NDT Advance Access originally published online on April 3, 2007
Nephrology Dialysis Transplantation 2007 22(8):2409-2411; doi:10.1093/ndt/gfm174
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Cinacalcet modifies the pH of solutions in vitro: possible implications for gastro-intestinal side effects in vivo
Correspondence and offprint requests to: Email: buemim{at}unime.itSir,
The US-based Federal Drug Agency (FDA) and the European Medicines Agency have approved the use of cinacalcet HCl for the treatment of secondary hyperparathyroidism in patients on dialysis, and in those with parathyroid carcinoma [1]. Cinacalcet is effective and, overall, well tolerated [2]. However, in clinical trials, it has been observed that certain patients on cinacalcet have episodes of hypocalcaemia (1.4% of patients), nausea (
31%) and vomiting (27%), much more than in patients receiving a placebo [3,4]. Gastrointestinal intolerance, with vomiting in particular, has been found to be dose-related, and is the most common reason for drug discontinuation. Moreover, cinacalcet therapy can exacerbate oesophago-gastro-duodenal disease in ESRD patients, gastric fluid pH ranging from acid excess to achlorhydria. The aim of our study was to clarify whether the in vitro dissolution of commercially available cinacalcet causes medium pH variations in solutions with different basal proton concentrations, simulating gastric, duodenal and intestinal pH, respectively.
Cinacalcet 60 mg (AMGEN Europe B.V.) was dissolved following the USP dissolution II paddle method at a rotation speed of 50 r.p.m. in 900 ml of dissolution medium at a stable temperature of 37 ± 0.01°C, maintained by a Haake cryostat.
pH variations were determined by a pH-meter in solutions at different pH, corresponding to the fluids of different gastro-intestinal segments: 1.90, 5.90, 7.51 [5]. The dissolution profile was obtained from the change of the area under the spectral profile observed using spectrophotometric UV measurements in the 230–320 nm range, while the profile of the change of pH was obtained by introducing a pH-meter into the solutions. Variations in pH were graphically reproduced using Prism Statistical software (version 4.00; Graphpad, San Diego, CA, USA). Each value represents the average of acquisition replicates of nine measurements. Dissolution of 60 mg of cinacalet in an acid pH (1.90) medium did not modify the acidity of the solution, whereas in an alkaline solution, the drug induced a rapid increase in acidity (from pH 7.50 to pH 6.70). Finally, the change in proton concentration of the solution at pH 5.90, simulating the duodenal environment, is of particular interest, since it changed towards significant acidity (5.30) Fig.1. Notably, pharmacokinetic findings showed that the absorption of cinacalet is dominantly duodenal. The observed pH changes in vitro would suggest that, in vivo, orally ingested cinacalcet might rapidly transform alkaline gastrointestinal fluids into acid fluids. This could be of clinical relevance in ESRD patients who ingest the drug.
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The acidifying action of cinacalcet derives from its chemical composition, a phenylalkylamine compound with a fluorine radical. We used trehalose in order to modulate the acidifying effect of cinacalcet. This disaccharide is used with increasing frequency to stabilize pharmaceutical products, and it has a significant effect on H-binding structures [6]. The addition of trehalose together with cinacalcet 60 mg to the medium at a pH of 5.9 allowed the pH value to remain stable, while the drug dissolved rapidly and completely.
In addition to this in vitro experiment, we performed 24-h oesophago-gastric pH measurement in a 56-year-old Helicobacter Pylori-negative male haemodialysis patient, who was receiving a proton pump inhibitor. He was given cinacalcet because of secondary hyperparathyroidism. After administration of the drug, a 5 cm electrode was positioned at the oesophago-gastric juncture and another in the stomach, to evaluate pH changes. The patient took three meals (breakfast, lunch and dinner). He was in the upright position for 14 h 30 min and in a supine position for 9 h 30 min. Both after breakfast and lunch the patient took a dose of cinacalcet orally. At 13.00 h, he had an episode of vomiting preceded by epigastric pain, which coincided with persistent acid reflux.
For the 24-h observation period, the patient had 208 episodes of acidic gastro-oesophageal reflux (pH < 4), 186 of which occurred in the upright and 22 in the supine position. There were three episodes of acid reflux that lasted more than 5 min, the most persistent episode lasting 14 min (after cinacalcet ingestion). Oesophageal acid exposure over 24 h was 7.1% (normal value 4.2%), with 11.2% during upright position, and 0.7% during supine position. These pH measurements demonstrate that cinacalcet can increase the degree of exposure to acid, and induce the oesophageal gastric reflux with its accompanying symptoms. During a second 24-h period, the oral administration of trehalose to the patient together with 60 mg cinacalcet on the same diet, led to a reduction in the acidic effects, with a marked reduction of side effects, and only 49 episodes of gastric reflux (pH < 4). No episodes of acid reflux longer than 5 min were recorded, the longest episode lasting 5 min after the administration of trehalose and cinacalcet.
In conclusion, cinacalcet appears to be able to enhance the acidification of gastrointestinal fluids. The effect is more marked in alkaline than in acid solutions. This could be of particular importance in uraemic patients, in whom gastrointestinal pH values are often abnormal. The association between the drug and the disaccharide trehalose that binds the proton loads responsible for acidification, could be a simple and economic solution for patients with gastrointestinal symptoms in response to cinacalcet administration.
Conflict of interest statement. None declared.
1Chair of Nephrology
Department of Internal Medicine
2Department of Inorganic
Analytic and Physical Chemistry
University of Messina, Italy
References
- Nagano N. Pharmacological and clinical properties of calcimimetics: calcium receptor activators that afford an innovative approach to controlling hyperparathyroidism. Pharmacol Ther (2005) 109:339–365.[CrossRef][Web of Science][Medline]
- Lien YH, Sliva A, Whittman D. Effects of cinacalcet on mineral density in patients with secondary hyperparathyroidism. Nephrol Dial Transplant (2005) 20:1232–1238.
[Abstract/Free Full Text] - Shahapuni I, Monge M, Oprisiu R, et al. Drug Insight: renal indications of calcimimetics. Nat Clin Pract Nephrol (2006) 2:316–325.[CrossRef][Web of Science][Medline]
- Strippoli GFA, Palmer S, Tong, et al. Meta-analysis of biochemical and patient-level effects of calcimimetic therapy. Am J Kidney Dis (2006) 47:715–726.[CrossRef][Web of Science][Medline]
- Zhou R, Moench P, Heran C, et al. pH-dependent dissolution in vitro and absorption in vivo of weakly basic drugs:development of a canine model. Pharm Res (2005) 22:188–92.[CrossRef][Web of Science][Medline]
- Richards AB, Krakowka S, Dexter LB, et al. Trehalose: a review of properties, history of use and human tolerance, and results of multiple safety studies. Food Chem Toxicol (2002) 40:871–898.[CrossRef][Web of Science][Medline]
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