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Atualização sobre os Ensaios Clínicos com Cinacalcete no Hiperparatireoidismo Secundário associado à Doença Renal Crônica

Update on Clinical Trials with Cinacalcet in Secondary Hyperparathyroidism due to Chronic Kidney Disease

William G. Goodman

Resumo:

Dados de vários ensaios clínicos recentes reafirmam a eficácia do tratamento com cinacalcete para controlar o nível plasmático do PTH em pacientes em diálise com hiperparatireoidismo secundário estabelecido. Em contraste com resultados previamente relatados, derivados de estudos onde cinacalcete era usado junto com doses relativamente altas porém constantes de vitamina D ou derivados, os níveis plasmáticos de PTH podem ser efetivamente reduzidos por cinacalcet em pacientes recebendo doses mais baixas de esteróides da vitamina D. Em comparação ao tratamento convencional com esteróides da vitamina D, os níveis séricos de cálcio e fósforo são melhor controlados com esta abordagem terapêutica e uma maior proporção de pacientes pode alcançar concentrações séricas de cálcio e fósforo e valores do produto Ca x P dentro das faixas recomendadas pelas diretrizes atuais. Entretanto, ensaios clínicos prospectivos adicionais são necessários para determinar se o uso de cinacalcete em pacientes em diálise com hiperparatireoidismo secundário afeta outras variáveis importantes e clinicamente relevantes como, por exemplo, a morfologia do osso, a massa e/ou a densidade óssea, a taxa de fraturas, e a necessidade de paratireoidectomia.

Descritores: Calcimiméticos, Hiperparatireoidismo secundário, Ensaios clínicos.

Abstract:

Data from several recent clinical trials reaffirm the efficacy of treatment with cinacalcet for controlling plasma PTH levels among dialysis patients with established secondary HPT. In contrast to results reported previously from studies where cinacalcet was used together with relatively large but constant doses of vitamin D sterols, plasma PTH levels can be reduced effectively during treatment with cinacalcet among patients receiving lower doses of vitamin D sterols. Compared to conventional treatment with vitamin D sterols, serum calcium and phosphorus levels are better controlled with this therapeutic approach, and a larger proportion of patients are able to achieve serum calcium and phosphorus concentrations and values for Ca x P with the ranges recommended in current practice guidelines. Additional prospective clinical trials are needed, however, to determine whether the use of cinacalcet among dialysis patients with secondary HPT affects other important and clinically relevant outcomes such bone morphology, bone mass and/or bone density, skeletal fracture rates, and the need for parathyroidectomy.

Descriptors: Calcimimetics. Secondary hyperparathyroidism. Clinical trials.

BACKGROUND

Secondary hyperparathyroidism (HPT) is common among patients with chronic kidney disease (CKD)1-3. The disorder develops early during the course of CKD due primarily to disturbances in vitamin D metabolism that alter calcium homeostasis systemically and lead to adaptive increases in the synthesis and secretion of parathyroid hormone (PTH) by the parathyroid glands4. Impairments in the synthesis of calcitriol, or 1,25-dihydroxyvitamin D, by the diseased kidney play an essential role in the pathogenesis of secondary HPT due to their adverse effect on intestinal calcium absorption4,5.

Calcitriol regulates the expression of several proteins that mediate intestinal calcium transport6,7. Among them are the calbindins and two constitutively activated calcium channels that belong to the vanilloid family of transient receptor potential (TRP) proteins, TRPV-5 and TRPV-68-10. The levels of expression of these key molecular determinants of epithelial calcium transport are reduced in intestinal cells when serum calcitriol levels decline due to CKD8,11. Accordingly, defects in intestinal calcium absorption are a prominent feature among patients with mild to moderate CKD, and they are largely responsible for the hypocalciuria that characterizes the disorder 12-15. As in other clinical conditions such as nutritional vitamin D deficiency and dietary calcium restriction where intestinal calcium absorption is suboptimal, secondary HPT represents an appropriate adaptive response that attenuates calcium excretion in the urine and mobilizes calcium from bone, changes that serve to maintain serum calcium concentrations and to preserve calcium homeostasis systemically4.

Among untreated patients with CKD, plasma PTH levels rise progressively as renal function declines3,16,17. Values exceed the upper limit of normal in most patients with a glomerular filtration rate below 30-40 ml/minute3,16. Histological changes of hyperparathyroidism are evident when plasma PTH levels are elevated in the majority of patients with stage 3 or stage 4 CKD18. As such, the prevention and management of metabolic bone disease represent key therapeutic objectives. Bone loss due to secondary HPT probably contributes to the high skeletal fracture rates among patients with mild to moderate CKD, and it may also explain the reductions in bone mass seen commonly among dialysis patients19-21.

