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BACKGROUND AND OBJECTIVE: The interstitial fluid of tissues is the effect site for antibiotics targeting extracellular pathogens. Microdialysis studies investigating these concentrations in muscle and subcutaneous tissue have reported notable variability in tissue penetration. This study aimed to comprehensively summarise the existing data on interstitial fluid penetration in these tissues and to identify potential factors influencing antibiotic distribution. METHODS: A literature review was conducted, focusing on subcutaneous and intramuscular microdialysis studies of antibiotics in both adult healthy volunteers and patients. Random-effect meta-analyses were used to aggregate effect size estimates of tissue penetration. The primary parameter of interest was the unbound penetration ratio, which represents the ratio of the area under the concentration-time curve in interstitial fluid relative to the area under the concentration-time curve in plasma, using unbound concentrations. RESULTS: In total, 52 reports were incorporated into this analysis. The unbound antibiotic exposure in the interstitial fluid of healthy volunteers was, on average, 22% lower than in plasma. The unbound penetration ratio values were higher after multiple dosing but did not significantly differ between muscle and subcutaneous tissue. Unbound penetration ratio values were lower for acids and bases compared with neutral antibiotics. Neither the molecular weight nor the logP of the antibiotics accounted for the variations in the unbound penetration ratio. Obesity was associated with lower interstitial fluid penetration. Conditions such as sepsis, tissue inflammation and tissue ischaemia were not significantly associated with altered interstitial fluid penetration. CONCLUSIONS: This study highlights the variability and generally lower exposure of unbound antibiotics in the subcutaneous and intramuscular interstitial fluid compared with exposure in plasma. Future research should focus on understanding the therapeutic relevance of these differences and identify key covariates that may influence them.
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Antibacterianos , Líquido Extracelular , Microdiálisis , Humanos , Líquido Extracelular/metabolismo , Líquido Extracelular/química , Microdiálisis/métodos , Antibacterianos/farmacocinética , Antibacterianos/administración & dosificación , Adulto , Tejido Subcutáneo/metabolismo , Distribución Tisular , Inyecciones Intramusculares , Inyecciones SubcutáneasRESUMEN
BACKGROUND AND OBJECTIVES: Nipocalimab is a high-affinity, fully human, effectorless immunoglobulin G1 monoclonal antibody targeting the neonatal Fc receptor and is currently under evaluation for the treatment of rare and prevalent immunoglobulin G autoantibody-mediated and alloantibody-mediated diseases. This phase I, randomized, double-blind, placebo-controlled, single-dose escalation study in healthy Japanese volunteers (N = 24) assessed the safety, pharmacokinetics, and effect on the serum immunoglobulin G level of single doses of nipocalimab. METHODS: Volunteers were grouped into three cohorts and received intravenous nipocalimab at 10, 30, or 60 mg/kg or placebo. To complement the study, genetic variation in the Fcγ receptor and transporter subunit of the neonatal Fc receptor was analyzed in Japanese and diverse populations. RESULTS: Nipocalimab was generally safe and well tolerated at all dose levels, with three (12.5% [3/24]) volunteers experiencing treatment-emergent adverse events across all nipocalimab doses. Mean serum immunoglobulin G levels decreased in a dose-dependent manner from baseline with nipocalimab treatment compared with placebo. Maximum serum nipocalimab concentrations demonstrated proportional increases with dose, while the area under the concentration-time curve was dose dependent and demonstrated non-linear increases with dose. Mean observed half-life was longer as the dose increased. Analysis of genetic variation in Fcγ receptor and transporter identified no unique Japanese variants or variants that alter amino acid sequences in or near the neonatal Fc receptor immunoglobulin G binding site targeted by nipocalimab. CONCLUSIONS: The comparable pharmacokinetic/pharmacodynamic profiles and highly conserved neonatal Fc receptor structure among diverse populations further support the clinical development of nipocalimab for the treatment of various immunoglobulin G autoantibody-mediated and alloantibody-mediated diseases across global sites and populations, including the Japanese population.
