduced by at least 65% and Oct1/2 knockout mice showed 3.2-fold higher AUCs in liver perfusion experiments. However, in humans, poor OCT1 transporters did not show any differences in berberine pharmacokinetics compared with reference participants. In contrast, CYP2D6 polymorphisms significantly affected berberine metabolism, but exclusively in females. Females who were poor CYP2D6 metabolizers had an 80% lower M1-to-berberine ratio. General linear model analyses suggest strong synergistic, rather than additive, effects between female sex and CYP2D6 genotype. Overall, berberine displayed low oral bioavailability, yet females had a 2.8-fold higher AUC and a 3.6-fold higher C<sub>max</sub> than males (P < 0.001). These effects were only partially attributable to the sex-CYP2D6 genotype interaction. In conclusion, despite berberine being an OCT1 substrate, OCT1 deficiency did not affect berberine pharmacokinetics in humans. In contrast, CYP2D6 emerges as a critical enzyme for berberine metabolism in females, but not in males, highlighting sex-specific differences. We suggest that factors beyond CYP2D6 metabolism are determining berberine's systemic exposure, especially in males (NCT05463003).</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":null,"pages":null},"PeriodicalIF":6.3,"publicationDate":"2024-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142566793","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Shao-Hsuan Chang, Roniel Cabrera, Jihaeng Heo, Chanhyun Park, Jingchuan Guo, Haesuk Park
The association between direct-acting antiviral (DAA) treatment and hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) is currently unclear. Hence, we aim to assess the association between DAA treatment and mortality rate among Medicare beneficiaries with HCV-related HCC. This retrospective cohort study screened 19,813 adults in 2013-2019 Surveillance, Epidemiology, and End Results data linked with Medicare data. Patients with HCV-related HCC initiating DAA therapy after their first HCC diagnosis were compared with patients with HCV-related HCC who received no HCV treatment. After inverse probability treatment weighting, multivariable Cox proportional hazards models compared mortality rates between the groups. Subgroup and sensitivity analyses were based on HCC stage (early vs. advanced), type of HCC treatment (curative, palliative, none), and DAA treatment duration. In total 3,777 patients with HCV-related HCC were identified (mean age: 68.2 years, 75.2% male, 61.8% White), of whom 19% initiated DAA therapy. Crude incidence mortality rates were 17.9 and 90.7 deaths per 100 person-years in the DAA and HCV-untreated groups, respectively. Cox regression models indicated that DAA therapy was associated with decreased risk of all-cause mortality (adjusted hazard ratio, 0.33; 95% CI 0.31-0.36). Median survival time was 45.7 (95% CI 40.9-57.9) months in the DAA group and 7.7 (95% CI 7.3-8.2) months in the HCV-untreated group (P < 0.001). All subgroup and sensitivity analyses were consistent with the main analyses. DAA therapy was associated with survival benefits for patients with HCV-related HCC regardless of the stage or type of HCC treatment and should not be withheld from this population of Medicare beneficiaries.
