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AIMS: To develop a non-linear mixed-effects population pharmacokinetic and pharmacodynamic (PK-PD) model describing the change in the concentration of methotrexate polyglutamates in erythrocytes (ery-MTX-PGn with "n" number of glutamate, representing PK component) and how this relates to modified 28-joint Disease Activity Score incorporating erythrocyte sedimentation rate (DAS-28-3) for rheumatoid arthritis (RA), representing PD component. METHODS: An existing PK model was fitted to data from a study consisting of 117 RA patients. The estimation of population PK-PD parameters was performed using stochastic approximation expectation maximisation algorithm in Monolix 2021R2. The model was used to perform Monte Carlo simulations of a loading dose regimen (50mg subcutaneous methotrexate as loading doses, then 20mg weekly oral methotrexate) compared to a standard dosing regimen (10mg weekly oral methotrexate for 2 weeks, then 20mg weekly oral methotrexate). RESULTS: Every 40 nmol/L increase in ery-MTX-PG3-5 total concentration correlated with 1-unit reduction in DAS-28-3. Significant covariate effects on the therapeutic response of methotrexate included the use of prednisolone in the first 4 weeks (positive use correlated with 25% reduction in DAS-28-3 when other variables were constant) and patient age (every 10-year increase in age correlated with 3.4% increase in DAS-28-3 when other variables were constant). 4 methotrexate loading doses led to a higher percentage of patients achieving a good/moderate response compared to the standard regimen (Week 4: 87.6% vs. 39.8%; Week 10: 64.7% vs. 57.0%). CONCLUSIONS: A loading dose regimen was more likely to achieve higher ery-MTX-PG concentration and better therapeutic response after 4 weeks of methotrexate treatment.
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Nearly two decades after the Peck and Cross article '"Getting the dose right: facts, a blueprint, and encouragements" was published, a review of dose recommendations for biologics shows that the success in getting the dose right appears to have improved given the relatively low incidence of drug withdrawals and dosing/label changes. However, the clinical experience with monoclonal antibodies (MAbs) following approval has been less than perfect. In inflammatory diseases, the disease burden changes with time and high treatment failure rates have been reported. In addition, the use of concomitant steroids and immunosuppressant drugs with MAbs is common. These concomitant agents have their own safety issues and many immunosuppressant agents are not well-tolerated although they have been shown to reduce the incidence of anti-drug antibodies (ADA). This same complexity is seen in MAbs used in oncology as well, although with these agents the doses appear to be higher than needed, which results in high treatment costs and incidence of adverse events. Given the complexity of MAb pharmacokinetics, which makes providing a detailed description of dose options difficult, product labeling should include the options for alternative dose strategies and potentially include the use of therapeutic drug monitoring with dose individualization which have been shown to improve clinical response and reduce the incidence of ADA. So, while the recommended dosing for biologics seems improved over the issues noted 17 years ago, we still have some work to do.
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Precision-dosing models forecast infliximab doses to achieve targeted trough concentrations in patients with inflammatory bowel disease (IBD). These models have shown to reduce nonresponse and improve patient outcomes. We compared infliximab doses determined by iDOSE precision dosing with standard dosing, and the associated drug costs, in patients with IBD. In this retrospective study, patients with IBD treated with infliximab every 8 weeks at 5 mg/kg were included. An infliximab dose was named dose X if 3 previous infliximab doses, laboratory values including trough infliximab concentrations, and the patient's weight were recorded. The actual dose X was compared to an iDOSE-predicted dose X. Net drug use and costs were evaluated. A total of 174 patients-56% men; median age, 36 (interquartile range, 29-47) years; 135 with Crohn disease; and 31 with ulcerative colitis-were included, with 417 dose X recordings. Median prior infliximab therapy was 2 (0-4) years. Comparing actual dose X with predicted dose X, 52% and 32% of doses were subtherapeutic when aiming for trough concentrations of 5-10 and 3-7 µg/mL, respectively. Treatment costs increased by 102% and 29% for the 2 trough ranges, respectively. On multivariate regression analysis, subtherapeutic infliximab concentrations were associated with ulcerative colitis compared with Crohn disease (odds ratio, 9.81; 95% confidence interval, 1.28-75.40; P = .028) and predose X infliximab trough concentration [odds ratio, 0.07; 95% confidence interval, 0.03-0.15; P < .001]. Over half of maintenance infliximab drug doses were too low to achieve infliximab blood concentrations of 5 µg/mL or greater. While applying precision dosing may improve patient outcomes, drug costs could be considerably greater.
