Journal of Clinical Pharmacology最新文献

{"title":"Indication-Specific Dosing and Dose-Evaluation Strategies in New Indications for Non-Oncology Monoclonal Antibodies.","authors":"Sherouk M Tawfik, Fei Tang","doi":"10.1002/jcph.70000","DOIUrl":"https://doi.org/10.1002/jcph.70000","url":null,"abstract":"<p><p>Compared to traditional small molecule drugs, monoclonal antibodies (mAbs) often display more complex pharmacokinetic (PK) and pharmacodynamic (PD) properties that may be impacted by disease-specific factors. For mAbs in non-oncology indications, where the same drug might be used for conditions involving different organ systems and/or having different degrees of severity, the need for indication-specific dosing and/or tailored dose evaluation strategies is more evident. However, a comprehensive analysis on this topic has not been conducted for approved non-oncology therapies. In this work, we extracted literature information for non-oncology mAbs approved in the past 20 years to provide a comprehensive exploration of indication-specific dosing and dose evaluation strategies in the new indications. Our analysis included 21 mAbs with 50 supplemental approvals for new indications. Indication-specific dosing was prevalent, with 15 out of 21 mAbs having different recommended dosing regimens across two or more indications. The majority of the new indications were supported by Phase 2 dose-ranging studies and/or Phase 3 studies that evaluated more than one dosing regimen. Importantly, our analysis uncovered a relationship between indication-specific dosing, dose evaluation strategies, and organ system classification of the original versus the new indication. We delved into dose justification supporting the new indications, including the types of data and modeling approaches used or considered. Through case studies, we highlighted factors that may influence dose selection in new indications, such as target expression levels, disease severity, and benefit-risk profile. Lastly, we made practical recommendations regarding dose optimization approaches in clinical drug development across multiple indications.</p>","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143391989","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mathematical Albumin Function for Neonates Undergoing Therapeutic Hypothermia in Comparison with Control Neonates.","authors":"Zoë Vander Elst, Thibault Stultjens, Pieter Annaert, Paul Clarke, Isabek Iglesias-Platas, Elisabeth Agathos, Gozdem Kaykı, Annouschka Laenen, Nadir Yalçın, Anne Smits, Karel Allegaert","doi":"10.1002/jcph.70003","DOIUrl":"https://doi.org/10.1002/jcph.70003","url":null,"abstract":"<p><p>Hypoxic-ischemic encephalopathy (HIE) resulting from perinatal asphyxia presents a substantial risk of mortality and long-term sequelae in neonates. Therapeutic hypothermia (TH) improves both short- and long-term outcomes in near-term/term neonates with moderate to severe HIE. While neonates with perinatal asphyxia and TH often require polypharmacy, the impact of both covariates on pharmacokinetics and pharmacodynamics is only partially described and quantified. In this pooled, multicenter retrospective study, longitudinal trends of human serum albumin (HSA, the major drug binding protein) and total protein (TP) concentrations in near-term/term neonates were described using linear mixed models and compared between cohorts (TH vs control neonates, and moderate vs severe HIE TH cases). A mathematical function for HSA concentrations in neonates with HIE undergoing TH was derived (AlbuCool function). The pooled dataset to estimate these functions contained 330 TH neonates and 425 controls with 1725 and 1415 HSA observations, respectively. The median (interquartile range) HSA concentration was 27.0 (23.0-31.0) g/L for the TH cohort, and 32.1 (28.4-35.7) g/L for the control cohort. Estimated mean HSA concentrations were significantly lower (P < .001) in TH compared to control cases, as well as in severe compared to moderate HIE cases (P < .001) over the first 7 postnatal days. The HSA function for neonates with HIE undergoing TH was: HSA (g/L) = 32.28 - 2.94 * PNA + 0.33 * PNA² (PNA is postnatal age). The integration of this function in pharmacokinetic models holds the promise to improve the predictive performance of these models, and consequently, the pharmacotherapy of HSA-bound drugs in this vulnerable population.