Artificial Intelligence and Machine Learning Approaches to Facilitate Therapeutic Drug Management and Model-Informed Precision Dosing.

BACKGROUND: Therapeutic drug monitoring (TDM) and model-informed precision dosing (MIPD) have greatly benefitted from computational and mathematical advances over the past 60 years. Furthermore, the use of artificial intelligence (AI) and machine learning (ML) approaches for supporting clinical research and support is increasing. However, AI and ML applications for precision dosing have been evaluated only recently. Given the capability of ML to handle multidimensional data, such as from electronic health records, opportunities for AI and ML applications to facilitate TDM and MIPD may be advantageous. METHODS: This review summarizes relevant AI and ML approaches to support TDM and MIPD, with a specific focus on recent applications. The opportunities and challenges associated with this integration are also discussed. RESULTS: Various AI and ML applications have been evaluated for precision dosing, including those related to concentration or exposure prediction, dose optimization, population pharmacokinetics and pharmacodynamics, quantitative systems pharmacology, and MIPD system development and support. These applications provide an opportunity for ML and pharmacometrics to operate in an integrated manner to provide clinical decision support for precision dosing. CONCLUSIONS: Although the integration of AI with precision dosing is still in its early stages and is evolving, AI and ML have the potential to work harmoniously and synergistically with pharmacometric approaches to support TDM and MIPD. Because data are increasingly shared between institutions and clinical networks and aggregated into large databases, these applications will continue to grow. The successful implementation of these approaches will depend on cross-field collaborations among clinicians and experts in informatics, ML, pharmacometrics, clinical pharmacology, and TDM.

EXOGENOUS Sex Hormones and Sex Hormone Receptor Modulators in COVID-19: Rationale and Clinical Pharmacology Considerations.

Male patients with coronavirus disease 2019 (COVID-19) fare much worse than female patients in COVID-19 severity and mortality according to data from several studies. Because of this sex disparity, researchers hypothesize that the use of exogenous sex hormone therapy and sex hormone receptor modulators might provide therapeutic potential for patients with COVID-19. Repurposing approved drugs or drug candidates at late-stage clinical development could expedite COVID-19 therapy development because their clinical formulation, routes of administration, dosing regimen, clinical pharmacology, and potential adverse events have already been established or characterized in humans. A number of exogenous sex hormones and sex hormone receptor modulators are currently or will be under clinical investigation for COVID-19 therapy. In this review, we discuss the rationale for exogenous sex hormones and sex hormone receptor modulators in COVID-19 treatment, summarize ongoing and planned clinical trials, and discuss some of the clinical pharmacology considerations on clinical study design. To inform clinical study design and facilitate the clinical development of exogenous sex hormones and sex hormone receptor modulators for COVID-19 therapy, clinical investigators should pay attention to clinical pharmacology factors, such as dosing regimen, special populations (i.e., geriatrics, pregnancy, lactation, and renal/hepatic impairment), and drug interactions.

Model-Informed Drug Development Approaches to Assist New Drug Development in the COVID-19 Pandemic.

Leveraging limited clinical and nonclinical data through modeling approaches facilitates new drug development and regulatory decision making amid the coronavirus disease 2019 (COVID-19) pandemic. Model-informed drug development (MIDD) is an essential tool to integrate those data and generate evidence to (i) provide support for effectiveness in repurposed or new compounds to combat COVID-19 and dose selection when clinical data are lacking; (ii) assess efficacy under practical situations such as dose reduction to overcome supply issues or emergence of resistant variant strains; (iii) demonstrate applicability of MIDD for full extrapolation to adolescents and sometimes to young pediatric patients; and (iv) evaluate the appropriateness for prolonging a dosing interval to reduce the frequency of hospital visits during the pandemic. Ongoing research activities of MIDD reflect our continuous effort and commitment in bridging knowledge gaps that leads to the availability of effective treatments through innovation. Case examples are presented to illustrate how MIDD has been used in various stages of drug development and has the potential to inform regulatory decision making.

