From the IADB-data base, 1,083 patients using sevelamer and 716 patients using polystyrene sulfonate for at least 90 days in a period of 12 months between January 2000 and December 2018 were identified. The patient characteristics are depicted in Table 1.
Table 1
|
Sevelamer
N = 1,083
|
Polystyrene sulfonate
N = 716
|
Age*, years (mean (sd) [range])
|
62 (17) [1–89]
|
58 (20) [10–95]
|
Gender (N (%))
Male
Female
|
619 (57)
464 (43)
|
471 (66)
245 (34)
|
Duration S / PSP use, days
(mean (sd) [range])
|
840 (759) [90-5247]
|
576 (628) [90-3813]
|
Unique drug-S/PSP combinations (N (%))
< 10
11–20
21–30
31–40
41–50
> 50
|
278 (25.7)
403 (37.2)
226 (20.9)
115 (10.6)
37 (3.4)
24 (2.2)
|
293 (40.9)
275 (38.4)
95 (13.3)
41 (5.7)
10 (1.4)
2 (0.3)
|
* Age measured on 1th July 2009 |
sd: standard deviation |
S: sevelamer |
PSP: polystyrene sulfonate |
Seven hundred and fifty-five different drugs were dispensed to the sevelamer users during this study period, which resulted in 20,801 unique drug-sevelamer combinations; 654 different drugs were dispensed to the polystyrene sulfonate users, which resulted in 10,311 unique drug-polystyrene sulfonate combinations.
We selected the 100 most frequently co-dispensed drugs with sevelamer and with polystyrene sulfonate. For these 100 drugs, 14,739 unique drug-sevelamer combinations and 7,123 unique drug-polystyrene sulfonate combinations were extracted from the database, which covered about 70% of the total unique drug-sevelamer/polystyrene sulfonate combinations.
Table 2 shows the categorization of these 100 drugs in ATC-class first level.
Table 2
One hundred most frequently co-dispensed drugs with sevelamer and polystyrene sulfonate, by ATC-class first level
Drug category
(ATC-first level)
|
Sevelamer (N*, (%))
Ntotal = 14,739
|
Polystyrene sulfonate (N*, (%))
Ntotal = 7,123
|
A. Alimentary tract and metabolism
|
3,597 (24.4)
|
1,660 (23.3)
|
B. Blood and blood forming organs
|
1,806 (12.3)
|
1,026 (14.4)
|
C. Cardiovascular system
|
3,231 (21.9)
|
2,074 (29.1)
|
D. Dermatologicals
|
958 (6.5)
|
416 (5.8)
|
G. Genito-urinary system and sex hormones
|
50 (0.3)
|
34 (0.5)
|
H. Systemic hormonal preparations, excluding sex hormones and insulines
|
541 (3.7)
|
259 (3.6)
|
J. Antiinfectives for systemic use
|
1,378 (9.3)
|
579 (8.1)
|
L. Antineoplastic and immunomodulating agents
|
66 (0.4)
|
72 (1.0)
|
M. Musculo-skeletal system
|
374 (2.5)
|
207 (2.9)
|
N. Nervous system
|
1,408 (9.6)
|
455 (6.4)
|
R. Respiratory system
|
474 (3.2)
|
156 (2.2)
|
S. Sensory organs
|
293 (2.0)
|
120 (1.7)
|
V. Various
|
563 (3.8)
|
65 (0.9)
|
* number of unique drug-sevelamer/polystyrene sulfonate combinations |
In sevelamer users, 58.6% of the co-dispensed drugs were from ATC-classes A, B and C and in polystyrene sulfonate users this was 66.8%. These included proton pump inhibitors, laxatives, vitamin D analoga, antidiabetic agents as insulins, drugs for treating renal anaemia, antiplatelet coagulation drugs, antithrombotics, antihypertensive drugs, heart failure treatment and lipid lowering treatment. Other frequently co-dispensed drugs were dermatologicals (indifferent dermatological products, dermal corticosteroids,anti-infective treatment), ATC class H (prednisolon, cincacalcet, levothyroxine) ATC class L (mycophenolic acid, tacrolimus), ATC class M (allopurinol, colchicine), and ATC-class N (pain medication, benzodiazepines). The individual top 10 drugs co-dispensed with sevelamer (with the percentage of patients who received the combination during the study period) were alfacalcidol (59.4%), metoprolol (50.0%), omeprazole (43.5%), calcium carbonate (39.6%), furosemide (38.9%), acetylsalicylic acid (36.3%), amlodipine (33.1%), macrogol (31.5%), ferrofumarate (28.3%) and prednisolone (26.8%). For polystyrene sulfonate the individual top 10 included alfacalcidol (45.4%), metoprolol (43.4%), omeprazole (35.5%), furosemide (32.5%), amlodipine (30.7%), calcium carbonate (29.6%), ferrofumarate (27.9%), acetylsalicylic acid (26.3%), simvastatin (24.4%) and prednisolone (22.9%).