</p>","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143392096","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical Assessment of the Drug-Drug Interaction Potential of Omaveloxolone in Healthy Adult Participants.","authors":"Hamim Zahir, Masako Murai, Lucy Wu, Michelle Valentine, Scott Hynes","doi":"10.1002/jcph.6189","DOIUrl":"https://doi.org/10.1002/jcph.6189","url":null,"abstract":"<p><p>Omaveloxolone is approved in the United States and the European Union for the treatment of patients with Friedreich ataxia aged ≥16 years. It is mainly metabolized by cytochrome P450 (CYP) 3A4 in vitro. Two drug-drug interaction studies (NCT04008186 and NCT05909644) were performed to evaluate (1) the effect of drug-metabolizing enzymes (DMEs) and drug transporter (DT) modulators on the pharmacokinetics of omaveloxolone and (2) the effect of omaveloxolone on the pharmacokinetics of DME and DT substrates. Additionally, the safety of coadministering these drugs with omaveloxolone was assessed. Coadministration of the strong CYP3A4 inhibitor itraconazole significantly increased omaveloxolone maximum plasma concentration (C_max) and area under the plasma concentration-time curve from time 0 extrapolated to infinity (AUC_0-∞) by approximately 3- and 4-fold, respectively. Conversely, coadministration with the moderate CYP3A4 inducer efavirenz decreased C_max and AUC_0-∞ of omaveloxolone by 38.0% and 48.5%, respectively. Omaveloxolone exposure was also increased following coadministration with verapamil, a moderate CYP3A4 and P-glycoprotein (P-gp) inhibitor, but it was unaffected by the strong CYP2C8 inhibitor gemfibrozil. Coadministration of omaveloxolone reduced systemic exposure of the substrates of CYP3A4, CYP2C8, breast cancer resistance protein, and organic anion transporting polypeptide 1B1 but had no effect on those of P-gp and organic cation transporter 1. Omaveloxolone was well tolerated when administered alone and in combination with the DME and DT modulators or substrates. These findings support concomitant medication precautions and dosing recommendations for omaveloxolone when coadministered with a moderate or strong CYP3A4 inhibitor or inducer, as well as the substrates of certain CYP450 enzymes or transporters.</p>","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143371157","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dose Evaluation and Optimization of Amoxicillin in Children Treated for Lyme Disease.","authors":"Anne Ravix, Verena Gotta, Marc Pfister, Christoph Berger, Antonia Glauser, Paolo Paioni, Chantal Csajka, Monia Guidi","doi":"10.1002/jcph.6190","DOIUrl":"https://doi.org/10.1002/jcph.6190","url":null,"abstract":"<p><p>Amoxicillin is commonly used to treat erythema migrans in the first stage of Lyme disease in children, with a recommended dose of 50 mg/kg/day, administered three times a day (q8h). This model-based simulation study aimed to determine whether splitting the same daily dose into two administrations (q12h) would provide comparable drug exposure. A pharmacokinetic model suitable for a pediatric population (age: 1 month to 18 years, weight: 4-80 kg) was selected through a literature review. Simulations were performed with 15,000 virtual patients receiving 16.67 mg/kg/dose q8h, 25 mg/kg/dose q12h, or other q12h dosing variations. The target therapeutic level was defined by the percentage of time that the unbound drug concentration remained above the minimum inhibitory concentration (% fT > MIC) specific to Borrelia burgdorferi, with MICs of 0.06, 0.25, 1, 2, and 4 mg/L, requiring at least 40% and 50% of time for effective treatment. Probability of target attainment (PTA) was considered acceptable if it exceeded 50%, allowing for comparison of dosing schedules. Results indicated that the 50 mg/kg/day divided q12h regimen provided similar drug exposure to the q8h regimen for MICs below 2 mg/L (PTAs >50%). For a MIC of 2 mg/L, PTA was achieved with a higher dose of 30 mg/kg/dose q12h. However, for a MIC of 4 mg/L, the PTA criterion was not met. These findings suggest that a twice-daily dosing of 25 mg/kg/dose provides comparable bactericidal activity to the thrice-daily regimen for MICs between 0.06 and 1 mg/L. This simplified regimen may improve adherence and treatment implementation in children.