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Colitis Ulcerosa , Enfermedad de Crohn , Enfermedades Inflamatorias del Intestino , Masculino , Humanos , Adulto , Femenino , Infliximab , Enfermedad de Crohn/tratamiento farmacológico , Colitis Ulcerosa/tratamiento farmacológico , Fármacos Gastrointestinales , Estudios Retrospectivos , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Costos y Análisis de Costo , Monitoreo de DrogasRESUMEN
With increasing global focus on planetary boundaries, food safety and quality, the presence of per- and polyfluoroalkyl substances (PFAS) in the food chain presents a challenge for the sustainable production and supply of quality assured food. Consumption of food is the primary PFAS exposure route for the general population. At contaminated sites, PFAS have been reported in a range of agricultural commodities including cattle. Consumer exposure assessments are complicated by the lack of validated modelling approaches to estimate PFAS bioaccumulation in cattle. Previous studies have shown that PFAS bioaccumulation in livestock is influenced by environmental, spatial and temporal factors that necessitate a dynamic modelling approach. This work presents an integrated exposure and population toxicokinetic (PopTK) model for cattle that estimates serum and tissue concentrations of PFAS over time. Daily exposures were estimated from intakes of water, pasture, and soil, and considered animal growth, seasonal variability (pasture moisture content and temperature) and variable PFAS concentrations across paddocks. Modelled serum and tissue estimates were validated against monitoring data from Australian and Swedish cattle farms. The models were also used to develop and test practical management options for reducing PFAS exposure and to prioritise remediation for farms. Model outputs for exposure management scenarios (testing cattle rotation and targeted supplementation of feed and water) showed potential for marked reductions in consumer exposures from cattle produce.
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Ácidos Alcanesulfónicos , Agua Potable , Fluorocarburos , Humanos , Bovinos , Animales , Carga Corporal (Radioterapia) , Australia , Inocuidad de los Alimentos , Agua Potable/análisisRESUMEN
The migration of per- and polyfluoroalkyl substances (PFAS) onto agricultural properties has resulted in the accumulation of PFAS in livestock. The environmental determinants of PFAS accumulation in livestock from the grazing environment are poorly understood, resulting in limited capacity to manage livestock exposure and subsequent transfer of PFAS through the food chain. Analytical- (n = 978 samples of soil, water, pasture, and serum matrices), farm management/practice- and livestock physiology data were collated and interrogated from environmental PFAS investigations across ten farms, from four agro-ecological regions of Victoria (Australia). Statistical analysis identified perfluorooctane sulfonate (PFOS) and perfluorohexane sulfonate (PFHxS) as key analytes of concern for livestock bioaccumulation. PFOS and PFHxS concentrations in livestock drinking water were positively correlated with serum concentrations while other intake pathways (pasture and soil) had weaker correlations. Seasonal trends in PFAS body burden (serum concentrations) were identified and suggested to be linked to seasonal grazing behaviours and physiological water requirements. The data showed for the first time that livestock exposure to PFAS is dynamic and with relatively short elimination half-lives, there is opportunity for exposure management. Meat from cattle, grazed on PFAS impacted sites, may exceed health-based guideline values for PFAS, especially for markets with low limits (like the European Commission Maximum Limits or EC MLs). This study found that sites with mean livestock drinking water concentrations as low as 0.003 µg PFOS/L may exceed the EC ML for PFOS in cattle meat. Risk assessment can be used to prioritise site cleanup and development of management plans to reduce PFAS body burden by considering timing of stock rotation and/or supplementation of primary exposure sources.
