Pharmacodynamics of evocalcet for secondary hyperparathyroidism in Japanese hemodialysis patients.

BACKGROUND: This study investigated the pharmacokinetics, pharmacodynamics, and safety of multiple doses of evocalcet in Japanese secondary hyperparathyroidism (SHPT) patients receiving hemodialysis. METHODS: In this multicenter, open-label study, conducted between August 2013 and March 2014, 27 patients received multiple doses of 1 and 4 mg evocalcet for 14 days, followed by an extension period of multiple doses of 8 and 12 mg evocalcet for 7 days using an intra-patient dose escalation protocol. Pharmacodynamic parameters consisted of measurement of intact parathyroid hormone (PTH), serum-corrected calcium, serum phosphorus and intact fibroblast growth factor 23 concentrations. Safety was assessed by analysis of adverse events. RESULTS: Plasma evocalcet levels reached steady state 3 days after the first day of administration. Pharmacodynamic analyses showed that evocalcet effectively reduced intact PTH and serum-corrected calcium levels. Adverse events (AEs) occurred in 29.6 and 62.5% of patients receiving multiple doses of 1 or 4 mg, respectively. The AE 'blood calcium decreased' occurred in eight patients (33.0%) after multiple doses of 4 mg. All events were mild, except for one patient with a moderate AE (abnormal liver function) and one patient with a severe adverse drug reaction (blood calcium decreased). CONCLUSION: Multiple doses of evocalcet reduced intact PTH levels with a concomitant decrease in serum calcium levels. Evocalcet was well tolerated in SHPT patients receiving hemodialysis.

A novel calcimimetic agent, evocalcet (MT-4580/KHK7580), suppresses the parathyroid cell function with little effect on the gastrointestinal tract or CYP isozymes in vivo and in vitro.

Cinacalcet hydrochloride (cinacalcet), an oral calcimimetic agent has been widely used for the management of secondary hyperparathyroidism (SHPT) in chronic kidney disease (CKD). In sharp contrast to vitamin D receptor activators, cinacalcet suppresses SHPT without inducing hypercalcemia or hyperphosphatemia. Nevertheless, some patients remain refractory to SHPT with this agent, as the dose cannot be sufficiently increased due to gastrointestinal symptoms. In order to resolve this issue, we have developed a newly synthesized calcimimetic agent, evocalcet (MT-4580/KHK7580). In a rat model of CKD induced by 5/6 nephrectomy, oral administration of evocalcet efficiently suppressed the secretion of parathyroid hormone (PTH). With regard to the gastro-intestinal effects, cinacalcet induced a significant delay in gastric emptying in rats, while evocalcet did no marked effects on it. Evocalcet also demonstrated the less induction of emesis compared to cinacalcet in common marmosets. The pharmacological effects of evocalcet were observed at lower doses because of its higher bioavailability than cinacalcet, which may have contributed to the reduced GI tract symptoms. In addition, evocalcet showed no substantial direct inhibition of any CYP isozymes in in vitro liver microsome assay, suggesting a better profile in drug interactions than cinacalcet that inhibits cytochrome P450 (CYP) 2D6. These findings suggest that evocalcet can be a better alternative to cinacalcet, an oral calcimimetic agent, with a wider safety margin.

Calcificaciones cardiovasculares en la enfermedad renal crónica: Potenciales implicaciones terapéuticas / Cardiovascular calcifications in chronic kidney disease: Potential therapeutic implications

La calcificación cardiovascular (CV) es una condición muy prevalente en todos los estadios de la enfermedad renal crónica (ERC) y se asocia directamente a una mayor morbimortalidad CV y global. En la primera parte de esta revisión hemos mostrado cómo las calcificaciones CV son una característica destacada del complejo CKD-MBD (chronic kidney disease-mineral and bone disorders) así como un predictor superior de la evolución clínica de nuestros pacientes. No obstante, es necesario también demostrar que la calcificación CV es un factor de riesgo modificable y con la posibilidad, como mínimo, de poder disminuir su progresión (o al menos no agravarla) con maniobras iatrogénicas. Aunque estrictamente solo se disponga de evidencias circunstanciales, sabemos que el uso de determinados fármacos puede modificar la progresión de las calcificaciones CV, aunque no se ha demostrado un vínculo directo causal sobre la mejoría de la supervivencia. En este sentido, el uso de quelantes del fósforo no cálcicos ha demostrado reducir la progresión de las calcificaciones CV en comparación con el uso liberal de quelantes cálcicos en varios ensayos clínicos aleatorizados. Por otra parte, aunque solo a nivel experimental, los activadores selectivos del receptor de la vitamina D parecen mostrar un mayor margen terapéutico contra la calcificación CV. Finalmente, los calcimiméticos también parece que podrían atenuar la progresión de la calcificación CV en pacientes en diálisis. Mientras se desarrollan nuevas estrategias terapéuticas (p. ej. vitamina K, SNF472…), proponemos que la valoración de las calcificaciones CV puede ser una herramienta usada por el nefrólogo para la toma individualizada de decisiones terapéuticas (AU)