Use of Propensity Scoring and Its Application to Real-World Data: Advantages, Disadvantages, and Methodological Objectives Explained to Researchers Without Using Mathematical Equations.

Real-time data collection of patient health status and medications is sped up with modern electronic devices and technologies. As real-world data provide enormous research opportunities, propensity score (PS) methods have been getting attention due to their theoretical grounds in a nonrandomized study setting. In contrast to randomized clinical trials, observational clinical data obtained from a real-world database may not have balanced distributions of patient characteristics between treatment and control groups at the beginning of the respective study. These imbalanced distributions may cause a bias in an estimated treatment effect, which needs to be eliminated. Propensity scoring is one class of statistical methods to address the imbalance issue of real-world data sets. This article provides basic concepts and assesses advantages, disadvantages, and methodological objectives of propensity scoring. Targeting clinical pharmacology researchers with limited statistical background, 5 representative methods are reviewed and visualized: matching, stratification, covariate modeling, inverse probability of treatment weighting, and doubly robust methods. Examples of applications of PS methods were selected from the literature of outcomes research and drug development, nephrology, and pediatrics. Opportunities of applications related to these examples are described. Furthermore, potential future applications of PS methods in clinical pharmacology are discussed. The 21st Century Cures Act signed in 2016 encourages scientists to find opportunities to apply propensity scoring to real-world data. This article underscores that scientists need to justify their choice of statistical methods, whether a PS method or an alternative method, based on their clinical study design, statistical assumptions, and research objectives.

Sex-tailored pharmacology and COVID-19: Next steps towards appropriateness and health equity.

Making gender bias visible allows to fill the gaps in knowledge and understand health records and risks of women and men. The coronavirus disease 2019 (COVID-19) pandemic has shown a clear gender difference in health outcomes. The more severe symptoms and higher mortality in men as compared to women are likely due to sex and age differences in immune responses. Age-associated decline in sex steroid hormone levels may mediate proinflammatory reactions in older adults, thereby increasing their risk of adverse outcomes, whereas sex hormones and/or sex hormone receptor modulators may attenuate the inflammatory response and provide benefit to COVID-19 patients. While multiple pharmacological options including anticoagulants, glucocorticoids, antivirals, anti-inflammatory agents and traditional Chinese medicine preparations have been tested to treat COVID-19 patients with varied levels of evidence in terms of efficacy and safety, information on sex-targeted treatment strategies is currently limited. Women may have more benefit from COVID-19 vaccines than men, despite the occurrence of more frequent adverse effects, and long-term safety data with newly developed vectors are eagerly awaited. The prevalent inclusion of men in randomized clinical trials (RCTs) with subsequent extrapolation of results to women needs to be addressed, as reinforcing sex-neutral claims into COVID-19 research may insidiously lead to increased inequities in health care. The huge worldwide effort with over 3000 ongoing RCTs of pharmacological agents should focus on improving knowledge on sex, gender and age as pillars of individual variation in drug responses and enforce appropriateness.

Quantitative Clinical Pharmacology Supports the Bridging From i.v. Dosing and Approval of s.c. Rituximab in B-Cell Hematological Malignancies.

