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Efficacy and tolerance of three different calcium acetate formulations in hemodialysis patients
The Netherlands Journal of Medicine 1999;55:222–228
Original article
Efficacy and tolerance of three different calcium acetate formulations in hemodialysis patients J.P.W. van den Bergh a , *, M.A.C.J. Gelens a , H.A.J. Klaassen a , B.G. Kaufmann c , b ¨ W.M. Bottger , V.M.C. Verstappen a a
Department of Internal Medicine, St. Maartens Hospital, Venlo, The Netherlands b Clinical Pharmacy, St. Maartens Hospital, Venlo, The Netherlands c Clinical Pharmacy, Laurentius Hospital, Roermond, The Netherlands
Received 1 April 1999; received in revised form 28 June 1999; accepted 24 August 1999
Abstract Background: Calcium acetate (CaAc) is an effective phosphate binder in patients with chronic renal failure. However, an important side effect is gastro-intestinal discomfort. Phos-ex (Cablon, The Netherlands) is the only commercially available non-coated CaAc formulation in our country. We developed two new CaAc formulations: neutral-coated CaAc (NCCaAc) and enteric-coated CaAc (ECCaAc). Methods: In a randomised double-blinded cross-over trial we compared efficacy and tolerance of the three formulations in 19 stable hemodialysis patients, with a mean age of 63 years (range, 36–85), who had been on hemodialysis for 19 months (range, 6–47). Patients were randomised to receive NCCaAc or ECCaAc, with meals, for a period of 10 weeks and after cross-over for another 10 weeks. During a third non-blinded period, patients received Phos-ex for 10 weeks. Results: Serum phosphate was significantly higher with ECCaAc compared to NCCaAc (1.8960.07 vs. 1.7060.08 mmol / l, P , 0.05). Serum Ca was significantly lower with ECCaAc compared to NCCaAc or Phos-ex (2.3860.04, 2.4760.04 and 2.4860.04 mmol / l, P , 0.05). There were less hypercalcemic and more hyperphosphatemic events in the ECCaAc period, compared to the other periods. The daily CaAc dose and dietary intake of calcium, phosphate, protein and calories were comparable in all three periods. With Phos-ex , patients noticed more gastro-intestinal complaints than with to NCCaAc and ECCaAc. Two patients stopped taking Phos-ex because of side effects. Conclusions: In hemodialysis patients, phosphate control and tolerance were both influenced by the formulation of CaAc. Although phosphate control was adequate with all three formulations of CaAc, ECCaAc was less effective compared to NCCaAc or Phos-ex . NCCaAc and ECCaAc were better tolerated than Phos-ex . Regarding efficacy and tolerance, NCCaAc was the best calcium acetate formulation. 1999 Elsevier Science B.V. All rights reserved. Keywords: Calcium acetate; Hemodialysis; Phosphate binder; Side effects; Tolerance
*Corresponding author. Department of Endocrinology, University Hospital Nijmegen, Postbus 9101, 6500 HB Nijmegen, The Netherlands. Tel.: 1 31-24-361-4599; fax: 1 31-24-3641484. E-mail address: [email protected] (J.P.W. van den Bergh)
Introduction In uremic patients correction of hyperphosphatemia and hypocalcemia is important in the prevention of secondary hyperparathyroidism. Cal-
0300-2977 / 99 / $ – see front matter 1999 Elsevier Science B.V. All rights reserved. PII: S0300-2977( 99 )00084-4
J.P.W. van den Bergh et al. / Calcium acetate formulations in hemodialysis patients
cium-containing phosphate binders are used preferably to control serum phosphate. Recent studies have shown that calcium acetate (CaAc) is an effective phosphate binder [1–12]. However, one of the most important side effects is gastro-intestinal discomfort [2,3,5,6,9,10]. In our experience this often results in discontinuation of the drug. It is not clear whether calcium acetate per se is less tolerable or whether it depends on the formulation. Tolerability may be better with improved formulation [9]. In The Netherlands, Phos-ex (Cablon, The Netherlands) is the only commercially available CaAc formulation, the tablets are not coated. In an attempt to reduce gastrointestinal discomfort, we developed two new formulations of CaAc; a neutral-coated tablet (NCCaAc) that easily disperses pH independently, and an enteric-coated tablet (ECCaAc) that disperses at pH . 6.5. When using different CaAc formulations, it is possible that efficacy of CaAc as phosphate binding agent is influenced. In a pilot study we previously evaluated the safety of the new formulations, ECCaAc and NCCaAc. We showed that it was possible to control hyperphosphatemia with both drugs in patients with pre-terminal renal failure [13]. For further evaluation of efficacy and tolerance of NCCaAc, ECCaAc and Phos-ex , we conducted a randomised crossover study in 19 stable hemodialysis patients.
