RESUMEN
Burosumab is a fully human monoclonal antibody against fibroblast growth factor 23, which has been approved to treat X-linked hypophosphatemia (XLH) in adult and pediatric patients. The present work describes the pharmacokinetics (PK) of burosumab and the pharmacokinetic-pharmacodynamic (PK-PD) relationship between burosumab and serum phosphorus in adult and pediatric patients with XLH. A total of 2844 measurable serum concentrations of burosumab and 6047 measurable serum concentrations of phosphorus in 277 subjects from 9 clinical studies were included in the population PK and PK-PD modeling. The serum concentration of burosumab following a subcutaneous administration was well described by a population PK model comprising a first-order absorption, 1-compartmental distribution, and a linear elimination. The relationship between serum burosumab and serum phosphorus was adequately described by a sigmoid maximal efficacy model. Body weight was the only covariate associated with PK and PK-PD parameters. No other intrinsic factors affected PK or PK-PD relationship in adult and pediatric patients with XLH. Further simulations helped to guide the dosing regimen of burosumab in adult and pediatric patients with XLH including age groups with no clinical data.
Asunto(s)
Anticuerpos Monoclonales Humanizados/farmacología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Raquitismo Hipofosfatémico Familiar/tratamiento farmacológico , Fósforo/sangre , Adolescente , Adulto , Factores de Edad , Anciano , Anticuerpos Monoclonales Humanizados/farmacocinética , Peso Corporal , Niño , Preescolar , Relación Dosis-Respuesta a Droga , Femenino , Factores de Crecimiento de Fibroblastos/inmunología , Humanos , Lactante , Inyecciones Subcutáneas , Masculino , Persona de Mediana Edad , Modelos Biológicos , Adulto JovenRESUMEN
OBJECTIVES: X-linked hypophosphatemic rickets (XLH) is a congenital fibroblast growth factor (FGF)23-related metabolic bone disease that is treated with active vitamin D and phosphate as conventional therapies. Complications of these therapies include nephrocalcinosis (NC) caused by excessive urine calcium and phosphate concentrations. Recently, an anti-FGF23 antibody, burosumab, was developed and reported to be effective in poorly-controlled or severe XLH patients. This study aimed to reveal the impact of switching treatments in relatively well-controlled XLH children with the Rickets Severity Scale less than 2.0. METHODS: The effects of the two treatments in eight relatively well-controlled XLH children with a mean age of 10.4 ± 1.9 years were compared retrospectively for the same treatment duration (31 ± 11 months) before and after the baseline. RESULTS: Actual doses of alfacalcidol and phosphate as conventional therapy were 150.9 ± 43.9 ng/kg and 27.5 ± 6.3 mg/kg per day, respectively. Renal echography revealed spotty NC in 8/8 patients, but no aggravation of NC was detected by switching treatments. Switching treatments increased TmP/GFR (p=0.002) and %TRP (p<0.001), and improved the high urine calcium/creatinine ratio to the normal range (p<0.001) although both treatments controlled disease markers equally. Additionally, low intact parathyroid hormone during conventional therapy was increased within the normal range by switching treatments. CONCLUSIONS: Our results suggest that a high dose of alfacalcidol was needed to control the disease, but it caused hypercalciuria and NC. We concluded that switching treatments in relatively well-controlled XLH children improved renal phosphate reabsorption and decreased urine calcium extraction, and may have the potential to prevent NC.