A fixed-dose subcutaneous (s.c.) formulation of the anti-CD20 antibody, rituximab, has been developed to address safety, infusion time, and patient comfort concerns relating to intravenous (i.v.) dosing, and has been approved based upon a pharmacokinetic (PK)-clinical bridging strategy, which demonstrated noninferiority of s.c. vs. i.v. dosing in malignancies, including follicular lymphoma (FL) and chronic lymphocytic leukemia (CLL). A clinical development plan was undertaken to identify rituximab s.c. doses achieving noninferior exposure to rituximab i.v., and to confirm PK-clinical bridging, with the same efficacy and similar safety. This drew upon data from 1,579 patients with FL, CLL, or diffuse large B-cell lymphoma in 5 clinical studies, and showed minimum steady-state serum concentration (Ctrough ) as the most appropriate exposure bridging measure. Population PK models were developed, simulations were run using covariates and PK parameters from clinical studies, and exposure-efficacy and -safety analyses performed. Population PKs showed a two-compartment model with time-dependent and -independent clearances. Clearance and volume were predominantly influenced by body surface area; disposition and elimination were similar for the s.c. and i.v. formulations. After s.c. administration, patients with FL and CLL achieved noninferior exposures to i.v. dosing. Overall, rituximab exposure and route of administration did not influence clinical responses in patients with FL or CLL, and there was no association between exposure and safety events. Ctrough was shown to be an effective pharmacologic-clinical bridging parameter for rituximab in patients with FL or CLL. Clinically effective exposures are achieved with either s.c. or i.v. dosing.

There is Only One Valid Definition of Clearance: Critical Examination of Clearance Concepts Reveals the Potential for Errors in Clinical Drug Dosing Decisions.

Drug dosing decisions in clinical medicine and in introducing a drug to market for the past 60 years are based on the pharmacokinetic/clinical pharmacology concept of clearance. We used chemical reaction engineering models to demonstrate the limitations of presently employed clearance measurements based upon systemic blood concentration in reflecting organ clearance. The belief for the last 49 years that in vivo clearance is independent of the mechanistic model for organ clearance is incorrect. There is only one valid definition of clearance. Defining organ clearance solely on the basis of systemic blood concentrations can lead to drug dosing errors when drug effect sites reside either in an eliminating organ exhibiting incremental clearance or in a non-eliminating organ where intraorgan concentration is governed by transporter actions. Attempts to predict clearance are presently hampered by the lack of recognition that what we are trying to predict is a well-stirred model clearance.

Clinical pharmacology strategies in supporting drug development and approval of antibody-drug conjugates in oncology.

Antibody-drug conjugates (ADCs) are important molecular entities in the treatment of cancer. These conjugates combine the target specificity of monoclonal antibodies with the potent anti-cancer activity of small-molecule therapeutics. The complex structure of ADCs poses unique challenges to characterize the drug's pharmacokinetics (PKs) and pharmacodynamics (PDs) since it requires a quantitative understanding of the PK and PD properties of multiple different molecular species (e.g., ADC conjugate, total antibody and unconjugated cytotoxic drug). As a result, clinical pharmacology strategy of an ADC is rather unique and dependent on the linker/cytotoxic drug technology, heterogeneity of the ADC, PK and safety/efficacy profile of the specific ADC in clinical development. In this review, we summarize the clinical pharmacology strategies in supporting development and approval of ADCs using the approved ADCs as specific examples to illustrate the customized approach to clinical pharmacology assessments in their clinical development.

Clinical Pharmacology Worldwide: A Global Health Perspective.

Low- and middle-income countries (LMICs) have the highest rates of mortality and morbidity globally, but lag behind high-income countries in the number of clinical trials and trained researchers, as well as research data pertaining to their populations. Lack of local clinical pharmacology and pharmacometrics expertise, limited training opportunities, and lack of local genomic data may contribute to health inequalities and limit the application of precision medicine. Continuing to develop health care infrastructure, including well-designed clinical pharmacology training and data collection in LMICs, can help address these challenges. International collaboration aimed at improving training and infrastructure and encouraging locally driven research and clinical trials will be of benefit. This review describes several examples where clinical pharmacology expertise could be leveraged, including opportunities for pharmacogenomic expertise that could drive improved recommendations for clinical guidelines. Also described are clinical pharmacology and pharmacometrics training programs in Africa, and the personal experience of a Tanzanian researcher currently on a training sabbatical in the United States, as illustrative examples of how training in clinical pharmacology can be effectively implemented in LMICs. These training efforts will benefit from advocacy for employment opportunities and career development pathways for clinical pharmacologists that are gradually being recognized and developed in LMICs. Clinical pharmacologists have a key role to play in global health, and development of training and research infrastructure to advance this expertise in LMICs will be of tremendous benefit.

