PHARMACOKINETICS-THERAPEUTICS
Clin. Phormocokinet. 27 (5): 393-408, 1994
03 12·5963/94/ 00IH)393/ S0B.OO/O
© Ad is Internotio nolUmited . All rights reserved.
Pharmacokinetic Optimisation of the Treatment of Peptic Ulcer in Patients with Renal Failure* Ulrich Gladziwa l and Ulrich Klotz 2 1 2
Department of Internal Medicine II, Technical University, Aachen, Germany Dr Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany
Contents Summary . .. .. . . . . . . . . . ... . .. .. .. ... . 1. Prevalence of Peptic Ulcer in Patients with Renal Failure . 2. Overview of Drug Treatment in Peptic Ulcer 2.1 Inhibition of Acid Secretion . .. . 2.2 Cytoprotective Agents . . . . . . . . . . 2.3 Eradication of Helicobacter pylori . . . 3. Pharmacokinetics of Histamine H2-Receptor Antagonists in Patients with Renal Failure 3.1 Cimetidine . 3.2 Ranitidine . 3.3 Famotidine 3.4 Nizatidine . 3.5 Roxatidine . 4. Pharmacodynamics of Histamine H2-Receptor Antagonists in Patients with Renal Failure ... . . .. .. . . . . . . . . . . . . 5. Pharmacokinetics of Pirenzepine in Patients with Renal Failure 6. Pharmacokinetics of Proton Pump Inhibitors in Patients with Renal Failure . 6.1 Omeprazole . 6.2 Lansoprazole . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3 Pantoprazole . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7. Pharmacokinetics of Cytoprotective Agents in Patients with Renal Failure 7. J Bismuth Salts . 7.2 Sucralfate . ... . . .. . 7.3 Antacids .. ... . . . . . 7.4 Prostaglandin Derivatives 8. Therapeutic Considerations in Patients with Renal Failure 9. Conclusions . . . . . . . . ... . . .. .. . . . .. . . . . .
Summary
393 394 394 394 395 395 395 395 396 397 397 398 398 399
400 400 400 401 401 401
402 402 403 403 404
The pathogenesis of peptic ulceration is not yet clear. It could be due to an imbalance between acid secretion and mucosal defensive and/or protective mechanisms, but the association between Helicobacter pylori and peptic ulceration has
* Dedicated to H.-G. Sieberth on the occasion of his 60th birthday.
394
Gladziwa & Klotz
questioned this hypothesis. Therefore, drugs inhibiting acid secretion and/or eradicating H. pylori are of major interest. Peptic ulcer disease is often associated with renal failure. For the selection of the proper dosage of these agents their pharmacokinetic properties and alterations in pharmacokinetics in various disease states, including renal failure, should be known. As histamine H2-receptor antagonists and pirenzepine are mainly eliminated by the renal route their elimination is dependent on creatinine clearance. Consequently, their elimination will be impaired in patients with renal insufficiency, which makes dosage reduction mandatory in these patients. No dosage supplementation is necessary after any type of dialysis because the drugs are removed in insignificant amounts by the various blood purification procedures. Misoprostol and proton pump inhibitors, such as omeprazole, lansoprazole and pantoprazole, are primarily eliminated by nonrenal routes. Therefore no dosage adjustments are necessary in patients with renal insufficiency. Bismuth salts, sucralfate and antacids should be avoided in patients with renal failure because of the accumulation of their cations and the associated risk of toxic reactions. For most agents more long term experience from comparative and doubleblinded studies is needed to define better their clinical efficacy and tolerability in patients with renal failure .
1. Prevalence of Peptic Ulcer in Patients with Renal Failure The results of some studies suggest that patients with renal failure have an increased risk (about 5fold) of developing peptic ulcer compared with patients with normal renal function .[1-4] However, recent larger surveys based on endoscopy reported only an overall prevalence of 4.2% for duodenal ulcer and of 0.7% for gastric ulcer, which are not higher than the prevalence of disease expected in the general population (from 4.7 to 11 % ).l5-12] Moreover, the prevalence of peptic ulcers seems to be increased in renal transplant recipients. When endoscopy was routinely performed after transplantation, duodenal ulcer prevalence was as high as 18 to 24%.[6,13,14] In those patients peptic ulcer was associated with a mortality rate of up to 34%.[12] Although the multifactorial pathogenesis of ulcers is poorly understood, it is generally believed that ulcerations develop when acid secretion and mucosal defensive and/or protective mechanisms are out of balance.l 15 ] A causative role is accepted for Helicobacter pylori in type B gastritis and H. pylori infection is regarded as a major factor in the development of peptic ulcer disease.l 16 ] We found © Adis International Limited. All rights reserved.
