Differences In Pharmacokinetics Research Articles

Pharmacokinetics and brain uptake of sodium selenate and selenium in naïve rats and a lateral fluid percussion injury ratmodel.

Post-traumatic epilepsy (PTE) is a life-long complication of traumatic brain injury (TBI). The development of PTE is associated with neurological morbidity and increases the risk of mortality. An aim of EpiBioS4Rx (Epilepsy Bioinformatics Study for Antiepileptogenic Therapy) was to test potential therapies to prevent the development of PTE in the lateral fluid percussion injury (LFPI) rat model of TBI, in which rats were subjected to injury at the left parietal cortex. Sodium selenate has been reported to be antiepileptogenic post-TBI in rodent models by activating protein phosphatase 2A and reducing phosphorylated tau (p-tau) protein. We aimed to characterize the pharmacokinetics (PK) and brain uptake of sodium selenate using naïve control and LFPI rats. Rats received either a single bolus dose or a single bolus dose followed by a 7-day subcutaneous minipump infusion of sodium selenate. Sodium selenate and selenium concentrations in plasma and brain were analyzed and used for PK estimation and brain exposure assessment. Selenium concentrations rapidly increased after sodium selenate administration, demonstrating biotransformation from sodium selenate to selenium. Sodium selenate and selenium PK parameters were estimated using non-compartmental analysis. Sodium selenate clearance (CL/F) and volume of distribution (Vd/F) varied by dose and route of administration, suggesting differences in bioavailability and nonlinear pharmacokinetics at the doses tested. Brain-to-plasma partition coefficients (AUCbrain/AUCplasma) for sodium selenate and selenium were found to be 0.7-1.3 and 0.1-0.3 following single-dose injection, respectively, indicating active transport of sodium selenate across the blood-brain barrier (BBB).

Pharmacokinetics of Antiretroviral Drugs in Older People Living with HIV, Part II: Drugs Licensed Before 2005.

Advances in antiretroviral therapy led to an increase in life expectancy among people living with human immunodeficiency virus (HIV). As aging is characterized by several physiological changes that can influence pharmacokinetics (PK), this systematic review aims to describe the impact of aging on the PK of antiretrovirals (ARV) approved by the Food and Drug Administration (FDA) before 2005. Searches were performed in BVS, EMBASE, and PubMed databases for publications until June 2024. Peer-reviewed published studies were included if they met the following criteria: adults (≥ 18 years) living with HIV; reporting at least one PK parameter or plasma concentration of any ARV approved by the US FDA before 2005 and still used in the clinic: lamivudine (3TC), emtricitabine (FTC), tenofovir disoproxil fumarate (TDF), abacavir (ABC), zidovudine (ZDV), efavirenz (EFV), nevirapine (NVP), atazanavir (ATV), lopinavir (LPV), ritonavir (RTV), tipranavir (TPV), and fosamprenavir (FPV); PK parameters stratified per age group as young (aged 18-49 years) or older (age ≥ 50 years) adults; and manuscripts published in English, Portuguese, or Spanish. All studies were evaluated for risk of bias. The review protocol was registered in the PROSPERO database (registration no. CRD42023463092). Among 106 studies included, only 22 evaluated the PK of participants aged 50 years or older and only 5 studies compared the PK between young and older adults for ATV, RTV, EFV, and 3TC. Our analysis revealed an increase in minimal concentration (Cmin) values for LPV, RTV, and ATV in older adults. While increased values of the area under the curve (AUC) and maximum concentration (Cmax) were observed in older adults using ATV, 3TC, and FTC, no differences in PK were apparent between young and older adults for ABC and EFV, with no estimation possible for ZDV. Exposure to 3TC, TDF, FTC, ATV, LPV, and RTV increases with age, while exposure to ABC and EFV appears to be unaffected. Despite the large quantity of data on PK in young adults, there is still a gap in knowledge about the effects of aging on the PK of these ARVs.

Curcumin ameliorates heatstroke-induced lung injury by activating the PI3K/AKT pathway.