Material and methods Patients Nineteen (14 men and five women) patients with a mean age of 63.6612.6 (range, 36–85) years, were
Table 1 Patient characteristics at the start of the study
Age (years) Weight (kg) Length (cm) Kt /V a nPCRb
Mean6SD
Range
63.6612.6 78.4616.7 17667 1.0660.18 0.9360.27
36–85 64.5–92.3 163–190 0.82–1.20 0.74–1.22
223
studied. Only patients with a creatinine clearance , 1 ml / min were included and all patients had to be stable on hemodialysis for at least 6 months. The mean hemodialysis treatment time was 19 months (range, 6–47 months). Patient characteristics at the start of the study are presented in Table 1. The patients were dialysed three times a week, for 4 h using a standard dialysate with a calcium concentration of 1.3 mmol / l. All patients were previously treated with calcium carbonate, three patients were also treated with aluminium hydroxide. Patients did not use H 2 -receptor antagonists or proton pump inhibitors. Three patients used vitamin D; the dose was not changed during the study. All patients gave their informed consent. Calcium acetate formulations NCCaAc and ECCaAc were developed by our hospital pharmacy. The tablets have a smooth surface and are prepared without flavour. They are spherical and identical in appearance, with a dimension of 7.0 3 11.2 mm. NCCaAc is coated with Eudragit-E and ECCaAc with Eudragit-L. Each tablet contains 500 mg CaAc (115 mg elementary calcium). Phos-ex is a commercially available noncoated formulation of CaAc, with a chalky surface and a dimension of 8.0 3 8.3 3 18 mm. The formulation has a lemon meringue flavour. Each tablet contains 1100 mg CaAc (250 mg elementary Ca). The tablets were analysed according to the European Pharmacopoeia, 2nd ed. (Table 2). For entericcoated tablets it is required that the disintegration time in 0.1 mol HCl (pH 1.1) is longer than 120 min, and in 0.2 mol phosphate buffer (pH 6.8) shorter than 30 min. For non- and neutral-coated tablets the disintegration time must be respectively shorter than 15 and 60 min at pH 1.1. The NC and EC formulations comply with these conditions. There is no specific requirement for disintegration time of neutral and non-coated tablets at pH 6.8, but for comparison with the enteric-coated tablets we report these data in Table 2. Study design
a
Dialysis adequacy is expressed as Kt /V. b nPCR is protein catabolic rate, corrected for body weight.
A randomised double-blinded cross-over design
The Netherlands Journal of Medicine 1999;55:222 – 228
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J.P.W. van den Bergh et al. / Calcium acetate formulations in hemodialysis patients
Table 2 Analysis of the three different formulations of CaAc according to the European Pharmacopoeia, 2nd ed.a
Mean weight (mg) Hardness (N) Thickness (mm) Diameter (mm) Wastage (%) Disintegration time (min) in 0.1 M HCl (pH 1.1) Disintegration time (min) in 0.2 M phosphate buffer (pH 6.5) Ca content (%) a
NCCaAc
ECCaAc
Phos-ex
668 128 7.0 11.2 0.06 41
668 125 7.0 11.2 0.04 . 120
1106 159 8.3 8.0 / 18.0 0.4 19
38
, 30
21
94
94
98
NCCaAc, neutral-coated calcium acetate; ECCaAc, enteric-coated calcium acetate; Phos-ex , non-coated calcium acetate.
was employed consisting of two treatment periods lasting 10 weeks. At the start of the study, the patients were randomised to receive NCCaAc or ECCaAc. A run in period of 2 weeks was used to find a stable dose of CaAc with a preferred phosphate level between 1.3 and 2.0 mmol / l. Both drugs were given with meals, as sole phosphate binder for a period of 10 weeks. After cross-over both drugs were given for another period of 10 weeks. After this second period the patients received Phos-ex for 10 weeks during a third non-blinded period. Because of the difference in size and flavour with NC or ECCaAc, the Phos-ex tablets could not be given in a blinded period. The data of the first 2 weeks of each period were not included in the analysis; in the first period to avoid the run-in effects, in the second and third periods to avoid carry-over effects. Blood samples were collected weekly just before the first dialysis of the week. Serum calcium levels were corrected for albumin concentration according to the formula: corrected serum calcium (in mmol / l) 5 (serum albumin (in g / l) 2 42) 3 serum calcium (in mmol / l). Dialysis adequacy is expressed as Kt /V, where K represents whole body urea clearance, t is time on dialysis and V is urea volume. At the end of each period our dietician calculated the dietary intake of phosphate, calcium, calories and protein per kg bodyweight. We also checked for possible alterations in the dietary compound. The tablets were dispensed at the beginning of each new period (10 weeks) and compliance was checked at the end of each period by the amount of tablets returned. The tablets were divided over the meals according to the amount of phosphate in each
meal, which was calculated by our dietician at the start of the study. The daily dose of CaAc was calculated at the end of the run in phase by multiplying the number of tablets with the dose elementary calcium in each tablet. In order to compare efficacy of CaAc in the three periods, the daily dose of CaAc was not changed during the study unless there were repeated (more than two times) serum calcium levels above 2.7 mmol / l or phosphate levels above 2.5 mmol / l. During the Phos-ex period, we distributed half of the number of tablets that were used during the EC or NCCaAc period. However, because the amount of elementary calcium in the Phos-ex tablets is more than twice the amount in the EC or NCCaAc tablets (250 vs. 115 mg per tablet, respectively), the total dose of elementary calcium used during the Phos-ex period would be higher. We tried to adjust the Phos-ex dose as much as possible by prescribing one or two Phos-ex tablets with each meal, when three or five EC or NCCaAc tablets, respectively, were used during the previous period. Two investigators at weekly interviews (JvdB, MG) evaluated tolerance. Independently from the interviews, a questionnaire with 10 items (pyrosis, ructus, diarrhoea, flatulence, vomiting, feeling of a full stomach, loss of appetite, nausea, borborygmus and loss or change of taste) was scored at the end of each period of 10 weeks. Patients were asked to score complaints they noticed in the last 8 weeks and that were not present at the start of the study. The results of the questionnaire were compared with the results obtained from the weekly interviews. Complaints reported at both evaluations were used for analysis.
