{"title":"Challenges, approaches and enablers: effectively triangulating towards dose selection in pediatric rare diseases.","authors":"Chandrasekar Durairaj, Indranil Bhattacharya","doi":"10.1007/s10928-023-09868-6","DOIUrl":"10.1007/s10928-023-09868-6","url":null,"abstract":"<p><p>Dose selection is an integral part of a molecule's journey to become medicine. On top of typical challenges faced in dose selection for more common diseases, pediatric rare disease has additional unique challenges due to the combination of 'rare' and 'pediatric' populations. Using the central theme of maximizing 'relevant' information to overcome information paucity, dose selection strategy in pediatric rare diseases is discussed using a triangulation concept involving challenges, approaches and very importantly, enablers. Using actual examples, unique scenarios are discussed where specific enablers allowed certain approaches to be used to overcome the challenges. The continued need for model-informed drug development is also discussed using examples of where modeling and simulation tools have been successfully used in bridging available information to select pediatric doses in rare disease. Additionally, challenges with translation and associated dose selection of new modalities such as gene therapy in rare diseases are examined with the lens of continuous learning and knowledge development that will enable pediatric dose selection of these modalities with confidence.</p>","PeriodicalId":16851,"journal":{"name":"Journal of Pharmacokinetics and Pharmacodynamics","volume":" ","pages":"445-459"},"PeriodicalIF":2.5,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9601329","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}
Jeffrey S Barrett, Alexandre Betourne, Ramona L Walls, Kara Lasater, Scott Russell, Amanda Borens, Shlok Rohatagi, Will Roddy
{"title":"The future of rare disease drug development: the rare disease cures accelerator data analytics platform (RDCA-DAP).","authors":"Jeffrey S Barrett, Alexandre Betourne, Ramona L Walls, Kara Lasater, Scott Russell, Amanda Borens, Shlok Rohatagi, Will Roddy","doi":"10.1007/s10928-023-09859-7","DOIUrl":"10.1007/s10928-023-09859-7","url":null,"abstract":"<p><p>Rare disease drug development is wrought with challenges not the least of which is access to the limited data currently available throughout the rare disease ecosystem where sharing of the available data is not guaranteed. Most pharmaceutical sponsors seeking to develop agents to treat rare diseases will initiate data landscaping efforts to identify various data sources that might be informative with respect to disease prevalence, patient selection and identification, disease progression and any data projecting likelihood of patient response to therapy including any genetic data. Such data are often difficult to come by for highly prevalent, mainstream disease populations let alone for the 8000 rare disease that make up the pooled patient population of rare disease patients. The future of rare disease drug development will hopefully rely on increased data sharing and collaboration among the entire rare disease ecosystem. One path to achieving this outcome has been the development of the rare disease cures accelerator, data analytics platform (RDCA-DAP) funded by the US FDA and operationalized by the Critical Path Institute. FDA intentions were clearly focused on improving the quality of rare disease regulatory applications by sponsors seeking to develop treatment options for various rare disease populations. As this initiative moves into its second year of operations it is envisioned that the increased connectivity to new and diverse data streams and tools will result in solutions that benefit the entire rare disease ecosystem and that the platform becomes a Collaboratory for engagement of this ecosystem that also includes patients and caregivers.</p>","PeriodicalId":16851,"journal":{"name":"Journal of Pharmacokinetics and Pharmacodynamics","volume":" ","pages":"507-519"},"PeriodicalIF":2.5,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10673974/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9392412","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}
Mariam A Ahmed, Janelle Burnham, Gaurav Dwivedi, Bilal AbuAsal
{"title":"Achieving big with small: quantitative clinical pharmacology tools for drug development in pediatric rare diseases.","authors":"Mariam A Ahmed, Janelle Burnham, Gaurav Dwivedi, Bilal AbuAsal","doi":"10.1007/s10928-023-09863-x","DOIUrl":"10.1007/s10928-023-09863-x","url":null,"abstract":"<p><p>Pediatric populations represent a major fraction of rare diseases and compound the intrinsic challenges of pediatric drug development and drug development for rare diseases. The intertwined complexities of pediatric and rare disease populations impose unique challenges to clinical pharmacologists and require integration of novel clinical pharmacology and quantitative tools to overcome multiple hurdles during the discovery and development of new therapies. Drug development strategies for pediatric rare diseases continue to evolve to meet the inherent challenges and produce new medicines. Advances in quantitative clinical pharmacology research have been a key component in advancing pediatric rare disease research to accelerate drug development and inform regulatory decisions. This article will discuss the evolution of the regulatory landscape in pediatric rare diseases, the challenges encountered during the design of rare disease drug development programs and will highlight the use of innovative tools and potential solutions for future development programs.