Heatstroke (HS) poses a significant threat to public health. Curcumin, a polyphenolic compound, has been reported to possess anti-inflammatory and antioxidant properties. This study aimed to investigate the potential therapeutic effects of curcumin on HS-induced lung injury and to elucidate its underlying molecular mechanisms. We utilized network pharmacology to predict the potential targets of curcumin and determine its possible protective effects against HS. Molecular docking was performed to assess the affinity of curcumin to proteins. Forty mice were used for in vivo experiments to evaluate the therapeutic effects of curcumin, divided into four groups (n = 10 per group): normal control (NC), high-temperature control (HTC), low-dose curcumin heatstroke (H100c, 100mg/kg/day), and high-dose curcumin heatstroke (H200c, 200mg/kg/day). Furthermore, we evaluated lung pathology, ultrastructural alterations, and protein expression levels of key molecules. Molecular docking indicated a high binding affinity between curcumin and PIK3R1, AKT, and CASP3. In vivo experiments confirm that curcumin pretreatment significantly mitigates HS-induced lung tissue pathology and ultrastructural damage, with the H200c group showing notably greater improvement. Furthermore, curcumin pretreatment markedly enhances the activation of the PI3K/AKT pathway and suppresses the expression of cleaved caspase3, particularly in the H200c group. Our study suggests curcumin may alleviate HS-induced lung injury via the PI3K/AKT pathway, but limitations exist. We did not test key protein knockdown/overexpression, and PI3K/AKT may not be the only pathway. Human and mouse pharmacokinetic differences could affect clinical translation.

The Cognitive Restoration Effects of Resveratrol: Insight Molecular through Behavioral Studies in Various Cognitive Impairment Models.

Cognition is essential for daily activities and progressively deteriorates with age due to various factors leading to cognitive decline. This decline often begins with memory impairment and advances to broader cognitive dysfunctions. Resveratrol (RES), a natural phenolic compound found in red wine, has garnered significant attention for its potential to prevent cognitive decline. This review aims to synthesize the latest preclinical data on the cognitive restorative effects of RES. We highlight RES activities from cellular mechanisms to behavioral outcomes. Evidence from various cognitive impairment models demonstrates that RES exerts neuroprotective effects through multiple mechanisms, including anti-inflammatory, antioxidative, anti-apoptotic, and neurotrophic actions, all of which contribute to cognitive enhancement in behavioral studies. Despite the established role of RES in mitigating memory decline, our review identifies a critical gap in behavioral studies regarding cognitive flexibility. Further research in this domain is recommended. Additionally, species-specific pharmacokinetic differences may account for the inconsistencies between preclinical and clinical outcomes, particularly in rats and humans. We propose that formulations designed to delay gut metabolism through enterohepatic circulation could enhance the translational potential of RES. Furthermore, long-term studies are needed to determine the optimal dose capable of maximizing health benefits without raising toxicity during chronic use.

Importance of sex-dependent differences for dosing selection and optimization of chemotherapeutic drugs.

Background Despite major advances in cancer treatment in the past years, there is a need to optimize chemotherapeutic drugs dosing strategies to reduce toxicities, suboptimal responses, and the risk of relapse. Most cancer drugs have a narrow therapeutic index with substantial pharmacokinetics variability. Yet, current dosing approaches do not fully account for the complex pathophysiological characteristics of the patients. In this regard, the effect of sex on anticancer chemotherapeutic drugs disposition is still underexplored. In this article, we review sex differences in chemotherapeutic drug pharmacokinetics, we suggest a novel approach that integrates sex into the traditional a priori body-surface-area (BSA) dosing selection model and finally, we provide an overview of the potential benefits of a broader use of therapeutic drug monitoring (TDM) in oncology. Summary To date, anticancer chemotherapeutic drugs dosing is most often determined by BSA, a method widely used for of its ease-of-practice, despite criticism for not accounting for individual factors, notably sex. Anatomical, physiological, and biological differences between males and females can affect pharmacokinetics, including drug metabolism and clearance. At equivalent doses, females tend to display higher circulating exposure and more organ toxicities, which has been formally demonstrated at present for about 20% of chemotherapeutic drugs. An alternative could be the Sex-Adjusted-BSA (SA-BSA), incorporating a 10% increase in dosing for males and a 10% decrease for females, though this approach still lacks formal clinical validation. Another strategy to reduce treatment-related toxicity and potentially enhance clinical outcomes could be a more widespread use of therapeutic drug monitoring (TDM), for which a benefit has been demonstrated for 5-fluorouracil, busulfan, methotrexate or thiopurines.

Sex-Dependent Effects of CYP2D6 on the Pharmacokinetics of Berberine in Humans.