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Agua Potable , Fluorocarburos , Animales , Bovinos , Agua Potable/análisis , Ganado , Medición de Riesgo , Alcanosulfonatos/análisisRESUMEN
BACKGROUND AND OBJECTIVES: Tramadol is commonly prescribed to manage chronic pain in older patients. However, there is a gap in the literature describing the pharmacokinetic parameters for tramadol and its active metabolite (O-desmethyltramadol [ODT]) in this population. The objective of this study was to develop and evaluate a population pharmacokinetic model for tramadol and ODT in older patients. METHODS: Twenty-one patients who received an extended-release oral tramadol dose (25-100 mg) were recruited. Tramadol and ODT concentrations were determined using a validated liquid chromatography/tandem mass spectrometry method. A population pharmacokinetic model was developed using non-linear mixed-effects modelling. The performance of the model was assessed by visual predictive check. RESULTS: A two-compartment, first-order absorption model with linear elimination best described the tramadol concentration data. The absorption rate constant was 2.96/h (between-subject variability [BSV] 37.8%), apparent volume of distribution for the central compartment (V1/F) was 0.373 l (73.8%), apparent volume of distribution for the peripheral compartment (V2/F) was 0.379 l (97.4%), inter-compartmental clearance (Q) was 0.0426 l/h (2.19%) and apparent clearance (CL/F) was 0.00604 l/h (6.61%). The apparent rate of metabolism of tramadol to ODT (kt) was 0.0492 l/h (78.5%) and apparent clearance for ODT (CLm) was 0.143 l/h (21.6%). Identification of Seniors at Risk score (ISAR) and creatinine clearance (CrCL) were the only covariates included in the final model, where a higher value for the ISAR increased the maximum concentration (Cmax) of tramadol and reduced the BSV in Q from 4.71 to 2.19%. A higher value of CrCL reduced tramadol Cmax and half-life (T1/2) and reduced the BSV in V2/F (from 148 to 97.4%) and in CL/F (from 78.9 to 6.61%). CONCLUSION: Exposure to tramadol increased with increased frailty and reduced CrCL. Prescribers should consider patients frailty status and CrCL to minimise the risk of tramadol toxicity in such cohort of patients.
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Fragilidad , Tramadol , Anciano , Cromatografía Liquida/métodos , Femenino , Semivida , Humanos , Masculino , Tramadol/análogos & derivadosRESUMEN
Exposure-response (ER) modeling for fixed-dose combinations (FDC) has previously been found to have an inflated false positive rate (FP), i.e., observing a significant effect of FDC components when no true effect exists. Longitudinal exposure-response (LER) analysis utilizes the time course of the data and is valid for several clinical endpoints for FDCs. The aim of the study was to investigate if LER is applicable for the validation of FDCs by demonstrating the contribution of each component to the overall effect without inflation of FP rates. FP and FN rates associated with ER and LER analysis were investigated using stochastic simulation and estimation. Four hundred thirty-two scenarios with varying numbers of patients, duration, sampling frequency, dose distribution, design, and drug activity were analyzed using a range of linear, log-linear, and non-linear models to asses FP and FN rates. Lastly, the impact of the clinical trial parameters was investigated. LER analyses provided well-controlled FP rates of the expected 5% or less; however, in low information clinical trials consisting of 30 patients, 4 samples, and 20 days, LER analyses lead to inflated FN rates. Parameter investigation showed that when the clinical trial includes sufficient patients, duration, samples, and an appropriate trial design, the FN rates are in general below the expected 5% for LER analysis. Based on the results, LER analysis can be used for the validation of FDCs and fixed ratio drug combinations. The method constitutes a new avenue for providing evidence that demonstrates the contribution of each component to the overall clinical effect.
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Combinación de Medicamentos , Modelos Biológicos , Farmacocinética , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Humanos , Modelos Lineales , Estudios Longitudinales , Dinámicas no Lineales , Reproducibilidad de los ResultadosRESUMEN
The clinical use of vasoactive drugs aims to improve hemodynamic variables and thereby maintain or restore adequate perfusion and oxygenation in accordance with metabolic demands. A main focus in the management of patients with brain pathology during surgery and neurointensive care is restoring and/or maintaining adequate cerebral perfusion pressure in order to ensure cerebral blood flow in accordance with metabolic demands. One commonly used clinical strategy is the administration of vasoactive drugs aiming to increase mean arterial blood pressure and thereby cerebral perfusion pressure. Here, we first describe the anatomic and physiological basis for the cerebrovascular effects of vasopressor agents. Next, we review the pharmacodynamics of commonly used vasopressors under normal circumstances and in the presence of head injury. We further discuss the role of blood-brain barrier disruption and microvascular dysfunction with regard to the effects of the reviewed vasopressor agents.
