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AIMS: C-reactive protein (CRP) is used to determine the effect of antibiotic treatment on sepsis in neonates/infants. We aimed to develop pharmacokinetic-pharmacodynamic (PKPD) model of meropenem and CRP in neonates/infants and evaluate its predictive performance of CRP dynamics. METHODS: Data from neonates/infants treated with meropenem in 3 previous studies were analysed. To the previously developed meropenem PK models, the addition of turnover, transit or effect compartment, delay differential equation PD models of CRP as a function of meropenem concentration or its cumulative area under the curve (AUC) were evaluated. The percentage of neonates/infants (P0.1 , P0.2 ) in whom the ratio of the fifth day CRP to its peak value was predicted with an error of <0.1 (<0.2) was calculated. RESULTS: A total of 60 meropenem treatment episodes (median [range] gestational age 27.6 [22.6-40.9] weeks, postnatal age 13 [2-89] days) with a total of 351 CRP concentrations (maximum value 65.5 [13-358.4] mg/L) were included. Turnover model of CRP as a function of meropenem cumulative AUC provided the best fit and included CRP at the start of treatment, use of prior antibiotics, study and causative agent Staphylococcus aureus or enterococci as covariates. Using meropenem population predictions and data available at 0, 24, 48, 72 h after the start of treatment, P0.1 (P0.2 ) was 36.4, 36.4, 60.6 and 66.7% (70.0, 66.7, 72.7 and 78.7%), respectively. CONCLUSION: The developed PKPD model of meropenem and CRP as a function of meropenem cumulative AUC incorporating several patient characteristics predicts CRP dynamics with an error of <0.2 in most neonates/infants.
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Proteína C-Reactiva , Sepsis , Humanos , Lactante , Recién Nacido , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Proteína C-Reactiva/análisis , Edad Gestacional , Meropenem , Sepsis/tratamiento farmacológicoRESUMEN
Survival is one of the most important endpoints in cancer therapy, and parametric survival analysis could comprehensively reveal the overall result of disease progression, drug efficacy, toxicity as well as their interactions. In this study we investigated the efficacy and toxicity of dexamethasone (DEX) combined with gemcitabine (GEM) in pancreatic cancer xenograft. Nude mice bearing SW1990 pancreatic cancer cells derived tumor were treated with DEX (4 mg/kg, i.g.) and GEM (15 mg/kg, i.v.) alone or in combination repeatedly (QD, Q3D, Q7D) until the death of animal or the end of study. Tumor volumes and net body weight (NBW) were assessed every other day. Taking NBW as a systemic safety indicator, an integrated pharmacokinetic/pharmacodynamic (PK/PD) model was developed to quantitatively describe the impact of tumor size and systemic safety on animal survival. The PK/PD models with time course data for tumor size and NBW were established, respectively, in a sequential manner; a parametric time-to-event (TTE) model was also developed based on the longitudinal PK/PD models to describe the survival results of the SW1990 tumor-bearing mice. These models were evaluated and externally validated. Only the mice with good tumor growth inhibition and relatively stable NBW had an improved survival result after DEX and GEM combination therapy, and the simulations based on the parametric TTE model showed that NBW played more important role in animals' survival compared with tumor size. The established model in this study demonstrates that tumor size was not always the most important reason for cancer-related death, and parametric survival analysis together with safety issues was also important in the evaluation of oncology therapies in preclinical studies.
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Gemcitabina , Neoplasias Pancreáticas , Humanos , Ratones , Animales , Línea Celular Tumoral , Xenoinjertos , Ratones Desnudos , Neoplasias Pancreáticas/tratamiento farmacológicoRESUMEN
The study aimed to explore the pharmacokinetic and pharmacodynamic alterations of the active components of Shenkang injection (i.e. hydroxy saffron yellow pigment A [HSYA], tanshinol, rheum emodin, and astragaloside IV) in rats with chronic renal failure (CRF), and establish a pharmacokinetic-pharmacodynamic model (PK-PD model) in order to provide a scientific and theoretical basis for the rational clinical use of Shenkang injection. Sprague-Dawley (SD) rats were randomly divided into a normal group, model group, and Shenkang injection group. A rat model of CRF was induced by adenine gavage and then followed by drug administration via tail vein injection. Orbital blood was collected at different timepoints and the blood concentrations of the four active components were measured by UHPLC-Q-Orbitrap HRMS. Serum levels of creatinine (Scr), urea nitrogen (BUN), and uric acid (UA) were determined using an automatic biochemical analyzer. A PK-PD model was established, and DAS 3.2.6 software was used for model fitting as well as statistical analysis. TGF-ß1 was utilized to induce normal rat kidney cells to construct a renal fibrosis model to investigate the protective effect of the pharmacological components on renal fibrosis. The pharmacokinetic analysis of hydroxy saffron yellow pigment A, tanshinol, rheum emodin, and astragaloside IV based on UHPLC-Q-Orbitrap HRMS was stable. The linear regression equations for the four active components were as follows: Y = 0.031X + 0.0091 (R2 = 0.9986) for hydroxy saffron yellow pigment A, Y = 0.0389X + 0.164 (R2 = 0.9979) for tanshinol, Y = 0.0257X + 0.0146 (R2 = 0.9973) for rheum emodin, and Y = 0.0763X + 0.0139 (R2 = 0.9993) for astragaloside IV, which indicated good linear relationships. The methodological investigation was stable, with the interday and intraday precision RSD <10%. Meanwhile, the recoveries ranged between 90% and 120%, in accordance with the requirements for in vivo analysis of drugs. Compared with the model group, the levels of Scr, BUN, and UA were significantly decreased after 20 min in the Shenkang injection group (p < 0.01). The PK-PD model showed that the four active components in the Shenkang injection group could fit well with the three effect measures (i.e. Scr, BUN, and UA), with the measured values similar to the predicted values. The cell model of renal fibrosis showed that the connective tissue growth factor and FN1 protein expression levels were significantly lower in the Shenkang injection group than those in the model group, and the cell fibrosis was improved. The established method for in vivo analysis of Shenkang injection was highly specific, with good separation of the components and simple operation. The total statistical moment could well integrate the pharmacokinetic parameters of the four active components. After treatment with Shenkang injection, all indexes in the administered group improved and showed significant inhibition of renal cell fibrosis in vitro. This study could provide scientific reference ideas for the clinical rational use of traditional Chinese medicine.
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Medicamentos Herbarios Chinos , Emodina , Fallo Renal Crónico , Insuficiencia Renal Crónica , Ratas , Animales , Emodina/farmacología , Ratas Sprague-Dawley , Riñón , Fallo Renal Crónico/tratamiento farmacológico , Fallo Renal Crónico/patología , Medicamentos Herbarios Chinos/farmacología , FibrosisRESUMEN
Drug-induced torsades de pointes (TdP) risks are responsible for the withdrawal of many drugs from the market. Nowadays, assessments of drug-induced TdP risks are mainly based on maximum effective free therapeutic plasma concentration (EFTPCmax) and cardiac ionic current inhibitions using the human ventricular myocytes model (Tor-ORd model). Myocytes are targets of drug-induced TdP. The TdP risks may be directly linked to myocyte drug concentrations. We aimed to develop a semi-physiologically based pharmacokinetic (Semi-PBPK) model linked to cardiac ionic current inhibition (pharmacodynamics, PD) (Semi-PBPK-PD) to simultaneously predict myocyte drug concentrations and their TdP risks in humans. Alterations in action potential duration (ΔAPD90) were simulated using the Tor-ORd model and ionic current inhibition parameters based on myocyte or plasma drug concentrations. The predicted ΔAPD90 values were translated into in vivo alterations in QT interval(ΔQTc) induced by moxifloxacin, dofetilide, or sotalol. Myocyte drug concentrations of moxifloxacin, dofetilide, and sotalol gave better predictions of ΔQTc than plasma. Following validating the developed semi-PBPK-PD model, TdP risks of 37 drugs were assessed using ΔAPD90 and early afterdepolarization occurrence, which were estimated based on 10 × EFTPCmax and 10 × EFTMCmax (maximum effective free therapeutic myocyte concentration). 10 × EFTMCmax gave more sensitive and accurate predictions of pro-arrhythmic cardiotoxicity and the predicted TdP risks were also closer to clinic practice than 10 × EFTPCmax. In conclusion, pharmacokinetics and TdP risks of 37 drugs were successfully predicted using the semi-PBPK-PD model. Myocyte drug concentrations gave better predictions of ΔQTc and TdP risks than plasma.
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PURPOSE: Treatment with recombinant human erythropoietin (rHuEPO) may correct anemia in patients with chronic kidney disease. However, up to 10% of these patients exhibit EPO resistance or hyporesponsiveness, which may be caused by the depletion of erythroid progenitor cells. Thrombopoietin (TPO) stimulates the self-renewal of stem cells and promotes the growth of early erythroid progenitor cells. The objective of this study was to determine whether the combination of recombinant human TPO (rHuTPO) and rHuEPO could correct the depletion of erythroid precursor cells to treat EPO-resistant anemia. METHODS: To test our hypothesis, pharmacokinetic (PK) and pharmacodynamic (PD) studies of rHuEPO and rHuTPO were performed in healthy rats. Rats received rHuEPO or rHuTPO alone or in combination. Plasma concentrations of rHuTPO and rHuEPO were measured. PD responses, including erythropoietic and thrombopoietic responses, were assessed in peripheral blood. RESULTS: On one hand, the results demonstrated the synergistic effect of the combination of rHuEPO and rHuTPO on erythropoiesis. Compared with rHuEPO monotherapy, the combination therapies further stimulated the production of red blood cells and hemoglobin. On the other hand, rHuEPO inhibited the platelet production induced by rHuTPO and mitigate the risk of blood clots. Furthermore, we successfully developed a mechanism-based PD model to simultaneously characterize the responses of the two molecules. CONCLUSIONS: Overall, our study indicated that a combination therapy of rHuTPO and rHuEPO could be used to treat EPO-resistant anemia and provided a quantitative basis for further optimizing the combination therapy for clinical use.