An over-the-counter product berberine (a major alkaloid in goldenseal) is a substrate of the uptake transporter OCT1 and the metabolizing enzyme CYP2D6. The two genes exhibit common functional polymorphisms. Approximately 9% of Europeans and white Americans are either poor CYP2D6 metabolizers or poor OCT1 transporters. In this study, we investigated the effects of OCT1 and CYP2D6 polymorphisms on berberine pharmacokinetics in humans. We confirmed in vitro that berberine is an OCT1 substrate (KM of 7.0 μM, CLint of 306 ± 29 μL/min/mg). Common OCT1 alleles *3 to *6 showed uptake reduced by at least 65% and Oct1/2 knockout mice showed 3.2-fold higher AUCs in liver perfusion experiments. However, in humans, poor OCT1 transporters did not show any differences in berberine pharmacokinetics compared with reference participants. In contrast, CYP2D6 polymorphisms significantly affected berberine metabolism, but exclusively in females. Females who were poor CYP2D6 metabolizers had an 80% lower M1-to-berberine ratio. General linear model analyses suggest strong synergistic, rather than additive, effects between female sex and CYP2D6 genotype. Overall, berberine displayed low oral bioavailability, yet females had a 2.8-fold higher AUC and a 3.6-fold higher Cmax than males (P < 0.001). These effects were only partially attributable to the sex-CYP2D6 genotype interaction. In conclusion, despite berberine being an OCT1 substrate, OCT1 deficiency did not affect berberine pharmacokinetics in humans. In contrast, CYP2D6 emerges as a critical enzyme for berberine metabolism in females, but not in males, highlighting sex-specific differences. We suggest that factors beyond CYP2D6 metabolism are determining berberine's systemic exposure, especially in males (NCT05463003).

Exploring gender differences in pharmacokinetics of central nervous system related medicines based on a systematic review approach.

Due to the inevitable differences in physiological and/or genetic factors between genders, the possibility that differences in pharmacokinetics between genders may occur when exposed to the same dose of the same drug is subject to reasonable inference and suspicion. Nevertheless, a significant number of medicines still rely on empirical usage and uniform clinical application without consideration of inter-individual diversity factors. In particular, in the pharmacokinetic diversity of medicines related to central nervous system (CNS) activity, consideration of gender factors and access to comparative analysis are very limited. The purpose of this study was to conduct an integrated analysis and review of differences in pharmacokinetics between genders that have not been specifically reported to date for medicines related to CNS effects, which are a group of drugs with relatively significant concerns about systemic side effects. This study was accessible through extensive data collection and analyzes using a web-based scientific literature search engine of pharmacokinetic results of CNS-related drugs performed on humans, taking gender into account. As a result, significant differences in pharmacokinetics between genders were identified for many drugs related to CNS. And most of the pharmacokinetic differences between genders suggested a higher in vivo exposure in females. This study suggests that consideration of gender factors cannot be ignored and will be an important point of interest in the precision medicine application of CNS-related medicines.

To explore pharmacodynamic substances and mechanism of Xuanfei Baidu Decoction on LPS-induced ALI / ARDS by pharmacochemistry and metabolomics

Ethnopharmacological relevanceXuanfei Baidu Decoction (XFBD) is made up of five classic prescriptions, which is composed of 13 traditional Chinese medicines, which have the effects of dispersing lung and resolving dampness, clearing heat and evil, purging lung and detoxification. It is used for epidemic diseases caused by damp toxin obstructing lung. In this paper, the endogenous and exogenous metabolites of ALI / ARDS rats after oral administration of XFBD were studied and the material basis and metabolic pathway of XFBD in relieving ALI / ARDS were explained. Materials and MethodsIn this study, UPLC-Q-TOF / MS qualitative analysis method was established, and plasma-urine-faeces pharmacochemistry was used to identify metabolites in plasma, urine and feces after oral administration of XFBD in rats. RT-PCR and immunohistochemistry were used to study the expression of CYP protein in XFBD and monomeric compounds. In addition, the functional mechanism of XFBD in ALI / ARDS rats was elucidated by non-targeted metabolomics. ResultsA total of 77 prototype components and 389 metabolites in plasma, urine and feces were identified by exogenous components, mainly including oxidation, reduction, hydrolysis, glucuronidation, sulfation and other reactions. The results of RT-PCR and immunohistochemistry showed that the activity of CYP was inhibited under the pathological state of ALI/ARDS. At the same time, XFBD and its monomeric compounds can change the metabolic process of drugs in vivo by inducing or inhibiting the activity of CYPs. The metabolic process of drugs in vivo is the result of the combined action of different CYPs. In addition, a total of 33 differential metabolites were identified in plasma, 45 in urine and 14 in feces, which were mainly related to the synthesis and degradation of ketone bodies, phenylalanine metabolism, tyrosine metabolism, histidine metabolism, butyric acid metabolism and other metabolic pathways. ConclusionsThis study conducted a relatively scientific and systematic analysis of XFBD. A UPLC-Q-TOF / MS qualitative analysis method was established to identify 77 prototype components and 389 metabolites in plasma, urine and feces of rats after oral administration of XFBD.An ARDS rat model was established to analyze the pharmacokinetic differences of XFBD in normal and ARDS model rats and its regulation effect on CYPs.Non-targeted metabolomics was used to identify the pattern recognition of ARDS pathological model, the diagnosis of disease and the intervention effect of XFBD on ARDS. Preliminary discussion was conducted to provide a theoretical basis for clinical rational drug use.

