The mechanism of upper-gastrointestinal complication after taking cinacalcet hydrochloride

Fukumoto, Kozo; Noguchi, Tomonaga; Toriie, Sayoko; Shimazu, E; Miyake, Susumu

doi:10.4009/jsdt.43.309

Cited by 6 publications

(5 citation statements)

References 13 publications

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“…The main adverse effects associated with cinacalcet are GI events, such as nausea, vomiting, and abdominal discomforts [ 18 ]. It has also been reported that cinacalcet inhibited gastric emptying in hemodialysis patients who developed GI events following its treatment [ 21 ]. Cancer chemotherapeutic agents are known to cause GI symptoms and have been shown to induce delayed gastric emptying in humans, similar to cinacalcet treatment [ 29 , 30 ].…”

Section: Discussionmentioning

confidence: 99%

“…Such GI intolerability limits the dose of cinacalcet and may result in poor compliance or discontinuation [ 19 , 20 ]. Given reports of cinacalcet inhibiting gastric emptying in hemodialysis patients [ 21 ], delayed gastric emptying seems to contribute to GI events caused by cinacalcet treatment. We therefore hypothesized that abnormal GI motility might be a mechanism underlying GI events and a good marker of side effects in the GI tract.…”

Section: Introductionmentioning

confidence: 99%

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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

et al. 2018

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2018

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“…Cinacalcet has been shown to promote an increase of blood flow and vascular ectasia under the condition of arterial brittleness [11]. Therefore, administration of this agent might play an important role in causing a renal hemorrhage subsequent to an increase of renal blood flow or vascular ectasia as in our cases.…”

Section: Discussionmentioning

confidence: 87%

Two cases of acute renal hemorrhage undergoing maintenance hemodialysis after concurrent administration of cinacalcet

Wada

Iino

2011

Clin Exp Nephrol

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We report here a rare complication of renal hemorrhage in 2 male patients under treatment with long-term hemodialysis subsequent to the administration of the calcimemetic agent, cinacalcet hydrochloride. The patients presented with flank pain, peripheral hypereosinophilia and severe anemia. Computed tomography revealed a massive subcapsular hematoma on the kidney. Extensive coagulation analyses were within normal ranges. They had not been administered new medication for their complications during the 6 months prior to admission, except for cinacalcet (Case 1, 14 days; Case 2, 13 days). A drug lymphocyte stimulating test for cinacalcet was positive in both cases. Eight percent of the patients in our hospital who were administered cinacalcet presented with complication of renal hemorrhage. Based on these findings, the final diagnosis was renal hemorrhage due to cinacalcet. They were treated conservatively because both the size of the hematoma and anemia improved. To the best of our knowledge, this is the first report concerning renal hemorrhage.

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“…Cinacalcet has been recently considered to cause digestive symptoms by decreasing GI motility via activating the CaSR in gut, since human antral gastrin cells express the CaSR [ 19 ]. The activation of the CaSR increases serum gastrin level and basal gastric acid secretion in healthy adults [ 20 ], whereas cinacalcet delayed GI motility associated with elevated serum gastrin concentration that was independent of gastric acid secretion in HD patients [ 21 ]. On the other hand, there was no association of antacids and past history of upper GI diseases with the GI adverse events of cinacalcet in the present study ( Table 3 ).…”

Section: Discussionmentioning

confidence: 99%

Gallstones were associated with the gastrointestinal adverse events of cinacalcet in hemodialysis patients with secondary hyperparathyroidism

Otsuka¹,

Ohno

Oshima³

2018

Renal Failure

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This study aimed to investigate the association of gastrointestinal (GI) adverse events of cinacalcet with gallstones in the hemodialysis (HD) patients with secondary hyperparathyroidism (SHPT). A total of 23 HD patients under the treatment with cinacalcet and 101 control patients were enrolled in this cross-sectional study. We investigated the prevalence of gallstones and the association of GI adverse events of cinacalcet with gallstones. The prevalence of gallstones was significantly higher in the HD patients with cinacalcet compared with the controls (47.8% vs. 15.8%). The longer time on HD, hypercalcemia, hyperphosphatemia and elevated parathyroid hormone level were observed in the HD patients with cinacalcet. Besides, GI adverse events of cinacalcet were observed more frequently in the HD patients with gallstones compared with those without gallstones (odds ratio 13.5, 95% CI: 1.80–101). Therefore, screening for gallstones before dosing cinacalcet may reduce the risk of GI adverse events in SHPT patients.

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The mechanism of upper-gastrointestinal complication after taking cinacalcet hydrochloride

Cited by 6 publications

References 13 publications

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

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

Two cases of acute renal hemorrhage undergoing maintenance hemodialysis after concurrent administration of cinacalcet

Gallstones were associated with the gastrointestinal adverse events of cinacalcet in hemodialysis patients with secondary hyperparathyroidism

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