Once established, secondary HPT is a progressive disorder that increases in severity as a function of the duration of CKD and/or the number years of treatment with dialysis22-24. The need for surgical parathyroidectomy also increases with the duration of renal replacement therapy22,25. Parathyroid gland hyperplasia probably accounts for these findings, and enlargement of the parathyroid glands is a key determinant not only of disease severity but also of disease progression. The monoclonal proliferation of subpopulations of parathyroid cells can be documented in more than half of parathyroid glands removed surgically from dialysis patients with secondary HPT26. Such changes occur both in the diffuse and in nodular forms of parathyroid gland hyperplasia26. There is little evidence that the hyperplastic process can be reversed or that the size of enlarged parathyroid glands diminishes either with medical treatment or after successful kidney transplantation.

Traditional approaches to the clinical management of secondary HPT have relied predominantly upon dietary phosphorus restriction and the use of phosphate-binding agents to manage phosphorus retention and hyperphosphatemia27. Indeed, current practice guidelines recommend dietary phosphorus restriction and phosphate-binding agents as initial therapeutic interventions to manage secondary HPT among patients with stage 3 or stage 4 CKD28. Additional treatment with vitamin D sterols is often required, however, to control plasma PTH levels among patients with CKD29. Unfortunately, such measures do not directly address key disturbances in vitamin D and calcium metabolism described previously that account for the development and progression of secondary HPT.

Furthermore, vitamin D sterols have proven to be only partially effective for the clinical management of secondary HPT among patients undergoing dialysis. A minority of patients achieve plasma PTH levels that fall within the therapeutic target range recommended in current practice guidelines, whereas serum calcium and phosphorus levels remain persistently elevated in many patients30. These biochemical abnormalities have been associated with adverse clinical outcomes in observational studies31-33. Although treatment with vitamin D sterols has been shown to lower plasma PTH levels among dialysis patients with secondary HPT in shortterm studies lasting a few months, the efficacy of treatment for more than two years of follow-up has not been assessed. There is a paucity of information from prospective clinical trials about other important outcomes such as skeletal fractures rates, effects on bone mass, and changes in bone histology following treatment with any vitamin D sterol.

Perhaps more importantly, annual parathyroidectomy rates have not changed appreciably despite the widespread use of vitamin D sterols among patients undergoing dialysis regularly25. Such findings suggest that traditional approaches to the management of secondary HPT do not effectively retard disease progression or diminish the need for surgical intervention to control the disorder. There is thus considerable interest in new strategies to manage secondary HPT among patients with CKD.


CALCIMIMETIC AGENTS

Calcimimetic agents are small organic molecules that act as allosteric activators of the calciumsensing receptor (CaR) in the parathyroid glands and selected other tissues34,35. The CaR represents the molecular mechanism by which parathyroid cells detect changes in blood ionized calcium concentration and modulate PTH secretion accordingly36. By lowering the threshold for activation of the CaR by extracellular calcium ions, calcimimetic agents inhibit PTH secretion and lower plasma PTH levels. Values decrease promptly and consistently within a few hours after the administration of calcimimetic agents both in humans and in experimental animals, and sustained reductions in plasma PTH levels are achieved with ongoing drug administration37.

Cinacalcet hydrochloride, hereafter called cinacalcet, is the first calcimimetic agent to become available for use clinically to manage secondary HPT among patients undergoing dialysis35. It is also used to treat hypercalcemia among patients with parathyroid carcinoma38. Because the mechanism of action differs fundamentally from that of the vitamin D sterols, cinacalcet provides another definitive pharmacological intervention for the management of secondary HPT among persons with CKD who require treatment with dialysis35,39.

Cinacalcet is a relatively hydrophobic compound, and it is not readily soluble in aqueous solutions. A formulation for intravenous administration during hemodialysis procedures is thus not available. Virtually all clinical studies reported to date have used single daily oral doses of cinacalcet to control plasma PTH levels among patients with established secondary HPT.

Despite these considerations, cinacalcet is absorbed rapidly from the gastrointestinal tract after oral administration40. Peak levels in plasma are achieved within 60-90 minutes, and they are largely dose-dependent40-42. Plasma PTH levels decrease abruptly after single oral doses of cinacalcet and reach a nadir two to four hours later, biochemical changes consistent with prompt activation of the CaR in parathyroid tissue. Plasma PTH levels rise subsequently, however, toward pre-dose levels during the remainder of the day as the serum concentration of cinacalcet declines and as the level of activation of the CaR diminishes37,40.