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Voluntarios Sanos , Inmunoglobulina G , Receptores Fc , Humanos , Método Doble Ciego , Adulto , Masculino , Femenino , Anticuerpos Monoclonales Humanizados/farmacocinética , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/farmacología , Pueblo Asiatico , Adulto Joven , Japón , Relación Dosis-Respuesta a Droga , Persona de Mediana Edad , Anticuerpos Monoclonales/farmacocinética , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/farmacología , Antígenos de Histocompatibilidad Clase I/genética , Pueblos del Este de AsiaRESUMEN
Physiologically based pharmacokinetic (PBPK) models were utilized to investigate potential interactions between aflatoxin B1 (AFB1) and efavirenz (EFV), a non-nucleoside reverse transcriptase inhibitor drug and inducer of several CYP enzymes, including CYP3A4. PBPK simulations were conducted in a North European Caucasian and Black South African population, considering different dosing scenarios. The simulations predicted the impact of EFV on AFB1 metabolism via CYP3A4 and CYP1A2. In vitro experiments using human liver microsomes (HLM) were performed to verify the PBPK predictions for both single- and multiple-dose exposures to EFV. Results showed no significant difference in the formation of AFB1 metabolites when combined with EFV (0.15 µM) compared to AFB1 alone. However, exposure to 5 µM of EFV, mimicking chronic exposure, resulted in increased CYP3A4 activity, affecting metabolite formation. While co-incubation with EFV reduced the formation of certain AFB1 metabolites, other outcomes varied and could not be fully attributed to CYP3A4 induction. Overall, this study provides evidence that EFV, and potentially other CYP1A2/CYP3A4 perpetrators, can impact AFB1 metabolism, leading to altered exposure to toxic metabolites. The results emphasize the importance of considering drug interactions when assessing the risks associated with mycotoxin exposure in individuals undergoing HIV therapy in a European and African context.
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Aflatoxina B1 , Alquinos , Benzoxazinas , Ciclopropanos , Interacciones Farmacológicas , Microsomas Hepáticos , Modelos Biológicos , Inhibidores de la Transcriptasa Inversa , Aflatoxina B1/farmacocinética , Aflatoxina B1/toxicidad , Humanos , Benzoxazinas/farmacocinética , Benzoxazinas/metabolismo , Microsomas Hepáticos/metabolismo , Microsomas Hepáticos/efectos de los fármacos , Inhibidores de la Transcriptasa Inversa/farmacocinética , Masculino , Citocromo P-450 CYP3A/metabolismo , Adulto , Femenino , Citocromo P-450 CYP1A2/metabolismo , Persona de Mediana Edad , Adulto Joven , Población BlancaAsunto(s)
Cisplatino , Hipertermia Inducida , Neoplasias Ováricas , Neoplasias Peritoneales , Humanos , Femenino , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Cisplatino/uso terapéutico , Neoplasias Peritoneales/secundario , Neoplasias Peritoneales/genética , Neoplasias Peritoneales/tratamiento farmacológico , Hipertermia Inducida/métodos , Antineoplásicos/uso terapéutico , Quimioterapia Intraperitoneal Hipertérmica , Expresión Génica , Terapia CombinadaRESUMEN
The objective of this study was to compare the efficacy of short interfering RNA therapeutics (siRNAs) in reducing hepatitis B surface antigen (HBsAg) levels in hepatitis B-infected (HBV) mice across multiple siRNA therapeutic classes using model-based meta-analysis (MBMA) techniques. Literature data from 10 studies in HBV-infected mice were pooled, including 13 siRNAs, formulated as liposomal nanoparticles (LNPs) or conjugated to either cholesterol (chol) or N-acetylgalactosamine (GalNAc). Time course of the baseline- and placebo-corrected mean HBsAg profiles were modeled using kinetics of drug effect (KPD) model coupled to an indirect response model (IRM) within a longitudinal non-linear mixed-effects MBMA framework. Single and multiple dose simulations were performed exploring the role of dosing regimens across evaluated siRNA classes. The HBsAg degradation rate (0.72 day-1) was consistent across siRNAs but exhibited a large between-study variability of 31.4% (CV%). The siRNA biophase half-life was dependent on the siRNA class and was highest for GalNAc-siRNAs (21.06 days) and lowest for chol-siRNAs (2.89 days). ID50 estimates were compound-specific and were lowest for chol-siRNAs and highest for GalNAc-siRNAs. Multiple dose simulations suggest GalNAc-siRNAs may require between 4 and 7 times less frequent dosing at higher absolute dose levels compared to LNP-siRNAs and chol-siRNAs, respectively, to reach equipotent HBsAg-lowering effects in HBV mice. In conclusion, non-clinical HBsAg concentration-time data after siRNA administration can be described using the presented KPD-IRM MBMA framework. This framework allows to quantitatively compare the effects of siRNAs on the HBsAg time course and inform dose and regimen selection across siRNA classes. These results may support siRNA development, optimize preclinical study designs, and inform data analysis methodology of future anti-HBV siRNAs; and ultimately, support siRNA model-informed drug development (MIDD) strategies.
