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Achieving big with small: quantitative clinical pharmacology tools for drug development in pediatric rare diseases
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. (Source: Journal of Pharmacokinetics and Pharmacodynamics)
Source: Journal of Pharmacokinetics and Pharmacodynamics - May 4, 2023 Category: Drugs & Pharmacology Source Type: research

The future of rare disease drug development: the rare disease cures accelerator data analytics platform (RDCA-DAP)
AbstractRare 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 co...
Source: Journal of Pharmacokinetics and Pharmacodynamics - May 2, 2023 Category: Drugs & Pharmacology Source Type: research

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
AbstractThe 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 s...
Source: Journal of Pharmacokinetics and Pharmacodynamics - April 29, 2023 Category: Drugs & Pharmacology Source Type: research

Special issue: Model-informed drug development in rare diseases: connecting the dots in an information rich ecosystem
(Source: Journal of Pharmacokinetics and Pharmacodynamics)
Source: Journal of Pharmacokinetics and Pharmacodynamics - April 27, 2023 Category: Drugs & Pharmacology Source Type: research

External control arms for rare diseases: building a body of supporting evidence
AbstractComparator 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 extern...
Source: Journal of Pharmacokinetics and Pharmacodynamics - April 24, 2023 Category: Drugs & Pharmacology Source Type: research

Operational characteristics of full random effects modelling ( ‘frem’) compared to stepwise covariate modelling (‘scm’)
In this study, the automated stepwise covariate modelling technique ( ‘scm’) was compared to full random effects modelling (‘frem’). We evaluated the power to identify a ‘true’ covariate (covariate with highest correlation to the pharmacokinetic parameter), precision, and accuracy of the parameter-covariate estimates. Furthermore, the predictive performanc e of the final models was assessed. The scenarios varied in covariate effect sizes, number of individuals (n = 20–500) and covariate correlations (0–90% cov-corr). The PsN ‘frem’ routine provides a 90% confidence intervals around the covariate ef...
Source: Journal of Pharmacokinetics and Pharmacodynamics - April 21, 2023 Category: Drugs & Pharmacology Source Type: research

Joint longitudinal model-based meta-analysis of FEV1 and exacerbation rate in randomized COPD trials
This study not only evaluated the predictability of a published MBMA for forced expiratory volume in one second (FEV1) and its link to annual exacerbation rate in patients with chronic obstructive pulmonary disease (COPD) but also included data from new RCTs. A comparative effectiveness analysis across all drugs was also performed. Aggregated level data were collected from RCTs published between July 2013 and November 2020 (n  = 132 references comprising 156 studies) and combined with data used in the legacy MBMA (published RCTs up to July 2013 - n = 142). The augmented data (n = 298) were used to evaluate the ...
Source: Journal of Pharmacokinetics and Pharmacodynamics - March 22, 2023 Category: Drugs & Pharmacology Source Type: research