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The AAPS Journal Jul 2023Interest and efforts to use recombinant adeno-associated viruses (AAV) as gene therapy delivery tools to treat disease have grown exponentially. However, gaps in... (Review)
Review
Interest and efforts to use recombinant adeno-associated viruses (AAV) as gene therapy delivery tools to treat disease have grown exponentially. However, gaps in understanding of the pharmacokinetics/pharmacodynamics (PK/PD) and disposition of this modality exist. This position paper comes from the Novel Modalities Working Group (WG), part of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ). The pan-industry WG effort focuses on the nonclinical PK and clinical pharmacology aspects of AAV gene therapy and related bioanalytical considerations.Traditional PK concepts are generally not applicable to AAV-based therapies due to the inherent complexity of a transgene-carrying viral vector, and the multiple steps and analytes involved in cell transduction and transgene-derived protein expression. Therefore, we explain PK concepts of biodistribution of AAV-based therapies and place key terminologies related to drug exposure and PD in the proper context. Factors affecting biodistribution are presented in detail, and guidelines are provided to design nonclinical studies to enable a stage-gated progression to Phase 1 testing. The nonclinical and clinical utility of transgene DNA, mRNA, and protein analytes are discussed with bioanalytical strategies to measure these analytes. The pros and cons of qPCR vs. ddPCR technologies for DNA/RNA measurement and qualitative vs. quantitative methods for transgene-derived protein are also presented. Last, best practices and recommendations for use of clinical and nonclinical data to project human dose and response are discussed. Together, the manuscript provides a holistic framework to discuss evolving concepts of PK/PD modeling, bioanalytical technologies, and clinical dose selection in gene therapy.
Topics: Humans; Dependovirus; Tissue Distribution; Genetic Therapy; Drug Development; Polymerase Chain Reaction
PubMed: 37523051
DOI: 10.1208/s12248-023-00842-1 -
Journal of Clinical Pharmacology Jan 2024Small interfering RNAs (siRNAs) represent a new class of drugs with tremendous potential for battling previously "undruggable" diseases. After nearly 2 decades of... (Review)
Review
Small interfering RNAs (siRNAs) represent a new class of drugs with tremendous potential for battling previously "undruggable" diseases. After nearly 2 decades of efforts in addressing the problems of the poor drug profile of naked unmodified siRNAs, this new modality has finally come to fruition, with 5 agents (patisiran, givosiran, lumasiran, inclisiran, and vutrisiran) being approved since 2018, and with many others in the different phases of clinical development. Unlike small-molecule drugs and protein therapeutics, siRNAs have different sizes, distinct mechanisms of action, differing physicochemical and pharmacological properties, and, accordingly, a unique pharmacokinetic/pharmacodynamic (PK/PD) relationship. To support the continuous development of siRNAs, it is important to have a thorough and deep understanding of the PK/PD and clinical pharmacology related features of siRNAs. As most of the current siRNA products are conjugated by N-acetylgalactosamine (GalNAc), this review focuses on the PK/PD relationships and clinical pharmacology of GalNAc-conjugated siRNAs, including their absorption, distribution, metabolism, excretion (ADME) properties, PK/PD models, drug-drug interactions, clinical pharmacology in special populations, and safety evaluation. In addition, necessary background information related to the development of siRNAs as a therapeutic modality, including the mechanisms of action, the advantages of siRNAs, the problems of naked siRNAs, as well as the strategies used to enhance the clinical utility of siRNAs, have also been covered. The goal of this review is to serve as a "primer" on siRNA PK/PD, and I hope the readers, especially those who have a limited background on siRNA therapeutics, will have a fundamental understanding of siRNA PK/PD and clinical pharmacology after reading this review.
Topics: Humans; RNA, Small Interfering; Drug Interactions; Pharmacology, Clinical; Pharmacokinetics
PubMed: 37589246
DOI: 10.1002/jcph.2337 -
Journal of Pharmacokinetics and... Feb 2024The current demand for pharmacometricians outmatches the supply provided by academic institutions and considerable investments are made to develop the competencies of...
The current demand for pharmacometricians outmatches the supply provided by academic institutions and considerable investments are made to develop the competencies of these scientists on-the-job. Even with the observed increase in academic programs related to pharmacometrics, this need is unlikely to change in the foreseeable future, as the demand and scope of pharmacometrics applications keep expanding. Further, the field of pharmacometrics is changing. The field largely started when Lewis Sheiner and Stuart Beal published their seminal papers on population pharmacokinetics in the late 1970's and early 1980's and has continued to grow in impact and use since its inception. Physiological-based pharmacokinetics and systems pharmacology have grown rapidly in scope and impact in the last decade and machine learning is just on the horizon. While all these methodologies are categorized as pharmacometrics, no one person can be an expert in everything. So how do you train future pharmacometricians? Leading experts in academia, industry, contract research organizations, clinical medicine, and regulatory gave their opinions on how to best train future pharmacometricians. Their opinions were collected and synthesized to create some general recommendations.