that H. pylori was present in 34 to 47% of patients with renal failure compared with 54% of patients with normal renal function.l 17 ] Several reports have implicated nonsteroidal anti-inflammatory drugs (NSAIDs) as causative factors for gastric ulcers.[18-20] Comparative trials have provided solid evidence that cigarette smoking impairs healing and promotes the recurrence of ulcers.l 21 ,22] Numerous mechanisms have been proposed to explain the effect of smoking, including stimulation of acid secretion, alteration of blood flow or motility, induction of reflux, and reduction in the generation of prostaglandins.[23-27]
2. Overview of Drug Treatment in PeptiC Ulcer 2.1 Inhibition of Acid Secretion
Histamine H2-receptor antagonists inhibit acid secretion by blocking the stimulation of H2-receptors in the gastric parietal cell.l 28 ] On a molar basis ranitidine is 5- to 8-fold, and famotidine at least 20-fold, more potent than cimetidine in reduction of basal and stimulated acid secretion. The effects of nizatidine and roxatidine are comparable to those of ranitidine.[29] Clin. Pharmacokinet. 27 (5) 1994
395
Treatment of Peptic Ulcer in Renal Insufficiency
Pirenzepine represents a selective muscarinic blocking agent that can reduce gastric acid secretion. [30] It is inferior to histamine H2-receptor antagonists in inhibiting acid secretion and promoting ulcer healing.!31] Proton pump inhibitors interact with the H+,K+-ATPase in the membrane of the parietal cell, resulting in a potent and longacting inhibition of gastric acid secretion.!32] Due to this effective control of acidity, healing of acidrelated diseases occurs rapidly with omeprazole[33] and lansoprazole.[34] 2.2 Cytoprotective Agents
Tripotassium dicitrato bismuthate (colloidal bismuth subcitrate) and sucralfate promote peptic ulcer healing probably by their local effects at the surface of the erosions. For a long time neutralisation of gastric acid by antacids was considered to be their mode of action, especially following high doses. The results of more recent studies demonstrated the efficacy of low dose antacids. Aluminium-containing antacids, bismuth salts and sucralfate stimulate protective and repair mechanisms in the gastric mucosa by increased synthesis and/or release of mucosal prostaglandins and epidermal growth factors. Prostaglandins are important for gastric mucosal defence and their stimulation renders the mucosa more resistant to injury (e.g. by NSAIDs). In higher therapeutic doses prostaglandins inhibit acid secretion by a mechanism different from that of the histamine H2-receptor antagonists. 2.3 Eradication of Helicobacter pylori
Bismuth salts can heal duodenal ulcers resistant to histamine H2-receptor antagonists. Furthermore, the rate of ulcer relapse is lower following bismuth therapy than after treatment with acidsuppressing drugs.!35] This advantage may be due to the potential of bismuth to suppress the growth of H. pylori. However, monotherapy with bismuth salts cannot completely eradicate H. pylori, but this goal can be achieved by concomitant use of antibiotics. At present, triple therapy (bismuth, amoxicillin, metronidazole) represents one of the © Adis International Limited. All rights reserved.
most effective regimens for the eradication of H. pylori, resulting in eradication rates of 80% to 90%.[36] A similar triple therapy without bismuth (ranitidine, metronidazole and amoxicillin) reaches almost 90% eradication.[37] However, antibioticinduced adverse effects, such as nausea and diarrhoea, and the development of resistant organisms must be taken into consideration. Indeed, approximately 25% of patients receiving the ranitidinecontaining regimens have their therapy terminated.[38] During treatment with omeprazole the colonisation of H. pylori can be reduced, but no eradication can be achieved. During combined therapy with amoxicillin and omeprazole eradication rates vary between 40% and 80%.[39,40] This treatment provides good tolerance and practicability, including improved compliance (see section 8). Annual relapse rates after eradicating H. pylori range between 0 and 10%, whereas the relapse rate is 60 to 90% if eradication fails after treatment with any H. pylori eradicative regimen.
3. Pharmacokinetics of Histamine H2-Receptor Antagonists in Patients with Renal Failure As all histamine H2-receptor antagonists are eliminated primarily by the renal route, impairment of renal function will affect the disposition of this group of drugs (table I). 3.1 Cimetidine
Studies in patients with renal insufficiency, including dialysis patients, are summarised in table J.l41] After oral administration, bioavailability was found to be 0.75 (ranging from 0.61 to 0.86). Bioavailability is not affected to any significant extent in patients with severely impaired renal function.[50] The apparent volume of distribution (Vd) was similar to that seen in healthy individuals (approximately 1 Ukg). The elimination half-life (t l/ 2) of 2.9 hours was prolonged 2 to 4 times compared with that in patients with normal renal function; the total body clearance (eL) of cimetidine of 272 ml/min (16.3 L/h) was reduced by the same Clin. Pharmacakinet. 27 (5) 1994
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Gladziwa & Klotz
Table I. Range of pharmacokinetic data for histamine H2-receptor antagonists in patients with renal insufficiency Renal function
F(%)
tlf" (h)
Vss (Ukg)
CL (ml/min)a
CLR (ml/min)a
0.8-1.4
449-808
293-600
CimetidineI42 ·52] Normal
30-84
1.5-2.3 2.2-3.5
Moderate renal failure
163
Severe renal failure
78
2.7-4.8
0.9-1.5
147-193
30-99
ESRD
75-89
2.1-5.6
0.8-1.2
51-272
0-25
Ran itid i neI53 ·66 ] Normal
39-88
1.6-3.1
1.2-1.8
543-709
430-520
Moderate renal failure
44-80
3.5-8.0
1.3-1.6
182-233
46-103
Severe renal failure
43
5.0-9.7
1.4
129-163
21-28
ESRD
54-88
7.1-12.1
1.1-1.5
126-147
10-13
40-55
FamotidineI 67 ·74]
2.2-4.0
1.1-1.3
309-464
222-314
Moderate renal failure
4.7-9.3
0.9-1.4
109-242
71-157
Severe renal failure
9.7-19.3
0.8-1.5
69-84
21-25
13.0-27.2
1.0-1.3
34-72
10
Normal
ESRD
49
Nizatidine[75·77]
1.1-1.6
1.2-1.3
667-850
Moderate renal failure
2.1
1.0
447
53
Severe renal failure
4.1
1.3
271
62
5.3-9.1
1.4
207
Normal
ESRD
100
75
450-600
RoxatidineI78 ·80] Normal
3.9-6.0
1.7-3.2
354-431
244-261
Moderate renal failure
7.7-9.3
1.8-2.2
157-231
46-114
Severe renal failure
12.1-14.6
1.4-2.0
85-111
18-32
ESRD
18.1-24.4
2.0
90
12
a
To convert to Uh multiply by 0.06.