The Netherlands Journal of Medicine 1999;55:222 – 228
J.P.W. van den Bergh et al. / Calcium acetate formulations in hemodialysis patients
Statistics All data are expressed as means6SEM. For an overall analysis of the treatment effect, a repeated measure analysis of variance was performed for each variable. Subsequently data analysis between two treatments was assessed using the paired Student’s t-test. Analysis of differences in the incidence of hypercalcemia or hyperphosphatemia between the treatment periods was assessed with Fischer’s exact test and analysis of differences in tolerance with the McNemar test. A P value , 0.05 was used as level of significance. Results Of the 19 patients originally enrolled, 16 completed all phases of the trial. Three patients were transplanted during the study. Two patients withdrew due to symptoms they attributed to the phosphatebinding agent Phos-ex in the last week of the trial. Because their blood samples were drawn before they stopped taking the phosphate-binding agent, the laboratory data were included in the analysis. Efficacy The data of the three treatment periods are sum-
225
marised in Table 3. Serum phosphate level was significantly higher in the ECCaAc period (1.8960.07) compared to the NCCaAc period (1.7060.08). There was no significant difference between phosphate levels in the NCCaAc and ECCaAc period compared to the Phos-ex period (1.7760.08). In the ECCaAc period serum Ca level was significantly lower compared to the NCCaAc or Phos-ex period (2.3860.04, 2.4760.04 and 2.4860.04). The incidence of hypercalcemia (corrected serum calcium . 2.6 mmol / l) was lower in the ECCaAc period compared to the other two periods, and the incidence of hyperphosphatemia (serum phosphate . 2.0 mmol / l) was lower in the NCCaAc period compared to the other two periods, but the differences were not statistically significant. The daily CaAc dose was the same in all three periods. There were no significant differences in the plasma levels of PTH, alkaline phosphatase, bicarbonate and creatinine. Dietary amount of calcium, phosphate, protein and calories was comparable in all three periods. Normalised protein catabolic rate (nPCR) and dialysis adequacy as measured by Kt /V were not significantly different in the three treatment periods (Kt /V was 1.0460.18, 1.1360.19 and 1.0560.14, and nPCR was 0.9660.20, 0.9660.15 and 0.9960.13, in the NCCaAc, ECCaAc and Phosex periods, respectively).
Table 3 Mean (and range) of daily dose of CaAc, serum concentrations of biochemical parameters, calculated dietary intake of phosphate, calcium, protein and calories, percent of events of hypercalcemia and hyperphosphatemia during the three CaAc treatment periods a
Dose (g calcium b / day) Calcium (mmol / l) Phosphate (mmol / l) PTH (pmol / l) Alk. phosphatase (U / l) Bicarbonate (mmol / l) Dietary phosphate (g / day) Dietary calcium (g / day) Dietary protein (g / kg per day) Dietary Energy (kcal / day) Ca . 2.6 mmol / l (% events) PO 4 . 2.0 mmol / l (% events)
NCCaAc
ECCaAc
Phos-ex
1.48 (0.69–2.76) 2.47* (2.22–2.70) 1.70* (0.86–2.15) 15.5 (1.0–26.0) 64.1 (38.0–89.0) 22.2 (18.0–29.0) 0.98 (0.69–1.97) 0.54 (0.20–0.98) 0.94 (0.53–1.16) 1632 (1162–2626) 17.7 19.5
1.48 (0.69–2.53) 2.38 (2.19–2.69) 1.89 (1.42–2.34) 12.3 (1.2–23.0) 64.8 (37.5–100.5) 20.8 (15.5–30.3) 1.04 (0.63–1.92) 0.57 (0.25–0.87) 0.95 (0.54–1.15) 1653 (1124–2618) 12.3 28.6
1.50 (0.75–2.75) 2.48* (2.22–2.78) 1.77 (1.19–2.25) 14.1 (2.6–27.0) 68.9 (38.5–97.0) 20.6 (16.6–28.4) 0.99 (0.62–1.87) 0.56 (0.24–0.78) 0.90 (0.51–1.22) 1601 (1018–2445) 17.2 22.0
NCCaAc, neutral-coated calcium acetate; ECCaAc, enteric-coated calcium acetate; Phos-ex , non-coated calcium acetate. Dose of elementary calcium. *P , 0.05 vs. ECCaAc. a
b
The Netherlands Journal of Medicine 1999;55:222 – 228
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J.P.W. van den Bergh et al. / Calcium acetate formulations in hemodialysis patients
Tolerance During the ECCaAc period, five patients noticed a total of nine new gastrointestinal complaints compared to baseline, in the NCCaAc period three patients noticed eight new complaints. In the Phosex period six patients noticed 19 new complaints, which is significantly more compared to the NCCaAc period tablets (the data are summarised in Table 4). Two patients stopped taking Phos-ex because of symptoms (vomiting, nausea and distaste) they attributed to the drug. According to the interviews five patients preferred the EC or NC tablets above Phos-ex , despite the larger number of tablets which had to be taken (mean number of daily tablets: NCCaAc, 12.9; ECCaAc, 12.9; and Phos-ex , 6.0). These patients appreciated the smaller size and the smooth surface, which made the tablets easier to swallow. two patients preferred Phos-ex because of the fewer number of tablets they had to take and because they needed less fluid to swallow the tablets. nine patients had no preference. The flavour was of no influence on the patients’ acceptance of Phos-ex .
Discussion In the present study, the mean serum phosphate level was significantly higher with ECCaAc than with NCCaAc and the mean serum calcium level was Table 4 Number of gastro-intestinal complaints during the three CaAc treatment periods a Phos-ex
ECCaAc
NCCaAc
Vomiting Diarrhoea Loss of appetite Flatulence Nausea Pyrosis Borborygmus Ructus Distaste Feeling of full stomach
1 1 0 1 1 0 2 2 1 0
0 1 0 2 2 1 2 0 0 0
2 1 1 2 1 2 3 4 1 2
Total
9
8*
19
a
NCCaAc, neutral-coated calcium acetate; ECCaAc, entericcoated calcium acetate; Phos-ex , non-coated calcium acetate. *P , 0.05 vs. Phos-ex .