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Lesiones Traumáticas del Encéfalo/tratamiento farmacológico , Circulación Cerebrovascular/efectos de los fármacos , Oxígeno/sangre , Vasoconstrictores/uso terapéutico , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/lesiones , Lesiones Traumáticas del Encéfalo/fisiopatología , Humanos , Vasoconstrictores/farmacologíaRESUMEN
Oral controlled-release formulations are playing an ever-increasing role in opioid therapy; however, little is known about their influence on the relationship between pharmacokinetics and pharmacodynamics. The study aim was to characterize the pharmacokinetic-pharmacodynamics of two controlled-release tablet formulations and a liquid formulation of oxycodone in healthy, opioid-naïve volunteers, which can serve as a reference for future patient studies. A semi-double-blinded, three-way crossover study was conducted, with fifteen healthy volunteers receiving two differently designed 20 mg monophasic controlled-release oxycodone tablets and 10 mg oral solution oxycodone in a randomized order. Venous plasma concentrations and pupil diameter were determined pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.33, 2.66, 3, 3.33, 3.66, 4, 5, 6, 8, 12 and 24 hour post-dose. Oxycodone pharmacokinetics was best described by a two-compartment model with first-order absorption. The controlled-release formulations had an absorption lag of 0.23 hour and a slower absorption rate constant (kaCR = 0.19 hour-1 ) compared to the oral solution (kaSOL = 0.94 hour-1 ). Effects on pupil diameter were delayed relative to plasma (14 minutes half-life) for all formulations and were best described by a proportional Emax model. The plasma concentration of oxycodone at half-maximum effect was lower in males (31.1 µg/L) compared to females (52.8 µg/L; P < .001). The absorption profile of controlled-release oxycodone formulations provided a prolonged onset and offset of action compared to oral solution oxycodone. The controlled-release formulations showed no differences in pharmacokinetic and pharmacodynamic parameters suggesting that both may be used interchangeably in human beings with normal gastrointestinal function.
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Analgésicos Opioides/administración & dosificación , Modelos Biológicos , Oxicodona/administración & dosificación , Administración Oral , Adulto , Analgésicos Opioides/farmacocinética , Analgésicos Opioides/farmacología , Estudios Cruzados , Preparaciones de Acción Retardada , Método Doble Ciego , Femenino , Semivida , Humanos , Masculino , Persona de Mediana Edad , Oxicodona/farmacocinética , Oxicodona/farmacologíaRESUMEN
PURPOSE: Lenalidomide is used widely in B-cell malignancies for its immunomodulatory activity. It is primarily eliminated via the kidneys, with a significant proportion of renal elimination attributed to active processes. Lenalidomide is a weak substrate of P-glycoprotein (P-gp), though it is unclear whether P-gp is solely responsible for lenalidomide transport. This study aimed to determine whether the current knowledge of lenalidomide was sufficient to describe the pharmacokinetics of lenalidomide in multiple tissues. METHODS: A physiologically based pharmacokinetic model was developed using the Open Systems Pharmacology Suite to explore the pharmacokinetics of lenalidomide in a variety of tissues. Data were available for mice dosed intravenously at 0.5, 1.5, 5, and 10 mg/kg, with concentrations measured in plasma, brain, heart, kidney, liver, lung, muscle, and spleen. P-gp expression and activity were sourced from the literature. RESULTS: The model predictions in plasma, liver, and lung were representative of the observed data (median prediction error 13%, - 10%, and 30%, respectively, with 90% confidence intervals including zero), while other tissue predictions showed sufficient similarity to the observed data. Contrary to the data, model predictions for the brain showed no drug reaching brain tissue when P-gp was expressed at the blood-brain barrier. The data were better described by basolateral transporters at the intracellular wall. Local sensitivity analysis showed that transporter activity was the most sensitive parameter in these models for exposure. CONCLUSION: As P-gp transport at the blood-brain barrier did not explain the observed brain concentrations alone, there may be other transporters involved in lenalidomide disposition.
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Antineoplásicos/administración & dosificación , Barrera Hematoencefálica/metabolismo , Lenalidomida/administración & dosificación , Modelos Biológicos , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Administración Intravenosa , Animales , Antineoplásicos/farmacocinética , Encéfalo/metabolismo , Relación Dosis-Respuesta a Droga , Lenalidomida/farmacocinética , Ratones , Ratones Endogámicos ICR , Distribución TisularRESUMEN
OBJECTIVES: The selection of sample times for a pharmacokinetic study is important when trapezoidal integration (e.g. non-compartmental analysis) is used to determine the area under the concentration-time curve (AUC). The aim of this study was to develop an algorithm that determines optimal times that provide the most accurate AUC by minimising trapezoidal integration error. METHODS: The algorithm required initial single individual or mean pooled concentration data but did not specifically require a prior pharmacokinetic model. Optimal sample intervals were determined by minimising trapezoidal error using a genetic algorithm followed by a quasi-Newton method. The method was evaluated against simulated and clinical datasets to determine the method's ability to estimate the AUC. KEY FINDINGS: The sample times produced by the algorithm were able to accurately estimate the AUC of pharmacokinetic profiles, with the relative AUC having 90% confidence intervals of 0.919-1.05 for profiles with two-compartment kinetics. When comparing the algorithm with rich sampling (e.g. phase I trial), the algorithm provided equivalent or superior sample times with fewer observations. CONCLUSIONS: The creation of the algorithm and its companion web application allows users with limited pharmacometric or programming training can obtain optimal sampling times for pharmacokinetic studies.