Abbreviations: CL = total body clearance; CLR = renal clearance; ESRD = end-stage renal disease; F = bioavailability; tlf" = elimination half-life; Vss = volume of distribution at steady-state.
factor.[50,52] A significant inverse relationship could be observed between t'/2 and creatinine clearance (CLCR).l42 ] In dialysed patients with CLCR <5 ml/min/1.73m2 (0.3 Llh/1.73m 2), the time period during which plasma concentrations above 0.5 mg/L (associated with 50% inhibition of stimulated acid secretion in healthy individuals) were observed was 11.1 hours compared with 3.5 hours in those with normal serum creatinine levels.l 43 ] As a significant linear relationship between the values of renal clearance (CLR) of cimetidine and CLCR (r = 0.46, P < 0.05) was found,[46] dosage adjustments should be based on CLcR. Minor amounts of drug (less than 15 to 20% of the administered dose) were removed by haemodialy© Adis International Limited. All rights reserved.
sis, [42,44,48,50,52,81] and approximately 2% of a cimetidine dose is removed by continuous ambulatory peritoneal dialysis (CAPD).£SI] As clearance of cimetidine is negligible during peritoneal dialysis [5 ml/min (0.3 L/h)], haemodialysis [28 ml/min (1.7 Llh)] and slightly higher in haemoperfusion [85 ml/min (5.1 Llh)], no dosage supplementation is necessary after any of these procedures.£44] 3.2 Ranitidine
In patients with renal failure, both absorption and elimination of ranitidine are delayed compared with those in individuals with normal renal function.[82] Bioavailability (54.3 ± 13.5%) is comparable to that found in healthy individuals (52%).£57,83 ,84] Clin. Pharmacokinet. 27 (5) 1994
397
Treatment of Peptic Ulcer in Renal Insufficiency
After oral administration of 150mg of ranitidine, the maximal plasma concentration (C max ) was 672 flg/L in patients with chronic renal failure compared with 356 flg/L in healthy volunteers.[S8] When half of the normal dose was administered to patients with renal failure, the C max values in these patients were comparable to those in healthy controls receiving the full dose.[56] When the dose of ranitidine was adjusted on the basis of CLCR, the area under the plasma concentration-time curve (AUC) data were similar in patients with varying degrees of renal function .[85] This is because there is a significant correlation between CLCR and CL of ranitidine (r = 0.87, P < 0.0 I) or the reciprocal relationship between CLCR and tl/2 (r = 0.77). The Vd at steady-state (Vss) averaged 1.62 Llkg.l59] The amount of drug removed by dialysis was Iess than 10% of the administered dose. [62,65,84J During haemofiItration, Gladziwa et al.[86] reported that 17.1 ± 6.3% of the administered dose was eliminated, whereas Pollock et al.l 87] found only 2.1 ± 1.4% of the dose was removed. The loss of ranitidine CAPD was low «2% of the administered dose) .I64,83] These data suggest that additional administration of ranitidine is not required after any mode of dialysis. A daily oral dose of ranitidine of 150mg will provide therapeutic serum concentrations without excessive accumulation. Concentrations above 100 flg/L could be considered as 'target' for a sufficient therapeutic effect, e.g. at least 50% inhibition of gastric acid output.[56,84] 3.3 Famotidine
After oral administration, bioavailability averaged 49.4% in patients with renal failure compared with 55.2% in those with normal renal function.[71] Depending on the degree of renal dysfunction, tl/2 of famotidine was prolonged from 3 to 27 hours with a simultaneous and parallel decrease in CL and CLR from 412 to 34 mil min (24.7 to 2.0 Llh) and 304 to 25 ml/min (18.2 to 1.5 Llh), respectively. The Vss was unchanged (0.8 to 1.3 Llkg) in patients with renal failure.l 67 ,68,70-73] © Adis International Limited. All rights reserved .