significantly lower with ECCaAc than with NCCaAc and Phos-ex . Furthermore, there were more hyperphosphatemic events and less hypercalcemic events with ECCaAc than with NCCaAc and Phosex , although there was no statistical significant difference. The daily dose of CaAc prescribed was the same in each period and comparable to the dose used in previous studies [4–6,9,10]. The dietary intake of calcium, phosphate, protein and calories and the dialysis adequacy were also equal in the three periods. These results show that phosphate control was influenced by the formulation of CaAc. It was possible to control hyperphosphatemia with calcium acetate as sole phosphate binder with all three formulations of CaAc, although ECCaAc was less effective as NCCaAc or Phos-ex . Recently, it was reported that different phosphate binder formulations had different phosphate-binding capacities in healthy subjects [14]. It was also reported, that the in vitro disintegration of CaAc was significantly affected by the pH of the medium used for disintegration [15]. These findings are in agreement with the results of our study in hemodialysis patients. We found different phosphate-binding capacities for the three CaAc formulations. These differences are related to the coating of the tablets, which determines the disintegration characteristics. The enteric-coated formulation disintegrates at pH . 6.5, and therefore binds phosphate after passage through the stomach, in the small intestine. Mixing of calcium acetate and food phosphate in the stomach is an important determinant of phosphate binding, so reduced phosphate binding with ECCaAc can be explained by incomplete mixing in the stomach [16]. Absorption of phosphate in the small intestine before binding occurs, and partial conversion of soluble calcium into poorly soluble salts in the small intestine may also attribute to reduced phosphate-binding capacity of ECCaAc [1]. When incomplete mixing of food phosphate with calcium acetate resulted in higher phosphate levels, we would have expected higher serum calcium levels and a higher incidence of hypercalcemia with ECCaAc, due to absorption of calcium from the disintegrated binder. However, we did not find this in our study. This may be explained by the conversion of calcium to poorly soluble salts, as mentioned previously, so that less disintegrated binder calcium was available
The Netherlands Journal of Medicine 1999;55:222 – 228
J.P.W. van den Bergh et al. / Calcium acetate formulations in hemodialysis patients
for absorption. It is also possible that less CaAc was available for binding due to impaired disintegration of ECCaAc, resulting in hyperphosphatemia and lower calcium levels. Based on our in vitro results with ECCaAc, showing a complete disintegration of CaAc within 30 min at pH . 6 this latter possibility is a less likely one. Phos-ex and the neutral-coated formulation disintegrate and bind phosphate in the stomach. Phosex disintegrates faster and is available for binding more rapidly than NCCaAc (Table 2). The more rapid disintegration of Phos-ex does not improve the phosphate binding capacity compared to NCCaAc. Apparently, the time of mixing in the stomach is long enough for adequate phosphate binding with NCCaAc. There were no significant differences of PTH, alkaline phosphatase and bicarbonate during the study, but the duration of the periods was probably not long enough to reveal a difference. This study also showed that gastro-intestinal side effects were related to the formulation of CaAc. ECCaAc and NCCaAc were equally well and both better tolerated than Phos-ex . With the EC and NCCaAc formulation, patients had fewer gastro-intestinal complaints compared to Phos-ex . Two patients withdrew from the study in the last week of the Phos-ex period, because of symptoms (vomiting, nausea and distaste) they attributed to the drug. We expected to find a better tolerance of ECCaAc, because it disintegrates after passage through the stomach. For NCCaAc, however, we expected to find more gastro-intestinal complaints compared to ECCaAc, and no difference compared to Phos-ex . The main complaints during the Phos-ex period were located in the upper gastro-intestinal tract (borborygmus, ructus, pyrosis, vomiting and the feeling of a full stomach). According to the interviews these side effects were not related to the tablet size or the flavour of the Phos-ex formulation. There may be a relation between the gastro-intestinal complaints and the rapid disintegration of Phos-ex in the stomach (20 min, see Table 2) compared to NCCaAc (40 min). Phos-ex disintegrates rapidly as a bolus, NCCaAc disintegrated more slowly and gradually. The rapid release of calcium acetate in the Phos-ex formulation may irritate the stomach wall before actual binding with food and therefore may cause
227
complaints of the upper abdomen. Apparently there was no difference in gastro-intestinal complaints between the more gradual release of (NC)CaAc in the stomach or release of (EC)CaAc in the small intestine. In conclusion, we have demonstrated that phosphate control and tolerance were both influenced by the formulation of CaAc in hemodialysis patients. Although phosphate control was adequate with all three formulations of CaAc, ECCaAc was less effective compared to NCCaAc or Phos-ex . NCCaAc and ECCaAc were better tolerated than Phos-ex . Regarding efficacy and tolerance, NCCaAc was the best calcium acetate formulation.
References [1] Sheikh MS, Maguire JA, Emmett M et al. Reduction of dietary phosphorus absorption by phosphorus binders. A theoretical, in vitro, and in vivo study. J Clin Invest 1989;83:66–73. [2] Emmett M, Sirmon MD, Kirkpatrick WG, Nolan CR, Schmitt GW, Cleveland MB. Calcium acetate control of serum phosphorus in hemodialysis patients. Am J Kidney Dis 1991;17:544–50. [3] Schaefer K, Scheer J, Asmus G, Umlaut E, Hagemann J, von-Herrath D. The treatment of uremic hyperphosphatemia with calcium acetate and calcium carbonate: a comparative study. Nephrol Dial Transplant 1991;6:170–5. [4] Slatopolsky E, Winous D, Norwood K. Short-term comparison of calcium carbonate and calcium actetate in hemodialysis patients treated with 2.5 mEq / l calcium dialysate. J Am Soc Nephrol 1990;1:378. [5] Caravaca F, Santos I, Cubero JJ et al. Calcium acetate vertsus calcium carbonate as phosphate binders in hemodialysis patients. Nephron 1992;60:423–7. [6] Moriniere P, Djerad M, Boudailliez B et al. Control of predialytic hyperphosphatemia by oral calcium acetate and calcium carbonate. Comparable efficacy for half the dose of elemental calcium given as acetate without lower incidence of hypercalcemia. Nephron 1992;60:6–11. [7] Delmez JA, Tindira CA, Windus DW et al. Calcium acetate as a phosphorus binder in hemodialysis patients. J Am Soc Nephrol 1992;3:96–102. [8] Mai ML, Emmett M, Sheikh MS, Santa-Ana CA, Schiller L, Fordtran JS. Calcium acetate, an effective phosphorus binder in patients with renal failure. Kidney Int 1989;36:690–5. [9] Pflanz S, Henderson IS, McElduff N, Jones MC. Calcium acetate versus calcium carbonate as phosphate-binding agents in chronic haemodialysis. Nephrol Dial Transplant 1994;9:1121–4.