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Preparaciones Farmacéuticas/metabolismo , Algoritmos , Área Bajo la Curva , Humanos , FarmacocinéticaRESUMEN
AIMS: Lenalidomide is an immunomodulatory imide drug used broadly in the treatment of multiple myeloma and lymphoma. It continues to be evaluated in chronic lymphocytic leukaemia (CLL) at lower doses due to dose-related toxicities including tumour flare and tumour lysis syndrome. This study aimed to develop a population pharmacokinetic model for lenalidomide in multiple cancers, including CLL, to identify any disease-related differences in disposition. METHODS: Lenalidomide concentrations from 4 clinical trials were collated (1999 samples, 125 subjects), covering 4 cancers (multiple myeloma, CLL, acute myeloid leukaemia and acute lymphoblastic leukaemia) and a large dose range (2.5-75 mg). A population pharmacokinetic model was developed with NONMEM and patient demographics were tested as covariates. RESULTS: The data were best fitted by a 1-compartment kinetic model with absorption described by 7 transit compartments. Clearance and volume of distribution were allometrically scaled for fat-free mass. The population parameter estimates for apparent clearance, apparent volume of distribution and transit rate constant were 12 L/h (10.8-13.6), 68.8 L (61.8-76.3), and 13.5 h-1 (11.9-36.8) respectively. Patients with impaired renal function (creatinine clearance <30 mL/min) exhibited a 22% reduction in lenalidomide clearance compared to patients with creatinine clearance of 90 mL/min. Cancer type had no discernible effect on lenalidomide disposition. CONCLUSIONS: This is the first report of a lenalidomide population pharmacokinetic model to evaluate lenalidomide pharmacokinetics in patients with CLL and compare its pharmacokinetics with other B-cell malignancies. As no differences in pharmacokinetics were found between the observed cancer-types, the unique toxicities observed in CLL may be due to disease-specific pharmacodynamics.
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Linfocitos B/inmunología , Factores Inmunológicos/farmacocinética , Lenalidomida/farmacocinética , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Eliminación Renal , Administración Oral , Adulto , Anciano , Disponibilidad Biológica , Ensayos Clínicos Fase I como Asunto , Creatinina/sangre , Creatinina/metabolismo , Creatinina/orina , Conjuntos de Datos como Asunto , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Factores Inmunológicos/administración & dosificación , Factores Inmunológicos/efectos adversos , Lenalidomida/administración & dosificación , Lenalidomida/efectos adversos , Leucemia Linfocítica Crónica de Células B/sangre , Leucemia Linfocítica Crónica de Células B/inmunología , Leucemia Mieloide Aguda/sangre , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/inmunología , Masculino , Persona de Mediana Edad , Modelos Biológicos , Mieloma Múltiple/sangre , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/inmunología , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangre , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/inmunología , Adulto JovenRESUMEN
BACKGROUND AND OBJECTIVE: SUBA-itraconazole and Sporanox are two oral formulations of itraconazole. Drug-drug interactions with omeprazole have been previously reported; however, mechanistic understanding of the pharmacological and physiological interactions of omeprazole with orally administered itraconazole within a population modeling paradigm is lacking. The objective of this analysis was to mechanistically describe and quantify the effect of omeprazole on the pharmacokinetics of itraconazole and its major metabolite, hydroxyitraconazole from the SUBA itraconazole and Sporanox formulations. METHODS: An in vitro-in vivo (IVIV) pharmacokinetic model of itraconazole and hydroxyitraconazole was developed including data from an omeprazole interaction study with SUBA itraconazole. Meta-models of gastric pH for healthy subjects and subjects receiving omeprazole were integrated into the IVIV model to capture omeprazole-mediated gastric pH changes on itraconazole dissolution and absorption. RESULTS: Omeprazole influenced the kinetics of itraconazole through altering the dissolution and absorption due to the pH-dependent solubility of itraconazole, inhibition of efflux transporters, and inhibiting the metabolism of itraconazole and hydroxyitraconazole. The model-predicted population effects of omeprazole on itraconazole from SUBA-itraconazole were to increase the area under the concentration-time curve (AUC0-24) and maximum concentration (Cmax) by 35 and 31%, respectively, and to decrease AUC0-24 and Cmax from Sporanox by 68 and 76%, respectively. CONCLUSION: Unlike SUBA itraconazole, which requires basic pH for itraconazole release, the omeprazole-induced pH-mediated reduction in Sporanox dissolution overrides any increased exposure from the drug-drug interaction at hepatic metabolizing enzymes or efflux transporters. The model presented here is the most complete quantitative description of the pharmacokinetics of itraconazole and hydroxyitraconazole currently available.