Efficiency of blood purification procedures varied considerably. Compared with a tl/2 of 27.2 hours during the dialysis-free interval in patients with end-stage renal disease (ESRD), mean tV2 was 10.4, 11.4,7.5 and 13.7 hours during 5 hours intermittent haemofiltration (polyacrylonitrile membrane), 5 hours haemodialysis with cuprophane and polysulphone membranes, and 24 hours of continuous haemofiltration, respectively. CAPD was less effective, removing only 4 to 5% of the administered dose, and tl/2 averaged 15.5 hours. Haemodialysis with polysulphone membranes seems to be most effective, removing 16.4% of the administered dose. However, supplementation during or after any form of blood purification procedure is not necessaryVO,74] Reducing the dosage to one-third of the normal dose is recommended in patients with severe renal failure who are undergoing blood purification procedures.l 70 ,88] 3.4 Nizatidine
Limited data are available on the pharmacokinetics of nizatidine in patients with renal dysfunction and those on haemodialysis therapy (table I). In patients with anuria, bioavailability was reduced from 100 to 75%[76] and CL decreased in patients with impaired renal function in correlation with CLCR (r =0.95). After intravenous administration, tl/2 increased 3-fold from 1.5 ± 0.2 hours in normal volunteers to 6.9 ± 3.3 hours in patients with renal failure. CL decreased to about 30% (0.14 ± 0.02 Llkg/h) of that in healthy individuals (0.59 ± 0.07 Llkg/h). Less than 25% of the dose of nizatidine was recovered in unchanged form in the urine of patients with moderately severe renal dysfunction . The apparent nonrenal clearance (CLNR) [0.23 Llkg/hJ and Vd (1.4 Llkg) did not change with worsening renal function.[76] Nizatidine is not substantially removed during a 6-hour dialysis period, only approximately 10% of the intravenous dose is cleared. Consequently, dose supplementation after haemodialysis is not necessary.[76] The metabolite of nizatidine, N2-monodemethylnizatidine, has approximately 60% of the histamine Clin. Phormacokinet. 27 (5) 1994
398
Gladziwa & Klotz
H2-receptor antagonist activity of nizatidine. After multiple oral or intravenous administration N2monodemethyl-nizatidine accumulated more slowly and to higher concentrations in patients with decreased renal function than in healthy individuals. These higher concentrations resulted from decreased elimination and increased formation . The tY2 of N2-monodemethyl-nizatidine increased 4-fold, i.e. from 3.8 ± 1.9 hours in healthy individuals to 14.0 ± 3.2 hours in functionally anephric patients. The AVC was more than 5-fold greater in patients with anuria than that in healthy individuals)76] 3.5 Roxatidine
Pharmacokinetic data on roxatidine in patients with renal insufficiency and in those on dialysis are limited (table I). Cumulative urinary excretion of roxatidine accounts for 60% of the dose in individuals with normal renal function and is reduced to less than 10% of the total dose in patients with renal failure. The tl/2 is prolonged in patients with severe renal insufficiency; 12 to 18 hours compared with 3.9 hours in healthy individuals. CL and CLR of roxatidine were significantly correlated with CLcR.[78.79] In contrast to Takabatake et al.,[78] Lameire et al.[79] found a decrease in Vd of roxatidine. A maximum of 12% of the administered dose was removed by haemodialysis. Therefore, no additional drug needs to be given to patients with renal failure who are treated by haemodialysis.l 89 .90 ]
4. Pharmacodynamics of Histamine H2-Receptor Antagonists in Patients with Renal Failure Long term pH-metry allows intragastric pH profiles to be monitored and the pharmacodynamic response of anti secretory drugs determined)91.92] As indicated by ambulatory 24-hour intragastric pHmetry, oral administration of cimetidine (300mg twice daily) or ranitidine (l50mg in the morning) induced significantly higher pH values compared with basal values for 7 and 8 hours, respectively, in 7 patients with chronic renal failure undergoing haemodialysis)93] However, there was no difference © Adls International Limited. All rights reserved.
between the gastric pH in patients receiving cimetidine or ranitidine and baseline pH-values for the second part of the day. Intravenous administration of famotidine (20mg) induced a 2-fold greater duration of acid suppression in patients with renal failure than that seen in patients with normal renal function, whereas tl/2 was prolonged approximately 5-fold.(70) In another pharmacodynamic study with roxatidine it was shown that in patients with renal insufficiency the recommended dosage of 75mg every other day[90] is not appropriate for suppressing acid secretion throughout the second night.[94] In addition, no consistent relationship was observed between the individual plasma concentrations (or pharmacokinetic parameters) of histamine H2-receptor antagonists and the inhibition of acid secretion; this being in accordance with previous reports)95.96] Therefore, dosage adjustments based solely on pharmacokinetic calculations are insufficient as additional pharmacodynamic alterations have to be considered. For example, patients with peptic ulcer disease have lower median 24-hour pH-values than do healthy individuals.[97.98] Patients undergoing haemodialysis have higher gastric acidity and attenuated alkalinisation of gastric acidity by food compared with healthy individuals,[70.99] or may have an abnormal gastric motility) 100] This could explain the delayed onset of action following administration of roxatidine to patients with renal failure. In patients with normal renal function, the intake of histamine H2-receptor antagonists at nighttime[101.I02] or in the early evening[I03-105] results in gastric acid suppression superior to that resulting from daytime administration of the drug. This seems to be due to food-induced stimulation of acid secretion) I06] In contrast to otherwise healthy individuals, no such time-dependent differences were found in patients with renal failure. Following the intravenous administration of famotidine 20mg in the afternoon or evening, independent of the time of administration, the duration of action lasted for 22 (after the evening administration) to 23 (after the afternoon administration) hours in the dialysis Clin. Pharmacokinet. 27 (5) 1994
Treatment of Peptic Ulcer in Renal Insufficiency
399
Table II. Clinical studies with drugs for peptic ulcer in patients undergoing regular haemodialysis Dose (mg) and duration of treatment
Diagnosis (no. of patients) _E_ff_ic_a-'cy'--_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ __
Dohertyet al.[107]
400/day' or 800/dalfor 6 weeks
Jones et al[108]
Reference
symptomatic improvement
no symptomatic improvement
Active DU (4), chronic DU (4), chronic GU (1)
8
1 (active ulcer crater)
200 twice daily for 6 weeks d
Active DU (1), chronic DU (1), gastric erosions (2), gastritis (1), oesophagitis (4)
2"
3x75/week for 8 weeks'
Erosive gastritis (2), GU(1)
2x75/week for 8 weeks 9
Erosive gastritis (2), erosive gastroduodenitis (1)
3x75/week for 8 weeks 9
Erosive gastritis (2), GU(1)
endoscopically detected healing
no endoscopically detected healing
7
2 slight inflammation only
Cimetidine
Roxatidine Hachisu & Yoshida[80]
Omeprazole Montemurro 20/day for et al[1091 4 weeks
Active DU (8), active GU (3), erosive gastritis (5)
3 2
2
a
Without HD.
b
WithHD.
c
Repeated endoscopy only in patients with active peptic ulcer.
d
Patients were undergoing HD 2 to 3 times per week.
e
None of the other patients had symptoms initially.
f
Patients were undergoing HD 3 times per week.
g
Patients were undergoing HD 2 times per week.