{"title":"Real-World Effectiveness of All-Oral Direct-Acting Antivirals in Patients With Hepatitis C Virus-Related HCC.","authors":"Shao-Hsuan Chang, Roniel Cabrera, Jihaeng Heo, Chanhyun Park, Jingchuan Guo, Haesuk Park","doi":"10.1002/cpt.3481","DOIUrl":"https://doi.org/10.1002/cpt.3481","url":null,"abstract":"<p><p>The association between direct-acting antiviral (DAA) treatment and hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) is currently unclear. Hence, we aim to assess the association between DAA treatment and mortality rate among Medicare beneficiaries with HCV-related HCC. This retrospective cohort study screened 19,813 adults in 2013-2019 Surveillance, Epidemiology, and End Results data linked with Medicare data. Patients with HCV-related HCC initiating DAA therapy after their first HCC diagnosis were compared with patients with HCV-related HCC who received no HCV treatment. After inverse probability treatment weighting, multivariable Cox proportional hazards models compared mortality rates between the groups. Subgroup and sensitivity analyses were based on HCC stage (early vs. advanced), type of HCC treatment (curative, palliative, none), and DAA treatment duration. In total 3,777 patients with HCV-related HCC were identified (mean age: 68.2 years, 75.2% male, 61.8% White), of whom 19% initiated DAA therapy. Crude incidence mortality rates were 17.9 and 90.7 deaths per 100 person-years in the DAA and HCV-untreated groups, respectively. Cox regression models indicated that DAA therapy was associated with decreased risk of all-cause mortality (adjusted hazard ratio, 0.33; 95% CI 0.31-0.36). Median survival time was 45.7 (95% CI 40.9-57.9) months in the DAA group and 7.7 (95% CI 7.3-8.2) months in the HCV-untreated group (P < 0.001). All subgroup and sensitivity analyses were consistent with the main analyses. DAA therapy was associated with survival benefits for patients with HCV-related HCC regardless of the stage or type of HCC treatment and should not be withheld from this population of Medicare beneficiaries.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":null,"pages":null},"PeriodicalIF":6.3,"publicationDate":"2024-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142566789","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Matthew W Hruska, Lamia Sid-Otmane, Nathalie H Gosselin, Emilia Quattrocchi, Sun Ku Lee, Mary Ann Mascelli, Krina Mehta, Suzanne M Jan de Beur, Douglas Marsteller
Burosumab is approved for the treatment of hypophosphatemia in persistent tumor-induced osteomalacia. This work exemplifies a model-informed drug development approach that evaluated burosumab pharmacokinetics and pharmacokinetic/pharmacodynamics in the ultrarare tumor-induced osteomalacia population to support adult and pediatric dosing. Data from tumor-induced osteomalacia participants were combined with data from X-linked hypophosphatemia to understand pharmacokinetic and pharmacokinetic/pharmacodynamic characteristics and covariates specific to tumor-induced osteomalacia. Pharmacokinetic and pharmacokinetic/pharmacodynamic simulations were performed using final models to support dosing recommendations for adults and extrapolation to pediatric patients. Burosumab pharmacokinetics were described using a one-compartment model with first-order absorption and body weight as a significant covariate. Pharmacokinetic/pharmacodynamic relationships were described using a sigmoidal Emax model with significant covariates of baseline fibroblast growth factor 23 on baseline fasting serum phosphate and potency of burosumab response and tumor-induced osteomalacia disease state resulting in a steep slope of response; however, the covariates are not clinically meaningful. Simulations demonstrated that, in pediatric patients, starting doses of burosumab 0.3 and 0.4 mg/kg every 2 weeks at steady state would achieve normal serum phosphate levels in ≥ 30% of patients with relatively low risk of hyperphosphatemia (< 3%). In adults, burosumab 0.3 and 0.5 mg/kg every 4 weeks achieves similar percentages of responders and a relative low risk of hyperphosphatemia (< 7%). Serum phosphate titration-based burosumab dosing increased the probability of achieving normal serum phosphate levels. The models supported a model-informed drug development approach for global approvals of titration-based burosumab dosing, guided by monitoring fasting serum phosphate levels.