Asunto(s)
Anticuerpos Monoclonales Humanizados/administración & dosificación , Sustitución de Medicamentos/métodos , Raquitismo Hipofosfatémico Familiar/tratamiento farmacológico , Factores de Crecimiento de Fibroblastos/antagonistas & inhibidores , Hidroxicolecalciferoles/uso terapéutico , Nefrocalcinosis/prevención & control , Conservadores de la Densidad Ósea/uso terapéutico , Niño , Raquitismo Hipofosfatémico Familiar/patología , Femenino , Factor-23 de Crecimiento de Fibroblastos , Factores de Crecimiento de Fibroblastos/inmunología , Estudios de Seguimiento , Humanos , Inyecciones Intravenosas , Masculino , Pronóstico , Estudios RetrospectivosRESUMEN
Exercise is considered to be the best approach to improve quality of life, and together with a healthy and adequate dietary pattern, exercise represents the best strategy to reduce the risk of chronic metabolic and inflammatory diseases, such as those related to obesity. The regularity and intensity of exercise is modulated at the molecular level in the skeletal muscle by two protein kinases, the mechanistic target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK), which act as sensors of external stimuli, showing the energy status of muscular fibers. The mTOR pathway is activated by insulin and amino acid availability, and its metabolic actions culminate in increased protein synthesis and reduced autophagy, leading to an increase in muscle mass. In contrast, AMPK activation induces a transcriptional program aimed to increase the mitochondrial content in skeletal muscle, transforming fast-twitch glycolytic fibers to slow-twitch oxidative fibers and increasing resistance to fatigue. In addition, inadequate exercise training induces imbalance in the immune response, generating excessive inflammation and/or immunosuppression. The purpose of this review is to summarize recent studies that provide insight into dietary protein interventions and/or amino acid supplementation that may improve outcomes after exercise by modulating 1) mTOR and AMPK activation during early exercise recovery, leading to increased muscle protein synthesis or increased oxidative capacity; 2) undesirable inflammatory responses; and 3) fibroblast growth factor 21 (FGF21) levels that may have relevant implications in skeletal muscle metabolism, particularly during the exercise recovery and performance of obese subjects.
Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Aminoácidos/metabolismo , Proteínas en la Dieta/metabolismo , Ejercicio Físico/fisiología , Factores de Crecimiento de Fibroblastos/metabolismo , Inmunidad/inmunología , Serina-Treonina Quinasas TOR/metabolismo , Proteínas Quinasas Activadas por AMP/inmunología , Aminoácidos/inmunología , Proteínas en la Dieta/inmunología , Suplementos Dietéticos , Factores de Crecimiento de Fibroblastos/inmunología , Humanos , Músculo Esquelético/inmunología , Músculo Esquelético/metabolismo , Aptitud Física/fisiología , Serina-Treonina Quinasas TOR/inmunologíaRESUMEN
Immunosuppression may occur for a number of reasons related to an individual's frailty, debility, disease or from therapeutic iatrogenic intervention or misadventure. A large percentage of morbidity and mortality in immunodeficient populations is related to an inadequate response to infectious agents with slow response to antibiotics, enhancements of antibiotic resistance in populations, and markedly increased prevalence of acute inflammatory response, septic and infection related death. Given known relationships between intracellular calcium ion concentrations and cytotoxicity and cellular death, we looked at currently available data linking blockade of calcium ion channels and potential decrease in expression of sepsis among immunosuppressed patients. Notable are relationships between calcium, calcium channel, vitamin D mechanisms associated with sepsis and demonstration of antibiotic-resistant pathogens that may utilize channels sensitive to calcium channel blocker. We note that sepsis shock syndrome represents loss of regulation of inflammatory response to infection and that vitamin D, parathyroid hormone, fibroblast growth factor, and klotho interact with sepsis defense mechanisms in which movement of calcium and phosphorus are part of the process. Given these observations we consider that further investigation of the effect of relatively inexpensive calcium channel blockade agents of infections in immunosuppressed populations might be worthwhile.