</p>","PeriodicalId":16851,"journal":{"name":"Journal of Pharmacokinetics and Pharmacodynamics","volume":" ","pages":"429-444"},"PeriodicalIF":2.5,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9404599","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":"Empirical bayes approach for dynamic bayesian borrowing for clinical trials in rare diseases.","authors":"Bernard Sebastien","doi":"10.1007/s10928-023-09860-0","DOIUrl":"10.1007/s10928-023-09860-0","url":null,"abstract":"<p><p>Application of Bayesian methods is one the tools that can be used to face the multiple challenges that are met when clinical trials must be conducted in rare diseases. We propose in this work to use a dynamic Bayesian borrowing approach, based on a mixture prior, to complement the control arm of a comparative trial and estimate the mixture parameter by an Empirical Bayes approach. The method is compared, using simulations, with an approach based on a pre-specified (non-adaptive) informative prior. The simulation study shows that the proposed method exhibits similar power as the non-adaptive prior and drastically reduce type I error in case of severe discrepancy between the informative prior and the study control arm data. In case of limited discrepancy between the informative prior and the study control arm data, then our proposed adaptive prior does not reduce the inflation of the type I error.</p>","PeriodicalId":16851,"journal":{"name":"Journal of Pharmacokinetics and Pharmacodynamics","volume":" ","pages":"495-499"},"PeriodicalIF":2.5,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9416054","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}
Artak Khachatryan, Stephanie H Read, Terri Madison
{"title":"External control arms for rare diseases: building a body of supporting evidence.","authors":"Artak Khachatryan, Stephanie H Read, Terri Madison","doi":"10.1007/s10928-023-09858-8","DOIUrl":"10.1007/s10928-023-09858-8","url":null,"abstract":"<p><p>Comparator arms in randomized clinical trials may be impractical and/or unethical to assemble in rare diseases. In the absence of comparator arms, evidence generated from external control studies has been used to support successful regulatory submissions and health technology assessments (HTA). However, conducting robust and rigorous external control arm studies is challenging and despite all efforts, residual biases may remain. As a result, regulatory and HTA agencies may request additional external control analyses so that decisions may be made based upon a body of supporting evidence.This paper introduces external control studies and provides an overview of the key methodological issues to be considered in the design of these studies. A series of case studies are presented in which evidence derived from one or more external controls was submitted to regulatory and HTA agencies to provide support for the consistency of findings.</p>","PeriodicalId":16851,"journal":{"name":"Journal of Pharmacokinetics and Pharmacodynamics","volume":" ","pages":"501-506"},"PeriodicalIF":2.5,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10673956/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9389762","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"An integrated modelling approach for targeted degradation: insights on optimization, data requirements and PKPD predictions from semi- or fully-mechanistic models and exact steady state solutions.","authors":"Sofia Guzzetti, Pablo Morentin Gutierrez","doi":"10.1007/s10928-023-09857-9","DOIUrl":"10.1007/s10928-023-09857-9","url":null,"abstract":"<p><p>The value of an integrated mathematical modelling approach for protein degraders which combines the benefits of traditional turnover models and fully mechanistic models is presented. Firstly, we show how exact solutions of the mechanistic models of monovalent and bivalent degraders can provide insight on the role of each system parameter in driving the pharmacological response. We show how on/off binding rates and degradation rates are related to potency and maximal effect of monovalent degraders, and how such relationship can be used to suggest a compound optimization strategy. Even convoluted exact steady state solutions for bivalent degraders provide insight on the type of observations required to ensure the predictive capacity of a mechanistic approach. Specifically for PROTACs, the structure of the exact steady state solution suggests that the total remaining target at steady state, which is easily accessible experimentally, is insufficient to reconstruct the state of the whole system at equilibrium and observations on different species (such as binary/ternary complexes) are necessary. Secondly, global sensitivity analysis of fully mechanistic models for PROTACs suggests that both target and ligase baselines (actually, their ratio) are the major sources of variability in the response of non-cooperative systems, which speaks to the importance of characterizing their distribution in the target patient population. Finally, we propose a pragmatic modelling approach which incorporates the insights generated with fully mechanistic models into simpler turnover models to improve their predictive ability, hence enabling acceleration of drug discovery programs and increased probability of success in the clinic.