{"title":"Model-Informed Approach to Recommend Burosumab Dosing Regimens for Pediatric and Adult Patients With the Ultrarare Disease Tumor-Induced Osteomalacia.","authors":"Matthew W Hruska, Lamia Sid-Otmane, Nathalie H Gosselin, Emilia Quattrocchi, Sun Ku Lee, Mary Ann Mascelli, Krina Mehta, Suzanne M Jan de Beur, Douglas Marsteller","doi":"10.1002/cpt.3468","DOIUrl":"https://doi.org/10.1002/cpt.3468","url":null,"abstract":"<p><p>Burosumab is approved for the treatment of hypophosphatemia in persistent tumor-induced osteomalacia. This work exemplifies a model-informed drug development approach that evaluated burosumab pharmacokinetics and pharmacokinetic/pharmacodynamics in the ultrarare tumor-induced osteomalacia population to support adult and pediatric dosing. Data from tumor-induced osteomalacia participants were combined with data from X-linked hypophosphatemia to understand pharmacokinetic and pharmacokinetic/pharmacodynamic characteristics and covariates specific to tumor-induced osteomalacia. Pharmacokinetic and pharmacokinetic/pharmacodynamic simulations were performed using final models to support dosing recommendations for adults and extrapolation to pediatric patients. Burosumab pharmacokinetics were described using a one-compartment model with first-order absorption and body weight as a significant covariate. Pharmacokinetic/pharmacodynamic relationships were described using a sigmoidal Emax model with significant covariates of baseline fibroblast growth factor 23 on baseline fasting serum phosphate and potency of burosumab response and tumor-induced osteomalacia disease state resulting in a steep slope of response; however, the covariates are not clinically meaningful. Simulations demonstrated that, in pediatric patients, starting doses of burosumab 0.3 and 0.4 mg/kg every 2 weeks at steady state would achieve normal serum phosphate levels in ≥ 30% of patients with relatively low risk of hyperphosphatemia (< 3%). In adults, burosumab 0.3 and 0.5 mg/kg every 4 weeks achieves similar percentages of responders and a relative low risk of hyperphosphatemia (< 7%). Serum phosphate titration-based burosumab dosing increased the probability of achieving normal serum phosphate levels. The models supported a model-informed drug development approach for global approvals of titration-based burosumab dosing, guided by monitoring fasting serum phosphate levels.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":null,"pages":null},"PeriodicalIF":6.3,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142491614","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ashish Sharma, Islam R Younis, Jitendra Kanodia, Vaishali Sahasrabudhe
The IQ CPLG Organ Impairment WG conducted a survey to understand how various IQ member companies develop dosing recommendations for patients with renal impairment. Eighteen IQ member companies participated in the survey. The survey results were summarized by the working group in light of the regulatory renal impairment guidance documents as well as recent publications from the pharmaceutical industry and nephrology community. There were two important learnings from the survey: (i) pharmaceutical companies do not use a consistent methodology to assess renal function in their drug development programs. (ii) there has been significant improvement in predicting how kidney function affects drug pharmacokinetics (PK) and thus dose recommendations. Applying model-based methods such as population PK, physiologically-based PK (PBPK), and virtual controls has enabled earlier prediction of how kidney function influences PK, leading to the participation of more patients with impaired kidney function in Phase 2 and 3 trials.
IQ CPLG 器官损伤工作组进行了一项调查,以了解各 IQ 成员公司如何为肾功能损伤患者制定用药建议。18 家 IQ 成员公司参与了调查。工作组根据监管部门的肾功能损害指导文件以及制药行业和肾病学界最近的出版物对调查结果进行了总结。调查有两个重要发现:(i) 制药公司在药物开发项目中没有使用统一的方法来评估肾功能。(ii) 在预测肾功能如何影响药物药代动力学 (PK) 以及剂量建议方面已经取得了重大进展。应用基于模型的方法,如群体 PK、基于生理的 PK (PBPK) 和虚拟对照,可以更早地预测肾功能对 PK 的影响,从而让更多肾功能受损的患者参与 2 期和 3 期试验。
