-
Neuron Dec 2021Psychiatric genomics is providing insights into the nature of psychiatric conditions that in time should identify new drug targets and improve patient care. Less... (Review)
Review
Psychiatric genomics is providing insights into the nature of psychiatric conditions that in time should identify new drug targets and improve patient care. Less attention has been paid to psychiatric pharmacogenomics research, despite its potential to deliver more rapid change in clinical practice and patient outcomes. The pharmacogenomics of treatment response encapsulates both pharmacokinetic ("what the body does to a drug") and pharmacodynamic ("what the drug does to the body") effects. Despite early optimism and substantial research in both these areas, they have to date made little impact on clinical management in psychiatry. A number of bottlenecks have hampered progress, including a lack of large-scale replication studies, inconsistencies in defining valid treatment outcomes across experiments, a failure to routinely incorporate adverse drug reactions and serum metabolite monitoring in study designs, and inadequate investment in the longitudinal data collections required to demonstrate clinical utility. Nonetheless, advances in genomics and health informatics present distinct opportunities for psychiatric pharmacogenomics to enter a new and productive phase of research discovery and translation.
Topics: Drug-Related Side Effects and Adverse Reactions; Genomics; Humans; Pharmacogenetics; Precision Medicine; Psychiatry
PubMed: 34619094
DOI: 10.1016/j.neuron.2021.09.011 -
CPT: Pharmacometrics & Systems... Aug 2022Antibody-drug conjugates (ADCs) have gained traction in the oncology space in the past few decades, with significant progress being made in recent years. Although the... (Review)
Review
Antibody-drug conjugates (ADCs) have gained traction in the oncology space in the past few decades, with significant progress being made in recent years. Although the use of pharmacometric modeling is well-established in the drug development process, there is an increasing need for a better quantitative biological understanding of the pharmacokinetic and pharmacodynamic relationships of these complex molecules. Quantitative systems pharmacology (QSP) approaches can assist in this endeavor; recent computational QSP models incorporate ADC-specific mechanisms and use data-driven simulations to predict experimental outcomes. Various modeling approaches and platforms have been developed at the in vitro, in vivo, and clinical scales, and can be further integrated to facilitate preclinical to clinical translation. These new tools can help researchers better understand the nature and mechanisms of these targeted therapies to help achieve a more favorable therapeutic window. This review delves into the world of systems pharmacology modeling of ADCs, discussing various modeling efforts in the field thus far.
Topics: Humans; Immunoconjugates; Models, Biological; Network Pharmacology; Pharmacology
PubMed: 35712824
DOI: 10.1002/psp4.12833 -
CPT: Pharmacometrics & Systems... Oct 2018Reliance on modeling and simulation in drug discovery and development has dramatically increased over the past decade. Two disciplines at the forefront of this activity,... (Review)
Review
Reliance on modeling and simulation in drug discovery and development has dramatically increased over the past decade. Two disciplines at the forefront of this activity, pharmacometrics and systems pharmacology (SP), emerged independently from different fields; consequently, a perception exists that only few examples integrate these approaches. Herein, we review the state of pharmacometrics and SP integration and describe benefits of combining these approaches in a model-informed drug discovery and development framework.
Topics: Pharmacology; Systems Integration
PubMed: 29761892
DOI: 10.1002/psp4.12313 -
International Journal of Molecular... Jan 2023Epilepsy is one of the most frequent chronic neurologic disorders that affects nearly 1% of the population worldwide, especially in developing countries. Currently,... (Review)
Review
Epilepsy is one of the most frequent chronic neurologic disorders that affects nearly 1% of the population worldwide, especially in developing countries. Currently, several antiepileptic drugs (AEDs) are available for its therapy, and although the prognosis is good for most patients, 20%-30% amongst them do not reach seizure freedom. Numerous factors may explain AED-resistance such as sex, age, ethnicity, type of seizure, early epilepsy onset, suboptimal dosing, poor drug compliance, alcohol abuse, and in particular, genetic factors. Specifically, the interindividual differences in drug response can be caused by single nucleotide polymorphisms (SNPs) in genes encoding for drug efflux transporters, for the brain targets of AEDs, and for enzymes involved in drug metabolism. In this review, we used the PubMed database to retrieve studies that assessed the influence of SNPs on the pharmacokinetic (PK), pharmacodynamic (PD), and efficacy of new antiepileptic drugs. Our results showed that polymorphisms in the ABCB1, ABCC2, UGT1A4, UGT2B7, UGT2B15, CYP2C9, and CYP2C19 genes have an influence on the PK and efficacy of AEDs, suggesting that a genetic pre-evaluation of epileptic patients could help clinicians in prescribing a personalized treatment to improve the efficacy and the safety of the therapy.