Clinical Pharmacology Regulatory Sciences in Drug Development and Precision Medicine: Current Status and Emerging Trends.

In the regulatory setting, clinical pharmacology focuses on the impact of intrinsic and extrinsic factors on inter-patient and intra-subject variability in drug exposure and response. This translational science contributes to the understanding of the benefit-risk profile in individual patients and the development of relevant therapeutic monitoring and management strategies. Clinical pharmacology also plays a major role in the development and qualification of drug development tools. This article presented some recent examples to illustrate the important roles of clinical pharmacology in drug development and evaluation. In addition, emerging trends in clinical pharmacology regulatory sciences were also discussed, including the Model-Informed Drug Development (MIDD) pilot program, the use of real-world data to generate real-world evidence, and leveraging advances in basic, biomedical, and clinical science into useful tools for drug development and evaluation. Continued advances in clinical pharmacology can be the basis of more rational and efficient drug development and improved access to new drug treatments that are tailored to the patient to achieve better efficacy and safety.

Harnessing formulation and clinical pharmacology knowledge for efficient pediatric drug development: Overview and discussions from M-CERSI pediatric formulation workshop 2019.

A pediatric formulation workshop entitled "Pediatric Formulations: Challenges of Today and Strategies for Tomorrow" was held to advance pediatric drug product development efforts in both pre-competitive and competitive environments. The workshop had four main sessions discussing key considerations of Formulation, Analytical, Clinical and Regulatory. This paper focuses on the clinical session of the workshop. It provides an overview of the discussion on the interconnection of pediatric formulation design and development, clinical development strategy and pediatric clinical pharmacology. The success of pediatric drug product development requires collaboration of multi-disciplinary teams across the pharmaceutical industry, consortiums, foundations, academia and global regulatory agencies. Early strategic planning is essential to ensure alignment among major stakeholders of different functional teams. Such an alignment is particularly critical in the collaboration between formulators and clinical pharmacology teams.

Mapping drug-target interactions and synergy in multi-molecular therapeutics for pressure-overload cardiac hypertrophy.

Advancements in systems biology have resulted in the development of network pharmacology, leading to a paradigm shift from "one-target, one-drug" to "target-network, multi-component therapeutics". We employ a chimeric approach involving in-vivo assays, gene expression analysis, cheminformatics, and network biology to deduce the regulatory actions of a multi-constituent Ayurvedic concoction, Amalaki Rasayana (AR) in animal models for its effect in pressure-overload cardiac hypertrophy. The proteomics analysis of in-vivo assays for Aorta Constricted and Biologically Aged rat models identify proteins expressed under each condition. Network analysis mapping protein-protein interactions and synergistic actions of AR using multi-component networks reveal drug targets such as ACADM, COX4I1, COX6B1, HBB, MYH14, and SLC25A4, as potential pharmacological co-targets for cardiac hypertrophy. Further, five out of eighteen AR constituents potentially target these proteins. We propose a distinct prospective strategy for the discovery of network pharmacological therapies and repositioning of existing drug molecules for treating pressure-overload cardiac hypertrophy.

The application of extreme value theory to pharmacometrics.

Clinical trials are often analyzed by examining the means, e.g., what is the mean treatment effect or what is the mean treatment difference, but there are times when analysis of the maximums (or minimums) are of interest. For instance, what is the highest heart rate that could be observed or what the smallest treatment effect that could be expected? While inference on the means is based on the central limit theorem, the corresponding theorem for maximums or minimums is the Fisher-Tippett theorem, also called the extreme value theorem (EVT). This manuscript will introduce EVT to pharmacometricians, particularly block maxima analysis and peak over threshold analysis, and provide examples for how it can be applied to pharmacometric data, particularly the analysis of pharmacokinetics and ECG safety data, like QTcF intervals.