Asunto(s)
Bloqueadores de los Canales de Calcio/uso terapéutico , Canales de Calcio/inmunología , Enfermedades Transmisibles/tratamiento farmacológico , Huésped Inmunocomprometido , Sepsis/tratamiento farmacológico , Calcio/inmunología , Calcio/metabolismo , Canales de Calcio/genética , Enfermedades Transmisibles/genética , Enfermedades Transmisibles/inmunología , Enfermedades Transmisibles/mortalidad , Farmacorresistencia Microbiana/genética , Factores de Crecimiento de Fibroblastos/genética , Factores de Crecimiento de Fibroblastos/inmunología , Regulación de la Expresión Génica , Glucuronidasa/genética , Glucuronidasa/inmunología , Humanos , Proteínas Klotho , Hormona Paratiroidea/genética , Hormona Paratiroidea/inmunología , Fósforo/inmunología , Fósforo/metabolismo , Riesgo , Sepsis/genética , Sepsis/inmunología , Sepsis/mortalidad , Análisis de Supervivencia , Vitamina D/inmunología , Vitamina D/metabolismoRESUMEN
Target receptor levels can influence pharmacokinetics (PK) or pharmacodynamics (PD) of monoclonal antibodies (mAbs), and can affect drug development of this class of molecules. We generated an effector-less humanized bispecific antibody that selectively activates fibroblast growth factor receptor (FGFR)1 and ßKlotho receptor, a FGF21 receptor complex highly expressed in both white and brown adipocytes. The molecule shows cross-species binding with comparable equilibrium binding affinity (Kd) for human, cynomolgus monkey, and mouse FGFR1/ßKlotho. To understand the PK/PD relationship in non-obese and obese animals, we evaluated the adipose tissue distribution of the antibody, serum exposures, and an associated PD marker (high-molecular-weight adiponectin), in both non-obese and obese mice and monkeys. Antibody uptake into fat tissue was found to be higher on a per gram basis in non-obese animals compared to obese animals. Since obesity has been reported to be associated with reduced expression of FGFR1 and ßKlotho receptor in white adipose tissues in mice, our results suggest that the distribution in adipose tissues was influenced by target expression levels. Even so, the overall dose-normalized serum exposures were comparable between non-obese and obese mice and monkeys, suggesting that adipose tissue uptake plays a limited role in overall systemic PK determination. It remains to be determined if and how obesity and receptor expression in humans influence the PK and PD profile of this novel therapeutic candidate.
Asunto(s)
Tejido Adiposo/metabolismo , Anticuerpos Monoclonales/farmacocinética , Evaluación Preclínica de Medicamentos/métodos , Obesidad/metabolismo , Adiponectina/sangre , Adiponectina/metabolismo , Animales , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/farmacología , Células CHO , Cricetinae , Cricetulus , Dieta Alta en Grasa/efectos adversos , Femenino , Factores de Crecimiento de Fibroblastos/antagonistas & inhibidores , Factores de Crecimiento de Fibroblastos/inmunología , Factores de Crecimiento de Fibroblastos/metabolismo , Macaca fascicularis , Masculino , Ratones Endogámicos C57BL , Obesidad/etiología , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/antagonistas & inhibidores , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/inmunología , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/metabolismo , Distribución TisularRESUMEN
Phytase hydrolyzes phytate rendering phosphorus available for intestinal absorption, while systemic neutralization of fibroblast growth factor 23 (FGF-23), using anti-FGF-23 antibody, has been shown to increase phosphate retention. Hence, neutralization of FGF-23 should be additive with phytase in reducing dietary non-phytate phosphorus (nPP) needs in chickens fed plant-based diets rich in phytic acid. This study was designed to test the additive effects of maternally derived anti-FGF-23 antibody and dietary phytase on the performance of chicks fed a low nPP diet from one to 14 d. Single Comb White Leghorn laying hens were vaccinated with either an adjuvant control or a synthetic FGF-23 peptide (GMNPPPYS). Chicks from vaccinated hens with control or anti-FGF-23 maternal antibodies were fed either a diet containing 0.2% nPP and 0.9% calcium with or without 500 unit phytase per kg of diet (2 × 2 factorial with main effects of antibody type and phytase addition, n = 15 pens of chicks/treatment). A significant interaction between dietary phytase and maternally derived anti-FGF-23 antibody on growth and feed efficiency was observed (P ≤ 0.05), in which chicks receiving either phytase or maternally derived anti-FGF-23 antibody had improved body weight gain (21 or 15%, respectively) and feed efficiency (16 or 18%, respectively) as compared to chicks with control antibody and not fed phytase. Both phytase and maternally derived anti-FGF-23 antibody independently increased (P ≤ 0.05) plasma phosphate (11 and 11%, respectively) and percent tibiotarsus ash (13 and 11%, respectively). Significant main effects and the lack of an interaction supported an additive effect of phytase and anti-FGF-23 antibody on plasma phosphate and percent tibiotarsus ash. Feeding phytase to chicks fed 0.2% nPP increased plasma FGF-23 levels by 22% (P ≤ 0.05); however, no effects of anti-FGF-23 antibody on plasma FGF-23 levels were observed. In conclusion, dietary phytase and presence of anti-FGF-23 antibody have an additive effect on plasma phosphate and tibiotarsus ash in chicks fed low nPP diets. Data support that phytase and anti-FGF-23 antibody increase phosphate utilization by different mechanisms.