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[10] Ben-Hamida F, el-Esper I, Compagnon M, Moriniere P, Fournier A. Long-term (6 months) cross-over comparison of calcium acetate with calcium carbonate as phosphate binder. Nephron 1993;63:258–62. [11] Lau AH, Kuk JM, Franson KL. Phosphate-binding capacities of calcium and aluminum formulations. Int J Artif Organs 1998;21:19–22. [12] Wallot M, Bonzel KE, Winter A, Georger B, Lettgen B, Bald M. Calcium acetate versus calcium carbonate as oral phosphate binder in pediatric and adolescent hemodialysis patients. Pediatr Nephrol 1996;10:625–30. [13] van den Bergh JP, Kaufmann BG, van-Riet GJ, Bottger WM, Verstappen VM. Comparison of three formulations of cal-
cium acetate tablets to evaluate tolerance and control of hyperphosphatemia in patients with chronic renal failure. Nephron 1994;68:505–6. [14] Lau AH, Kuk JM, Franson KL. Phosphate-binding capacities of calcium and aluminium formulations. Int J Artif Organs 1998;21:19–21. [15] Stamatakis MK, Alderman JM, Meyer-Stout PJ. Influence of pH on in vitro disintegration of phosphate binders. Am J Kidney Dis 1998;32:808–12. [16] Schiller LR, Santa-Ana CA, Sheikh MS, Emmett M, Fordtran JS. Effect of the time of administration of calcium acetate on phosphorus binding. New Engl J Med 1989;320:1110–3.
The Netherlands Journal of Medicine 1999;55:222 – 228
Original article
Efficacy and tolerance of three different calcium acetate formulations in hemodialysis patients J.P.W. van den Bergh a , *, M.A.C.J. Gelens a , H.A.J. Klaassen a , B.G. Kaufmann c , b ¨ W.M. Bottger , V.M.C. Verstappen a a
Department of Internal Medicine, St. Maartens Hospital, Venlo, The Netherlands b Clinical Pharmacy, St. Maartens Hospital, Venlo, The Netherlands c Clinical Pharmacy, Laurentius Hospital, Roermond, The Netherlands
Received 1 April 1999; received in revised form 28 June 1999; accepted 24 August 1999
Abstract Background: Calcium acetate (CaAc) is an effective phosphate binder in patients with chronic renal failure. However, an important side effect is gastro-intestinal discomfort. Phos-ex (Cablon, The Netherlands) is the only commercially available non-coated CaAc formulation in our country. We developed two new CaAc formulations: neutral-coated CaAc (NCCaAc) and enteric-coated CaAc (ECCaAc). Methods: In a randomised double-blinded cross-over trial we compared efficacy and tolerance of the three formulations in 19 stable hemodialysis patients, with a mean age of 63 years (range, 36–85), who had been on hemodialysis for 19 months (range, 6–47). Patients were randomised to receive NCCaAc or ECCaAc, with meals, for a period of 10 weeks and after cross-over for another 10 weeks. During a third non-blinded period, patients received Phos-ex for 10 weeks. Results: Serum phosphate was significantly higher with ECCaAc compared to NCCaAc (1.8960.07 vs. 1.7060.08 mmol / l, P , 0.05). Serum Ca was significantly lower with ECCaAc compared to NCCaAc or Phos-ex (2.3860.04, 2.4760.04 and 2.4860.04 mmol / l, P , 0.05). There were less hypercalcemic and more hyperphosphatemic events in the ECCaAc period, compared to the other periods. The daily CaAc dose and dietary intake of calcium, phosphate, protein and calories were comparable in all three periods. With Phos-ex , patients noticed more gastro-intestinal complaints than with to NCCaAc and ECCaAc. Two patients stopped taking Phos-ex because of side effects. Conclusions: In hemodialysis patients, phosphate control and tolerance were both influenced by the formulation of CaAc. Although phosphate control was adequate with all three formulations of CaAc, ECCaAc was less effective compared to NCCaAc or Phos-ex . NCCaAc and ECCaAc were better tolerated than Phos-ex . Regarding efficacy and tolerance, NCCaAc was the best calcium acetate formulation. 1999 Elsevier Science B.V. All rights reserved. Keywords: Calcium acetate; Hemodialysis; Phosphate binder; Side effects; Tolerance
*Corresponding author. Department of Endocrinology, University Hospital Nijmegen, Postbus 9101, 6500 HB Nijmegen, The Netherlands. Tel.: 1 31-24-361-4599; fax: 1 31-24-3641484. E-mail address: [email protected] (J.P.W. van den Bergh)
Introduction In uremic patients correction of hyperphosphatemia and hypocalcemia is important in the prevention of secondary hyperparathyroidism. Cal-
0300-2977 / 99 / $ – see front matter 1999 Elsevier Science B.V. All rights reserved. PII: S0300-2977( 99 )00084-4
J.P.W. van den Bergh et al. / Calcium acetate formulations in hemodialysis patients
cium-containing phosphate binders are used preferably to control serum phosphate. Recent studies have shown that calcium acetate (CaAc) is an effective phosphate binder [1–12]. However, one of the most important side effects is gastro-intestinal discomfort [2,3,5,6,9,10]. In our experience this often results in discontinuation of the drug. It is not clear whether calcium acetate per se is less tolerable or whether it depends on the formulation. Tolerability may be better with improved formulation [9]. In The Netherlands, Phos-ex (Cablon, The Netherlands) is the only commercially available CaAc formulation, the tablets are not coated. In an attempt to reduce gastrointestinal discomfort, we developed two new formulations of CaAc; a neutral-coated tablet (NCCaAc) that easily disperses pH independently, and an enteric-coated tablet (ECCaAc) that disperses at pH . 6.5. When using different CaAc formulations, it is possible that efficacy of CaAc as phosphate binding agent is influenced. In a pilot study we previously evaluated the safety of the new formulations, ECCaAc and NCCaAc. We showed that it was possible to control hyperphosphatemia with both drugs in patients with pre-terminal renal failure [13]. For further evaluation of efficacy and tolerance of NCCaAc, ECCaAc and Phos-ex , we conducted a randomised crossover study in 19 stable hemodialysis patients.