Cardiovascular (CV) calcification is a highly prevalent condition at all stages of chronic kidney disease (CKD) and is directly associated with increased CV and global morbidity and mortality. In the first part of this review, we have shown that CV calcifications represent an important part of the CKD-MBD complex and are a superior predictor of clinical outcomes in our patients. However, it is also necessary to demonstrate that CV calcification is a modifiable risk factor including the possibility of decreasing (or at least not aggravating) its progression with iatrogenic manoeuvres. Although, strictly speaking, only circumstantial evidence is available, it is known that certain drugs may modify the progression of CV calcifications, even though a direct causal link with improved survival has not been demonstrated. For example, non-calcium-based phosphate binders demonstrated the ability to attenuate the progression of CV calcification compared with the liberal use of calcium-based phosphate binders in several randomised clinical trials. Moreover, although only in experimental conditions, selective activators of the vitamin D receptor seem to have a wider therapeutic margin against CV calcification. Finally, calcimimetics seem to attenuate the progression of CV calcification in dialysis patients. While new therapeutic strategies are being developed (i.e. vitamin K, SNF472, etc.), we suggest that the evaluation of CV calcifications could be a diagnostic tool used by nephrologists to personalise their therapeutic decisions (AU)

Vitamina D, receptor de la vitamina D e importancia de su activación en el paciente con enfermedad renal crónica / Vitamin D, vitamin D receptor and the importance of its activation in patients with chronic kidney disease

El déficit de vitamina D se asocia a distintas patologías, siendo especialmente significativa con la morbimortalidad en pacientes con enfermedad renal crónica (ERC). La pérdida progresiva de la función renal conduce a una reducción de calcitriol y alteración de la homeostasis de calcio, fósforo, FGF-23 y PTH, entre otros, los cuales influyen a su vez sobre la activación del receptor de vitamina D (RVD) y el desarrollo de hiperparatiroidismo secundario (HPS). El RVD media las acciones biológicas tanto de la vitamina D como de sus análogos sintéticos, actuando sobre distintos genes; existe una estrecha asociación entre niveles bajos de calcitriol y la prevalencia del HPS. Así, la activación de los RVD y la restricción de fósforo, entre otros, desempeñan un papel importante en el tratamiento de la «alteración óseo-mineral asociada a la ERC». La Sociedad Española de Nefrología, dada la uniforme e importante asociación con mortalidad y niveles altos de fósforo, aconseja su normalización, así como la de los niveles de calcidiol. Igualmente considera que, aparte de la utilización de activadores selectivos/no selectivos de RVD para la prevención y tratamiento del HPS, se podría asegurar la activación de los RVD en pacientes en diálisis, con vitamina D nativa o incluso bajas dosis de paricalcitol, independientemente de la PTH, dado que algunos estudios de cohortes y un metaanálisis reciente han observado una asociación entre el tratamiento con vitamina D activa y la disminución de la mortalidad en pacientes con ERC. En general, se considera que es razonable utilizar toda esta información para individualizar la toma de decisiones (AU)

Vitamin D deficiency has been linked to many different pathologies, especially with morbimortality in patients with chronic kidney disease. The progressive loss of renal function leads to calcitriol deficiency and homeostatic changes in calcium, phosphorus, FGF-23 and PTH, among others. All these changes can also influence vitamin D receptor (VDR) activation and the development of secondary hyperparathyroidism (SHPT). The biologic actions of both vitamin D and its synthetic analogues are mediated by binding to the same VDR, acting on different genes. There is a narrow relationship between low levels of calcitriol and SHPT. The combined approach of VDR activation and phosphate restriction, among others, plays an important role in the early treatment of the chronic kidney disease-mineral and bone disorder (CKD-MBD). The Spanish Society of Nephrology, in order to reduce the uniform and significant association with CKD-associated mortality, calcidiol and high phosphate levels suggests normalization of phosphate as well as calcidiol levels in both CKD and dialysis patients. Moreover, it considers that, in addition to selective/non selective activation of VDR for the prevention and treatment of SHPT, VDR could be activated in dialysis patients by native vitamin D or even low paricalcitol doses, independently of PTH levels, as some cohort studies and a recent metaanalysis have found an association between treatment with active vitamin D and decreased mortality in patients with CKD. In general it is considered reasonable to use all this information to individualise decision making (AU)