{"title":"An IQ Industry Perspective on Informing Dosing Recommendations in Patients With Renal Impairment.","authors":"Ashish Sharma, Islam R Younis, Jitendra Kanodia, Vaishali Sahasrabudhe","doi":"10.1002/cpt.3463","DOIUrl":"https://doi.org/10.1002/cpt.3463","url":null,"abstract":"<p><p>The IQ CPLG Organ Impairment WG conducted a survey to understand how various IQ member companies develop dosing recommendations for patients with renal impairment. Eighteen IQ member companies participated in the survey. The survey results were summarized by the working group in light of the regulatory renal impairment guidance documents as well as recent publications from the pharmaceutical industry and nephrology community. There were two important learnings from the survey: (i) pharmaceutical companies do not use a consistent methodology to assess renal function in their drug development programs. (ii) there has been significant improvement in predicting how kidney function affects drug pharmacokinetics (PK) and thus dose recommendations. Applying model-based methods such as population PK, physiologically-based PK (PBPK), and virtual controls has enabled earlier prediction of how kidney function influences PK, leading to the participation of more patients with impaired kidney function in Phase 2 and 3 trials.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":null,"pages":null},"PeriodicalIF":6.3,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142491612","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Julie C Ullman, Ryan A Dick, Daniela Linzner, Todd Minga, Samnang Tep, Terrence F Satterfield, Yannan Xi, David T Beattie, Tonya Marmon, Joel M Neutel, Bernard Chung, Janet M Leeds, Sarah B Noonberg, Eric M Green, Harold S Bernstein
Pompe disease is a rare glycogen storage disease caused by mutations in the enzyme acid α-glucosidase (GAA) resulting in pathological accumulation of glycogen in muscle tissues leading to progressive weakness and respiratory dysfunction. Enzyme replacement therapy (ERT) with GAA is currently the sole treatment option for patients with Pompe disease. ERT burdens patients with frequent intravenous infusions while insufficiently halting disease progression due to incomplete ERT skeletal muscle distribution. Glycogen synthase 1 (GYS1) has been proposed as a substrate reduction therapy (SRT) target for Pompe disease. Here, we report results from the first-in-human study of the orally available GYS1 inhibitor MZE001 in healthy subjects. In 88 participants, MZE001 was well-tolerated up to a single dose of 480 mg BID and multiple doses of 720 mg BID for 10 days. Noncompartmental analysis determined that the half-life and Ctrough concentrations of MZE001 could provide efficacious exposures with once or twice daily oral dosing. Change from baseline of peripheral blood mononuclear cell (PBMC) glycogen, which correlated with muscle glycogen levels in preclinical models, was significantly reduced dose-dependently following 10 days of MZE001 treatment in healthy subjects. A muscle biopsy sub-study demonstrated that 10 days of MZE001 (480 mg BID) dosing safely and substantially lowered muscle glycogen stores in healthy adults. This correlated with the PBMC exposure response and supports the use of PBMC glycogen reduction as a surrogate for muscle response, and MZE001 potential for development as the first oral substrate reduction therapy for patients with Pompe disease.
{"title":"First-in-Human Evaluation of Safety, Pharmacokinetics and Muscle Glycogen Lowering of a Novel Glycogen Synthase 1 Inhibitor for the Treatment of Pompe Disease.","authors":"Julie C Ullman, Ryan A Dick, Daniela Linzner, Todd Minga, Samnang Tep, Terrence F Satterfield, Yannan Xi, David T Beattie, Tonya Marmon, Joel M Neutel, Bernard Chung, Janet M Leeds, Sarah B Noonberg, Eric M Green, Harold S Bernstein","doi":"10.1002/cpt.3470","DOIUrl":"https://doi.org/10.1002/cpt.3470","url":null,"abstract":"<p><p>Pompe disease is a rare glycogen storage disease caused by mutations in the enzyme acid α-glucosidase (GAA) resulting in pathological accumulation of glycogen in muscle tissues leading to progressive weakness and respiratory dysfunction. Enzyme replacement therapy (ERT) with GAA is currently the sole treatment option for patients with Pompe disease. ERT burdens patients with frequent intravenous infusions while insufficiently halting disease progression due to incomplete ERT skeletal muscle distribution. Glycogen synthase 1 (GYS1) has been proposed as a substrate reduction therapy (SRT) target for Pompe disease. Here, we report results from the first-in-human study of the orally available GYS1 inhibitor MZE001 in healthy subjects. In 88 participants, MZE001 was well-tolerated up to a single dose of 480 mg BID and multiple doses