</p>","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143048396","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacokinetic and Exposure-Response Modeling Support Body Surface Area-Based Dosing of Farletuzumab Ecteribulin in Japanese Patients with Solid Tumors.","authors":"Seiichi Hayato, Lora Hamuro, Toshio Shimizu, Kan Yonemori, Shin Nishio, Mayu Yunokawa, Tatsuya Yoshida, Makoto Nishio, Koji Matsumoto, Kazuhiro Takehara, Kosei Hasegawa, Toshiyuki Kozuki, Yasuyuki Hirashima, Hidenori Kato, Takuma Miura, Maiko Nomoto, Yue Zhao, Li Zhu, Sanae Yasuda","doi":"10.1002/jcph.6187","DOIUrl":"https://doi.org/10.1002/jcph.6187","url":null,"abstract":"<p><p>The first-in-human, Phase 1 Study 101 showed antitumor activity and a tolerable safety profile of farletuzumab ecteribulin in Japanese patients with platinum-resistant ovarian and non-small cell lung cancer. A pharmacometric assessment evaluated farletuzumab ecteribulin pharmacokinetics and exposure-response (E-R) relationships for efficacy and safety to support dose optimization. Patients received 0.3-1.2 mg/kg of farletuzumab ecteribulin intravenously every 3 weeks. A pharmacokinetics (PK) model was developed and used for E-R analyses. Efficacy was assessed via tumor response and safety via known treatment-emergent adverse events (TEAEs) of farletuzumab ecteribulin, particularly pneumonitis/interstitial lung disease (ILD). Dosing scenarios were simulated to identify dosing that maximizes the probability of an objective response while minimizing the risk of ILD. The farletuzumab ecteribulin PK dataset included 1261 observations from 82 patients. The final model included an estimated population mean value for farletuzumab ecteribulin clearance of 0.0162 L/h. Body surface area (BSA) was a significant PK covariate and was included in the model. Body weight (BW) was associated with higher farletuzumab ecteribulin exposure. Using BW-based dosing, farletuzumab ecteribulin AUC (area under the serum concentration-time curve) was higher in patients with tumor response or stable disease versus patients with progressive disease and higher in patients with ILD and other TEAEs. Dosing simulations showed that BSA-based dosing (33 mg/m²) yielded similar tumor responses to BW-based dosing (0.9 mg/kg) and decreased ILD rates. This study showed that BW-based dosing resulted in higher risks of ILD events for patients with a high BW versus low BW, whereas BSA-based dosing is predicted to reduce this risk while maintaining clinical efficacy.</p>","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143034680","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Extended Treatment Duration of Artemether-Lumefantrine in Ugandan Children with HIV on Efavirenz-Based Antiretroviral Therapy: A Randomized Controlled Pharmacokinetic and Pharmacodynamic Trial.","authors":"Meghan E Whalen, Richard Kajubi, Justin Goodwin, Francis Orukan, McKenzie Colt, Liusheng Huang, Kacey Richards, Thomas J Hoffmann, Francesca T Aweeka, Sunil Parikh, Norah Mwebaza","doi":"10.1002/jcph.6193","DOIUrl":"https://doi.org/10.1002/jcph.6193","url":null,"abstract":"<p><p>Malaria and HIV co-infection are prevalent in sub-Saharan Africa causing significant drug interactions with co-treatment. We previously reported a 30%-70% reduction in exposure to the standard 3-day (6-dose) artemether-lumefantrine (AL) treatment for malaria when given with efavirenz-based HIV therapy, impacting malaria reinfection risk. We conducted a prospective, randomized study comparing the 3-day regimen to an extended 5-day (10-dose) regimen with pharmacokinetic sampling for artemether, dihydroartemisinin, lumefantrine, and desbutyl-lumefantrine (DBL) over 42 days. The primary outcome was comparative pharmacokinetics between regimens compared among children with HIV and among children without HIV receiving a 3-day regimen as controls (median age 5.3 years [range 1.4-13.9]; median weight 17.3 kg [range 8.7-39.1]). Children with HIV (n = 57; median age 10.8 years [range 3.4-17.1]; median weight 26.6 kg [range 14.6-54.5]) contributed 76 malaria episodes, with 71 included in the analysis. Another 97 children without HIV (median age 5.3 years [range 1.4-13.9]; median weight 17.3 kg [range 8.7-39.1]) contributed 114 episodes of malaria, with 109 included in the analysis. In the setting of efavirenz, artemether, dihydroartemisinin, lumefantrine, and DBL cumulative exposure was 2.09, 2.31, 1.90, and 1.65 fold higher with 5-day versus 3-day AL (all P < .001), and comparable to 3-day AL in children without HIV. The extended regimen in children with HIV did not result in a statistically significant reduction in recurrence risk at 28 or 42 days. Extending the duration of AL to 5 days compensated for a clinically significant reduction in all components of AL in the context of EFV-based antiretroviral therapy in young children.