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Anemia , Eritropoyetina , Anemia/tratamiento farmacológico , Anemia/etiología , Animales , Células Precursoras Eritroides , Humanos , Ratas , Proteínas Recombinantes/farmacología , Trombopoyetina/farmacología , Trombopoyetina/uso terapéuticoRESUMEN
Myelosuppression is a dose-limiting toxicity of uracil-tegafur (UFT), which contains uracil and the 5fluorouracil prodrug tegafur, and inhibits the continuation of chemotherapy, causing treatment failure. A proper dosing strategy to avoid severe myelosuppression-induced discontinuation of chemotherapy is required.Plasma drug concentrations were determined in rats after single oral UFT administration of 15, 30, or 60 mg/kg. Blood cell counts were also measured after oral UFT administration for 5 days. Pharmacokinetic-toxicodynamic (PK-TD) modelling and simulation were performed to describe the time-course alterations in the blood cell counts.Severe neutropenia was observed in rats treated with 60 mg/kg UFT on day 7. A significant decrease in neutrophil counts from baseline levels prior to UFT administration was observed on day 3, whereas leukocyte and lymphocyte counts decreased on day 7. The semi-physiological PK-TD model successfully captured alterations in neutrophil counts after UFT administration, whereas the model could not well describe the platelet, leukocyte, and lymphocyte counts, possibly due to the absence of severe thrombocytopenia, leukocytopenia, and lymphocytopenia, respectively.Neutrophils are sensitive markers for estimating the grade of haematological toxicity of UFT, and a PK-TD model might be an attractive tool for quantitatively evaluating the onset and degree of myelosuppression.
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Tegafur , Animales , Ratas , Tegafur/toxicidadRESUMEN
Polymyxin-based combination therapy is commonly used to treat carbapenem-resistant Acinetobacter baumannii (CRAB) infections. In the present study, the bactericidal effect of polymyxin B and minocycline combination was tested in three CRAB strains containing blaOXA-23 by the checkerboard assay and in vitro dynamic pharmacokinetics/pharmacodynamics (PK/PD) model. The combination showed synergistic or partial synergistic effect (fractional inhibitory concentration index ≤0.56) on the tested strains in checkboard assays. The antibacterial activity was enhanced in the combination group compared with either monotherapy in in vitro PK/PD model. The combination regimen (simultaneous infusion of 0.75 mg/kg polymyxin B and 100 mg minocycline via 2 h infusion) reduced bacterial colony counts by 0.9-3.5 log10 colony forming units per milliliter (CFU/mL) compared with either drug alone at 24 h. In conclusion, 0.75 mg/kg polymyxin B combined with 100 mg minocycline via 2 h infusion could be a promising treatment option for CRAB bloodstream infections.
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Infecciones por Acinetobacter/tratamiento farmacológico , Acinetobacter baumannii/efectos de los fármacos , Antibacterianos/farmacología , Enterobacteriaceae Resistentes a los Carbapenémicos/efectos de los fármacos , Sinergismo Farmacológico , Minociclina/farmacología , Polimixina B/farmacología , Infecciones por Acinetobacter/microbiología , Antibacterianos/farmacocinética , Carbapenémicos/farmacología , Quimioterapia Combinada , Técnicas In Vitro , Minociclina/farmacocinética , Polimixina B/farmacocinética , Distribución Tisular , beta-Lactamasas/genéticaRESUMEN
PURPOSE: Peptide-conjugated phosphorodiamidate morpholino oligomers (PPMOs) have shown promise in treating Duchenne muscular dystrophy (DMD). We evaluated a semi-mechanistic pharmacokinetic (PK) and pharmacodynamic (PD) model to capture the relationship between plasma and muscle tissue exposure/response in mdx mice treated by mouse surrogate PPMO. METHODS: A single or repeated (every 4 weeks for 20 weeks) intravenous PPMO dose was administered to mdx mice (n = 6/timepoint). A PK/PD model was built to characterize data via sequential modeling. A 2-compartment model was used to describe plasma PK. A simultaneous tissue PK/PD model was subsequently developed: 2-compartment model to describe muscle PK; linked to an indirect response model describing stimulation of synthesis of skipped transcript, which was in turn linked to stimulation of synthesis of dystrophin protein expression. RESULTS: Model performance assessment via goodness-of-fit plots, visual predictive checks, and accurate parameter estimation indicated robust fits of plasma PK and muscle PK/PD data. The model estimated a PPMO tissue half-life of 5 days-a useful parameter in determining the longevity of PPMOs in tissue and their limited accumulation after multiple doses. Additionally, the model successfully described dystrophin expression after single dosing and associated protein accumulation after multiple dosing (increasing ~ twofold accumulation from the first to last dose). CONCLUSIONS: This first PK/PD model of a PPMO in a DMD disease model will help characterize and predict the time course of PK/PD biomarkers in mdx mice. Furthermore, the model framework can be used to develop clinical PK/PD models and can be extended to other exon-skipping therapies and species.