of 720 mg BID for 10 days. Noncompartmental analysis determined that the half-life and C<sub>trough</sub> concentrations of MZE001 could provide efficacious exposures with once or twice daily oral dosing. Change from baseline of peripheral blood mononuclear cell (PBMC) glycogen, which correlated with muscle glycogen levels in preclinical models, was significantly reduced dose-dependently following 10 days of MZE001 treatment in healthy subjects. A muscle biopsy sub-study demonstrated that 10 days of MZE001 (480 mg BID) dosing safely and substantially lowered muscle glycogen stores in healthy adults. This correlated with the PBMC exposure response and supports the use of PBMC glycogen reduction as a surrogate for muscle response, and MZE001 potential for development as the first oral substrate reduction therapy for patients with Pompe disease.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":null,"pages":null},"PeriodicalIF":6.3,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142491613","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cheng Chen, Todd A Miano, Colleen M Brensinger, Charles E Leonard, Warren B Bilker, Sean Hennessy
Methadone has a high potential for risky drug-drug interactions that can lead to opioid overdose, yet evidence on the magnitude of this risk remains limited. Since methadone is transported via P-glycoprotein (P-gp), the use of statins that inhibit P-gp may elevate methadone plasma concentrations, potentially leading to opioid overdose. We explored this hypothesis by examining whether concomitant use of methadone and P-gp-inhibiting statins was associated with opioid overdose. Using Medicaid claims data from 2003 to 2020, we conducted a cohort study among new concomitant users of methadone and statins. We compared overdose rates among individuals exposed to P-gp-inhibiting statins (simvastatin, atorvastatin, or lovastatin) vs. those exposed to rosuvastatin (negative control), adjusting for baseline covariates. We identified 69,263 individuals newly exposed to methadone and a statin of interest; the overall incidence rate of opioid overdose was 26.0 per 1,000 person-years. Adjusted hazard ratios (HRs) for methadone + P-gp-inhibiting statins consistently showed no association, ranging from 0.76 (95% CI = 0.48-1.22) for atorvastatin to 0.78 (95% CI = 0.50-1.22) for simvastatin, compared with methadone + rosuvastatin. Similar results were observed in sensitivity analysis that treated all P-gp-inhibiting statins as a single exposure group, as well as analyses stratified by baseline diagnosis of opioid use disorder or overdose, the duration of baseline methadone use, and calendar year intervals. Our findings suggest that concomitant use of methadone with simvastatin, atorvastatin, or lovastatin is not associated with the risk of opioid overdose compared to concomitant use of methadone and rosuvastatin.
{"title":"Risk of Opioid Overdose Associated with Concomitant Use of Methadone and Statins.","authors":"Cheng Chen, Todd A Miano, Colleen M Brensinger, Charles E Leonard, Warren B Bilker, Sean Hennessy","doi":"10.1002/cpt.3479","DOIUrl":"https://doi.org/10.1002/cpt.3479","url":null,"abstract":"<p><p>Methadone has a high potential for risky drug-drug interactions that can lead to opioid overdose, yet evidence on the magnitude of this risk remains limited. Since methadone is transported via P-glycoprotein (P-gp), the use of statins that inhibit P-gp may elevate methadone plasma concentrations, potentially leading to opioid overdose. We explored this hypothesis by examining whether concomitant use of methadone and P-gp-inhibiting statins was associated with opioid overdose. Using Medicaid claims data from 2003 to 2020, we conducted a cohort study among new concomitant users of methadone and statins. We compared overdose rates among individuals exposed to P-gp-inhibiting statins (simvastatin, atorvastatin, or lovastatin) vs. those exposed to rosuvastatin (negative control), adjusting for baseline covariates. We identified 69,263 individuals newly exposed to methadone and a statin of interest; the overall incidence rate of opioid overdose was 26.0 per 1,000 person-years. Adjusted hazard ratios (HRs) for methadone + P-gp-inhibiting statins consistently showed no association, ranging from 0.76 (95% CI = 0.48-1.22) for atorvastatin to 0.78 (95% CI = 0.50-1.22) for simvastatin, compared with methadone + rosuvastatin. Similar results were observed in sensitivity analysis that treated all P-gp-inhibiting statins as a single exposure group, as well as analyses stratified by baseline diagnosis of opioid use disorder or overdose, the duration of baseline methadone use, and calendar year intervals. Our findings suggest that concomitant use of methadone with simvastatin, atorvastatin, or lovastatin is not associated with the risk of opioid overdose compared to concomitant use of methadone and rosuvastatin.