Topics: Humans; Pharmacology; Pharmacokinetics; Career Choice
PubMed: 37573528
DOI: 10.1007/s10928-023-09878-4 -
Pharmaceutical Research Feb 2024To revise the IVIVC considering the physiologically sound Finite Absorption Time (F.A.T.) and Finite Dissolution Time (F.D.T.) concepts.
PURPOSE
To revise the IVIVC considering the physiologically sound Finite Absorption Time (F.A.T.) and Finite Dissolution Time (F.D.T.) concepts.
METHODS
The estimates τ and τ for F.A.T. and F.D.T., respectively are constrained by the inequality τ ≤ τ; their relative magnitude is dependent on drug's BCS classification. A modified Levy plot, which includes the time estimates for τ and τ was developed. IVIVC were also considered in the light of τ and τ estimates. The modified Levy plot of theophylline, a class I drug, coupled with the rapid (30 min) and very rapid (15 min) dissolution time limits showed that drug dissolution/absorption of Class I drugs takes place in less than an hour. We reanalyzed a carbamazepine (Tegretol) bioequivalence study using PBFTPK models to reveal its complex absorption kinetics with two or three stages.
RESULTS
The modified Levy plot unveiled the short time span (~ 2 h) of the in vitro dissolution data in comparison with the duration of in vivo dissolution/absorption processes (~ 17 h). Similar results were observed with the modified IVIVC plots. Analysis of another set of carbamazepine data, using PBFTPK models, confirmed a three stages absorption process. Analysis of steady-state (Tegretol) data from a paediatric study using PBFTPK models, revealed a single input stage of duration 3.3 h. The corresponding modified Levy and IVIVC plots were found to be nonlinear.
CONCLUSIONS
The consideration of Levy plots and IVIVC in the light of the F.A.T. and F.D.T. concepts allows a better physiological insight of the in vitro and in vivo drug dissolution/absorption processes.
Topics: Humans; Child; Solubility; Drug Liberation; Carbamazepine; Biological Availability; Therapeutic Equivalency
PubMed: 38191705
DOI: 10.1007/s11095-024-03653-x -
Nature Chemical Biology Nov 2023
Topics: Biodegradation, Environmental; Biotransformation
PubMed: 37845551
DOI: 10.1038/s41589-023-01446-8 -
Pharmacological Research Sep 2023Organ-on-chip (OoC) technology has led to in vitro models with many new possibilities compared to conventional in vitro and in vivo models. In this review, the potential... (Review)
Review
Organ-on-chip (OoC) technology has led to in vitro models with many new possibilities compared to conventional in vitro and in vivo models. In this review, the potential of OoC models to improve the prediction of human oral bioavailability and intrinsic clearance is discussed, with a focus on the functionality of the models and the application in current drug development practice. Multi-OoC models demonstrating the application for pharmacokinetic (PK) studies are summarized and existing challenges are identified. Physiological parameters for a minimal viable platform of a multi-OoC model to study PK are provided, together with PK specific read-outs and recommendations for relevant reference compounds to validate the model. Finally, the translation to in vivo PK profiles is discussed, which will be required to routinely apply OoC models during drug development.
Topics: Humans; Models, Biological; Drug Development; Biological Availability; Microphysiological Systems
PubMed: 37473876
DOI: 10.1016/j.phrs.2023.106853 -
Molecules (Basel, Switzerland) Aug 2023Tectorigenin is a well-known natural flavonoid aglycone and an active component that exists in numerous plants. Growing evidence suggests that tectorigenin has multiple... (Review)
Review
Tectorigenin is a well-known natural flavonoid aglycone and an active component that exists in numerous plants. Growing evidence suggests that tectorigenin has multiple pharmacological effects, such as anticancer, antidiabetic, hepatoprotective, anti-inflammatory, antioxidative, antimicrobial, cardioprotective, and neuroprotective. These pharmacological properties provide the basis for the treatment of many kinds of illnesses, including several types of cancer, diabetes, hepatic fibrosis, osteoarthritis, Alzheimer's disease, etc. The purpose of this paper is to provide a comprehensive summary and review of the sources, extraction and synthesis, pharmacological effects, toxicity, pharmacokinetics, and delivery strategy aspects of tectorigenin. Tectorigenin may exert certain cytotoxicity, which is related to the administration time and concentration. Pharmacokinetic studies have demonstrated that the main metabolic pathways in rats for tectorigenin are glucuronidation, sulfation, demethylation and methoxylation, but that it exhibits poor bioavailability. From our perspective, further research on tectorigenin should cover: exploring the pharmacological targets and mechanisms of action; finding an appropriate concentration to balance pharmacological effects and toxicity; attempting diversified delivery strategies to improve the bioavailability; and structural modification to obtain tectorigenin derivatives with higher pharmacological activity.