Topics: Humans; Anticonvulsants; Pharmacogenetics; Epilepsy; Polymorphism, Single Nucleotide; Drug Resistance
PubMed: 36768858
DOI: 10.3390/ijms24032535 -
Dialogues in Clinical Neuroscience Dec 2014It is timely to consider the ethical and social questions raised by progress in pharmacogenomics, based on the current importance of pharmacogenomics for avoidance of... (Review)
Review
It is timely to consider the ethical and social questions raised by progress in pharmacogenomics, based on the current importance of pharmacogenomics for avoidance of predictable side effects of drugs, and for correct choice of medications in certain cancers. It has been proposed that the entire population be genotyped for drug-metabolizing enzyme polymorphisms, as a measure that would prevent many untoward and dangerous drug reactions. Pharmacologic treatment targeting based on genomics of disease can be expected to increase greatly in the coming years. Policy and ethical issues exist on consent for large-scale genomic pharmacogenomic data collection, public vs corporate ownership of genomic research results, testing efficacy and safety of drugs used for rare genomic indications, and accessibility of treatments based on costly research that is applicable to relatively few patients. In major psychiatric disorders and intellectual deficiency, rare and de novo deletion or duplication of chromosomal segments (copy number variation), in the aggregate, are common causes of increased risk. This implies that the policy problems of pharmacogenomics will be particularly important for the psychiatric disorders.
Topics: Humans; Pharmacogenetics; Public Policy
PubMed: 25733960
DOI: 10.31887/DCNS.2014.16.4/egershon -
The Journal of Pharmacology and... Sep 2019The use of drug delivery systems (DDS) is an attractive approach to facilitate uptake of therapeutic agents at the desired site of action, particularly when free drug... (Review)
Review
The use of drug delivery systems (DDS) is an attractive approach to facilitate uptake of therapeutic agents at the desired site of action, particularly when free drug has poor pharmacokinetics/biodistribution (PK/BD) or significant off-site toxicities. Successful translation of DDS into the clinic is dependent on a thorough understanding of the in vivo behavior of the carrier, which has, for the most part, been an elusive goal. This is, at least in part, due to significant differences in the mechanisms controlling pharmacokinetics for classic drugs and DDSs. In this review, we summarize the key physiologic mechanisms controlling the in vivo behavior of DDS, compare and contrast this with classic drugs, and describe engineering strategies designed to improve DDS PK/BD. In addition, we describe quantitative approaches that could be useful for describing PK/BD of DDS, as well as critical steps between tissue uptake and pharmacologic effect.
Topics: Animals; Drug Delivery Systems; Drug Therapy; Humans; Pharmacokinetics; Pharmacology; Tissue Distribution
PubMed: 30837281
DOI: 10.1124/jpet.119.257113 -
Indian Journal of Pharmacology Oct 2016Competency-based medical education (CBME) is gaining momentum across the globe. The Medical Council of India has described the basic competencies required of an Indian... (Review)
Review
Competency-based medical education (CBME) is gaining momentum across the globe. The Medical Council of India has described the basic competencies required of an Indian Medical Graduate and designed a competency-based module on attitudes and communication. Widespread adoption of a competency-based approach would mean a paradigm shift in the current approach to medical education. CBME, hence, needs to be reviewed for its usefulness and limitations in the Indian context. This article describes the rationale of CBME and provides an overview of its components, i.e., competency, entrustable professional activity, and milestones. It elaborates how CBME could be implemented in an institute, in the context of basic sciences in general and pharmacology in particular. The promises and perils of CBME that need to be kept in mind to maximize its gains are described.