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Antígenos de Superficie de la Hepatitis B , Hepatitis B , ARN Interferente Pequeño , Animales , ARN Interferente Pequeño/administración & dosificación , ARN Interferente Pequeño/farmacología , Antígenos de Superficie de la Hepatitis B/sangre , Ratones , Hepatitis B/tratamiento farmacológico , Modelos Animales de Enfermedad , Acetilgalactosamina/farmacología , Liposomas , Modelos Biológicos , Nanopartículas , Virus de la Hepatitis B/genéticaRESUMEN
A proof-of-concept study with the combination of guselkumab and golimumab in patients with ulcerative colitis (UC) has shown that the combination therapy resulted in greater efficacy than the individual monotherapies. The current analysis evaluated the pharmacokinetics (PK) and immunogenicity of guselkumab and golimumab in both the combination therapy and individual monotherapies. Blood samples were collected to evaluate serum concentrations and immunogenicity of guselkumab and golimumab. Population PK (PopPK) models were developed to assess the effects of combination therapy and other potential covariates on the PK of guselkumab and golimumab. The guselkumab PK was comparable between monotherapy and combination therapy, whereas golimumab concentrations were slightly higher with combination therapy. The anti-guselkumab antibody incidence was low with both monotherapy and combination therapy, and guselkumab immunogenicity did not impact the clearance. Conversely, the anti-golimumab antibody incidence with combination therapy was lower than that for monotherapy. PopPK analysis suggested that the slightly higher golimumab concentrations with combination therapy were partially due to lower immunogenicity and thus lower clearance with combination therapy. C-reactive protein (CRP) was also a significant covariate on golimumab clearance. The greater improvement of inflammation with combination therapy, as shown by reductions in CRP, may have also contributed to the higher golimumab concentrations. Combination therapy slightly decreased the clearance of golimumab, but not guselkumab clearance, in patients with UC. Lower immunogenicity and greater improvement of inflammation with combination therapy were potential mechanisms for slightly increased golimumab concentrations with combination therapy as compared with golimumab monotherapy.
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Anticuerpos Monoclonales Humanizados , Anticuerpos Monoclonales , Colitis Ulcerosa , Interacciones Farmacológicas , Quimioterapia Combinada , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Anticuerpos Monoclonales/farmacocinética , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales Humanizados/farmacocinética , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/inmunología , Fármacos Gastrointestinales/farmacocinética , Fármacos Gastrointestinales/administración & dosificación , Fármacos Gastrointestinales/uso terapéutico , Fármacos Gastrointestinales/inmunología , Modelos Biológicos , Prueba de Estudio Conceptual , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
Introduction: Nipocalimab is a high-affinity, fully human, aglycosylated, effectorless, immunoglobulin G (IgG) 1 monoclonal antibody that targets the neonatal Fc receptor (FcRn), decreases systemic IgG including autoantibodies, and is under development in several IgG autoantibody- and alloantibody-mediated diseases, including generalized myasthenia gravis, chronic inflammatory demyelinating polyneuropathy, maternal-fetal medicine, and multiple other therapeutic areas. An initial phase 1 study with single and multiple ascending doses of nipocalimab infused intravenously (IV) over 2 h demonstrated dose-dependent serum pharmacokinetics and IgG reductions, with an adverse event (AE) profile comparable to placebo. Methods: The current investigation evaluates the safety, tolerability, pharmacokinetics, and pharmacodynamics of single doses of nipocalimab across various IV infusion rates in a randomized, double-blind, placebo-controlled, sequential-dose study. Forty participants were randomized to receive nipocalimab 30 mg/kg over 60, 30, 15 or 7.5 min (0.5, 1, 2, or 4 mg/kg/min); nipocalimab 60 mg/kg over 15 min (4 mg/kg/min); or matching placebo. Results: At doses up to 60 mg/kg and infusion rates up to 4 mg/kg/min (maximum clinically feasible rate), single doses of nipocalimab were tolerable, with 12 (40%) participants experiencing AEs across nipocalimab cohorts compared with 1 (10%) participant in the placebo cohort. AEs deemed treatment related occurred in 6 (20%) participants receiving nipocalimab and 1 (10%) participant receiving placebo. None of the AEs were severe, and no participants discontinued treatment due to AEs. Nipocalimab provided consistent, dose-dependent serum pharmacokinetics and IgG reductions, regardless of infusion rate. Discussion: This study supports the use of shortened durations of nipocalimab infusion for future studies.