Prospecting Pharmacologically Active Biocompounds from the Amazon Rainforest: In Vitro Approaches, Mechanisms of Action Based on Chemical Structure, and Perspectives on Human Therapeutic Use

The Amazon rainforest is an important reservoir of biodiversity, offering vast potential for the discovery of new bioactive compounds from plants. In vitro studies allow for the investigation of biological processes and interventions in a controlled manner, making them fundamental for pharmacological and biotechnological research. These approaches are faster and less costly than in vivo studies, providing standardized conditions that enhance the reproducibility and precision of data. However, in vitro methods have limitations, including the inability to fully replicate the complexity of a living organism and the absence of a complete physiological context. Translating results to in vivo models is not always straightforward, due to differences in pharmacokinetics and biological interactions. In this context, the aim of this literature review is to assess the advantages and disadvantages of in vitro approaches in the search for new drugs from the Amazon, identifying the challenges and limitations associated with these methods and comparing them with in vivo testing. Thus, bioprospecting in the Amazon involves evaluating plant extracts through bioassays to investigate pharmacological, antimicrobial, and anticancer activities. Phenolic compounds and terpenes are frequently identified as the main bioactive agents, exhibiting antioxidant, anti-inflammatory, and antineoplastic activities. Chemical characterization, molecular modifications, and the development of delivery systems, such as nanoparticles, are highlighted to improve therapeutic efficacy. Therefore, the Amazon rainforest offers great potential for the discovery of new drugs; however, significant challenges, such as the standardization of extraction methods and the need for in vivo studies and clinical trials, must be overcome for these compounds to become viable medications.

JAK inhibitors: an evidence-based choice of the most appropriate molecule

Janus kinase inhibitors (JAKis) represent a fundamental therapeutic tool for the treatment of patients with immune-mediated inflammatory diseases. Although JAKis are often considered a homogeneous class of drugs whose members are thought to be largely interchangeable, there are significant differences in their efficacy and safety profiles. This narrative review analyzes the pharmacokinetic and pharmacodynamic differences among JAKIs, highlighting their clinical relevance based on the most recent available evidence. The article aims to provide rheumatologists, gastroenterologists and dermatologists with practical guidance for choosing the most appropriate JAKi for each patient, given the lack of evidence-based recommendations on this topic, to improve clinical outcomes. Due to its preferential action on JAK1, intestinal metabolization and proven absence of impact on male fertility, filgotinib may be characterized by an improved benefit/risk ratio compared with other less selective JAKis.

Evaluation of Effective Half-Life and Its Impact on Time to Steady State for Oral MeltDose Tacrolimus (LCPT) in De Novo Kidney Transplant Recipients.

For extended-release drug formulations, effective half-life (t1/2eff) is a relevant pharmacokinetic parameter to inform dosing strategies and time to reach steady state. Tacrolimus, an immunosuppressant commonly used for the prophylaxis of organ rejection in transplant patients, is available as both immediate- and extended-release formulations. To the best of our knowledge, the t1/2eff of tacrolimus from these different formulations has not yet been assessed. The objective of this study was to characterize the t1/2eff and terminal half-life (t1/2z) of an extended-release once-daily tacrolimus formulation (LCPT) and twice-daily immediate-release tacrolimus (IR-Tac). A noncompartmental analysis of pharmacokinetic data obtained from a phase 2 study in de novo kidney transplant recipients receiving either LCPT or IR-Tac was conducted. Intensive blood sampling was performed on days 1, 7, and 14, and tacrolimus whole blood concentrations were measured using a validated liquid chromatography with tandem mass spectrometry method. T1/2eff was estimated using within-participant accumulation ratios. T1/2z was estimated by linear regression of the terminal phase of the concentration versus time profile. The median accumulation ratios of LCPT and IR-Tac on day 14 were 3.18 and 2.06, respectively.The median (interquartile range; IQR) t1/2eff for LCPT at day 14 of dosing was 48.4 (37.4-77.9) hours, whereas the t1/2z was 20.3 (17.6-22.9) hours. For IR-Tac, the median (IQR) t1/2eff and t1/2z on day 14 were 12.5 (8.8-23.0) hours and 12.2 (9.2-15.7) hours, respectively. Consistent with its prolonged release of tacrolimus, LCPT demonstrated a higher accumulation ratio and a longer t1/2eff compared with IR-Tac. These findings underscore the pharmacokinetic differences between different drug formulations of the same moiety and may help inform dose adjustments for LCPT in kidney transplantation.