</p>","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143034679","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Drug-Drug Interaction Between Rifampicin and Albuvirtide: A Phase 1, Randomized, Open-Label Study.","authors":"Li Zhang, Jun Chen, Xiao-Yan Lin, Yan Lu, Yan Wu, Yi-Jun Wu, Xian-Min Meng","doi":"10.1002/jcph.6191","DOIUrl":"https://doi.org/10.1002/jcph.6191","url":null,"abstract":"<p><p>Albuvirtide (ABT) is a novel long-acting fusion inhibitor for human immunodeficiency virus type 1 (HIV-1), and may be co-administered with rifampicin (RIF) in patients concurrent with tubercle bacillus and HIV-1. This study was conducted to investigate the pharmacokinetic effect of co-administration of the two drugs. In the study, 24 healthy volunteers were randomized to receive ABT alone or with RIF. Plasma concentrations were measured using liquid chromatography-tandem mass spectrometry for RIF and competitive enzyme-linked immunosorbent assay for ABT. Co-administration with RIF increased the maximum concentration (C_max) of ABT by 6.93%, and the area under the plasma concentration-time curve (AUC) from time 0 to the last quantifiable concentration (AUC_0-t) by 21.31%; the geometric mean ratio values (GMRs) for C_max and AUC_0-t of ABT when co-administered with RIF, relative to administered alone, were 106.93% (90% confidence interval [CI] 97.53%-117.23%) and 121.31% (90% CI 108.68%-135.40%), respectively. Co-administration with ABT decreased the steady-state C_max (C_max,ss) of RIF by 10.19%, and the steady-state AUC from time 0 to 24 h (AUC_{0-24 h,ss}) by 19.93%; the GMRs for C_max,ss and AUC_{0-24 h,ss} of RIF when co-administered with ABT, relative to administered alone, were 89.81% (90% CI, 79.97%-104.79%) and 80.07% (90% CI 75.68%-84.72%), respectively. The time to reach Cmax (Tmax) of both ABT and RIF demonstrated no statistically significant difference, whether administered alone or concurrently. The pharmacokinetics profiles of both RIF and ABT changed to some extent when co-administered, while no clinically significant impact on these two drugs was observed, indicating that ABT and RIF can be used together without necessitating dose adjustments.</p>","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143014352","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Examining the Impact of Diet-and-Exercise-Induced Weight Loss on Drug Metabolism and Gastric Emptying in Patients with Obesity.","authors":"Shuhan Liu, Lu Wang, Nicole Miller, Andrea Waltje, Mohamed Abdelnabi, Hao-Jie Zhu, Duxin Sun, Amy E Rothberg, Manjunath P Pai","doi":"10.1002/jcph.6192","DOIUrl":"10.1002/jcph.6192","url":null,"abstract":"<p><p>Obesity significantly influences drug pharmacokinetics (PK), which challenges optimal dosing. This study examines the effects of diet-and-exercise-induced weight loss on key drug-metabolizing enzymes and gastric emptying in patients with obesity, who frequently require medications for comorbidities. Participants followed a structured weight management program promoting weight loss over 3-6 months and were not concomitantly on potential CYP inducers or inhibitors. Using a drug cocktail of acetaminophen, caffeine, omeprazole, and midazolam, we assessed UGT1A1, CYP1A2, CYP2C19, and CYP3A4 enzyme activities before and after weight loss, respectively, by measuring parent and metabolite concentrations. The time to maximum acetaminophen plasma concentrations reflected the gastric emptying time. PK profiles were compared across two phases: baseline (Phase 1) and post-weight loss (Phase 2). Twenty-four participants enrolled, 21 completed Phase 1 and 12 completed both phases. Statistically significant (N = 12, P < .05) gains in CYP2C19 and CYP3A4 activity were observed after weight loss of 7.6% to 26.2%, with a median [25th, 75th percentile] increase in activity of 90.5 [15.0, 194.3] % and 43.0 [7.5, 68.0] %, respectively. A 2- or 3-h single plasma sample-based ratio of the metabolite to parent concentration strongly correlated with the respective AUC ratio for the drug metabolism phenotype (N = 21). Our findings provide provisional data for evaluation of the effects of non-pharmacologically and non-surgically induced weight loss on gastric emptying and drug metabolism for future physiologically based PK models. Development of mechanistic models to optimize drug dosing in obesity are necessary since weight and body composition shifts are expected with emerging new treatments.