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Péptidos de Penetración Celular/química , Morfolinos/farmacocinética , Distrofia Muscular de Duchenne/tratamiento farmacológico , Animales , Área Bajo la Curva , Simulación por Computador , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Distrofina/genética , Distrofina/metabolismo , Semivida , Humanos , Masculino , Ratones Endogámicos mdx , Modelos Biológicos , Modelos Estadísticos , Morfolinos/sangreRESUMEN
BACKGROUND: Target-controlled infusion (TCI) systems incorporating pharmacokinetic (PK) or PK-pharmacodynamic (PK-PD) models can be used to facilitate drug administration. Existing models were developed using data from select populations, the use of which is, strictly speaking, limited to these populations. Recently a propofol PK-PD model was developed for a broad population range. The aim of the study was to prospectively validate this model in children, adults, older subjects, and obese adults undergoing general anaesthesia. METHODS: The 25 subjects included in each of four groups were stratified by age and weight. Subjects received propofol through TCI with the Eleveld model, titrated to a bispectral index (BIS) of 40-60. Arterial blood samples were collected at 5, 10, 20, 30, 40, and 60 min after the start of propofol infusion, and every 30 min thereafter, to a maximum of 10 samples. BIS was recorded continuously. Predictive performance was assessed using the Varvel criteria. RESULTS: For PK, the Eleveld model showed a bias < ±20% in children, adults, and obese adults, but a greater bias (-27%) in older subjects. Precision was <30% in all groups. For PD, the bias and wobble were <5 BIS units and the precision was close to 10 BIS units in all groups. Anaesthetists were able to achieve intraoperative BIS values of 40-60 using effect-site target concentrations about 85-140% of the age-adjusted Ce50. CONCLUSIONS: The Eleveld propofol PK-PD model showed predictive precision <30% for arterial plasma concentrations and BIS predictions with a low (population) bias when used in TCI in clinical anaesthesia practice.
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Anestesia General , Anestésicos Intravenosos/farmacocinética , Estado de Conciencia/efectos de los fármacos , Modelos Biológicos , Propofol/farmacocinética , Adolescente , Adulto , Factores de Edad , Anciano , Anestésicos Intravenosos/administración & dosificación , Anestésicos Intravenosos/sangre , Peso Corporal , Niño , Preescolar , Femenino , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Obesidad , Propofol/administración & dosificación , Propofol/sangre , Estudios Prospectivos , Reproducibilidad de los Resultados , Adulto JovenRESUMEN
Clinically, Wangbi Capsule (WBC) is widely used in the treatment of Rheumatoid arthritis (RA) because of its remarkable therapeutic effect. To reveal the mechanism, a pharmacokinetic-pharmacodynamic (PK-PD) model was developed for the first time to assess the relationship between time-concentration (dose)-effect. Freund's Complete Adjuvant was used to induce the adjuvant-induced arthritis model. Multi-indices were used to evaluate the therapeutic effect and an S-Imax PK-PD model was established based on the concentrations of osthole, 5-O-methylvisamminoside, cimifugin, albiflorin, paeoniflorin and icariin and the levels of interleukin-1ß and prostaglandin E2 using a two-compartment PK model together with a PD model with an effect-site compartment. The results suggest that WBC can treat RA by regulating the levels of prostaglandin E2 and interleukin-1ß. For the PK-PD model, the parameters indicated that WBC had a large safety margin and all six bioactive ingredients of WBC have therapeutic effects on RA. Among them icariin, osthole and 5-O-methylvisamminoside may be the main effective substances. This study provided a scientific basis for further study of population pharmacokinetics / population pharmacodynamics (PPK/PPD), to develop a reasonable administration plan and improve individualized drug therapy.