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Irinotecan (CPT-11), an antineoplastic drug, is used for the treatment of colorectal and pancreatic cancer due to its topoisomerase I inhibitory activity. CPT-11 is a prodrug which is converted to its active metabolite SN-38 by carboxylesterases. SN-38 is further metabolized to its inactive metabolite SN-38 glucuronide. When evaluating the pharmacokinetic properties of CPT-11 and its metabolites, it is important to accurately assess the concentrations in both plasma as well as tumor tissues. Therefore, the aim of the current study was to develop and validate a robust and sensitive ultra-high performance liquid chromatography-tandem mass spectrometry method to quantify the concentration of CPT-11 and its metabolites (SN-38 and SN-38 glucuronide) in human plasma and peritoneal tumor tissue. The sample preparation of plasma and tumor tissue consisted of protein precipitation and enzymatic digestion/liquid-liquid extraction, respectively. Chromatographic separation was achieved with an Acquity UPLC BEH C18 column combined with a VanGuard pre-column. The mobile phases consisted of water +0.1 % formic acid (mobile phase A) and acetonitrile +0.1 % formic acid (mobile phase B). Mass analysis was performed using a Xevo TQS tandem mass spectrometer in the positive electrospray ionization mode. Method validation was successfully performed by assessing linearity, precision and accuracy, lower limit of quantification, carry over, selectivity, matrix effect and stability according to the following guidelines: "Committee for Medicinal Products for Human use, Guideline on Bioanalytical Method Validation". A cross-validation of the developed method was performed in a pilot pharmacokinetic study, demonstrating the usefulness of the current method to quantify CPT-11 and its metabolites in the different matrices.
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Camptotecina/análogos & derivados , Formiatos , Glucurónidos , Neoplasias Peritoneales , Humanos , Irinotecán , Espectrometría de Masas en Tándem/métodos , Cromatografía Liquida/métodos , Cromatografía Líquida con Espectrometría de Masas , Cromatografía Líquida de Alta Presión/métodos , Reproducibilidad de los ResultadosRESUMEN
AIMS: Lisinopril, an angiotensin-converting enzyme inhibitor, is a frequently prescribed antihypertensive drug in the paediatric population, while being used off-label under the age of 6 years in the USA and for all paediatric patients globally. The SAFEPEDRUG project (IWT-130033) investigated lisinopril pharmacokinetics in hypertensive paediatric patients corresponding with the day-to-day clinical population. METHODS: The dose-escalation pilot study included 13 children with primary and secondary hypertension who received oral lisinopril once daily in the morning; doses ranged from 0.05 to 0.2 mg kg-1 . Patients were aged between 1.9 and 17.9 years (median 13.5 years) and weight ranged between 9.62 and 97.2 kg (median 53.2 kg). All data were analysed using Monolix version 2020R1 (Lixoft, France) and R version 3.6.2. RESULTS: A 1-compartment model with first-order absorption and first-order elimination optimally describes the data. Parameter estimates of absorption rate constant (0.075 h-1 [0.062, 0.088], typical value [95% confidence interval]), volume of distribution (31.38 L 70 kg-1 [10.5, 52.3]) and elimination clearance (24.2 L h-1 70 kg-1 [19.5, 28.9]) show good predictive ability. Significant covariate effects include total body weight on elimination clearance, and distribution volume and estimated glomerular filtration rate (eGFR) on elimination clearance. The effects of eGFR on the elimination clearance are optimally described by a linear effect centred around 105 mL min-1 1.73 m-2 . The effects of body weight were implemented using fixed allometric exponents centred around an adult weight of 70 kg. CONCLUSION: Lisinopril dose and regimen adjustments for paediatric patients should include eGFR on top of weight adjustments. An expanded model characterizing the pharmacodynamic effect is required to identify the optimal dose and dosing regimen.