The percentage reduction in plasma PTH levels after single oral doses of cinacalcet does not differ substantially among patients with mild, moderate, or severe secondary HPT as judged by baseline, or pre-treatment, plasma PTH values. The therapeutic response to cinacalcet is thus largely unaffected by disease severity. Moreover, the efficacy of cinacalcet for lowering plasma PTH levels is maintained when treatment is continued for as long as three years43. As such, the sustained use of cinacalcet thus does not attenuate its effect to inhibit PTH secretion and to lower plasma PTH levels among patients with secondary HPT due to CKD.


RESULTS FROM CLINICAL TRIALS AMONG PATIENTS WITH SECONDARY HPT

The therapeutic efficacy of cinacalcet for lowering plasma PTH levels was documented initially in large prospective, randomized, double-blinded clinical trials among hemodialysis patients with inadequately controlled secondary HPT despite previous management with vitamin D sterols and phosphate-binding agents44,45. Two of the studies enrolled more than 700 patients and lasted 26 weeks44. Treatment with cinacalcet was started using single daily oral doses of 30mg, and doses were subsequently titrated upwards to a maximum of 180mg per day. Forty-three percent of subjects achieved a mean plasma PTH level equal to, or less than, 250pg/ml, as measured by a conventional first-generation immunometric PTH assay, during a 14-week efficacy-assessment period44. Similar responses were observed when PTH measurements were done using a second-generation immunometric PTH assay that detects PTH1-84 exclusively44,46.

In 60% of patients assigned to treatment with cinacalcet, plasma PTH levels decreased by 30% or more44. Such changes have been used traditionally to assess the therapeutic efficacy of vitamin D sterols in clinical trials among patients with secondary HPT due to CKD. Interestingly, the proportion of patients who responded in this manner did not differ according to disease severity as judged pre-treatment plasma PTH values. Several reports indicate that the level of expression of the CaR is reduced in hyperplastic parathyroid tissue obtained either from patients or from experimental animals with kidney disease and secondary HPT47,48. Moreover, CaR expression is lower in the nodular than in the diffuse form of parathyroid gland hyperplasia49. Although such changes might be expected to attenuate the effect of cinacalcet to inhibit PTH secretion and to lower plasma PTH levels, variations in disease severity have not been shown to influence the biochemical response to treatment in controlled clinical trials.

Serum calcium concentrations decline modestly during treatment with cinacalcet, and serum phosphorus levels also decrease44,45. Such changes are due not only to reductions in the mobilization of calcium and phosphorus from bone as plasma PTH levels fall but also to the uptake of calcium and phosphorus into a miscible pool within bone50,51. As a result, calculated values for the calciumphosphorus ion product in serum, or Ca x P, decrease during treatment44. The use of cinacalcet thus lowers plasma PTH levels and favorably affects several indices of calcium and phosphorus metabolism among patients with secondary HPT receiving constant, but relatively high doses, of vitamin D sterols44,45.

Some of the patients who participated in the early clinical trials with cinacalcet were managed without concurrent vitamin D therapy44. Plasma PTH levels declined substantially in these subjects44. Such findings indicate that cinacalcet can be used alone as a primary therapeutic intervention for secondary HPT among patients undergoing dialysis. Indeed, unlike the vitamin D sterols, neither hypercalcemia nor hyperphosphatemia preclude the use of cinacalcet to lower plasma PTH levels among patients who require medical treatment for secondary HPT. Additional studies are required, however, to determine the efficacy of this therapeutic approach.

In post hoc analyses, the use of cinacalcet compared to conventional treatment increased the proportion of patients who achieved plasma PTH levels, serum calcium and phosphorus concentrations, and values for Ca x P in serum that fell within the ranges recommended in current practice guidelines52. Among cinacalcet-treated patients, serum calcium concentrations were maintained between 8.4 and 9.5mg/dL in 49% of subjects, whereas serum phosphorus levels were maintained between 3.5 and 5.5mg/dL in 46%. Sixty-five percent had Ca x P values equal to, or less than, 55 mg2/dL2.

Because vitamin D therapy often raises serum calcium and phosphorus levels among patients with secondary HPT, additional studies have been done to determine whether the use of cinacalcet together with lower doses of vitamin D sterols can attenuate these biochemical abnormalities. This alternative therapeutic approach was assessed initially in a study of patients with adequately controlled plasma PTH levels but persistently elevated values of Ca x P during treatment with vitamin D sterols53. Treatment with cinacalcet was shown to maintain plasma PTH levels below 300 pg/mL while doses of vitamin D sterols were reduced to obviate elevations in serum calcium and phosphorus concentrations53. As a result, a larger proportion of patients given cinacalcet rather than vitamin D sterols alone achieved serum calcium and phosphorus concentrations that fell within the ranges recommended by current practice guidelines28,53.