A Phase 1 Study to Assess the Pharmacokinetics, Food Effect, Safety, and Tolerability of Sepiapterin in Healthy Japanese and Non-Japanese Participants

Background: Sepiapterin is a natural precursor of tetrahydrobiopterin (BH4), a key cofactor for phenylalanine hydroxylase. It is being developed for the treatment of patients with phenylketonuria. In this study, the ethnic differences in pharmacokinetics and safety of sepiapterin in Japanese and non-Japanese participants and food effects were evaluated. Methods: Healthy participants (n = 60) received a single oral dose of sepiapterin at either 20, 40, or 60 mg/kg with a low-fat diet. The Japanese participants received two doses at 40 mg/kg, either under fasted conditions or with a low-fat diet with a 3-day washout period in between. Results: Sepiapterin was well tolerated in all participants, with no serious adverse events. Sepiapterin was quickly absorbed (Tmax 1.4–4.5 h) and rapidly and extensively converted to BH4 (Tmax ~4 h). Exposures to sepiapterin were &lt;1% of BH4. BH4 exposures were essentially dose-independent between 20 and 60 mg/kg. A low-fat diet increased BH4 exposures in Japanese participants by 1.7-fold compared with fasted conditions. Conclusions: BH4 exposures (Cmax and AUC0–last) in Japanese participants were 10–30% higher than in non-Japanese participants, which is deemed not clinically relevant; no dose adjustment is warranted. The slightly higher BH4 exposures in Japanese participants are likely due to the higher frequency of ABCG2 c.421C&gt;A mutation in the Japanese population.

Factors Influencing the Central Nervous System (CNS) Distribution of the Ataxia Telangiectasia Mutated and Rad3-Related Inhibitor Elimusertib (BAY1895344): Implications for the Treatment of CNS Tumors.

Glioblastoma (GBM) is a disease of the whole brain, with infiltrative tumor cells protected by an intact blood-brain barrier (BBB). GBM has a poor prognosis despite aggressive treatment, in part due to the lack of adequate drug permeability at the BBB. Standard of care GBM therapies include radiation and cytotoxic chemotherapy that lead to DNA damage. Subsequent activation of DNA damage response (DDR) pathways can induce resistance. Various DDR inhibitors, targeting the key regulators of these pathways such as ataxia telangiectasia mutated and Rad3-related (ATR), are being explored as radio- and chemosensitizers. Elimusertib, a novel ATR kinase inhibitor, can prevent repair of damaged DNA, increasing efficacy of DNA-damaging cytotoxic therapies. Robust synergy was observed in vitro when elimusertib was combined with the DNA-damaging agent temozolomide; however, we did not observe improvement with this combination in in vivo efficacy studies in GBM orthotopic tumor-bearing mice. This in vitro-in vivo disconnect was explored to understand factors influencing central nervous system (CNS) distribution of elimusertib and reasons for lack of efficacy. We observed that elimusertib is rapidly cleared from systemic circulation in mice and would not maintain adequate exposure in the CNS for efficacious combination therapy with temozolomide. CNS distribution of elimusertib is partially limited by P-glycoprotein efflux at the BBB, and high binding to CNS tissues leads to low levels of pharmacologically active (unbound) drug in the brain. Acknowledging the potential for interspecies differences in pharmacokinetics, these data suggest that clinical translation of elimusertib in combination with temozolomide for treatment of GBM may be limited. SIGNIFICANCE STATEMENT: This study examined the disconnect between the in vitro synergy and in vivo efficacy of elimusertib/temozolomide combination therapy by exploring systemic and central nervous system (CNS) distributional pharmacokinetics. Results indicate that the lack of improvement in in vivo efficacy in glioblastoma (GBM) patient-derived xenograft (PDX) models could be attributed to inadequate exposure of pharmacologically active drug concentrations in the CNS. These observations can guide further exploration of elimusertib for the treatment of GBM or other CNS tumors.

A First-Passage Model of Intravitreal Drug Delivery and Residence Time-Influence of Ocular Geometry, Individual Variability, and Injection Location.