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":null,"pages":null},"PeriodicalIF":6.3,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142454182","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Andrew E Beck, Melissa Kampman, Cindy Huynh, Craig Simon, Kelly Plueschke, Catherine Cohet, Patrice Verpillat, Kelly Robinson, Peter Arlett
The International Coalition of Medicines Regulatory Authorities (ICMRA), comprising 38 global medicines regulatory authorities, collaborates on shared challenges, notably during the COVID-19 pandemic. This article focuses on the ICMRA COVID-19 Real-World Evidence (RWE) and Observational Studies Working Group. The Working Group aimed to address challenges related to RWE and observational studies during the pandemic, resulting in impactful studies and ICMRA statements on international collaboration for RWE and COVID-19 vaccine safety. Reflecting on 3 years of collaboration, the Working Group surveyed members for insights, and recommendations were formulated to enhance research preparedness, collaboration, and response to future public health emergencies. The lessons learned highlight the importance of global collaborations, governance structures for rapid decision-making, and effective utilization of existing networks. Recommendations include the establishment of an international governance structure, a "coalition of the willing" for swift research collaboration, dedicated sub-groups, periodic workshops, common protocols, joint timelines, and data model templates, leveraging existing infrastructure, and strengthening outreach for transparency and engagement. The Working Group envisions repurposing into an RWE strategic and operational entity, contributing to global public health emergency response mechanisms. In conclusion, the Working Group's success lies in effective communication, collaborative research, and leveraging existing infrastructure, with ongoing contributions to global emergency response mechanisms.
{"title":"Collaborative Real-World Evidence Among Regulators: Lessons and Perspectives.","authors":"Andrew E Beck, Melissa Kampman, Cindy Huynh, Craig Simon, Kelly Plueschke, Catherine Cohet, Patrice Verpillat, Kelly Robinson, Peter Arlett","doi":"10.1002/cpt.3457","DOIUrl":"https://doi.org/10.1002/cpt.3457","url":null,"abstract":"<p><p>The International Coalition of Medicines Regulatory Authorities (ICMRA), comprising 38 global medicines regulatory authorities, collaborates on shared challenges, notably during the COVID-19 pandemic. This article focuses on the ICMRA COVID-19 Real-World Evidence (RWE) and Observational Studies Working Group. The Working Group aimed to address challenges related to RWE and observational studies during the pandemic, resulting in impactful studies and ICMRA statements on international collaboration for RWE and COVID-19 vaccine safety. Reflecting on 3 years of collaboration, the Working Group surveyed members for insights, and recommendations were formulated to enhance research preparedness, collaboration, and response to future public health emergencies. The lessons learned highlight the importance of global collaborations, governance structures for rapid decision-making, and effective utilization of existing networks. Recommendations include the establishment of an international governance structure, a \"coalition of the willing\" for swift research collaboration, dedicated sub-groups, periodic workshops, common protocols, joint timelines, and data model templates, leveraging existing infrastructure, and strengthening outreach for transparency and engagement. The Working Group envisions repurposing into an RWE strategic and operational entity, contributing to global public health emergency response mechanisms. In conclusion, the Working Group's success lies in effective communication, collaborative research, and leveraging existing infrastructure, with ongoing contributions to global emergency response mechanisms.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":null,"pages":null},"PeriodicalIF":6.3,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142454174","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Esben Iversen, Line Juel Nielsen, Viktor Rotbain Curovic, Anne Byriel Walls, Mie Klessen Eickhoff, Marie Frimodt-Møller, Frederik Persson, Peter Rossing, Morten Baltzer Houlind