After application of the described exclusion criteria, a list of 39 drugs co-dispensed with sevelamer and 47 drugs co-dispensed with polystyrene sulfonate was compiled for further exploration of interaction potential (Fig. 2). Table 3 presents the selected drugs, the number of unique drug-sevelamer/polystyrene sulfonate combinations, the percentage of sevelamer/polystyrene sulfonate users having received these drugs and the results of the analysis of potential new binding interactions based on pKa- and Log P values. We identified 22 and 27 potentially clinically relevant new binding interactions for sevelamer and polystyrene sulfonate, respectively.
Table 3
Most frequently co-dispensed drugs with sevelamer and polystyrene sulfonate and assessment of potential binding interactions
|
Sevelamer (N = 1,083)
|
|
Polystyrene sulfonate (N = 716)
|
Drug
|
pKa
(acid)
[31]
|
Log P
[31]
|
Unique drug combination (N)
|
Patients
(%)
|
Potential new binding interaction (Yes/No)
|
Drug
|
pKa
(base)
[31]
|
Unique drug combination (N)
|
Patients
(%)
|
Potential new binding interaction (Yes/No)
|
Calcium carbonate
|
6.1
|
0.3
|
429
|
39.6
|
Noa
|
Alfacalcidol
|
-2.8
|
325
|
45.4
|
No
|
Acetylsalicylic acid
|
3.4
|
1.2
|
393
|
36.3
|
Yes
|
Metoprolol
|
9.7
|
311
|
43.4
|
Yes
|
Amlodipine
|
19.1
|
1.6
|
358
|
33.0
|
No
|
Omeprazol
|
4.8
|
254
|
35.5
|
Yes
|
Macrogol
|
-
|
-
|
341
|
31.5
|
No
|
Furosemide
|
-1.5
|
233
|
32.5
|
No
|
Ferrofumarate
|
3.4
|
< 0
|
307
|
28.3
|
Noa
|
Amlodipine
|
9.5
|
220
|
30.7
|
Yes
|
Prednisolone
|
12.6
|
1.27
|
290
|
26.8
|
No
|
Calcium carbonate
|
-
|
212
|
29.6
|
Nob
|
Amoxicillin/clavulanic acid
|
3.2/3.3
|
< 0
|
285
|
26.3
|
Yes / Yes
|
Ferrofumarate
|
-
|
200
|
27.9
|
Yesc
|
Acenocoumarol
|
5.8
|
2.7
|
272
|
25.1
|
Yes
|
Acetylsalicylic acid
|
-7.1
|
188
|
26.3
|
No
|
Lanthanum carbonate
|
6.1
|
0.3
|
259
|
23.9
|
Noa
|
Prednisolone
|
-2.9
|
164
|
22.9
|
No
|
Polystyrene sulfonate
|
-
|
-
|
245
|
22.6
|
No
|
Macrogol
|
-
|
157
|
21.9
|
No
|
Acetaminophen
|
9.5
|
0.9
|
214
|
19.8
|
No
|
Acenocoumarol
|
-6.8
|
149
|
20.8
|
No
|
Lactulose
|
10.3
|
< 0
|
213
|
19.7
|
No
|
Enalapril
|
5.2
|
138
|
19.3
|
Yes
|
Tramadol
|
13.8
|
2.5
|
212
|
19.6
|
Yes
|
Pantoprazol
|
3.6
|
121
|
16.9
|
Yes
|
Cinacalcet
|
-
|
6.3
|
184
|
17.0
|
Yes
|
Amoxicillin/clavulanic acid
|
7.4/
-2.6
|
111
|
15.5
|
Yes / No
|
Bumetanide
|
4.7
|
2.4
|
165
|
15.2
|
Yes
|
Acetaminophen
|
-4.4
|
102
|
14.2
|
No
|
Doxycycline
|
3.3
|
< 0
|
156
|
14.4
|
Yes
|
Ciprofloxacin
|
8.7
|
95
|
13.3
|
Yes
|
Doxazosin
|
12.7
|
2.1
|
145
|
13.4
|
Yes
|
Allopurinol
|
1.3
|
88
|
12.3
|
No
|
Flucloxacillin
|
3.8
|
2.4
|
125
|
11.5
|