Standard of care for various retinal diseases involves recurrent intravitreal injections. This motivates mathematical modeling efforts to identify influential factors for ocular drug residence time, aiming to minimize administration frequency. We sought to describe the vitreal diffusion of therapeutics in nonclinical species frequently used during drug development assessments. In human eyes, we investigated the impact of variability in vitreous cavity size and eccentricity, and in injection location, on drug disposition. Using a first-passage time approach, we modeled the transport-controlled distribution of two standard therapeutic protein formats (Fab and IgG) and elimination through anterior and posterior pathways. Anatomical three-dimensional geometries of mouse, rat, rabbit, cynomolgus monkey, and human eyes were constructed using ocular images and biometry datasets. A scaling relationship was derived for comparison with experimental ocular half-lives. Model simulations revealed a dependence of residence time on ocular size and injection location. Delivery to the posterior vitreous resulted in increased vitreal half-life and retinal permeation. Interindividual variability in human eyes had a significant influence on residence time (half-life range of 5-7days), showing a strong correlation to axial length and vitreal volume. Anterior exit was the predominant route of drug elimination. Contribution of the posterior pathway displayed a 3% difference between protein formats but varied between species (10%-30%). The modeling results suggest that experimental variability in ocular half-life is partially attributed to anatomical differences and injection site location. Simulations further suggest a potential role of the posterior pathway permeability in determining species differences in ocular pharmacokinetics.

Obesity-related drug transporter expression alterations in human liver and kidneys.

Pathophysiological changes associated with obesity might impact various drug pharmacokinetics (PK) parameters. The liver and kidneys are the primary organs involved in drug clearance, and the function of hepatic and renal transporters is critical to efficient drug elimination (or reabsorption). Considering the impact of an increased BMI on the drug's PK is crucial in directing dosing decisions. Given the critical role of transporters in drug biodisposition, this study investigated how overweight and obesity affect the gene expression of renal and hepatic drug transporters. Human liver and kidney samples were collected post-mortem from 32 to 28 individuals, respectively, which were divided into the control group (lean subjects; 18.5 ≤ BMI < 25kg/m2) and the study group (overweight/obese subjects; BMI ≥ 25kg/m2). Real-time quantitative PCR was performed for the analysis of 84 drug transporters. Our results show significant changes in the expression of genes involved in human transporters, both renal and hepatic. In liver tissue, we found that ABCC4 was up-regulated in overweight/obese subjects. In kidney tissue, up-regulation was only observed for ABCC10, while the other differentially expressed genes were down-regulated: ABCA1, ABCC3, and SLC15A1. The observed alterations may be reflected by the differences in drug PK between lean and obese populations. However, these findings need further evaluation through the proteomic and functional study of these transporters in this patient population.

Safety, tolerability, pharmacokinetics and pharmacodynamics of a single intravenous dose of SHR-1707 in healthy adult subjects: two randomized, double-blind, single-ascending-dose, phase 1 studies

BackgroundSHR-1707 is a novel humanized anti-Aβ IgG1 monoclonal antibody that binds to Aβ fibrils and monomers to block the formation of Aβ plaques or to promote the microglial phagocytosis of Aβ. Preclinical studies showed that SHR-1707 reduced brain Aβ deposition in 5xFAD transgenic mice. Herein, we conducted two phase 1 studies to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of a single intravenous dose of SHR-1707 in healthy adult subjects.MethodsTwo randomized, double-blind, single-ascending-dose, phase 1 studies were conducted in China (Study CHN) and Australia (Study AUS). Study CHN consisted of 2 parts. In Part 1, eligible healthy young adults (18–45 years) were sequentially randomized 8:2 to receive SHR-1707 (five cohorts: 2, 6, 20, 40, and 60 mg/kg) or placebo in each cohort; in Part 2, elderly subjects (55–80 years) were randomized 8:4 to receive SHR-1707 (20 mg/kg) or placebo. A similar design was used in Study AUS, but with only healthy young adults enrolled across three dosing cohorts (2, 20, and 60 mg/kg).ResultsSixty-two (part 1/2, n = 50/12; age range, 18–42/55–63 years) and 30 subjects (age range, 18–42 years) received SHR-1707 or placebo in Study CHN and Study AUS, respectively. In Study CHN, all treatment-related adverse events (TRAEs) were mild, with the most common being transient laboratory abnormalities. In Study AUS, TRAEs were mostly mild (1 moderate event each with SHR-1707/placebo); the most common TRAEs with SHR-1707 were dysgeusia and fatigue (8.3% each). In both studies, the exposure of SHR-1707 increased in a slightly greater than dose-proportional manner over the dose range of 2–60 mg/kg in young adults; there was a dose-dependent increase in plasma Aβ42 concentration following SHR-1707 administration compared with the placebo group. The safety and PK and PD profiles of SHR-1707 in the elderly subjects were consistent with the younger counterpart at the same dose level. No ethnic difference in safety, PK and PD of SHR-1707 was observed.ConclusionsA single intravenous dose of SHR-1707 at 2–60 mg/kg was safe and well tolerated in healthy young adult and elderly subjects. The PK and PD profiles are supportive for further clinical development.Trial registrationNCT04973189 (retrospectively registered on Jul.21, 2021) and NCT04745104 (registered on Feb.6, 2021) on clinicaltrials.gov.