Sodium-glucose cotransporter 2 (SGLT2) inhibitors can cause a reversible decline in glomerular filtration rate (GFR), which may influence dosing recommendations for renally excreted medications. In practice, GFR is typically estimated by serum creatinine concentration, but creatinine may not be a reliable indicator of GFR decline in the setting of SGLT2 inhibitor use. Alternative filtration markers such as cystatin C, β-trace protein (BTP), and β2-microglobulin (B2M) may be more appropriate, but little is known about how these markers are affected by SGLT2 inhibitor use. Therefore, we determined creatinine, cystatin C, BTP, and B2M concentration in a crossover study of 35 people with type 2 diabetes receiving 12 weeks of dapagliflozin treatment or placebo. Estimated GFR (eGFR) based on creatinine (eGFRcre), cystatin C (eGFRcys), their combination (eGFRcomb), or a panel of all four markers (eGFRpanel) was compared with measured GFR (mGFR) based on plasma clearance of chromium-51 labeled ethylenediamine tetraacetic acid (51Cr-EDTA). Dapagliflozin treatment was associated with a significant decrease in mGFR (-9 mL/min/1.73 m2, P < 0.001) but not a corresponding increase in concentration of any filtration marker. No eGFR equation accurately predicted change in mGFR between treatment periods, but eGFRcomb and eGFRpanel yielded the highest overall accuracy relative to mGFR across both treatment periods. These findings highlight the stability in performance gained by combining multiple filtration markers but suggest that eGFR in general is not an ideal metric for assessing short-term GFR decline in people initiating SGLT2 inhibitor therapy.
{"title":"Effect of Dapagliflozin on Measured vs. Panel-Estimated Glomerular Filtration Rate.","authors":"Esben Iversen, Line Juel Nielsen, Viktor Rotbain Curovic, Anne Byriel Walls, Mie Klessen Eickhoff, Marie Frimodt-Møller, Frederik Persson, Peter Rossing, Morten Baltzer Houlind","doi":"10.1002/cpt.3480","DOIUrl":"https://doi.org/10.1002/cpt.3480","url":null,"abstract":"<p><p>Sodium-glucose cotransporter 2 (SGLT2) inhibitors can cause a reversible decline in glomerular filtration rate (GFR), which may influence dosing recommendations for renally excreted medications. In practice, GFR is typically estimated by serum creatinine concentration, but creatinine may not be a reliable indicator of GFR decline in the setting of SGLT2 inhibitor use. Alternative filtration markers such as cystatin C, β-trace protein (BTP), and β2-microglobulin (B2M) may be more appropriate, but little is known about how these markers are affected by SGLT2 inhibitor use. Therefore, we determined creatinine, cystatin C, BTP, and B2M concentration in a crossover study of 35 people with type 2 diabetes receiving 12 weeks of dapagliflozin treatment or placebo. Estimated GFR (eGFR) based on creatinine (eGFRcre), cystatin C (eGFRcys), their combination (eGFRcomb), or a panel of all four markers (eGFRpanel) was compared with measured GFR (mGFR) based on plasma clearance of chromium-51 labeled ethylenediamine tetraacetic acid (<sup>51</sup>Cr-EDTA). Dapagliflozin treatment was associated with a significant decrease in mGFR (-9 mL/min/1.73 m<sup>2</sup>, P < 0.001) but not a corresponding increase in concentration of any filtration marker. No eGFR equation accurately predicted change in mGFR between treatment periods, but eGFRcomb and eGFRpanel yielded the highest overall accuracy relative to mGFR across both treatment periods. These findings highlight the stability in performance gained by combining multiple filtration markers but suggest that eGFR in general is not an ideal metric for assessing short-term GFR decline in people initiating SGLT2 inhibitor therapy.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":null,"pages":null},"PeriodicalIF":6.3,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142454176","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}