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Antifúngicos/farmacocinética , Itraconazol/farmacocinética , Omeprazol/farmacocinética , Inhibidores de la Bomba de Protones/farmacocinética , Adolescente , Adulto , Anciano , Disponibilidad Biológica , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas/fisiología , Femenino , Voluntarios Sanos , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
Inflammatory diseases (ID) are incurable, progressive diseases. Literature evidence cites increasing incidence of these diseases worldwide. When treatments with chemical immunosuppressive agents fail, patients are often treated with monoclonal antibodies (MAbs). However, MAb failure rates are generally high, with approximately half the patients being discontinued within 4 years, necessitating switching to another MAb. One potential cause of treatment failure is subtherapeutic exposure. Several studies demonstrated associations between trough MAb concentrations and clinical response, supporting the notion that improving drug exposure may result in improved outcomes. MAbs exhibit complex and highly variable pharmacokinetics in ID patients with numerous factors affecting clearance. Bayesian-guided dosing with dashboard systems is a new tool being investigated in the treatment of ID to reduce variability in exposure. Simulations suggest dashboards will be effective at maintaining patients at target troughs. However, when patients are dosed using doses or intervals outside those listed in prescribing information, there is concern that patients may have drug exposures beyond or below the ranges found to be safe and efficacious. This manuscript reviews the rationale behind dashboard development, evaluations of expected performance, and a simulated assessment of MAb exposure with dashboard-based dosing versus dosing based on the prescribing information. We introduce the concept of pharmacologic equivalence-if patients are dosed based on individual pharmacokinetics, the resulting exposure is consistent with exposures achieved using labeled dosing. We further show that dashboard-based dosing results in observed exposures that are generally contained within the range of exposures achieved with labeled dosing.
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Anticuerpos Monoclonales/administración & dosificación , Inmunosupresores/administración & dosificación , Inflamación/tratamiento farmacológico , Modelos Biológicos , Anticuerpos Monoclonales/farmacocinética , Teorema de Bayes , Variación Biológica Poblacional , Simulación por Computador , Relación Dosis-Respuesta a Droga , Humanos , Inmunosupresores/farmacocinética , Inflamación/inmunología , Insuficiencia del TratamientoRESUMEN
The aim of this study was to develop a population in vitro-in vivo pharmacokinetic model that simultaneously describe the absorption and accumulation kinetics of itraconazole (ICZ) and hydroxy-itraconazole (HICZ) in healthy subjects. The model integrated meta-models of gastrointestinal pH and gastrointestinal transit time and in vitro dissolution models of ICZ with the absorption and disposition kinetics of ICZ and HICZ. Mean concentration intravenous data, and single- and multi-dose oral data were used for model development. Model development was conducted in NONMEM in a stepwise manner. First, a model of intravenous data (systemic kinetics) was established and then extended to include the oral data. The latter was then extended to establish the in vitro-in vivo pharmacokinetic model. The systemic disposition of ICZ was best described by a 3-compartment model with oral absorption described by 4-transit compartments and HICZ distribution by a 1-compartment model. ICZ clearance was best described using a mixed inhibition model that allowed HICZ concentrations to inhibit the clearance of parent drug. HICZ clearance was described by Michaelis-Menten elimination kinetics. An in vitro-in vivo model was successfully established for both formulations. The presented model was able to describe ICZ and HICZ plasma concentrations over a wide range of oral and intravenous doses and allowed the exploration of complexities associated with the non-linear ICZ and HICZ kinetics. The model may provide insight into the variability in exposure of ICZ with respect to relating in vivo dissolution characteristics with in vivo disposition kinetics.