Asunto(s)
6-Fitasa/farmacología , Anticuerpos Monoclonales/farmacología , Calcio de la Dieta/metabolismo , Pollos/metabolismo , Factores de Crecimiento de Fibroblastos/antagonistas & inhibidores , Fósforo Dietético/metabolismo , 6-Fitasa/administración & dosificación , Alimentación Animal/análisis , Fenómenos Fisiológicos Nutricionales de los Animales , Animales , Anticuerpos Monoclonales/inmunología , Dieta/veterinaria , Suplementos Dietéticos/análisis , Femenino , Factor-23 de Crecimiento de Fibroblastos , Factores de Crecimiento de Fibroblastos/inmunología , Fósforo/metabolismoRESUMEN
Novel means to reduce phosphate input into poultry feeds and increase its retention would preserve world phosphate reserves and reduce environmental impact of poultry production. Here we show that a maternally derived antibody to a fibroblast growth factor-23 (FGF-23) peptide (GMNPPPYS) alleviated phosphorus deficiency in chicks fed low non-phytate phosphorus (nPP) diets. White Leghorn laying hens were vaccinated with either an adjuvant control or the synthetic FGF-23 peptide, and chicks with control or anti-FGF-23 maternal antibodies were fed a diet containing either 0.13 or 0.45% nPP (experiment 1), and 0.20 or 0.45% nPP (experiment 2) for 14 d. In both experiments, decreasing nPP from 0.45 to 0.13 or 0.20% decreased BW gain, G:F, excreta phosphorus, plasma phosphate, and plasma FGF-23 at all time periods examined (nPP main effect, P < 0.05). In experiment 1, chicks with maternal anti-FGF-23 antibody had increased tibiotarsi ash (d 14), and decreased excreta phosphate (d 7, 14) and plasma intact parathyroid hormone (d 7) when compared to chicks with control antibody (antibody main effect, P < 0.05). Mortality (d 7 to 14, 1 to 14), posture scores (d 7, 14) and bone lesion scores (d 14) decreased and plasma phosphate (d 14) increased in anti-FGF-23 chicks fed 0.13% nPP, compared to those with control antibody on the same diet (P < 0.05). In experiment 2, chicks with maternal anti-FGF-23 antibody had increased tibiotarsi ash (d 14), and plasma phosphate (d 14) and 1,25(OH)2D3 (d 14) levels, compared to chicks with control antibody (antibody main effect, P < 0.05). BW gain and G:F were increased in chicks with anti-FGF-23 antibody fed 0.20% nPP, compared to control antibody chicks on the same diet, at all time periods examined (P < 0.05). In conclusion, maternally-derived anti-FGF-23 antibody increased phosphorus retention in chicks fed diets containing either 0.13 or 0.20% nPP and thereby, reduced signs of phosphorus deficiency.