</p>","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143014463","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluation of Cannabis Per Se Laws: A Semi-Mechanistic Pharmacometrics Model for Quantitative Characterization of THC and Metabolites in Oral Users.","authors":"Peizhi Li, Guohua An","doi":"10.1002/jcph.6181","DOIUrl":"https://doi.org/10.1002/jcph.6181","url":null,"abstract":"<p><p>Recreational cannabis use has increased notably in the United States in the past decade, with a recent surge in oral consumption. This trend has raised concerns about driving under the influence. Current cannabis-impaired driving laws lack standardization, with some states implementing blood Δ9-tetrahydrocannabinol (THC) per se limits (1, 2, and 5 ng/mL). However, these limits have been criticized for their inaccuracy and unreliability, highlighting the need for legal refinement. Addressing this issue requires understanding the complex pharmacokinetics (PK) and pharmacodynamics (PD) of THC, cannabis's primary psychoactive component, which can be characterized using a population PK model. However, existing PK models mainly focus on inhalation data and do not account for the growing number of oral cannabis users. To bridge this gap, a semi-mechanistic population PK model was developed using data from 10 published studies following intravenous or oral administration of cannabis to characterize THC and its metabolites in oral users. Simulated THC plasma concentrations for doses from 2.5 mg to 100 mg in frequent and occasional users were used to evaluate the effectiveness of existing per se limits. Results showed that the 1 ng/mL limit was least effective due to a high risk of false positives, while the 2 and 5 ng/mL limits remain inconclusive due to limited PD data linking blood THC levels to impairment. These findings suggest that the existing per se laws may not fully address the complexity of cannabis impairment, underscoring the need for further research and refinement of cannabis-impaired driving laws.</p>","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143014461","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Understanding and Streamlining Dose Finding: From Dose Simulation to Dose Estimation.","authors":"Dominic Bräm, Freya Bachmann, Johannes Schropp, Verena Gotta, Britta Steffens, John van den Anker, Marc Pfister, Gilbert Koch","doi":"10.1002/jcph.6188","DOIUrl":"https://doi.org/10.1002/jcph.6188","url":null,"abstract":"<p><p>Understanding drug dosing to fulfill safety and efficacy requirements in a patient population is an essential part of dose finding in clinical practice and drug development. The majority of current dose finding methods are simulation-based, which can be time consuming and resource intensive. Model-based simulations also do not guarantee that the dose, that will optimally fulfill the safety and efficacy endpoints, will be found. In this work, an advanced dose estimation approach based on the OptiDose concept is utilized to understand therapeutic doses in a patient population and to streamline dose finding. To demonstrate the potential of this concept, two illustrative case studies are presented, each representing specific challenges for dose finding, including different safety and efficacy requirements, complex dose-response relationships, and changes of dynamics in special populations. For both applications, the distributions of therapeutic doses in the population were estimated, such that therapeutic population doses can be determined for any proportion of patients to fulfill the safety and efficacy endpoints. In addition, the therapeutic population dose with which 50% and 95% of the population will fulfill the safety and efficacy requirements was estimated. Dose estimation for both drug applications was implemented in Monolix. The presented OptiDose approach has the potential to identify the \"optimal\" dose for any pharmacometric and clinical pharmacology scenario, allowing to guide clinical practice and facilitate dose selection in drug development, particularly in special populations such as pediatric or cancer patients. As such, we suggest moving from current \"dose simulation\" approaches toward a more efficient \"dose estimation\" paradigm.</p>","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143014468","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}