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Antifúngicos/farmacocinética , Itraconazol/farmacocinética , Administración Oral , Tracto Gastrointestinal/metabolismo , Tránsito Gastrointestinal/fisiología , Humanos , Concentración de Iones de Hidrógeno , Cinética , Modelos Biológicos , Adulto JovenRESUMEN
Objective: To develop a model to predict buprenorphine plasma concentrations during transition from transdermal to buccal administration. Design: Population pharmacokinetic model-based meta-analysis of published data. Methods: A model-based meta-analysis of available buprenorphine pharmacokinetic data in healthy adults, extracted as aggregate (mean) data from published literature, was performed to explore potential conversion from transdermal to buccal buprenorphine. The time course of mean buprenorphine plasma concentrations following application of transdermal patch or buccal film was digitized from available literature, and a meta-model was developed using specific pharmacokinetic parameters (e.g., absorption rate, apparent clearance, and volumes of distribution) derived from analysis of pharmacokinetic data for intravenously, transdermally, and buccally administered buprenorphine. Results: Data from six studies were included in this analysis. The final transdermal absorption model employed a zero-order input rate that was scaled to reflect a nominal patch delivery rate and time after patch application (with decline in rate over time). The transdermal absorption rate constant became zero following patch removal. Buccal absorption was a first-order process with a time lag and bioavailability term. Simulations of conversion from transdermal 20 mcg/h and 10 mcg/h to buccal administration suggest that transition can be made rapidly (beginning 12 hours after patch removal) using the recommended buccal formulation titration increments (75-150 mcg) and schedule (every four days) described in the product labeling. Conclusions: Computer modeling and simulations using a meta-model built from data extracted from publications suggest that rapid and straightforward conversion from transdermal to buccal buprenorphine is feasible.
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Analgésicos Opioides/farmacocinética , Buprenorfina/farmacocinética , Administración Bucal , Administración Cutánea , Analgésicos Opioides/administración & dosificación , Analgésicos Opioides/sangre , Buprenorfina/administración & dosificación , Buprenorfina/sangre , Voluntarios Sanos , HumanosRESUMEN
Infliximab is an anti-tumour necrosis factor alpha monoclonal antibody used to treat inflammatory diseases. Many patients fail during induction and others respond initially but relapse during maintenance therapy. Although anti-drug antibodies (ADA) are associated with some clinical failures, there is evidence that some failures may be due to subtherapeutic exposure. Adapting doses based on clinical outcomes and trough concentrations can improve response and reduce the proportion that develop ADA, but identification of appropriate doses in the presence of time-varying patient factors is complicated. Several adaptive dosing strategies (label recommendations versus therapeutic drug monitoring with an established stepwise algorithm or proportional dose adjustments or Bayesian population pharmacokinetic model-based dosing) were simulated on a virtual population (constructed with time-varying covariates and random effects on individual pharmacokinetic parameters) using R to assess their relative performance. Strategies were evaluated on their ability to maintain trough infliximab concentrations above an established target, 3 mg/L, during maintenance phase. Model-based dosing was superior in maintaining target trough concentrations, showing individuals in maintenance achieving concentrations above the target faster and a lower proportion of individuals who developed ADA. Model-based dosing results were consistent across a range of baseline covariate groups. This in silico assessment of adaptive dosing strategies demonstrated that, when challenged with dynamic covariate and random effect changes occurring in individual pharmacokinetic parameters, model-based approaches were superior to other strategies. Model-based dosing has not been tested clinically; however, the potential benefits of model-based dosing for infliximab suggest that it should be investigated to reduce subtherapeutic exposure.
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Fármacos Gastrointestinales/administración & dosificación , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Infliximab/administración & dosificación , Simulación por Computador , Relación Dosis-Respuesta a Droga , Fármacos Gastrointestinales/farmacocinética , Fármacos Gastrointestinales/uso terapéutico , Humanos , Infliximab/farmacocinética , Infliximab/uso terapéuticoRESUMEN
Non-compartmental analysis (NCA) is regarded as the standard for establishing bioequivalence, despite its limitations and the existence of alternative methods such as non-linear mixed effects modelling (NLMEM). Comparisons of NCA and NLMEM in bioequivalence testing have been limited to drugs with one-compartment kinetics and have included a large number of different approaches. A simulation tool was developed with the ability to rapidly compare NCA and NLMEM methods in determining bioequivalence using both R and NONMEM and applied to a drug with two-compartment pharmacokinetics. Concentration-time profiles were simulated where relative bioavailability, random unexplained variability (RUV) at the lower limit of quantification (LLOQ) differed between simulations. NLMEM analyses employed either the M1 or M3 methods for dealing with values below the LLOQ. It was used to elucidate the impact of changes in (i) RUV at the LLOQ, (ii) the extent of censoring data below the LLOQ and (iii) the concentration sampling times. The simulations showed NLMEM having a consistent 20-40% higher accuracy and sensitivity in identifying bioequivalent studies when compared to NCA, while NCA was found to have a 1-10% higher specificity than NLMEM. Increasing data censoring by increasing the LLOQ resulted in decreases of ~10% to the accuracy and sensitivity of NCA, with minimal effects on NLMEM. The tool provides a platform for comparing NCA and NLMEM methods and its use can be extended beyond the scenarios reported here. In the situations examined it is seen that NLMEM is more accurate than NCA and may offer some advantages in the determination of bioequivalence.