Material and methods Patients Nineteen (14 men and five women) patients with a mean age of 63.6612.6 (range, 36–85) years, were
Table 1 Patient characteristics at the start of the study
Age (years) Weight (kg) Length (cm) Kt /V a nPCRb
Mean6SD
Range
63.6612.6 78.4616.7 17667 1.0660.18 0.9360.27
36–85 64.5–92.3 163–190 0.82–1.20 0.74–1.22
223
studied. Only patients with a creatinine clearance , 1 ml / min were included and all patients had to be stable on hemodialysis for at least 6 months. The mean hemodialysis treatment time was 19 months (range, 6–47 months). Patient characteristics at the start of the study are presented in Table 1. The patients were dialysed three times a week, for 4 h using a standard dialysate with a calcium concentration of 1.3 mmol / l. All patients were previously treated with calcium carbonate, three patients were also treated with aluminium hydroxide. Patients did not use H 2 -receptor antagonists or proton pump inhibitors. Three patients used vitamin D; the dose was not changed during the study. All patients gave their informed consent. Calcium acetate formulations NCCaAc and ECCaAc were developed by our hospital pharmacy. The tablets have a smooth surface and are prepared without flavour. They are spherical and identical in appearance, with a dimension of 7.0 3 11.2 mm. NCCaAc is coated with Eudragit-E and ECCaAc with Eudragit-L. Each tablet contains 500 mg CaAc (115 mg elementary calcium). Phos-ex is a commercially available noncoated formulation of CaAc, with a chalky surface and a dimension of 8.0 3 8.3 3 18 mm. The formulation has a lemon meringue flavour. Each tablet contains 1100 mg CaAc (250 mg elementary Ca). The tablets were analysed according to the European Pharmacopoeia, 2nd ed. (Table 2). For entericcoated tablets it is required that the disintegration time in 0.1 mol HCl (pH 1.1) is longer than 120 min, and in 0.2 mol phosphate buffer (pH 6.8) shorter than 30 min. For non- and neutral-coated tablets the disintegration time must be respectively shorter than 15 and 60 min at pH 1.1. The NC and EC formulations comply with these conditions. There is no specific requirement for disintegration time of neutral and non-coated tablets at pH 6.8, but for comparison with the enteric-coated tablets we report these data in Table 2. Study design
a
Dialysis adequacy is expressed as Kt /V. b nPCR is protein catabolic rate, corrected for body weight.
A randomised double-blinded cross-over design
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Table 2 Analysis of the three different formulations of CaAc according to the European Pharmacopoeia, 2nd ed.a
Mean weight (mg) Hardness (N) Thickness (mm) Diameter (mm) Wastage (%) Disintegration time (min) in 0.1 M HCl (pH 1.1) Disintegration time (min) in 0.2 M phosphate buffer (pH 6.5) Ca content (%) a
NCCaAc
ECCaAc
Phos-ex
668 128 7.0 11.2 0.06 41
668 125 7.0 11.2 0.04 . 120
1106 159 8.3 8.0 / 18.0 0.4 19
38
, 30
21
94
94
98
NCCaAc, neutral-coated calcium acetate; ECCaAc, enteric-coated calcium acetate; Phos-ex , non-coated calcium acetate.
was employed consisting of two treatment periods lasting 10 weeks. At the start of the study, the patients were randomised to receive NCCaAc or ECCaAc. A run in period of 2 weeks was used to find a stable dose of CaAc with a preferred phosphate level between 1.3 and 2.0 mmol / l. Both drugs were given with meals, as sole phosphate binder for a period of 10 weeks. After cross-over both drugs were given for another period of 10 weeks. After this second period the patients received Phos-ex for 10 weeks during a third non-blinded period. Because of the difference in size and flavour with NC or ECCaAc, the Phos-ex tablets could not be given in a blinded period. The data of the first 2 weeks of each period were not included in the analysis; in the first period to avoid the run-in effects, in the second and third periods to avoid carry-over effects. Blood samples were collected weekly just before the first dialysis of the week. Serum calcium levels were corrected for albumin concentration according to the formula: corrected serum calcium (in mmol / l) 5 (serum albumin (in g / l) 2 42) 3 serum calcium (in mmol / l). Dialysis adequacy is expressed as Kt /V, where K represents whole body urea clearance, t is time on dialysis and V is urea volume. At the end of each period our dietician calculated the dietary intake of phosphate, calcium, calories and protein per kg bodyweight. We also checked for possible alterations in the dietary compound. The tablets were dispensed at the beginning of each new period (10 weeks) and compliance was checked at the end of each period by the amount of tablets returned. The tablets were divided over the meals according to the amount of phosphate in each
meal, which was calculated by our dietician at the start of the study. The daily dose of CaAc was calculated at the end of the run in phase by multiplying the number of tablets with the dose elementary calcium in each tablet. In order to compare efficacy of CaAc in the three periods, the daily dose of CaAc was not changed during the study unless there were repeated (more than two times) serum calcium levels above 2.7 mmol / l or phosphate levels above 2.5 mmol / l. During the Phos-ex period, we distributed half of the number of tablets that were used during the EC or NCCaAc period. However, because the amount of elementary calcium in the Phos-ex tablets is more than twice the amount in the EC or NCCaAc tablets (250 vs. 115 mg per tablet, respectively), the total dose of elementary calcium used during the Phos-ex period would be higher. We tried to adjust the Phos-ex dose as much as possible by prescribing one or two Phos-ex tablets with each meal, when three or five EC or NCCaAc tablets, respectively, were used during the previous period. Two investigators at weekly interviews (JvdB, MG) evaluated tolerance. Independently from the interviews, a questionnaire with 10 items (pyrosis, ructus, diarrhoea, flatulence, vomiting, feeling of a full stomach, loss of appetite, nausea, borborygmus and loss or change of taste) was scored at the end of each period of 10 weeks. Patients were asked to score complaints they noticed in the last 8 weeks and that were not present at the start of the study. The results of the questionnaire were compared with the results obtained from the weekly interviews. Complaints reported at both evaluations were used for analysis.