</p>","PeriodicalId":16851,"journal":{"name":"Journal of Pharmacokinetics and Pharmacodynamics","volume":"50 5","pages":"327-349"},"PeriodicalIF":2.5,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10460745/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10096654","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Clinical validation of translational antibody PBPK model using tissue distribution data generated with <sup>89</sup>Zr-immuno-PET imaging.","authors":"Shufang Liu, Zhe Li, Marc Huisman, Dhaval K Shah","doi":"10.1007/s10928-023-09869-5","DOIUrl":"10.1007/s10928-023-09869-5","url":null,"abstract":"<p><p>The main objective of this manuscript was to validate the ability of the monoclonal antibody physiologically-based pharmacokinetic (PBPK) model to predict tissue concentrations of antibodies in the human. To accomplish this goal, preclinical and clinical tissue distribution and positron emission tomography imaging data generated using zirconium-89 (<sup>89</sup>Zr) labeled antibodies were obtained from the literature. First, our previously published translational PBPK model for antibodies was expanded to describe the whole-body biodistribution of <sup>89</sup>Zr labeled antibody and the free <sup>89</sup>Zr, as well as residualization of free <sup>89</sup>Zr. Subsequently, the model was optimized using mouse biodistribution data, where it was observed that free <sup>89</sup>Zr mainly residualizes in the bone and the extent of antibody distribution in certain tissues (e.g., liver and spleen) may be altered by labeling with <sup>89</sup>Zr. The mouse PBPK model was scaled to rat, monkey, and human by simply changing the physiological parameters, and a priori simulations performed by the model were compared with the observed PK data. It was found that model predicted antibody PK in majority of the tissues in all the species superimposed over the observed data, and the model was also able to predict the PK of antibody in human tissues reasonably well. As such, the work presented here provides unprecedented evaluation of the antibody PPBK model for its ability to predict tissue PK of antibodies in the clinic. This model can be used for preclinical-to-clinical translation of antibodies and for prediction of antibody concentrations at the site-of-action in the clinic.</p>","PeriodicalId":16851,"journal":{"name":"Journal of Pharmacokinetics and Pharmacodynamics","volume":"50 5","pages":"377-394"},"PeriodicalIF":2.5,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10103317","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}
Satyawan B Jadhav, Benny M Amore, Howard Bockbrader, Ryan L Crass, Sunny Chapel, William J Sasiela, Maurice G Emery
{"title":"Population pharmacokinetic and pharmacokinetic-pharmacodynamic modeling of bempedoic acid and low-density lipoprotein cholesterol in healthy subjects and patients with dyslipidemia.","authors":"Satyawan B Jadhav, Benny M Amore, Howard Bockbrader, Ryan L Crass, Sunny Chapel, William J Sasiela, Maurice G Emery","doi":"10.1007/s10928-023-09864-w","DOIUrl":"10.1007/s10928-023-09864-w","url":null,"abstract":"<p><p>Population pharmacokinetics (popPK) of bempedoic acid and the popPK/pharmacodynamic (popPK/PD) relationship between bempedoic acid concentrations and serum low-density lipoprotein cholesterol (LDL-C) from baseline were characterized. A two-compartment disposition model with a transit absorption compartment and linear elimination best described bempedoic acid oral pharmacokinetics (PK). Multiple covariates, including renal function, sex, and weight, had statistically significant effects on the predicted steady-state area under the curve. Mild (estimated glomerular filtration rate (eGFR) 60 to < 90 mL/min vs. ≥ 90 mL/min) and moderate (eGFR 30 to < 60 mL/min vs. ≥ 90 mL/min) renal impairment, female sex, low (< 70 kg vs. 70-100 kg) and high (> 100 kg vs. 70-100 kg) body weight were predicted to have a 1.36-fold (90% confidence interval (CI) 1.32, 1.41), 1.85-fold (90% CI 1.74, 2.00), 1.39-fold (90% CI 1.34, 1.47), 1.35-fold (90% CI 1.30, 1.41), and 0.75-fold (90% CI 0.72, 0.79) exposure difference relative to their reference populations, respectively. An indirect response model described changes in serum LDL-C with a model-predicted 35% maximal reduction and bempedoic acid IC<sub>50</sub> of 3.17 µg/mL. A 28% reduction from LDL-C baseline was predicted for a steady-state average concentration of 12.5 µg/mL after bempedoic acid (180 mg/day) dosing, accounting for approximately 80% of the predicted maximal LDL-C reduction. Concurrent statin therapy, regardless of intensity, reduced the maximal effect of bempedoic acid but resulted in similar steady-state LDL-C levels. While multiple covariates had statistically significant effects on PK and LDL-C lowering, none were predicted to warrant bempedoic acid dose adjustment.</p>","PeriodicalId":16851,"journal":{"name":"Journal of Pharmacokinetics and Pharmacodynamics","volume":"50 5","pages":"351-364"},"PeriodicalIF":2.5,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10460718/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10473398","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}