16
12 (3 partial)
Abbreviations: DU = duodenal ulcer; GU = gastric ulcer; HD = haemodialysis.
patients compared with 6 (after the afternoon administration) to 11 (after the evening administration) hours in those with normal renal function.l 99J The difference between both populations could be explained by the prolonged action of famotidine masking the effect of food. Therefore, the drug can be given at any time of day to patients with renal failure. In uraemic patients only few studies are available assessing the pharmacodynamics of histamine H2-antagonists. Likewise, clinical data and data on the healing rates of peptic ulcer in patients with renal insufficiency are very limited (table II). Therefore dosage recommendations are normally based on pharmacokinetic parameters (e.g. AUC, CL, tJ;2) according to the extent of renal impairment (see table Ill). © Adis International limited. All rights reserved.
5. Pharmacokinetics of Pirenzepine in Patients with Renal Failure According to the results of studies undertaken at steady-state with pirenzepine in patients with differing degrees of renal dysfunction, CLR, CL and t'/2 of pirenzepine correlated with CLCR (table IV). However, Vd and CLNR were independent of renal function. Haemodialysis did not significantly contribute to the elimination of pirenzepine; during a 4-hour haemodialysis session only 0.9 to 1.3% of a lOmg dose could be recovered in the dialysate corresponding to a mean dialysis clearance of 9 ml/min (0.54 LIh).lIIO] Dosage adjustments need only to be considered in patients with a CLCR <25 mUm in (1.5 LIh) to reduce the incidence of adverse effects, e.g. sinus tachycardia and anticholinergic symptoms. elin. Pharmacokinet. 27 (5) 1994
400
Gladziwa & Klotz
Table III. Dosages for antiulcer drugs in patients with renal impairment Drug
Recommended dosage in patients with normal renal function (mg/day)
Cimetidine
800
Ranitidine
300
30-75 800 (150-)300 20-40
Famotidine
40
Nizatidine
300
Roxatidine
150
Pirenzepine
50mg bid
Omeprazole
20-40
Lansoprazole
Recommended dosage (mg/day) for patients with renal impairment [CLCA (ml/min)]a
150 75·150
30
50mg bid
30·15
5-15
<5
600
400
200-400
150 10·20 150
75-150 10-20
Aesp ("!o) HD 8-14.5 0.9-8.0
2.1-17.1
6.0-16.4
4.1-16.2 4.5
70
10.0
75mg q48h 75mg or 40mg q24h q48h or 40mg q24h
75mg 3/week
60
12.0
25mg bid
25mg bid
50
No dosage adjustment required
<1
No dosage adjustment required
<1
Should be avoided
Sucralfate (aluminium content)
1000mg qid (190mg qid) or 2000mg bid (380mg bid)
Should be avoided
Antacids (AI. Ca. Mg)
various regimens
Should be avoided
Misoprostol
2oo~g
No dosage adjustment required
0.26-0.28
10
PO
50-80
75
25mg bid
HF
70
150 q48h
624mg bid (215mg bid)
bid to qid
10
150 q48h
CBS (bismuth content)
a
75·150
Ae ("!o)
1.6-2.2 0.9-1.8
1.9
0.9-1.3
0.2
<1
To convert to Uh multiply by 0.06.
Abbreviations and symbols: Ae = cumulative amount of drug excreted unchanged in the urine; Aesp = amount of unchanged drug removed by the blood purification procedure; bid =twice daily; CBS =tripotassium dicitrato bismuthate (colloidal bismuth subcitrate); CLCA =creatinine clearance; HD =haemodialysis; HF =haemofiltration; PO =peritoneal dialysis; 3/week =3 times weekly; qxh =every x hours; qid =4 times daily.
6. Pharmacokinetics of Proton Pump Inhibitors in Patients with Renal Failure So far, omeprazole, lansoprazole, and pantoprazole are clinically available. Their elimination is primarily accomplished by the hepatic route as negligible amounts of unchanged drug are recovered in the urine. 6.1 Omeprazole
Pharmacokinetic data of omeprazole in patients with renal insufficiency and those undergoing dialysis procedures are summarised in table V. Absorption and pharmacokinetic profiles of omeprazole were not affected by dialysis.l lll ] Omeprazole could not be detected in dialysis fluids from any haemodialysis patient. The results from a single case report demonstrated that the AVe was lower during haemodialysis, suggesting indirectly that omep© Adis International Limited. All rights reserved.