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Statistics All data are expressed as means6SEM. For an overall analysis of the treatment effect, a repeated measure analysis of variance was performed for each variable. Subsequently data analysis between two treatments was assessed using the paired Student’s t-test. Analysis of differences in the incidence of hypercalcemia or hyperphosphatemia between the treatment periods was assessed with Fischer’s exact test and analysis of differences in tolerance with the McNemar test. A P value , 0.05 was used as level of significance. Results Of the 19 patients originally enrolled, 16 completed all phases of the trial. Three patients were transplanted during the study. Two patients withdrew due to symptoms they attributed to the phosphatebinding agent Phos-ex in the last week of the trial. Because their blood samples were drawn before they stopped taking the phosphate-binding agent, the laboratory data were included in the analysis. Efficacy The data of the three treatment periods are sum-
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marised in Table 3. Serum phosphate level was significantly higher in the ECCaAc period (1.8960.07) compared to the NCCaAc period (1.7060.08). There was no significant difference between phosphate levels in the NCCaAc and ECCaAc period compared to the Phos-ex period (1.7760.08). In the ECCaAc period serum Ca level was significantly lower compared to the NCCaAc or Phos-ex period (2.3860.04, 2.4760.04 and 2.4860.04). The incidence of hypercalcemia (corrected serum calcium . 2.6 mmol / l) was lower in the ECCaAc period compared to the other two periods, and the incidence of hyperphosphatemia (serum phosphate . 2.0 mmol / l) was lower in the NCCaAc period compared to the other two periods, but the differences were not statistically significant. The daily CaAc dose was the same in all three periods. There were no significant differences in the plasma levels of PTH, alkaline phosphatase, bicarbonate and creatinine. Dietary amount of calcium, phosphate, protein and calories was comparable in all three periods. Normalised protein catabolic rate (nPCR) and dialysis adequacy as measured by Kt /V were not significantly different in the three treatment periods (Kt /V was 1.0460.18, 1.1360.19 and 1.0560.14, and nPCR was 0.9660.20, 0.9660.15 and 0.9960.13, in the NCCaAc, ECCaAc and Phosex periods, respectively).
Table 3 Mean (and range) of daily dose of CaAc, serum concentrations of biochemical parameters, calculated dietary intake of phosphate, calcium, protein and calories, percent of events of hypercalcemia and hyperphosphatemia during the three CaAc treatment periods a
Dose (g calcium b / day) Calcium (mmol / l) Phosphate (mmol / l) PTH (pmol / l) Alk. phosphatase (U / l) Bicarbonate (mmol / l) Dietary phosphate (g / day) Dietary calcium (g / day) Dietary protein (g / kg per day) Dietary Energy (kcal / day) Ca . 2.6 mmol / l (% events) PO 4 . 2.0 mmol / l (% events)
NCCaAc
ECCaAc
Phos-ex
1.48 (0.69–2.76) 2.47* (2.22–2.70) 1.70* (0.86–2.15) 15.5 (1.0–26.0) 64.1 (38.0–89.0) 22.2 (18.0–29.0) 0.98 (0.69–1.97) 0.54 (0.20–0.98) 0.94 (0.53–1.16) 1632 (1162–2626) 17.7 19.5
1.48 (0.69–2.53) 2.38 (2.19–2.69) 1.89 (1.42–2.34) 12.3 (1.2–23.0) 64.8 (37.5–100.5) 20.8 (15.5–30.3) 1.04 (0.63–1.92) 0.57 (0.25–0.87) 0.95 (0.54–1.15) 1653 (1124–2618) 12.3 28.6
1.50 (0.75–2.75) 2.48* (2.22–2.78) 1.77 (1.19–2.25) 14.1 (2.6–27.0) 68.9 (38.5–97.0) 20.6 (16.6–28.4) 0.99 (0.62–1.87) 0.56 (0.24–0.78) 0.90 (0.51–1.22) 1601 (1018–2445) 17.2 22.0
NCCaAc, neutral-coated calcium acetate; ECCaAc, enteric-coated calcium acetate; Phos-ex , non-coated calcium acetate. Dose of elementary calcium. *P , 0.05 vs. ECCaAc. a
b
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Tolerance During the ECCaAc period, five patients noticed a total of nine new gastrointestinal complaints compared to baseline, in the NCCaAc period three patients noticed eight new complaints. In the Phosex period six patients noticed 19 new complaints, which is significantly more compared to the NCCaAc period tablets (the data are summarised in Table 4). Two patients stopped taking Phos-ex because of symptoms (vomiting, nausea and distaste) they attributed to the drug. According to the interviews five patients preferred the EC or NC tablets above Phos-ex , despite the larger number of tablets which had to be taken (mean number of daily tablets: NCCaAc, 12.9; ECCaAc, 12.9; and Phos-ex , 6.0). These patients appreciated the smaller size and the smooth surface, which made the tablets easier to swallow. two patients preferred Phos-ex because of the fewer number of tablets they had to take and because they needed less fluid to swallow the tablets. nine patients had no preference. The flavour was of no influence on the patients’ acceptance of Phos-ex .