7483 The Pharmacokinetic Profile of Lanreotide Autogel® Improved Long-Term Arrhythmia Fluctuations in Acromegalic Cardiomyopathy

Abstract Disclosure: M. Iwabuchi: None. Background: The prognosis of acromegaly is related to the status of cardiac complications. Ventricular premature contractions (VPC) are frequently observed in acromegaly, and it is very important to suppress fatal arrhythmias to improve long-term prognosis. Somatostatin analogs are widely used as pharmacotherapy for acromegaly, and they have been reported to improve cardiac prognosis. In comparison to LAR, lanreotide Autogel® has a unique property of self-aggregation under favorable conditions, leading to a stable structure of highly organized nanotubules and has a long half-life after subcutaneous injection determined by pseudo-first order kinetics. CASE: 55-year-old man visited a cardiologist for the treatment of PVCs and heart failure. Because of his acromegalic features, endocrinological and image examinations were performed, and diagnosis of acromegaly was confirmed. His GH was 7.17 ng/mL, IGF-1 566 ng/mL (Normal range: 59-215). Concerning excess of GH may cause nonischemic cardiomyopathy, administration of 20 mg of LAR once a month was started. GH and IGF-1 improved to1.52 ng/mL and 217 ng/mL respectively. The dose of LAR was increased to 30mg because of a remaining fluctuation of VPCs. Considering a possibility of the problem of bioavailability due to method of injection and the pharmacokinetics of LAR, administration of lanreotide Autogel® was started instead of LAR, with the result that an improvement of the fluctuation of the symptom was observed without remarkable change in GH and IGF-1. Arrhythmia status was assessed over time using Holter electrocardiography. Pretreatment Holter electrocardiogram showed 18% of total heart rates in PVCs. After LAR injection, the frequency of PVCs decreased to 3%, and 6 years after changing LAR to lanreotide, the frequency of PVCs decreased to 2%. Clinical Lessons: Simulated steady state pharmacokinetic profiles of LAR and lanreotide Autogel® differ significantly. During LAR treatment, serum concentrations of the drug are approximately stable, whereas the characteristic first-order kinetics of lanreotide Autogel® is superimposed on levels just before the next administration. The pharmacokinetic differences indicate that LAR can be better tailored to therapeutic levels, whereas serum levels of lanreotide must be high for part of the interval between injections to be effective in the period before the next administration. Lanreotide Autogel® has similar clinical effects compared to LAR for the treatment of cardiomyopathy of acromegaly and has the advantage of being available in a convenient pre-filled syringe and no necessity of injection by healthcare professionals. It is suggested that the pharmacokinetic profile of Lanreotide Autogel® resulted in decreased arrhythmia fluctuation in acromegalic hearts, which has been maintained for the past 6 years. Presentation: 6/3/2024

Pharmacokinetics and related gender difference studies of four active components of Codonopsis Pilosula by LC-MS/MS determination

Ethnopharmacological relevanceCodonopsis pilosula (C. pilosula), commonly known as Dangshen in Chinese, had been used to regulate the immune, digestive, and circulatory systems of human. The reported pharmacokinetic studies on C. pilosula are mainly limited to in vivo profile studies of a single component. It has not been detected simultaneously the in vivo pharmacokinetic profiles of multiple active components as well as related gender difference after oral dosing of the extraction of C. pilosula. Aim of the studyThis study aims to reveal the pharmacokinetic characteristics of the four main active components of C. pilosula after oral dosing of its extraction in rats, and to explain the gender differences in absorption and metabolism. Materials and methodsThe plasma pharmacokinetic characteristics of four main active components of C. pilosula was explored using the established LC-MS/MS method after oral dosing of the extraction of C. pilosula in male and female rats. In vitro intestinal pouch permeability and liver microsome metabolic stability were also observed to classify the possible mechanism of gender difference existed in the pharmacokinetic profiles of the four active components in rats. ResultsFour effective components were absorbed quickly in rats after oral administration of alcoholic extract of C. pilosula (1.36 g/mL, equivalent to 2 g/mL as crude drug), and their exposure order was as follows: Atractylenolide III > Lobetyolin > Tangshenoside I > Syringin. The exposure (AUC) and peak concentration (Cmax) of Atractylenolide III in female rats were much higher than those in male rats, indicating a significant gender difference in pharmacokinetics of Atractylenolide III between female and male animals. With the help of the rat model of intestinal sac in vitro, it was found that Lobetyolin was a hypertonic compound, and both Tangshenoside I and Syringin were compounds with medium permeabiltiy. Notably, the Papp of Atractylenolide III was 3.3 × 10−6 cm/s in male rat intestinal sac assay, while that was 10 × 10−6 cm/s in female rat intestinal sac model, showing a significant gender difference in intestinal permeability (P < 0.05). After the addition of NADPH, the four compounds were reduced in a time-dependent manner, suggesting that CYP450s could catalyze their metabolism. After incubation, the remaining content of Atractylenolide III in the liver microsomes of male and female rats was 27% and 57%, respectively, suggesting slower metabolic rate of in female rat liver microsomes. ConclusionA simple, efficient and reliable LC-MS/MS method for the simultaneous determination of four active index components of C. pilosula, Lobetyolin, Tangshenoside I, Atractylenolide III and Syringin, in rat plasma was established and verified. This method was successfully applied in the pharmacokinetic study after single oral administration of the alcoholic extract of C. pilosula in rats. Gender difference was observed in the pharmacokinetic profile of Atractylenolide III in rats. Intestinal absorption and liver metabolism might be two key factors that resulted in the gender difference in exposure and pharmacokinetics of Atractylenolide III in rats. This study provides supportive data for clinical rational application of C. pilosula in individualized medication therapy.