Yes
|
Bumetanide
|
2.7
|
86
|
12.0
|
Yes
|
Allopurinol
|
8.5
|
0
|
125
|
11.5
|
No
|
Doxazosin
|
7.2
|
84
|
11.7
|
Yes
|
Metoclopramide
|
14.5
|
1.4
|
121
|
11.2
|
No
|
Colecalciferol
|
-1.3
|
81
|
11.3
|
No
|
Oxazepam
|
10.6
|
2.9
|
121
|
11.2
|
Yes
|
Lactulose
|
-3.0
|
78
|
10.9
|
No
|
Codeine
|
13.8
|
1.3
|
121
|
11.2
|
No
|
Bisoprolol
|
9.7
|
75
|
10.5
|
Yes
|
Oxycodone
|
13.6
|
1.0
|
120
|
11.1
|
No
|
Tramadol
|
9.2
|
74
|
10.3
|
Yes
|
Nifedipine
|
-
|
1.8
|
116
|
10.7
|
No
|
Isosorbide mononitrate
|
-3.5
|
72
|
10.0
|
No
|
Colchicine
|
15.1
|
1.5
|
116
|
10.7
|
No
|
Colchicine
|
0
|
70
|
9.8
|
No
|
Bisoprolol
|
14.1
|
2.2
|
112
|
10.3
|
Yes
|
Doxycyclin
|
8.3
|
69
|
9.6
|
Yes
|
Isosorbide mononitrate
|
13.3
|
< 0
|
105
|
9.7
|
No
|
Hydrochlorothiazide
|
-2.7
|
69
|
9.6
|
No
|
Lisinopril
|
3.2
|
< 0
|
103
|
9.5
|
Yes
|
Lanthanum carbonate
|
-
|
65
|
9.1
|
Yesb
|
Clopidogrel
|
-
|
4.0
|
101
|
9.3
|
Yes
|
Nifedipine
|
5.3
|
65
|
9.1
|
Yes
|
Clindamycin
|
12.4
|
1.0
|
97
|
9.0
|
No
|
Lisinopril
|
10.2
|
64
|
8.9
|
Yes
|
Amitriptyline
|
-
|
4.8
|
88
|
8.1
|
Yes
|
Oxazepam
|
-1.5
|
62
|
8.7
|
No
|
Sulfamethoxazol/trimethoprim
|
6.2/17.3
|
0.8/1.3
|
88
|
8.1
|
Yes / No
|
Oxycodone
|
8.8
|
58
|
8.1
|
Yes
|
Losartan
|
7.4
|
5.1
|
85
|
7.8
|
Yes
|
Flucloxacillin
|
-0.9
|
52
|
7.3
|
No
|
Diclofenac
|
4.0
|
4.3
|
84
|
7.8
|
Yes
|
Irbesartan
|
4.1
|
52
|
7.3
|
Yes
|
Irbesartan
|
7.4
|
5.5
|
81
|
7.5
|
Yes
|
Spironolactone
|
-4.9
|
50
|
7.0
|
No
|
Hydrochlorothiazide
|
9.1
|
< 0
|
71
|
6.6
|
No
|
Diclofenac
|
-2.1
|
49
|
6.8
|
No
|
Loperamide
|
14.0
|
4.8
|
71
|
6.6
|
Yes
|
Clopidogrel
|
5.1
|
48
|
6.7
|
Yes
|
Vitamin B complex/vitamin C
|
15.5/4.4
|
< 0 /< 0
|
64
|
5.9
|
No / Yes
|
Cinacalcet
|
10.3
|
48
|
6.7
|
Yes
|
Bisacodyl
|
-
|
3.6
|
55
|
5.1
|
Yes
|
Perindopril
|
5.5
|
48
|
6.7
|
Yes
|
|
|
|
|
|
|
Mycophenolic acid
|
-4.1
|
46
|
6.4
|
No
|
|
|
|
|
|
|
Codeine
|
9.2
|
44
|
6.1
|
Yes
|
|
|
|
|
|
|
Amitriptyline
|
9.8
|
43
|
6.0
|
Yes
|
|
|
|
|
|
|
Gliclazide
|
1.4
|
43
|
6.0
|
No
|
|
|
|
|
|
|
Esomeprazole
|
4.8
|
43
|
6.0
|
Yes
|
|
|
|
|
|
|
Losartan
|
4.1
|
37
|
5.2
|
Yes
|
|
|
|
|
|
|
Dipyridamole
|
6.6
|
36
|
5.0
|
Yes
|
|
|
|
|
|
|
Metformin
|
12.3
|
36
|
5.0
|
Yes
|
a Sevelamer may bind carbonate or fumarate but not the clinically effective ions calcium, iron and lanthanum |
b Although theoretically polystyrene sulfonate could bind the positively charged calcium, this would not lead to a binding interaction in clinical practice, considering the availability of a polystyrene sulfonate product as a calcium-salt |
c Polystyrene sulfonate may bind the positively charged iron and lanthanum ions |