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Antiinflamatorios , Artritis Experimental , Medicamentos Herbarios Chinos , Animales , Antiinflamatorios/administración & dosificación , Antiinflamatorios/química , Antiinflamatorios/farmacocinética , Antiinflamatorios/farmacología , Artritis Experimental/tratamiento farmacológico , Artritis Experimental/metabolismo , Benzopiranos/sangre , Benzopiranos/farmacocinética , Hidrocarburos Aromáticos con Puentes/sangre , Hidrocarburos Aromáticos con Puentes/farmacocinética , Modelos Animales de Enfermedad , Medicamentos Herbarios Chinos/administración & dosificación , Medicamentos Herbarios Chinos/química , Medicamentos Herbarios Chinos/farmacocinética , Medicamentos Herbarios Chinos/farmacología , Flavonoides/sangre , Flavonoides/farmacocinética , Adyuvante de Freund/efectos adversos , Glucósidos/sangre , Glucósidos/farmacocinética , Articulaciones/efectos de los fármacos , Articulaciones/metabolismo , Masculino , Medicina Tradicional China , Monoterpenos/sangre , Monoterpenos/farmacocinética , Ratas , Ratas Sprague-DawleyRESUMEN
Tuberculosis has been described as a global health crisis since the 1990s, with an estimated 1.4 million deaths in the last year. Herein, a series of 20 1H-indoles were synthesized and evaluated as in vitro inhibitors of Mycobacterium tuberculosis (Mtb) growth. Furthermore, the top hit compounds were active against multidrug-resistant strains, without cross-resistance with first-line drugs. Exposing HepG2 and Vero cells to the molecules for 72 h showed that one of the evaluated structures was devoid of apparent toxicity. In addition, this 3-phenyl-1H-indole showed no genotoxicity signals. Finally, time-kill and pharmacodynamic model analyses demonstrated that this compound has bactericidal activity at concentrations close to the Minimum Inhibitory Concentration, coupled with a strong time-dependent behavior. To the best of our knowledge, this study describes the activity of 3-phenyl-1H-indole against Mtb for the first time.
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Antituberculosos/síntesis química , Antituberculosos/farmacología , Indoles/síntesis química , Indoles/farmacología , Mycobacterium tuberculosis/efectos de los fármacos , Tuberculosis/tratamiento farmacológico , Animales , Línea Celular Tumoral , Chlorocebus aethiops , Células Hep G2 , Humanos , Pruebas de Sensibilidad Microbiana/métodos , Relación Estructura-Actividad , Células VeroRESUMEN
Dihydroartemisinin-piperaquine has shown excellent efficacy and tolerability in malaria treatment. However, concerns have been raised of potentially harmful cardiotoxic effects associated with piperaquine. The population pharmacokinetics and cardiac effects of piperaquine were evaluated in 1,000 patients, mostly children enrolled in a multicenter trial from 10 sites in Africa. A linear relationship described the QTc-prolonging effect of piperaquine, estimating a 5.90-ms mean QTc prolongation per 100-ng/ml increase in piperaquine concentration. The effect of piperaquine on absolute QTc interval estimated a mean maximum QTc interval of 456 ms (50% effective concentration of 209 ng/ml). Simulations from the pharmacokinetic-pharmacodynamic models predicted 1.98 to 2.46% risk of having QTc prolongation of >60 ms in all treatment settings. Although piperaquine administration resulted in QTc prolongation, no cardiovascular adverse events were found in these patients. Thus, the use of dihydroartemisinin-piperaquine should not be limited by this concern. (This study has been registered at ClinicalTrials.gov under identifier NCT02199951.).
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Antimaláricos , Malaria Falciparum , Malaria , Quinolinas , África , Antimaláricos/efectos adversos , Niño , Humanos , Malaria/tratamiento farmacológico , Malaria Falciparum/tratamiento farmacológico , Quinolinas/efectos adversosRESUMEN
Vonoprazan is characterized as having a long-lasting antisecretory effect on gastric acid. In this study we developed a physiologically based pharmacokinetic (PBPK)-pharmacodynamic (PD) model linking to stomach to simultaneously predict vonoprazan pharmacokinetics and its antisecretory effects following administration to rats, dogs, and humans based on in vitro parameters. The vonoprazan disposition in the stomach was illustrated using a limited-membrane model. In vitro metabolic and transport parameters were derived from hepatic microsomes and Caco-2 cells, respectively. We found the most predicted plasma concentrations and pharmacokinetic parameters of vonoprazan in rats, dogs and humans were within twofold errors of the observed data. Free vonoprazan concentrations (fu × C2) in the stomach were simulated and linked to the antisecretory effects of the drug (I) (increases in pH or acid output) using the fomula dI/dt = k × fu × C2 × (Imax - I) - kd × I. The vonoprazan dissociation rate constant kd (0.00246 min-1) and inhibition index KI (35 nM) for H+/K+-ATPase were obtained from literatures. The vonoprazan-H+/K+-ATPase binding rate constant k was 0.07028 min-1· µM-1 using ratio of kd to KI. The predicted antisecretory effects were consistent with the observations following intravenous administration to rats (0.7 and 1.0 mg/kg), oral administration to dogs (0.3 and 1.0 mg/kg) and oral single dose or multidose to humans (20, 30, and 40 mg). Simulations showed that vonoprazan concentrations in stomach were 1000-fold higher than those in the plasma at 24 h following administration to human. Vonoprazan pharmacokinetics and its antisecretory effects may be predicted from in vitro data using the PBPK-PD model of the stomach. These findings may highlight 24-h antisecretory effects of vonoprazan in humans following single-dose or the sustained inhibition throughout each 24-h dosing interval during multidose administration.