razole might be dialysable.l 112 ] However, omeprazole was not measured in the dialysate. Disposition of omeprazole was unaltered in patients with renal failure compared with healthy individuals.fI13 ] However, the elimination of the total pool of metabolites was decreased in those patients. It could be speculated whether, in patients with renal dysfunction, extrarenal routes play a compensatory role in the elimination of omeprazole metabolites. Apparently omeprazole has no direct effect on the kidney and it does not affect urinary pH or renal handling of electrolytes, which is consistent with the specific effect of omeprazole on parietal cells.l 114 ] 6.2 Lansoprazole
Table VI provides the limited data available on the pharmacokinetics of lansoprazole in patients with renal failure.l 115 ] Because lansoprazole Clin. Pharmacokinet. 27 (5) 1994
401
Treatment of Peptic Ulcer in Renal Insufficiency
is hepatically eliminated, renal failure does not cause changes in its pharmacokinetics; however, in severe hepatic failure, a prolonged tl/2due to reduced CL can be seen. Lansoprazole is presystemically metabolised during absorption and its metabolites are eliminated via bile as well as renally. The changes in tl/b AUC and oral clearance seen in patients with mild renal failure [CLCR = 40 to 60 mUmin (2.4 to 3.6 Llh)] were attributed to the old age (>70 years) of the patients. Renal elimination of lansoprazole's principle metabolites (sulphone and sulphide metabolites, hydroxylated metabolites of the sui phone and sulphide, and glucuronidated metabolites) is decreased in relation to CLCR)115] 6,3 Pantoprazole
Pantoprazole has been administered intravenously as 2 single 40mg doses to 8 patients with stable renal impairment undergoing haemodialysis. In these patients AUC was only 46% of that observed in healthy volunteers; CL increased by 117 %, t 1;2 was 60% of that in healthy volunteers, and V d was increased by 45%. These results are consistent with a decrease in protein binding, which is frequently observed for acidic drugs in patients with renal impairment. It was not considered necessary to reduce the dose of pantoprazole in patients with renal impairment.[116]
7. Pharmacokinetics of Cytoprotective Agents in Patients with Renal Failure 7,1 Bismuth Salts
In patients with different degrees of impaired renal function, absorption and accumulation of tripotassium dicitrato bismuthate was studied} 117] Small amounts of bismuth (mean values of 0.26 to 0.28% of the administered dose) were rapidly absorbed; transient C max values between 40 and 134 Jlg/L were reached within 30 to 40 minutes. Absorption profiles were not altered during the 4-week treatment course. However, trough plasma concentrations of bismuth accumulated about 3- to 5-fold in patients with impaired renal function, concentrations increasing from about 5 to 15 Jlg/L (normal renal function) to 20 to 25 Jlg/L (impaired renal function). The increase in trough plasma concentrations appeared to correlate inversely with CLCR. Prestudy bismuth concentrations (2 to 10 Jlg/L) could be detected in all individuals within 2 to 4 weeks of stopping therapy, whereas urinary concentrations were still elevated 6 weeks after the course of treatment was completed in patients with renal insufficiency. [117] Thus, it appears prudent to halve the bismuth dosage in patients with moderately impaired renal function [CLCR ~25 ml/min (1.5 Llh)] to avoid any accumulation and associated possible toxic risks. Whether such reduced
Table IV. Mean (± SO) steady-state pharmacokinetic data (range in parenthesis) for pirenzepine after intravenous administration of 10mg twice daily to patients with normal renal function and those with renal insufficiency[1101 No. of patients
CLCR (ml/min)"
l1,,, (h)
13
126 (94-166)
12
68 (54-85)
12
7 (33-24)
CLNR (ml/min)"
C~n (mg/L)
78 ± 6.5
134 ± 71
36± 16
46 ± 18
119±74
45±20
102±40
71 ± 30
Vss (Ukg)
CL (ml/min)"
CLR (ml/min)"
11.1 ± 3.8
1.7 ± 0.3
180 ± 47
15.0 ± 2.0
1.7±0,4
165 ± 75
15.9 ± 3.5
1.3±0.3
113 ± 39
6.8 ± 5.3
10
HOb
16.3 ± 2.5
1.3±0.5
86±26
86±26
81 ± 33
10
HOC
18.9 ± 4.0
1.4 ± 0.4
101 ± 24
101 ± 24
75 ± 16
a
To convert to Uh multiply by 0,06.
b
Anuric patients (CLCR <5 ml/min) during the period that haemodialysis (HO) was not performed.
c
Anuric patients (CLCR <5 milmin) during the period that HO was performed,
Abbreviations: CLCR =creatinine clearance; CL =total body clearance; CLR = renal clearance; CLNR concentration at steady-state; tl;, = elimination half-life; Vss = volume of distribution at steady-state.
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=nonrena[ clearance; C~;n =minimum
Clin . Pharmacokinet. 27 (5) 1994
402
Gladziwa & Klotz
Table V. Mean (± SO) pharmacokinetic data (range in parenthesis) for single dose omeprazole in patients with renal insufficiency No. of CLcR patients (ml/min)a
6
12
Oose (mg)
F (%)
Imax (h)
Cmax (flglL)
AUC (mglL' h)
t'l, (h)
HOb
30 PO
0.92±0.58
478 ± 370
0.89 ± 1.17
HOc
30 PO
1.75 ± 2.16
549±437
0.84 ± 0.86
Vc
V,
(Ukg)
(Ukg)
CL (ml/min)a
108
HOb
1.25
3.0
220
HOc
0.97
1.8
378
40lV 40lV 28.1 ± 15.7 20lV
0.57
re 0.21
References
0.17 ± 0.05
109
0.35 ± 0.06 562 ± 217 110
(10-62)
40 PO
69 ± 31
0.24 ± 0.10
1099 ± 524
0.60 ± 0.26
a
To convert to Uh multiply by 0.06.
b
Anuric patients (CLCR <5 ml/min) during the period that they were not undergoing haemodialysis (HO) .
c
Anuric patients (CLCR <5 ml/min) during the period that they were undergoing HO.