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Hipertensión , Lisinopril , Adulto , Humanos , Adolescente , Niño , Lactante , Preescolar , Lisinopril/efectos adversos , Proyectos Piloto , Hipertensión/tratamiento farmacológico , Hipertensión/inducido químicamente , Riñón , Peso CorporalRESUMEN
In recent years, pre-packed ready-to-eat (RTE) food products on the Belgian market have shifted to a more plant-based composition due to a variety of reasons, including consumer concerns about health, animal welfare, and sustainability. However, similar to animal-based RTE foods, plant-based RTE foods can be susceptible to the presence and outgrowth of Listeria monocytogenes (L. monocytogenes). Three innovative, pre-packed, plant-based RTE food product categories on the Belgian market were identified based upon data gaps regarding the prevalence and growth potential of this pathogen. These were vegetarian and vegan deli sandwich slices (category 1), fresh-cut (mixes of) leafy vegetables (category 2), and multi-ingredient salad bowls (category 3). Reports on associated listeriosis outbreaks and recalls were collected and a comprehensive literature review on the prevalence of L. monocytogenes (i.e. detection in 25 g food) was performed. In addition, the prevalence of L. monocytogenes was also determined through an exploratory retail survey of ca. 50 different RTE products of each category. A batch was considered positive if L. monocytogenes was detected in a food item, either on the day of purchase, at the end of shelf life, or both. During the retail survey, L. monocytogenes was not detected in category 2 (0 out of 51 batches), while 1 out of 51 and 6 out of 48 batches were found positive for respectively category 1 and 3. The observed L. monocytogenes concentration did not exceed 10 CFU/g at any point in time in any batch. Furthermore, challenge tests were performed to determine the growth potential of L. monocytogenes in nine pre-packed, plant-based RTE food products (two to four different products of each category, and three different batches per product). After inoculation, products were stored for half of their shelf life at 7 °C and half of their shelf life at 9 °C (simulation of resp. retail and consumer storage). In six of the nine challenge tests executed, growth of L. monocytogenes was supported (i.e. growth potential ≥0.50 log10 CFU/g during shelf life). The highest growth potential was observed for fresh-cut iceberg lettuce (3.60 log10 CFU/g in 9 days), but a large variation regarding the growth potential of L. monocytogenes was noted both between and within the three studied pre-packed, plant-based RTE food product categories. This variation was mainly caused by differences in product composition, physicochemical product characteristics, present (competitive) microbiota such as lactic acid bacteria, applied preservation techniques, and shelf life.
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Listeria monocytogenes , Productos de la Carne , Animales , Microbiología de Alimentos , Prevalencia , Bélgica , Recuento de Colonia Microbiana , Seguridad de Productos para el Consumidor , Contaminación de Alimentos/análisis , Productos de la Carne/microbiologíaRESUMEN
Physiologically based pharmacokinetic (PBPK) models can be used to leverage physiological and in vitro data to predict monoclonal antibody (mAb) concentrations in serum and tissues. However, it is currently not known how consistent predictions of mAb disposition are across PBPK modelling platforms. In this work PBPK simulations of IgG, adalimumab and infliximab were compared between three platforms (Simcyp, PK-Sim, and GastroPlus). Accuracy of predicted serum and tissue concentrations was assessed using observed data collected from the literature. Physiological and mAb related input parameters were also compared and sensitivity analyses were carried out to evaluate model behavior when input values were altered. Differences in serum kinetics of IgG between platforms were minimal for a dose of 1 mg/kg, but became more noticeable at higher dosages (> 100 mg/kg) and when reference (healthy) physiological input values were altered. Predicted serum concentrations of both adalimumab and infliximab were comparable across platforms, but were noticeably higher than observed values. Tissue concentrations differed remarkably between the platforms, both for total- and interstitial fluid (ISF) concentrations. The accuracy of total tissue concentrations was within a three-fold of observed values for all tissues, except for brain tissue concentrations, which were overpredicted. Predictions of tissue ISF concentrations were less accurate and were best captured by GastroPlus. Overall, these simulations show that the different PBPK platforms generally predict similar mAb serum concentrations, but variable tissue concentrations. Caution is therefore warranted when PBPK models are used to simulate effect site tissue concentrations of mAbs without data to verify the predictions.