In a subsequent clinical study called TARGET, patients undergoing hemodialysis with inadequately controlled secondary HPT, as judged by plasma PTH levels persistently above 300pg/mL, were treated with cinacalcet during an eight-week dose-titration phase followed by an eight-week efficacy assessment phase54. Initial doses of 30 mg of cinacalcet were titrated as needed to a maximum daily dose of 180mg to achieve a plasma PTH level less than 160pg/mL as determined by a second generation immunometric PTH assay, a value equivalent to 300pg/mL when measured using a first generation immunometric PTH assay46. During the second week of study, the doses of vitamin D sterols among patients already receiving these compounds were reduced to an amount equivalent to 2mcg of paricalcitol with each thrice weekly hemodialysis session, a total weekly dose of 6mcg. Therapeutic efficacy was assessed by the proportion of patients who achieved a mean plasma PTH level less than, or equal to, 160pg/mL, a mean Ca x P less than, or equal to, 55mg2/dL2, or a mean value for both biochemical parameters that was below these two pre-determined thresholds during the assessment phase of the study.

Sixty-two percent of subjects in the TARGET trial achieved the therapeutic objective for PTH, 83% reached the therapeutic target for Ca x P, and 54% of study participants reached both biochemical endpoints during the efficacy-assessment phase. During the 16-week study, plasma PTH levels decreased by 35% from baseline values, serum calcium concentrations decreased by 11%, serum phosphorus levels decreased by 7%, and Ca x P values fell by 17%. The average daily dose of cinacalcet was 69 mg. Compared to earlier reports where cinacalcet was used among patients receiving larger doses of vitamin D sterols, the results from the TARGET study suggest that treatment with cinacalcet together with smaller doses of vitamin D sterols is similarly effective for lowering plasma PTH levels but provides better control of serum calcium and phosphorus concentrations in hemodialysis patients with secondary HPT.

In a separate multi-center clinical trial called OPTIMA that was done in Europe, the therapeutic efficacy of cinacalcet was compared to conventional treatment with flexible doses of vitamin D sterols and phosphate- binding agents among patients with inadequately controlled secondary HPT55. Patients qualified for study if plasma PTH levels were greater than 300 pg/mL, but less than 800 pg/mL, as measured by a first-generation immunometric PTH assay. Treatments were adjusted during a 16-week dose optimization phase, and efficacy was evaluated using mean values for plasma PTH and serum calcium and phosphorus concentrations during a seven-week efficacy assessment phase. The primary outcome of the study was the proportion of patients in each treatment group who achieved a mean plasma PTH level below 300pg/mL during the efficacy-assessment phase55.

For patients assigned to treatment with cinacalcet, the initial dose was 30mg per day. Doses were raised incrementally to a maximum daily dose of 180mg to control plasma PTH levels if serum calcium concentrations remained above 8.0mg/dL. Among cinacalcettreated patients who were also receiving vitamin D sterols at the start of the trial, the doses of vitamin D were adjusted as needed to maintain serum calcium levels equal to, or less than, 9.5mg/dL and serum phosphorus levels equal to, or less than, 5.5mg/dL as recommended by current practice guidelines. For patients assigned to treatment with flexible doses of vitamin D sterols, doses were adjusted to achieve control of plasma PTH levels while maintaining serum calcium levels equal to, or less than, 9.5mg/dL and serum phosphorus levels equal to, or less than, 5.5mg/dL.

Overall, 71% of patients treated with cinacalcet but only 22% of those managed with flexible doses of vitamin D sterols achieved a mean plasma PTH level below 300pg/mL, p<0.001, during the efficacy-assessment phase of the study55. Seventy-six percent of patients given cinacalcet maintained a serum calcium level equal to, or less than, 9.5mg/dL and 63% had a serum phosphorus level equal to, or less than, 5.5mg/dL during the final seven weeks of study. In contrast, serum calcium and phosphorus levels below these thresholds were achieved in only 33% and 50%, respectively, of patients managed with flexible doses of vitamin D55.

Not unexpectedly, patients with pre-treatment plasma PTH levels between 300 and 500pg/mL were more likely to achieve a plasma PTH value within the therapeutic target range compared to those with baseline values between 500 and 800pg/mL55. The average daily dose of cinacalcet for patients in the OPTIMA study was 56 mg, but smaller doses were required among those with pre-treatment PTH levels between 300 and 500pg/mL. For this subset of patients, the median daily dose of cinacalcet was 30 mg, whereas the median daily dose among patients with baseline plasma PTH levels between 500 and 800pg/mL was 60mg55.


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1. Clinical Research Director, Global Development, Amgen Inc, Thousand Oaks, CA


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