Abbreviations: AUC =area under the plasma concentration-time curve; CL =total body clearance; CLcR =creatinine clearance; Cmax =maximal plasma concentration; F =bioavailability; IV =intravenous; PO =orally; t max =time taken to achieve C max; t'li =elimination half-life; Vc =volume of distribution of the central compartment; V, = volume of distribution during the terminal elimination phase.
dosage will affect the therapeutic efficacy of the drug remains to be clarified. In patients with renal failure [CLCR <25 ml/min (1.5 L/h)] bismuth salts are contraindicated. Monotherapy with tripotassium dicitrato bismuthate resulted in the eradication of H. pylori in 28% of our patients with renal insufficiency[ 117] compared with eradication of the pathogen in 6 to 37% of patients with normal renal function.[118] In a single patient with chronic renal failure who took twice the recommended dose of tripotassium dicitrato bismuthate (864mg daily for 2 months), bismuth-induced encephalopathy was reported.[119] Therefore, the authors concluded, correctly, that bismuth is contraindicated in patients with renal failure . 7.2 Sucralfate
Sucralfate is the aluminium salt of sulphated sucrose and by weight it contains 21 % aluminium. Aluminium can dissociate from sucralfate at a low pH and become systemically available. In patients on dialysis, sucralfate caused a decrease in serum phosphate, but plasma concentrations of aluminium increased after 3 weeks of therapy to concentrations similar to those seen when patients are treated with aluminium hydroxide.l 120] As aluminium toxicity may occur during therapy with sucralfate in patients with renal failure (see also section © Adis InternotionolUmited. All rights reserved.
7.3),[120,121] this drug should not be used in these patients. 7.3 Antacids
The majority of antacids contain aluminium, calcium and/or magnesium, which will be absorbed partly in the gastrointestinal tract and subsequently excreted mainly by the kidneys. In patients with renal failure, elimination of these cations is reduced and thus accumulation will result in hyperaluminaemia, hypercalcaemia and hypermagnesaemia. Plasma aluminium concentrations are poor indices of aluminium absorption in healthy individuals ; increments in urinary excretion of aluminium are much more sensitive indicators of its absorption.l 122 ] Antacids represent effective ulcer healing agents.l 123 ] In addition, calcium carbonate has been used in several studies in patients undergoing dialysis (to avoid the risk of aluminium toxicity) and its efficacy in lowering serum phosphate levels has been demonstrated.l 124,125] About one-quarter of patients receiving calcium carbonate develop hypercalcaemia, which resolves upon stopping the drug or when a low-calcium dialysate is used. Risks concerning metastatic calcinosis with long term calcium carbonate therapy have never been completely evaluated and thus serum calcium levels should be monitored. Magnesium salts alone or combined Clin. Phormocokinet. 27 (5) 1994
403
Treatment of Peptic UIcer in Renal Insufficiency
with calcium carbonate have also been used to control serum phosphate. The high frequency of adverse effects together with the need for a lowmagnesium dialysate have impeded its widespread use. We found that prophylactic antacid therapy with magaldrate, a complex of hydroxymagnesium aluminate, caused elevated aluminium serum concentrations in critically ill patients with normal renal function. Additional impairment of renal function further aggravates aluminium accumulation due to disturbed renal elimination and, possibly, enhanced intestinal absorption of aluminium) 126]
served between 3 groups of individuals with impaired renal function. Moreover, there was no correlation between AVC and the rate of clearance of 5ICr-EDTA, as a measure of the glomerular filtration rate. Values for C m ax , AUC and tIl2 of misoprostol acid were significantly higher if all patients with renal impairment were compared with healthy individuals, possibly reflecting the changes in Vd. These differences do not result in a need to modify misoprostol dosage in patients with renal impairment; however, we would suggest that lower doses are used to start treatment in these patients.
8. TherapeutiC Considerations in Patients with Renal Failure
7.4 Prostaglandin Derivatives
Misoprostol, a synthetic prostaglandin El analogue, is well absorbed and undergoes extremely rapid presystemic de-esterification to its biologically active metabolite, misoprostol acid. No unchanged drug is found in urine. Misoprostol acid has a very short tIl2of about 1.5 hours and is rapidly biotransformed to a number of metabolites that are excreted by the kidneys.[I27] Only 1 to 4% ofmisoprostol acid is found in the urine. Renal insufficiency does not change the pharmacokinetic profile of misoprostol to any great extent and thus dosage reduction is not required in renal failure . Table VII summarises the pharmacokinetic parameters of misoprostol in patients with renal insufficiency.[128] No statistically significant differences in mean plasma concentrations were ob-
Ulcer treatment should aim to provide rapid pain relief, complete healing of ulcer, as well as prevention of relapses and complications of the disease. These goals can be achieved, for instance, by histamine H2-receptor antagonists, which also demonstrate good safety records. In equipotent doses (in terms of inhibition of acid secretion), histamine H2-antagonists are almost equally effective in the treatment of peptic ulcer disease. As they are eliminated primarily by the kidneys as unchanged drug, renal insufficiency or old age will result in decreased CL and increased t1/2. Consequently, during multiple administration, accumulation of drug will occur under such clinical conditions and the frequency and/or intensity of adverse effects will increase. For example, increased CNS toxicity and
Table VI. Pharmacokinetic data (mean ± SD; range in parenthesis) after administration of a single oral dose of lansoprazole 30mg to patients with normal renal function and renal insufficiency (data from Delhotal-Landes et a/. I115J ) No. of patients
CLCR (ml/min)a
tmax (h)
C max (Jlg/L)
18
t,f.2 (h)
AUC (mg/L· h)
Vd/F (Ukg)
CUF (Uh/kg)
Aem ("!o)
>90
1.5±0.5
1033 ± 408
1.4 ± 0.8
2.7± 1.7
0.45 ± 0.18
0.26 ± 0.14
23.0
6
53.7 ± 5.7 (43-59)
1.6±0.5
1279 ±508
4.1 ±2.0
5.5 ±2.9
0.37±0.16
0.13 ± 0.10
11.8
6
29.8 ±8.5 (20-39)
1.7 ±0.5
940 ± 476
2.6 ± 2.2
3.3 ± 4.4
0.85 ±0.88
0.43 ± 0.45
7.6
5
12.8 ± 5.3 (8.2-19)
1.4±0.2
942 ±282
1.6±0.7
2.8± 1.7
0.41 ±0.11
0.21 ±0.11
4.3
Abbreviations: Aem = amount of free and conjugated metabolites excreted in the urine; AUC =area under the plasma concentration-time curve; Cmax = maximal plasma concentration ; CUF = apparent oral clearance; CLCR = creatinine clearance; tmax = time taken to achieve Cmax; t'f.2 =elimination half-life; Vd/F =apparent oral volume of distribution.