Yukio Otsuka, Srinivasu Poondru, Peter L Bonate, Rachel H Rose, Masoud Jamei, Fumihiko Ushigome, Tsuyoshi Minematsu
{"title":"Physiologically-based pharmacokinetic modeling to predict drug-drug interaction of enzalutamide with combined P-gp and CYP3A substrates.","authors":"Yukio Otsuka, Srinivasu Poondru, Peter L Bonate, Rachel H Rose, Masoud Jamei, Fumihiko Ushigome, Tsuyoshi Minematsu","doi":"10.1007/s10928-023-09867-7","DOIUrl":"10.1007/s10928-023-09867-7","url":null,"abstract":"<p><p>Enzalutamide is known to strongly induce cytochrome P450 3A4 (CYP3A4). Furthermore, enzalutamide showed induction and inhibition of P-glycoprotein (P-gp) in in vitro studies. A clinical drug-drug interaction (DDI) study between enzalutamide and digoxin, a typical P-gp substrate, suggested enzalutamide has weak inhibitory effect on P-gp substrates. Direct oral anticoagulants (DOACs), such as apixaban and rivaroxaban, are dual substrates of CYP3A4 and P-gp, and hence it is recommended to avoid co-administration of these DOACs with combined P-gp and strong CYP3A inducers. Enzalutamide's net effect on P-gp and CYP3A for apixaban and rivaroxaban plasma exposures is of interest to physicians who treat patients for venous thromboembolism with prostate cancer. Accordingly, a physiologically-based pharmacokinetic (PBPK) analysis was performed to predict the magnitude of DDI on apixaban and rivaroxaban exposures in the presence of 160 mg once-daily dosing of enzalutamide. The PBPK models of enzalutamide and M2, a major metabolite of enzalutamide which also has potential to induce CYP3A and P-gp and inhibit P-gp, were developed and verified as perpetrators of CYP3A-and P-gp-mediated interaction. Simulation results predicted a 31% decrease in AUC and no change in C<sub>max</sub> for apixaban and a 45% decrease in AUC and a 25% decrease in C<sub>max</sub> for rivaroxaban when 160 mg multiple doses of enzalutamide were co-administered. In summary, enzalutamide is considered to decrease apixaban and rivaroxaban exposure through the combined effects of CYP3A induction and net P-gp inhibition. Concurrent use of these drugs warrants careful monitoring for efficacy and safety.</p>","PeriodicalId":16851,"journal":{"name":"Journal of Pharmacokinetics and Pharmacodynamics","volume":"50 5","pages":"365-376"},"PeriodicalIF":2.5,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10460728/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10455063","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}
Alessandro De Carlo, Elena Maria Tosca, Nicola Melillo, Paolo Magni
{"title":"A two-stages global sensitivity analysis by using the δ sensitivity index in presence of correlated inputs: application on a tumor growth inhibition model based on the dynamic energy budget theory.","authors":"Alessandro De Carlo, Elena Maria Tosca, Nicola Melillo, Paolo Magni","doi":"10.1007/s10928-023-09872-w","DOIUrl":"10.1007/s10928-023-09872-w","url":null,"abstract":"<p><p>Global sensitivity analysis (GSA) evaluates the impact of variability and/or uncertainty of the model parameters on given model outputs. GSA is useful for assessing the quality of Pharmacometric model inference. Indeed, model parameters can be affected by high (estimation) uncertainty due to the sparsity of data. Independence between model parameters is a common assumption of GSA methods. However, ignoring (known) correlations between parameters may alter model predictions and, then, GSA results. To address this issue, a novel two-stages GSA technique based on the δ index, which is well-defined also in presence of correlated parameters, is here proposed. In the first step, statistical dependencies are neglected to identify parameters exerting causal effects. Correlations are introduced in the second step to consider the real distribution of the model output and investigate also the 'indirect' effects due to the correlation structure. The proposed two-stages GSA strategy was applied, as case study, to a preclinical tumor-in-host-growth inhibition model based on the Dynamic Energy Budget theory. The aim is to evaluate the impact of the model parameter estimate uncertainty (including correlations) on key model-derived metrics: the drug threshold concentration for tumor eradication, the tumor volume doubling time and a new index evaluating the drug efficacy-toxicity trade-off. This approach allowed to rank parameters according to their impact on the output, discerning whether a parameter mainly exerts a causal or 'indirect' effect. Thus, it was possible to identify uncertainties that should be necessarily reduced to obtain robust predictions for the outputs of interest.</p>","PeriodicalId":16851,"journal":{"name":"Journal of Pharmacokinetics and Pharmacodynamics","volume":"50 5","pages":"395-409"},"PeriodicalIF":2.5,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10460734/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10155402","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}