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Because peritoneal metastasis (PM) from ovarian cancer is characterized by non-specific symptoms, it is often diagnosed at advanced stages. Pressurized intraperitoneal aerosol chemotherapy (PIPAC) can be considered a promising drug delivery method for unresectable PM. Currently, the efficacy of intraperitoneal (IP) drug delivery is limited by the off-label use of IV chemotherapeutic solutions, which are rapidly cleared from the IP cavity. Hence, this research aimed to improve PM treatment by evaluating a nanoparticle-loaded, pH-switchable supramolecular polymer hydrogel as a controlled release drug delivery system that can be IP nebulized. Moreover, a multidirectional nozzle was developed to allow nebulization of viscous materials such as hydrogels and to reach an even IP gel deposition. We demonstrated that acidification of the nebulized hydrogelator solution by carbon dioxide, used to inflate the IP cavity during laparoscopic surgery, stimulated the in situ gelation, which prolonged the IP hydrogel retention. In vitro experiments indicated that paclitaxel nanocrystals were gradually released from the hydrogel depot formed, which sustained the cytotoxicity of the formulation for 10 days. Finally, after aerosolization of this material in a xenograft model of PM, tumor progression could successfully be delayed, while the overall survival time was significantly increased compared to non-treated animals.
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Dióxido de Carbono , Neoplasias Peritoneales , Animales , Humanos , Neoplasias Peritoneales/tratamiento farmacológico , Hidrogeles/química , Polímeros/química , Concentración de Iones de HidrógenoRESUMEN
The volume of distribution at steady state (Vss) in neonates is still often estimated through isometric scaling from adult values, disregarding developmental changes beyond body weight. This study aimed to compare the accuracy of two physiologically based pharmacokinetic (PBPK) Vss prediction methods in neonates (Poulin & Theil with Berezhkovskiy correction (P&T+) and Rodgers & Rowland (R&R)) with isometrical scaling. PBPK models were developed for 24 drugs using in-vitro and in-silico data. Simulations were done in Simcyp (V22) using predefined populations. Clinical data from 86 studies in neonates (including preterms) were used for comparison, and accuracy was assessed using (absolute) average fold errors ((A)AFEs). Isometric scaling resulted in underestimated Vss values in neonates (AFE: 0.61), and both PBPK methods reduced the magnitude of underprediction (AFE: 0.82-0.83). The P&T+ method demonstrated superior overall accuracy compared to isometric scaling (AAFE of 1.68 and 1.77, respectively), while the R&R method exhibited lower overall accuracy (AAFE: 2.03). Drug characteristics (LogP and ionization type) and inclusion of preterm neonates did not significantly impact the magnitude of error associated with isometric scaling or PBPK modeling. These results highlight both the limitations and the applicability of PBPK methods for the prediction of Vss in the absence of clinical data.
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Balenine possesses some of carnosine's and anserine's functions, yet it appears more resistant to the hydrolysing CN1 enzyme. The aim of this study was to elucidate the stability of balenine in the systemic circulation and its bioavailability in humans following acute supplementation. Two experiments were conducted in which (in vitro) carnosine, anserine and balenine were added to plasma to compare degradation profiles and (in vivo) three increasing doses (1-4-10 mg/kg) of balenine were acutely administered to 6 human volunteers. Half-life of balenine (34.9 ± 14.6 min) was respectively 29.1 and 16.3 times longer than that of carnosine (1.20 ± 0.36 min, p = 0.0044) and anserine (2.14 ± 0.58 min, p = 0.0044). In vivo, 10 mg/kg of balenine elicited a peak plasma concentration (Cmax) of 28 µM, which was 4 and 18 times higher than with 4 (p = 0.0034) and 1 mg/kg (p = 0.0017), respectively. CN1 activity showed strong negative correlations with half-life (ρ = - 0.829; p = 0.0583), Cmax (r = - 0.938; p = 0.0372) and incremental area under the curve (r = - 0.825; p = 0.0433). Overall, balenine seems more resistant to CN1 hydrolysis resulting in better in vivo bioavailability, yet its degradation remains dependent on enzyme activity. Although a similar functionality as carnosine and anserine remains to be demonstrated, opportunities arise for balenine as nutraceutical or ergogenic aid.