Topics: Rats; Animals; Isoflavones; Biological Availability; Flavonoids; Liver Cirrhosis
PubMed: 37570873
DOI: 10.3390/molecules28155904 -
Molecules (Basel, Switzerland) Jan 2024Cannabidiol (CBD), a non-psychoactive compound derived from Cannabis Sativa, has garnered increasing attention for its diverse therapeutic potential. This comprehensive... (Review)
Review
Cannabidiol (CBD), a non-psychoactive compound derived from Cannabis Sativa, has garnered increasing attention for its diverse therapeutic potential. This comprehensive review delves into the complex pharmacokinetics of CBD, including factors such as bioavailability, distribution, safety profile, and dosage recommendations, which contribute to the compound's pharmacological profile. CBD's role as a pharmacological inhibitor is explored, encompassing interactions with the endocannabinoid system and ion channels. The compound's anti-inflammatory effects, influencing the Interferon-beta and NF-κB, position it as a versatile candidate for immune system regulation and interventions in inflammatory processes. The historical context of Cannabis Sativa's use for recreational and medicinal purposes adds depth to the discussion, emphasizing CBD's emergence as a pivotal phytocannabinoid. As research continues, CBD's integration into clinical practice holds promise for revolutionizing treatment approaches and enhancing patient outcomes. The evolution in CBD research encourages ongoing exploration, offering the prospect of unlocking new therapeutic utility.
Topics: Humans; Cannabidiol; Biological Availability; Hallucinogens; Cannabinoid Receptor Agonists; Cannabis; Carbidopa
PubMed: 38257386
DOI: 10.3390/molecules29020473 -
Expert Opinion on Drug Metabolism &... Dec 2023Advances in research and development (R&D) have enabled many approvals of antisense oligonucleotides (ASOs). Its administration expanded from systemic to local for... (Review)
Review
INTRODUCTION
Advances in research and development (R&D) have enabled many approvals of antisense oligonucleotides (ASOs). Its administration expanded from systemic to local for treating various diseases, where predicting target tissue exposures and pharmacokinetics (PK) and pharmacodynamics (PD) in human can be critical.
AREAS COVERED
A literature search for PBPK/PD models of ASOs was conducted using PubMed and Embase (to 1 April 2023). ASO PK and PD in animals and humans and modeling approaches including physiologically based (PB) are summarized; and relevance and impacts of PBPK/PD modeling are assessed.
EXPERT OPINION
Allometric scaling and compartmental PK/PD modeling have been successful to predict human ASO PK/PD, addressing most R&D needs. Understanding tissue distribution of ASOs can be crucial for their efficacy and safety especially for intrathecal (IT), pulmonary, or other local routes. PBPK/PD modeling is expected to improve such understanding, for which, efforts have been sporadic. However, developing a PBPK/PD model requires careful review of known biology/pharmacology and thoughtful experimental designs. Resulting models have the potential to predict target/specified tissue exposures and responses in human adults and pediatrics. Ultimately, a PBPK/PD modeling approach can lead to more efficient and rational clinical development, resulting in well-informed decision making and a shortened timeline.
Topics: Adult; Animals; Humans; Child; Oligonucleotides, Antisense; Models, Biological; Tissue Distribution; Lung; Pharmacokinetics
PubMed: 37970635
DOI: 10.1080/17425255.2023.2283524 -
Journal of Aerosol Medicine and... Oct 2023The pharmacokinetic (PK) profile of a drug after inhalation may differ quite markedly from that seen after dosing by other routes of administration. Drugs may be...
The pharmacokinetic (PK) profile of a drug after inhalation may differ quite markedly from that seen after dosing by other routes of administration. Drugs may be administered to the lung to elicit a local action or as a portal for systemic delivery of the drug to its site of action elsewhere in the body. Some knowledge of PK is important for both locally- and systemically-acting drugs. For a systemically-acting drug, the plasma concentration-time profile shares some similarities with drug given by the oral or intravenous routes, since the plasma concentrations (after the distribution phase) will be in equilibrium with concentrations at the site of action. For a locally-acting drug, however, the plasma concentrations reflect its fate after it has been absorbed and removed from the airways, and not what is available to its site of action in the lung. Consequently, those typical PK parameters which are determined from plasma concentration measurements, e.g., area under the curve (AUC), C, t and post-peak t1/2 may provide information on the deposition and absorption of drugs from the lung; however, the information from these parameters becomes more complicated to decipher for those drugs which are locally-acting in the lung. Additionally, the plasma concentration profile for both locally- and systemically-acting drugs will not only reflect drug absorbed from the lung but also that absorbed from the gastrointestinal (GI) tract from the portion of the dose which is swallowed. This absorption from the GI tract adds a further complication to the interpretation of plasma concentrations, particularly for locally-acting drugs. The influence of physiological and pathological factors needs to be considered in the absorption of some inhaled drugs. The absorption of some hydrophilic drugs is influenced by the inspiratory maneuver used during initial inhalation of the drug, and at later times after deposition. Similarly, the effects of smoking have been shown to increase lung permeability and increase the absorption of certain hydrophilic drugs. The effects of different disease states of the lung have less defined influences on absorption into the systemic circulation.
Topics: Administration, Inhalation; Smoking; Pharmaceutical Preparations; Lung; Area Under Curve
PubMed: 37851977
DOI: 10.1089/jamp.2023.29091.gt