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Ácido Gástrico/metabolismo , Modelos Biológicos , Pirroles/metabolismo , Pirroles/farmacocinética , Sulfonamidas/metabolismo , Sulfonamidas/farmacocinética , Administración Intravenosa , Administración Oral , Animales , Transporte Biológico , Células CACO-2 , Perros , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Cinética , Masculino , Microsomas Hepáticos/química , Microsomas Hepáticos/metabolismo , Pirroles/administración & dosificación , Ratas , Ratas Sprague-Dawley , Sulfonamidas/administración & dosificación , Distribución TisularRESUMEN
Previous studies show that dopamine D2-like receptor (D2DR) antagonist sulpiride (SUL) enhances the antitumor efficacy of dexamethasone (DEX) in drug-resistant breast cancer involving cancer stem-like cells (CSCs). In this study, we investigated the pharmacokinetic (PK) properties of SUL in nude mice and developed a semi-mechanism PK/PD model to quantitatively characterize the synergistic effect of DEX and SUL in preclinical breast cancer xenografts. After nude mice received oral administration of a single dose of SUL (50 mg/kg, ig), plasma concentrations were assessed using LC-MS/MS. A two-compartment model with double first-order absorption rate was developed to describe the PK profiles of SUL. The pharmacodynamic (PD) study was conducted in nude mice bearing human breast cancer MCF-7/Adr xenografts, which received oral administration of DEX (1, 8 mg·kg-1·d-1) or SUL (25, 50 mg·kg-1·d-1) alone or in various combination. Tumor volumes were measured every other day. The PK model of SUL as well as that of DEX with a time-dependent clearance were integrated into the final PK/PD model both using Hill's function, where DEX exerted its antitumor efficacy by inhibiting the proliferation of tumor cells, and SUL enhanced DEX responses by decreasing the sensitivity parameter EC50. The PK/PD model was evaluated and subjected external validation. Finally, simulations were performed to predict the antitumor efficacy of DEX combined with SUL under various dose regimens, where changing dosing frequency of SUL had little effect, while the antitumor efficacy was predicted to be improved when DEX was given more frequently. The established PK/PD model in this study quantitatively characterizes the antitumor efficacy of the DEX combined with SUL as well as their synergism, and the simulations could provide reference for dose optimization of the combination in future studies.
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Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Dexametasona/uso terapéutico , Sulpirida/uso terapéutico , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Línea Celular Tumoral , Dexametasona/farmacocinética , Dexametasona/farmacología , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Femenino , Humanos , Ratones Desnudos , Modelos Biológicos , Sulpirida/farmacocinética , Sulpirida/farmacología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Rising evidence has shown the development of resistance to vascular endothelial growth factor receptor (VEGFR) inhibitors in the practices of cancer therapy. It is reported that the efficacy of axitinib (AX), a VEGFR inhibitor, is limited in the treatment of breast cancer as a single agent or in combination with other chemotherapeutic drugs due to the probability of rising population of cancer stem-like cells (CSCs) caused by AX. The present study evaluated the effect of dopamine (DA) improving AX's efficacy on MCF-7/ADR breast cancer in vitro and in vivo, and developed a pharmacokinetic-pharmacodynamic (PK-PD) model describing the in vivo experimental data and characterizing the interaction of effect between AX and DA. The results showed that AX up-regulated the expression of breast CSC (BCSC) markers (CD44+/CD24-/low) in vivo, and DA significantly synergized the inhibitory effect on tumor growth by deducting the BCSC frequency. The PK-PD model quantitatively confirmed the synergistic interaction with the parameter estimate of interaction factor ψ 2.43. The dose regimen was optimized as 60 mg/kg AX i.g. b.i.d. combined with 50 mg/kg DA i.p. q3d in the simulation study on the basis of the PK-PD model. The model where DA synergistically enhances the effect of AX in an all-or-none manner provides a possible solution in modeling the agents like DA. Moreover, the outcome of AX and DA combination therapy in MCF-7/ADR breast cancer provided further insight of co-administering DA in the treatment of the possible CSC-causing AX-resisting breast cancer. And this combination therapy has the prospect of clinical translation.