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Carnosina , Humanos , Carnosina/metabolismo , Anserina/metabolismo , Suplementos DietéticosRESUMEN
Mycotoxins such as aflatoxin B1 (AFB1) are secondary fungal metabolites present in food commodities and part of one's daily exposure, especially in certain regions, e.g., sub-Saharan Africa. AFB1 is mostly metabolised by cytochrome P450 (CYP) enzymes, namely, CYP1A2 and CYP3A4. As a consequence of chronic exposure, it is interesting to check for interactions with drugs taken concomitantly. A physiologically based pharmacokinetic (PBPK) model was developed based on the literature and in-house-generated in vitro data to characterise the pharmacokinetics (PK) of AFB1. The substrate file was used in different populations (Chinese, North European Caucasian and Black South African), provided by SimCYP® software (v21), to evaluate the impact of populations on AFB1 PK. The model's performance was verified against published human in vivo PK parameters, with AUC ratios and Cmax ratios being within the 0.5-2.0-fold range. Effects on AFB1 PK were observed with commonly prescribed drugs in South Africa, leading to clearance ratios of 0.54 to 4.13. The simulations revealed that CYP3A4/CYP1A2 inducer/inhibitor drugs might have an impact on AFB1 metabolism, altering exposure to carcinogenic metabolites. AFB1 did not have effects on the PK of drugs at representative exposure concentrations. Therefore, chronic AFB1 exposure is unlikely to impact the PK of drugs taken concomitantly.
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Accurate characterization of longitudinal exposure-response of clinical trial endpoints is important in optimizing dose and dosing regimens in drug development. Clinical endpoints are often categorical, for which much progress has been made recently in latent variable indirect response (IDR) modeling with single drugs. However, such applications have not yet been used for trials employing multiple drugs administered concurrently. This study aims to demonstrate that the latent variable IDR approach provides a convenient longitudinal exposure-response modeling framework to assess potential interaction effects of combination therapies. This is illustrated by an application to the exposure-response modeling of guselkumab, a monoclonal antibody in clinical development that blocks the interleukin-23p19 subunit, and golimumab, a monoclonal antibody that binds with high affinity to tumor necrosis factor-alpha. A Phase 2a study was conducted in 214 patients with moderate-to severe active ulcerative colitis for which longitudinal assessments of disease severity based on patient-reported measures of rectal bleeding, stool frequency, and symptomatic remission were evaluated as categorical endpoints, and fecal calprotectin as a continuous endpoint. The modeling results suggested independent pharmacodynamic guselkumab and golimumab effects on fecal calprotectin as a continuous endpoint, as well as interaction effects on the categorical endpoints that may be explained by an additional pathway of competitive interaction.
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Colitis Ulcerosa , Humanos , Colitis Ulcerosa/tratamiento farmacológico , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/uso terapéutico , Resultado del Tratamiento , Índice de Severidad de la EnfermedadRESUMEN
Physiologically based pharmacokinetic (PBPK) models consist of compartments representing different tissues. As most models are only verified based on plasma concentrations, it is unclear how reliable associated tissue profiles are. This study aimed to assess the accuracy of PBPK-predicted beta-lactam antibiotic concentrations in different tissues and assess the impact of using effect site concentrations for evaluation of target attainment. Adipose, bone, and muscle concentrations of five beta-lactams (piperacillin, cefazolin, cefuroxime, ceftazidime, and meropenem) in healthy adults were collected from literature and compared with PBPK predictions. Model performance was evaluated with average fold errors (AFEs) and absolute AFEs (AAFEs) between predicted and observed concentrations. In total, 26 studies were included, 14 of which reported total tissue concentrations and 12 unbound interstitial fluid (uISF) concentrations. Concurrent plasma concentrations, used as baseline verification of the models, were fairly accurate (AFE: 1.14, AAFE: 1.50). Predicted total tissue concentrations were less accurate (AFE: 0.68, AAFE: 1.89). A slight trend for underprediction was observed but none of the studies had AFE or AAFE values outside threefold. Similarly, predictions of microdialysis-derived uISF concentrations were less accurate than plasma concentration predictions (AFE: 1.52, AAFE: 2.32). uISF concentrations tended to be overpredicted and two studies had AFEs and AAFEs outside threefold. Pharmacodynamic simulations in our case showed only a limited impact of using uISF concentrations instead of unbound plasma concentrations on target attainment rates. The results of this study illustrate the limitations of current PBPK models to predict tissue concentrations and the associated need for more accurate models. SIGNIFICANCE STATEMENT: Clinical inaccessibility of local effect site concentrations precipitates a need for predictive methods for the estimation of tissue concentrations. This is the first study in which the accuracy of PBPK-predicted tissue concentrations of beta-lactam antibiotics in humans were assessed. Predicted tissue concentrations were found to be less accurate than concurrent predicted plasma concentrations. When using PBPK models to predict tissue concentrations, this potential relative loss of accuracy should be acknowledged when clinical tissue concentrations are unavailable to verify predictions.