The pharmacokinetic differences between 10- and 15-μg daily vitamin D doses.

The reference nutrient intake for vitamin D in people aged ≥4years is 10μg/day (400 IU/day) in the UK, but the recommended daily allowance is 15 μg/day (600 IU/day) for people aged 1-70 years in the USA. Here, we aim to compare the 25-hydroxyvitamin D (25(OH)D) serum concentration profiles between the 2 doses. With world-wide trial data of adults aged ≥18 years, 45-93 kg, we constructed a minimal physiologically based pharmacokinetics model of serum concentrations of vitamin D and 25(OH)D using nonlinear mixed effects modelling. We used this model to forecast the mean, 2.5th and 97.5th percentiles for serum 25(OH)D concentrations in British adults aged ≥16 years. Our final model used bodyweight to adjust volume of each compartment and maximum clearance of 25(OH)D. No other covariate was identified. The model accurately predicted independent data from trials of a broad range of dosing regimens. We simulated British adults and showed that circulating 25(OH)D concentrations in 95% of people taking 10μg/day for a year is predicted to reach 50 nmol/L in 32 weeks, while 97.5% of those on 15 μg/day were predicted to attain this threshold within 28 weeks. Both doses are efficacious in >95% of the British population. The daily dose of 15 μg can help 97.5% of the British adults achieve 50 nmol/L serum 25(OH)D and reach the 25 nmol/L threshold in 4weeks.

Enantioselective Binding of Proton Pump Inhibitors to Alpha1-Acid Glycoprotein and Human Serum Albumin-A Chromatographic, Spectroscopic, and In Silico Study.

The enantioselective binding of three proton pump inhibitors (PPIs)-omeprazole, rabeprazole, and lansoprazole-to two key plasma proteins, α1-acid glycoprotein (AGP) and human serum albumin (HSA), was characterized. The interactions between PPI enantiomers and proteins were investigated using a multifaceted analytical approach, including high-performance liquid chromatography (HPLC), fluorescence and UV spectroscopy, as well as in silico molecular docking. HPLC analysis demonstrated that all three PPIs exhibited enantioseparation on an AGP-based chiral stationary phase, suggesting stereoselective binding to AGP, while only lansoprazole showed enantioselective binding on the HSA-based column. Quantitatively, the S-enantiomers of omeprazole and rabeprazole showed higher binding affinity to AGP, while the R-enantiomer of lansoprazole displayed greater affinity for AGP, with a reversal in the elution order observed between the two protein-based columns. Protein binding percentages, calculated via HPLC, were greater than 88% for each enantiomer across both transport proteins, with all enantiomers displaying higher affinity for AGP compared to HSA. Thermodynamic analysis indicated that on the HSA, the more common, enthalpy-controlled enantioseparation was found, while in contrast, on the AGP, entropy-controlled enantioseparation was observed. The study also identified limitations in using fluorescence titration due to the high native fluorescence of the compounds, whereas UV titration was effective for both proteins. The determined logK values were in the range of 4.47-4.83 for AGP and 4.02-4.66 for HSA. Molecular docking supported the experimental findings by revealing the atomic interactions driving the binding process, with the predicted enantiomer elution orders aligning with experimental data. The comprehensive use of these analytical methods provides detailed insights into the enantioselective binding properties of PPIs, contributing to the understanding of their pharmacokinetic differences and aiding in the development of more effective therapeutic strategies.