Asunto(s)
Anticuerpos/inmunología , Factores de Crecimiento de Fibroblastos/inmunología , Necesidades Nutricionales , Fosfatos/deficiencia , Fósforo Dietético/metabolismo , Alimentación Animal/análisis , Fenómenos Fisiológicos Nutricionales de los Animales , Animales , Pollos , Dieta/veterinaria , Femenino , Factor-23 de Crecimiento de FibroblastosRESUMEN
CONTEXT: In X-linked hypophosphatemia (XLH), elevated fibroblast growth factor 23 (FGF23) decreases the renal tubular maximum reabsorption rate of phosphate/glomerular filtration rate (TmP/GFR) and serum inorganic phosphorus (Pi), resulting in rickets and/or osteomalacia. OBJECTIVE: The objective was to test the hypothesis that monthly KRN23 (anti-FGF23 antibody) would safely improve serum Pi in adults with XLH. DESIGN: Two sequential open-label phase 1/2 studies were done. SETTING: Six academic medical centers were used. PARTICIPANTS: Twenty-eight adults with XLH participated in a 4-month dose-escalation study (0.05-0.6 mg/kg); 22 entered a 12-month extension study (0.1-1 mg/kg). INTERVENTION: KRN23 was injected sc every 28 days. MAIN OUTCOME MEASURE: The main outcome measure was the proportion of subjects attaining normal serum Pi and safety. RESULTS: At baseline, mean TmP/GFR, serum Pi, and 1,25-dihydroxyvitamin D [1,25(OH)2D] were 1.6 ± 0.4 mg/dL, 1.9 ± 0.3 mg/dL, and 36.6 ± 14.3 pg/mL, respectively. During dose escalation, TmP/GFR, Pi, and 1,25(OH)2D increased, peaking at 7 days for TmP/GFR and Pi and at 3-7 days for 1,25(OH)2D, remaining above (TmP/GFR, Pi) or near [1,25(OH)2D] pre-dose levels at trough. After each of the four escalating doses, peak Pi was between 2.5 and 4.5 mg/dL in 14.8, 37.0, 74.1, and 88.5% of subjects, respectively. During the 12-month extension, peak Pi was in the normal range for 57.9-85.0% of subjects, and ≥25% maintained trough Pi levels within the normal range. Serum Pi did not exceed 4.5 mg/dL in any subject. Although 1,25(OH)2D levels increased transiently, mean serum and urinary calcium remained normal. KRN23 treatment increased biomarkers of skeletal turnover and had a favorable safety profile. CONCLUSIONS: Monthly KRN23 significantly increased serum Pi, TmP/GFR, and 1,25(OH)2D in all subjects. KRN23 has potential for effectively treating XLH.
Asunto(s)
Anticuerpos Monoclonales/administración & dosificación , Raquitismo Hipofosfatémico Familiar/sangre , Raquitismo Hipofosfatémico Familiar/tratamiento farmacológico , Factores de Crecimiento de Fibroblastos/inmunología , Inmunoglobulina G/administración & dosificación , Fósforo/sangre , Adulto , Anciano , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales Humanizados , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Factor-23 de Crecimiento de Fibroblastos , Tasa de Filtración Glomerular/efectos de los fármacos , Humanos , Inmunoglobulina G/efectos adversos , Masculino , Persona de Mediana Edad , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/efectos adversos , Resultado del Tratamiento , Adulto JovenRESUMEN
In the last decade, Fibroblast growth factor (FGF) 23 has been shown to be a causative factor of hypophosphatemic rickets/osteomalacia, and considered as potential therapeutic target for this disease. Now the most attention is paid to FGF23 blockades as a new category of therapy that may replace the current supplementation of phosphate and active vitamin D. In this chapter, pharmacological actions of the FGF23-neutralizing antibodies in murine hypophosphatemic rickets/osteomalacia model are reviewed. In addition, other types of FGF23 blockades are also briefly discussed.
Asunto(s)
Anticuerpos Neutralizantes/farmacología , Factores de Crecimiento de Fibroblastos/inmunología , Raquitismo Hipofosfatémico/inmunología , Animales , Anticuerpos Neutralizantes/sangre , Modelos Animales de Enfermedad , Factor-23 de Crecimiento de Fibroblastos , Glucuronidasa/metabolismo , Humanos , Proteínas Klotho , Fosfatos/sangre , Raquitismo Hipofosfatémico/metabolismoRESUMEN
The mechanisms by which inorganic phosphate (P(i)) homeostasis controls bone biology are poorly understood. Here we used Dmp1 null mice, a hypophosphatemic rickets/osteomalacia model, combined with a metatarsal organ culture and an application of neutralizing fibroblast growth factor 23 (FGF-23) antibodies to gain insight into the roles of P(i) in bone biology. We showed (1) that abnormal bone remodeling in Dmp1 null mice is due to reduced osteoclast number, which is secondary to a reduced ratio of RANKL/OPG expressed by osteoclast supporting cells and (2) that osteoblast extracellular matrix mineralization, growth plate maturation, secondary ossification center formation, and osteoblast differentiation are phosphate-dependent. Finally, a working hypothesis is proposed to explain how phosphate and DMP1 control osteocyte maturation.