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Modelos Biológicos , Monobactamas , Adulto , Humanos , Ceftazidima , Antibacterianos , MúsculosRESUMEN
Therapeutic proteins may first be developed as intravenous (i.v.) therapies with new subcutaneous (s.c.) dosage forms being subsequently developed to provide an alternative route of administration. As of August 2022, there have been 9 therapeutic proteins which were developed as a new s.c. dosage form after the approval of the corresponding i.v. product. This article provides a systematic review of prior experiences in the i.v. to s.c. switch development programs. We describe what types of clinical studies were conducted to support the i.v. to s.c. switch for these nine therapeutic proteins. Publicly available scientific advice from health authorities is summarized, particularly regarding recommendations on overall development strategy, dose selection, immunogenicity assessment, and indication extrapolation. The clinical data from these i.v. to s.c. development programs demonstrate that: (1) when switching from i.v. dosing to s.c. dosing, trough drug concentration (Ctrough ) from s.c. dosing should not be inferior to i.v. dosing with average drug concentration (Cavg ; equivalent to AUC, area under the curve after correcting for dosing intervals between i.v. and s.c. administration) being matched or non-inferior to i.v. dosing; and (2) with appropriate s.c. dose regimens, treatment with s.c. therapeutic proteins can generally achieve similar efficacy and safety as the corresponding i.v. products, suggesting that the much higher maximum concentration (Cmax ) after i.v. infusion as compared with that from s.c. injection is often not relevant to the treatment effect.
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Administración Intravenosa , Humanos , Inyecciones SubcutáneasRESUMEN
To date, food-drug interactions in the pediatric population remain understudied. The current food effect studies are mostly performed in adults and do not mimic the real-life situation in the pediatric population. Since the potential benefits of food effect studies performed in pediatrics should be counterbalanced with the burden that these studies pose to the patients, alternative research strategies should be evaluated. The present study aimed to evaluate whether population pharmacokinetics (popPK) using data in beagle dogs and human adults could reliably assess food effects relevant for the pediatric population. PopPK was utilized to understand the performance of paracetamol under different dosing conditions (when the participants were fasted, with a reference meal, and with infant formula) in human adults (n = 8) and beagle dogs (n = 6) by constructing models to derive the pharmacokinetic parameters and to evaluate the food effects in both species. A two-compartment model with a single input function for the absorption phase best described the profiles of paracetamol in the beagle dogs. In the human adults, a one-compartment model with a dual input function for the absorption phase best described the data. The simulated profiles for the different dosing conditions demonstrated that both the human adults' and beagle dogs' simulations were able to acceptably describe the plasma concentration-time profiles of paracetamol observed in a representative pediatric population, which opens up perspectives on pediatric-relevant food effect predictions. However, the obtained results should be carefully interpreted, since an accurate validation of these findings was not possible due to the scarcity of the literature on observed pediatric data.
RESUMEN
Formulating aqueous suspensions is an attractive strategy to incorporate poorly water-soluble drugs, where the drug release can be tailored to maintain desired release profiles of several weeks to months after parenteral (i.e., intramuscular or subcutaneous) administration. A sustained drug release can be desirable to combat chronic diseases by overcoming pill fatigue of a daily oral intake, hence, improving patient compliance. Although the marketed aqueous suspensions for intramuscular injection efficiently relieve the daily pill burden in chronic diseases, the exact drug release mechanisms remain to be fully unraveled. The in vivo drug release and subsequent absorption to the systemic circulation are influenced by a plethora of variables, resulting in a complex in vivo behavior of aqueous suspensions after intramuscular administration. A better understanding of the factors influencing the in vivo performance of aqueous suspensions could advance their drug development. An overview of the potential influential variables on the drug release after intramuscular injection of aqueous suspensions is provided with, where possible, available pharmacokinetic parameters in humans or other species derived from literature, patents, and clinical trials. These variables can be categorized into drug substance and formulation properties, administration site properties, and the host response towards drug particles. Based on the findings, the most critical factors are particle size, dose level, stabilizing excipient, drug lipophilicity, gender, body mass index, and host response.