Asunto(s)
Preparaciones Farmacéuticas/metabolismo , Farmacocinética , Equivalencia Terapéutica , Disponibilidad Biológica , Humanos , Cinética , Dinámicas no LinealesRESUMEN
The literature presently lacks a population pharmacokinetic analysis of doxycycline. This study aimed to develop a population pharmacokinetic model of doxycycline plasma concentrations that could be used to assess the power of bioequivalence between Doryx delayed-release tablets and Doryx MPC. Doxycycline pharmacokinetic data were available from eight phase 1 clinical trials following single/multiple doses of conventional-release doxycycline capsules, Doryx delayed-release tablets, and Doryx MPC under fed and fasted conditions. A population pharmacokinetic model was developed in a stepwise manner using NONMEM, version 7.3. The final covariate model was developed according to a forward inclusion (P < 0.01) and then backward deletion (P < 0.001) procedure. The final model was a two-compartment model with two-transit absorption compartments. Structural covariates in the base model included formulation effects on relative bioavailability (F), absorption lag (ALAG), and the transit absorption rate (KTR) under the fed status. An absorption delay (lag) for the fed status (FTLAG2 = 0.203 h) was also included in the model as a structural covariate. The fed status was observed to decrease F by 10.5%, and the effect of female sex was a 14.4% increase in clearance. The manuscript presents the first population pharmacokinetic model of doxycycline plasma concentrations following oral doxycycline administration. The model was used to assess the power of bioequivalence between Doryx delayed-release tablets and Doryx MPC, and it could potentially be used to critically examine and optimize doxycycline dose regimens.
Asunto(s)
Antibacterianos/farmacocinética , Doxiciclina/farmacocinética , Modelos Estadísticos , Administración Oral , Adolescente , Adulto , Anciano , Antibacterianos/sangre , Área Bajo la Curva , Disponibilidad Biológica , Ensayos Clínicos Fase I como Asunto , Doxiciclina/sangre , Esquema de Medicación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores Sexuales , Comprimidos , Equivalencia TerapéuticaRESUMEN
Leflunomide's active metabolite teriflunomide inhibits dihydro-oroate dehydrogenase, an enzyme essential to proliferation of T lymphocytes. As teriflunomide must reach the target site to have this effect, this study assessed the distribution of teriflunomide into T lymphocytes, as intracellular concentrations may be a superior response biomarker to plasma concentrations. CD3 MicroBeads (Miltenyi Biotec, Bergisch Gladbach, Germany) were used to extract CD3+ T cells from the peripheral blood of patients with rheumatoid arthritis who were taking a stable dose of leflunomide. Unbound plasma and intra-CD3+ T cell teriflunomide concentrations were quantified using liquid chromatography-mass spectrometry. Concentration (log transformed) and partition differences were assessed through paired Student t tests. Sixteen patients provided plasma steady-state teriflunomide samples, and eight provided a sample 6-12 weeks later. At time-point one, the geometric mean teriflunomide concentration (range) in CD3+ T cells was 18.12 µg/L (6.15-42.26 µg/L) compared with 69.75 µg/L (32.89-263.1 µg/L) unbound in plasma (P < 0.001). The mean partition coefficient (range) for unbound plasma teriflunomide into CD3+ T cells was 0.295 (0.092-0.632), which was significantly different from unity (P < 0.001). The median (range) change in teriflunomide concentration between the two time points was 14% (-10% to 40%) in unbound plasma and -29% (-69 to 138%) for CD3+ T cells. Because teriflunomide concentrations in CD3+ T cells were lower and displayed a higher intraindividual variability than the unbound plasma concentrations, its applicability as a therapeutic drug-monitoring marker may be limited.