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Clin. Pharmacokinet. 27 (5) J994
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Gladziwa & Klotz
Table VII. Pharmacokinetic data (mean ± SO) after administration of a single oral dose of misoprostol 400l1g to healthy individuals and patients with various degrees of renal impairment (data from Nicholson et al.11281) No. of patients
CLof 51Cr-EOTA (ml/min)·
Cmax (ng/L)
AUC (nglL· h)
tl;' (min)
10
healthy individuals
407 ± 167
302 ± 128
25.6 ±5.9
8
11-40
973 ± 973
876 ±905
39.9 ± 14.7
6
5-10
716 ± 288
624 ± 173
54.6 ±23.9
6
<5
684 ±330
565± 191
32.0 ±34.1
809 ±647'
707 ± 583'
41.9 ± 19.1'
All patients (20) a
To convert to Uh multiply by 0.06.
Abbreviations and symbols: AUC = area under the plasma concentration-time curve; CL = clearance; Cm., = maximal plasma concentration; tl;' = elimination half-life; • indicates a statistically significant difference compared with healthy individuals, p < 0.05.
mental confusion has been described with cimetidine)129] Therefore, appropriate dosage reduction of histamine H2-receptor antagonists, on the basis of CLCR, is mandatory. Histamine H2-antagonists are minimally cleared by dialysis and do not need to be supplemented after dialysis. Ulcer relapse is associated with presence of H. pylori. Presently, concomitant treatment with omeprazole 20mg twice a day preprandially and amoxicillin Ig twice a day postprandially for 2 weeks is favoured for eradication of H. pylori.! 130] It is important to recognise that the pharmacokinetics of amoxicillin are affected by renal impairment: t'!2 is increased from 1.0 hour in healthy volunteers to about 14 hours in patients with chronic renal failure)I3I .132] Maintenance doses of amoxicillin should be administered after haemodialysis sessions, because dialysis leads to a significant decrease in the t'!2 of amoxicillin with a tl/2 on dialysis of 2.5 hours)131 ,132] In patients with renal insufficiency, a reduction of the normal dose between two-thirds to one-third is recommended.
9. Conclusions Histamine H2-receptor antagonists can still be considered as a kind of 'gold' standard for the treat© Adis International Limited. All rights reserved.
ment of peptic lesions based on their large therapeutic margins, extensive safety records and well-documented clinical efficacy. However, the elimination of histamine H2-receptor antagonists is subject to significant and clinically relevant alterations in patients with impaired renal function. This is not surprising since renal excretion represents the predominant route of their elimination. Therefore modifications of the dosage regimen are required in this population, and should be based on the actual renal function (i.e. as reflected by the CLCR) of the patient. Blood purification procedures employed in such patients, however, have no major effect on the dosage schedule because only negligible quantities of histamine H2-receptor antagonists are removed by this route. Thus, histamine H2-receptor antagonists can be categorised as poorly dialysable drugs. The pharmacodynamic response to histamine H2-receptor antagonists in patients with renal insufficiency is less well defined. The limited data available show a prolonged duration of action in those patients. In the future, clinical aspects should be addressed more extensively because the pharmacodynamic response is the key factor that actually determines therapeutic efficacy. Proton pump inhibitors can offer an alternative treatment of peptic ulcer disease in patients with renal impairment without the need for dosage adjustment. However, further long term studies are required in this patient group to assess the safety and efficacy of these agents. The remaining substances described in this review have a limited role in the treatment of peptic ulcer in patients with renal failure because of their need to be administered several times a day (resulting in a lower compliance), or because of more frequent (and sometimes severe) adverse effects and/or lower clinical efficacy. As bismuth and aluminium (from sucralfate or antacids) as well as calcium and magnesium will accumulate to potentially toxic concentrations during long term use in patients with renal insufficiency, such drugs should be avoided. Clin. Pharmacokinet. 27 (5) 1994
Treatment of Peptic Ulcer in Renal Insufficiency
Acknowledgements This work was supported by the Robert Bosch Foundation , Stuttgart, Germany.
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Clin. Pharmacokinet. 27 (5) 1994
Treatment of Peptic Ulcer in Renal Insufficiency
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Correspondence and reprints: Prof. Dr U. Klotz, Dr. Margarete Fischer-Bosch-Institut fur Klinische Pharmakoiogie, AuerbachstrafSe 112, D-70376 Stuttgart, Germany.
Clin. Pharmacokinet. 27 (5) 1994