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Adenocarcinoma/tratamiento farmacológico , Antineoplásicos/farmacología , Axitinib/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Dopamina/farmacología , Animales , Antineoplásicos/farmacocinética , Apoptosis/efectos de los fármacos , Axitinib/farmacocinética , Docetaxel/farmacología , Dopamina/farmacocinética , Sinergismo Farmacológico , Femenino , Humanos , Células MCF-7 , Ratones Desnudos , Modelos Biológicos , Células Madre Neoplásicas/efectos de los fármacos , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
This study developed the pharmacokinetic (PK)-pharmacodynamic (PD) model of the testosterone-suppressive effect of leuprolide for evaluation of the sustained release (SR) depot and leuprolide solution in rats with or without prostate cancer. Six groups of rats were divided by the routes of administration (intravenous and subcutaneous injection) and kinds of formulation (vehicle, leuprolide solution, and SR depot). The PK profile after subcutaneous injection of leuprolide solution could be well-described by the one-compartment model. The absorption rate constant, the total body clearance, and the volume of distribution were estimated at 16.67 h-1, 514.46 mL/h, and 487.40 mL. Using PK parameters in the solution-administered group, the PK model for the SR depot was developed. The PK-PD model was constructed by describing the testosterone-suppressive effect of leuprolide using the feedback turnover model. The response of testosterone after administration of each formulation was well described using this PK-PD model for the estimation of PD parameters (EC50, Emax, h) and systemic parameters (kin, kout, kf on, kf off). The developed PK-PD model containing an inhibitory feedback system could successfully describe the testosterone-suppressive effect of leuprolide in the type of formulation. The PK-PD model developed would be useful for evaluating the formulation of similar drugs whose effect is regulated through the feedback mechanism.
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Leuprolida/farmacocinética , Leuprolida/uso terapéutico , Modelos Biológicos , Neoplasias de la Próstata/tratamiento farmacológico , Testosterona/antagonistas & inhibidores , Animales , Área Bajo la Curva , Preparaciones de Acción Retardada , Liberación de Fármacos , Leuprolida/administración & dosificación , Leuprolida/química , Masculino , Ratas WistarRESUMEN
The MIC of an antimalarial drug for a particular infection is the drug level associated with a net parasite multiplication rate of one per asexual cycle. To ensure the cure of malaria, the MIC must be exceeded until all parasites have been eliminated. The development of highly sensitive and accurate PCR quantitation of low-density malaria parasitemia enables the prospective pharmacokinetic-pharmacodynamic (PK-PD) characterization of antimalarial drug effects and now allows identification of the in vivo MIC. An adaptive design and a PK-PD modeling approach were used to determine prospectively the MIC of the new antimalarial cipargamin (KAE609) in adults with uncomplicated Plasmodium falciparum malaria in an open-label, dose-ranging phase 2a study. Vietnamese adults with acute P. falciparum malaria were allocated sequentially to treatment with a single 30-mg (n = 6), 20-mg (n = 5), 10-mg (n = 7), or 15-mg (n = 7) dose of cipargamin. Artemisinin-based combination therapy was given after parasite densities had fallen and then risen as cipargamin levels declined below the MIC but before a return of signs or symptoms. The rates of parasite clearance were dose dependent, with near saturation of the effect being seen at an adult dose of 30 mg. The developed PK-PD model accurately predicted the therapeutic responses in 23/25 patients. The predicted median in vivo MIC was 0.126 ng/ml (range, 0.038 to 0.803 ng/ml). Pharmacometric characterization of the relationship between antimalarial drug concentrations and parasite clearance rates following graded subtherapeutic antimalarial drug dosing is safe and provides a rational framework for dose finding in antimalarial drug development. (This study has been registered at ClinicalTrials.gov under identifier NCT01836458.).
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Antimaláricos/farmacocinética , Antimaláricos/uso terapéutico , Indoles/farmacocinética , Indoles/uso terapéutico , Malaria Falciparum/tratamiento farmacológico , Malaria Falciparum/metabolismo , Compuestos de Espiro/farmacocinética , Compuestos de Espiro/uso terapéutico , Adulto , Antimaláricos/efectos adversos , Pueblo Asiatico , Humanos , Indoles/efectos adversos , Masculino , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Compuestos de Espiro/efectos adversos , Adulto JovenRESUMEN
AIMS: The aims of the present study were to evaluate the pharmacokinetic properties of dihydroartemisinin (DHA) and piperaquine, potential drug-drug interactions with concomitant primaquine treatment, and piperaquine effects on the electrocardiogram in healthy volunteers. METHODS: The population pharmacokinetic properties of DHA and piperaquine were assessed in 16 healthy Thai adults using an open-label, randomized, crossover study. Drug concentration-time data and electrocardiographic measurements were evaluated with nonlinear mixed-effects modelling. RESULTS: The developed models described DHA and piperaquine population pharmacokinetics accurately. Concomitant treatment with primaquine did not affect the pharmacokinetic properties of DHA or piperaquine. A linear pharmacokinetic-pharmacodynamic model described satisfactorily the relationship between the individually corrected QT intervals and piperaquine concentrations; the population mean QT interval increased by 4.17 ms per 100 ng ml-1 increase in piperaquine plasma concentration. Simulations from the final model showed that monthly and bimonthly mass drug administration in healthy subjects would result in median maximum QT interval prolongations of 18.9 ms and 16.8 ms, respectively, and would be very unlikely to result in prolongation of more than 50 ms. A single low dose of primaquine can be added safely to the existing DHA-piperaquine treatment in areas of multiresistant Plasmodium falciparum malaria. CONCLUSIONS: Pharmacokinetic-pharmacodynamic modelling and simulation in healthy adult volunteers suggested that therapeutic doses of DHA-piperaquine in the prevention or treatment of P. falciparum malaria are unlikely to be associated with dangerous QT prolongation.