Topics: Competency-Based Education; Curriculum; Education, Medical; Humans; Pharmacology
PubMed: 28031599
DOI: 10.4103/0253-7613.193312 -
Clinical Pharmacology and Therapeutics Jul 2015The scaling up of data in clinical pharmacology and the merger of systems biology and pharmacology has led to the emergence of a new discipline of Quantitative and... (Review)
Review
The scaling up of data in clinical pharmacology and the merger of systems biology and pharmacology has led to the emergence of a new discipline of Quantitative and Systems Pharmacology (QSP). This new research direction might significantly advance the discovery, development, and clinical use of therapeutic drugs. Research communities from computational biology, systems biology, and biological engineering--working collaboratively with pharmacologists, geneticists, biochemists, and analytical chemists--are creating and modeling large data on drug effects that is transforming our understanding of how these drugs work at a network level. In this review, we highlight developments in a new and rapidly growing field--pharmacometabolomics--in which large biochemical data-capturing effects of genome, gut microbiome, and environment exposures is revealing information about metabotypes and treatment outcomes, and creating metabolic signatures as new potential biomarkers. Pharmacometabolomics informs and complements pharmacogenomics and together they provide building blocks for QSP.
Topics: Biomarkers; Biomarkers, Pharmacological; Drug Discovery; Humans; Metabolic Networks and Pathways; Metabolome; Pharmacogenetics; Pharmacology; Phenotype; Precision Medicine
PubMed: 25871646
DOI: 10.1002/cpt.134 -
Cancer Treatment and Research... 2022Clinical responses to anticancer therapies in advanced soft tissue sarcoma (STS) are unfortunately limited to a small subset of patients. Much of the inter-individual... (Review)
Review
Clinical responses to anticancer therapies in advanced soft tissue sarcoma (STS) are unfortunately limited to a small subset of patients. Much of the inter-individual variability in treatment efficacy and risk of toxicities is as result of polymorphisms in genes encoding proteins involved in drug pharmacokinetics and pharmacodynamics. Therefore, the detection of pharmacogenomics (PGx) biomarkers that might predict drug response and toxicity can be useful to explain the genetic basis for the differences in treatment efficacy and toxicity among STS patients. PGx markers are frequently located in transporters, drug-metabolizing enzyme genes, drug targets, or HLA alleles. Along this line, genetic variability harbouring in the germline genome of the patients can influence systemic pharmacokinetics and pharmacodynamics of the treatments, acting as predictive biomarkers for drug-induced toxicity and treatment efficacy. By linking drug activity to the functional complexity of cancer genomes, also systematic pharmacogenomic profiling in cancer cell lines and primary STS samples represents area of active investigation that could eventually lead to enhanced efficacy and offer a powerful biomarker discovery platform to optimize current treatments and improve the knowledge about the individual's drug response in STS patients into the clinical practice.
Topics: Biomarkers; Humans; Pharmacogenetics; Sarcoma
PubMed: 35123198
DOI: 10.1016/j.ctarc.2022.100528 -
Pediatric Research Jun 2018Pharmacodynamic (PD) endpoints are essential for establishing the benefit-to-risk ratio for therapeutic interventions in children and neonates. This article discusses... (Review)
Review
Pharmacodynamic (PD) endpoints are essential for establishing the benefit-to-risk ratio for therapeutic interventions in children and neonates. This article discusses the selection of an appropriate measure of response, the PD endpoint, which is a critical methodological step in designing pediatric efficacy and safety studies. We provide an overview of existing guidance on the choice of PD endpoints in pediatric clinical research. We identified several considerations relevant to the selection and measurement of PD endpoints in pediatric clinical trials, including the use of biomarkers, modeling, compliance, scoring systems, and validated measurement tools. To be useful, PD endpoints in children need to be clinically relevant, responsive to both treatment and/or disease progression, reproducible, and reliable. In most pediatric disease areas, this requires significant validation efforts. We propose a minimal set of criteria for useful PD endpoint selection and measurement. We conclude that, given the current heterogeneity of pediatric PD endpoint definitions and measurements, both across and within defined disease areas, there is an acute need for internationally agreed, validated, and condition-specific pediatric PD endpoints that consider the needs of all stakeholders, including healthcare providers, policy makers, patients, and families.
Topics: Biomarkers; Child; Child, Preschool; Clinical Trials as Topic; Disease Progression; Dose-Response Relationship, Drug; Drug Evaluation; Drug Therapy; Endpoint Determination; Health Policy; Humans; Infant; Infant, Newborn; Patient Compliance; Pharmaceutical Preparations; Pharmacokinetics; Pharmacology; Practice Guidelines as Topic; Reproducibility of Results; Research Design; Risk; United States; United States Food and Drug Administration
PubMed: 29667952
DOI: 10.1038/pr.2018.38