Discussion In the present study, the mean serum phosphate level was significantly higher with ECCaAc than with NCCaAc and the mean serum calcium level was Table 4 Number of gastro-intestinal complaints during the three CaAc treatment periods a Phos-ex
ECCaAc
NCCaAc
Vomiting Diarrhoea Loss of appetite Flatulence Nausea Pyrosis Borborygmus Ructus Distaste Feeling of full stomach
1 1 0 1 1 0 2 2 1 0
0 1 0 2 2 1 2 0 0 0
2 1 1 2 1 2 3 4 1 2
Total
9
8*
19
a
NCCaAc, neutral-coated calcium acetate; ECCaAc, entericcoated calcium acetate; Phos-ex , non-coated calcium acetate. *P , 0.05 vs. Phos-ex .
significantly lower with ECCaAc than with NCCaAc and Phos-ex . Furthermore, there were more hyperphosphatemic events and less hypercalcemic events with ECCaAc than with NCCaAc and Phosex , although there was no statistical significant difference. The daily dose of CaAc prescribed was the same in each period and comparable to the dose used in previous studies [4–6,9,10]. The dietary intake of calcium, phosphate, protein and calories and the dialysis adequacy were also equal in the three periods. These results show that phosphate control was influenced by the formulation of CaAc. It was possible to control hyperphosphatemia with calcium acetate as sole phosphate binder with all three formulations of CaAc, although ECCaAc was less effective as NCCaAc or Phos-ex . Recently, it was reported that different phosphate binder formulations had different phosphate-binding capacities in healthy subjects [14]. It was also reported, that the in vitro disintegration of CaAc was significantly affected by the pH of the medium used for disintegration [15]. These findings are in agreement with the results of our study in hemodialysis patients. We found different phosphate-binding capacities for the three CaAc formulations. These differences are related to the coating of the tablets, which determines the disintegration characteristics. The enteric-coated formulation disintegrates at pH . 6.5, and therefore binds phosphate after passage through the stomach, in the small intestine. Mixing of calcium acetate and food phosphate in the stomach is an important determinant of phosphate binding, so reduced phosphate binding with ECCaAc can be explained by incomplete mixing in the stomach [16]. Absorption of phosphate in the small intestine before binding occurs, and partial conversion of soluble calcium into poorly soluble salts in the small intestine may also attribute to reduced phosphate-binding capacity of ECCaAc [1]. When incomplete mixing of food phosphate with calcium acetate resulted in higher phosphate levels, we would have expected higher serum calcium levels and a higher incidence of hypercalcemia with ECCaAc, due to absorption of calcium from the disintegrated binder. However, we did not find this in our study. This may be explained by the conversion of calcium to poorly soluble salts, as mentioned previously, so that less disintegrated binder calcium was available
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for absorption. It is also possible that less CaAc was available for binding due to impaired disintegration of ECCaAc, resulting in hyperphosphatemia and lower calcium levels. Based on our in vitro results with ECCaAc, showing a complete disintegration of CaAc within 30 min at pH . 6 this latter possibility is a less likely one. Phos-ex and the neutral-coated formulation disintegrate and bind phosphate in the stomach. Phosex disintegrates faster and is available for binding more rapidly than NCCaAc (Table 2). The more rapid disintegration of Phos-ex does not improve the phosphate binding capacity compared to NCCaAc. Apparently, the time of mixing in the stomach is long enough for adequate phosphate binding with NCCaAc. There were no significant differences of PTH, alkaline phosphatase and bicarbonate during the study, but the duration of the periods was probably not long enough to reveal a difference. This study also showed that gastro-intestinal side effects were related to the formulation of CaAc. ECCaAc and NCCaAc were equally well and both better tolerated than Phos-ex . With the EC and NCCaAc formulation, patients had fewer gastro-intestinal complaints compared to Phos-ex . Two patients withdrew from the study in the last week of the Phos-ex period, because of symptoms (vomiting, nausea and distaste) they attributed to the drug. We expected to find a better tolerance of ECCaAc, because it disintegrates after passage through the stomach. For NCCaAc, however, we expected to find more gastro-intestinal complaints compared to ECCaAc, and no difference compared to Phos-ex . The main complaints during the Phos-ex period were located in the upper gastro-intestinal tract (borborygmus, ructus, pyrosis, vomiting and the feeling of a full stomach). According to the interviews these side effects were not related to the tablet size or the flavour of the Phos-ex formulation. There may be a relation between the gastro-intestinal complaints and the rapid disintegration of Phos-ex in the stomach (20 min, see Table 2) compared to NCCaAc (40 min). Phos-ex disintegrates rapidly as a bolus, NCCaAc disintegrated more slowly and gradually. The rapid release of calcium acetate in the Phos-ex formulation may irritate the stomach wall before actual binding with food and therefore may cause
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complaints of the upper abdomen. Apparently there was no difference in gastro-intestinal complaints between the more gradual release of (NC)CaAc in the stomach or release of (EC)CaAc in the small intestine. In conclusion, we have demonstrated that phosphate control and tolerance were both influenced by the formulation of CaAc in hemodialysis patients. Although phosphate control was adequate with all three formulations of CaAc, ECCaAc was less effective compared to NCCaAc or Phos-ex . NCCaAc and ECCaAc were better tolerated than Phos-ex . Regarding efficacy and tolerance, NCCaAc was the best calcium acetate formulation.
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