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Antimaláricos/farmacocinética , Electrocardiografía , Frecuencia Cardíaca/efectos de los fármacos , Modelos Biológicos , Adulto , Antimaláricos/administración & dosificación , Antimaláricos/efectos adversos , Artemisininas/administración & dosificación , Artemisininas/farmacocinética , Simulación por Computador , Estudios Cruzados , Combinación de Medicamentos , Interacciones Farmacológicas , Voluntarios Sanos , Humanos , Modelos Lineales , Síndrome de QT Prolongado/inducido químicamente , Síndrome de QT Prolongado/diagnóstico , Síndrome de QT Prolongado/fisiopatología , Persona de Mediana Edad , Dinámicas no Lineales , Primaquina/administración & dosificación , Primaquina/efectos adversos , Quinolinas/administración & dosificación , Quinolinas/farmacocinética , Medición de Riesgo , Tailandia , Adulto JovenRESUMEN
Luseogliflozin is a selective sodium glucose co-transporter 2 (SGLT2) inhibitor that reduces hyperglycemia in type 2 diabetes mellitus (T2DM) by promoting urinary glucose excretion (UGE). A clinical pharmacology study conducted in Japanese patients with T2DM confirmed dose-dependency of UGE with once-daily administration of luseogliflozin; however, the reason for sustained UGE after plasma luseogliflozin decreased was unclear. To elucidate the effect of inhibition rate constants, Kon and Koff, and to explain the sustained UGE, a pharmacokinetic-pharmacodynamic (PK-PD) model was built based on the mechanisms of glucose filtration in the glomerulus and reabsorption in the renal proximal tubule of kidney as well as the kinetics of competitive inhibition of SGLT1/2 and inhibition rate constants of SGLT2, by using UGE and plasma glucose levels and luseogliflozin concentrations. This acquired population PK-PD model adequately described the sustained UGE and the estimated population means of the inhibition constant for SGLT2 (Ki2) and inhibition-rate constants for SGLT2 (Kon and Koff) were 0.31- and 3.6-fold lower or higher than the in vitro values. Because the dissociation half-time of luseogliflozin from SGLT2 calculated from Koff, 6.81 h, was consistent with the value in vitro, we considered that the sustained UGE could be explained by the long dissociation half-time. Moreover, by calculating the SGLT2 inhibition ratio using the model, we discuss other properties of the UGE time course after luseogliflozin administration.
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Hipoglucemiantes/farmacología , Hipoglucemiantes/farmacocinética , Modelos Biológicos , Sorbitol/análogos & derivados , Adulto , Anciano , Pueblo Asiatico , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/metabolismo , Femenino , Glucosa/metabolismo , Humanos , Hipoglucemiantes/sangre , Glomérulos Renales/metabolismo , Túbulos Renales Proximales/metabolismo , Masculino , Persona de Mediana Edad , Transportador 2 de Sodio-Glucosa/metabolismo , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Sorbitol/sangre , Sorbitol/farmacocinética , Sorbitol/farmacologíaRESUMEN
The study of the magnitude and variation of drug response is defined as pharmacodynamics (PDs). PD models examine plasma concentration and effect relationship. It can predict the archetypal effect ([Formula: see text]) of a drug as a function of the drug concentration ([Formula: see text]) and estimate an unknown PD parameter ([Formula: see text]). The PD models have been described as fixed, linear, log-linear, [Formula: see text], sigmoid [Formula: see text], and indirect PD response. Ligand binding model is an example of a PD model that works on the underpinning PD principle of a drug, eliciting its pharmacological effect at the receptor site. The pharmacological effect is produced by the drug binding to the receptor to either activate or antagonise the receptor. Ligand binding models describe a system of interacting components, i.e. the interaction of one or more ligands with one or more binding sites. The [Formula: see text] model is the central method that provides an empirical justification for the concentration/dose-effect relationship. However, for ligand binding models justification is provided by theory of receptor occupancy. In essence, for ligand binding models, the term [Formula: see text] is best used to describe the fraction of receptors occupied at a particular ligand concentration. It is stated that the [Formula: see text], which means the effect of a drug should depend on the fraction of receptors that are occupied. In the future, network-based systems pharmacology models using ligand binding principles could be an effective way of understanding drug-related adverse effects. This will facilitate and strengthen the development of rational drug therapy in clinical practice.