Control of clofibrate toxicity in uremic hypertriglyceridemia A daily dose of 1 .5 to 2.0 gm of clofibrate lowers serum triglyceride (TG) levels in patients with normal renal function but causes muscle toxicity and elevated creatine phosphokinase (CPK) levels in patients with long-term renal failure. Plasma clofibrate disappearance is prolonged as much as seven times normal in severely uremic patients. A marked reduction in the standard 14 gm/wk clofibrate dose to a total dose of 1.0 to 1.5 gm/wk effectively lowered serum TG levels (-28%, p < 0.02) in hypertriglyceridemic hemodialysis patients without toxicity. The serum clofibrate level at this dose was comparable to that in hypertriglyceridemic nonuremic patients receiving 14 gm/wk of clofibrate. The dose of clofibrate administered to hemodialysis patients can be adjusted to avoid toxicity and provide the desired therapeutic effect by monitoring serum CPK and TG levels.
Andrew P. Goldberg, M.D., Donald J. Sherrard, M.D., Linda B. Haas, R.N., and John D. Brunzell, M.D. Seattle, Wash. Department of Medicine, University of Washington, and Seattle Veterans Administration Hospital
Patients maintained on chronic hemodialysis are subject to the development of several metabolic abnormalities 21 which may shorten their survival. The frequency of hypertension, carbohydrate intolerance, and hypertriglyceridemia, risk factors for atherosclerosis ,2, 11, 17, 24, 29, 3t, 38, 39, 41 is high in patients on Supported by a grant from Ayerst Laboratories, New York, N. Y., and Grants AM-02456 and HL-18697 from the National Institutes of Health. Part of this work was performed on the Metabolic Ward, Seattle Veterans Administration Hospital, and at the Clinical Research Center, University of Washington Hospital (Public Health Service Grant FR-37). Presented at the annual meeting of the Western Society for Clinical Research, Carmel, Calif., Feb. 6, 1976. Received for pUblication Aug. 20, 1976. Accepted for pUblication Nov. II, 1976. Reprint requests to: John D. Brunzell, M.D., University of Washington Medical Center, Department of Medicine RG-20, Seattle, Wash. 98195.
long-tenn hemodialysis. 2.3.4,9,20-22,27,32,34,35 A premature mortality rate related to atherosclerotic complications, especially myocardial infarction and stroke, has been reported, 20, 22, 32, 34, 35 but the mechanism for the accelerated cardiovascular risk in dialysis patients has not been detennined. It seems warranted that therapeutic intervention be directed at the potentially reversible risk factors for vascular disease that occur in dialysis patients until the specific etiologic factors can be defined. There is evidence suggesting that patients with hypertriglyceridemia are at an increased risk for coronary artery disease. 10, 11, 24, 41 This association appears to apply particularly to patients with diabetes mellitus, 42 chronic renal failure, 20, 22, 32 and with other risk factors for coronary artery disease. 10, 17, 29, 38, 41 The re317
318
Goldberg et al.
Clinical Pharmacology and Therapeutics
Table I. Clofibrate kinetics: Patient data Age (yr)
Serum creatinine (mg/dl)
Uremic group (N = 5) 44 ± 12 11.7 ± 3.6* Nephrotic group (N = 5) 48 ± 7 1.3 ± 0.1
Creatinine clearance (mlimin)
3.9 ± 100
4.8*
± 24
Nonuremic control group (N = 8) 47 ± 9 1.2 ± 0.2 98 ± 20
Serum albumin (gm/dl)
Plasma clofibrate half-life (hr)
3.8 ± 0.3
109.6 ± 35.9*
2.3 ± 0.5*
8.7 ±
4.0 ± 0.4
16.5 ±
3.5t 4.7
Protein excretion (gm/day)
1.3 ±
0.8
13.2 ± 11.9*
o
*p < 0.00 I compared with nonuremic control subjects. tp < 0.01 compared with nonuremic subjects.
sults obtained from the relevant intervention trials 14 , 15, 36. 37 undertaken' to evaluate the efficacy of lipid-lowering drugs or dietary modification in the prevention of new events of coronary artery disease have been equivocal and inconclusive. l The importance of lowering plasma triglycerides in hyperlipidemic patients therefore remains to be proved. Clofibrate effectively lowers plasma triglyceride levels in nonuremic hypertriglyceridemi~ patients. 5. 13. 26. 33 Most patients with normal renal function tolerate clofibrate without difficultyY' 26. 33 On the other hand, an acute manifestation of clofibrate toxicity, severe myositis and elevated creatine phosphokinase (CPK) levels has been reported in patients with varying degrees of chronic renal failure,16. 40 the nephrotic syndrome,7 and normal renal function. 30. 43. 44 In nonuremic patients the reason for this syndrome is not apparent, but its presence suggests the necessity for the measurement of CPK, in addition to other tests, during clofibrate therapy. 18. 19 Gugler and associates 25 have documented the importance of the kidney in the metabolism of clofibrate, but no kinetic data for clofibrate has been reported in severe uremia. This study was designed to: (I) determine the rate of plasma clofibrate disappearance in patients with long-term renal failure and patients with the nephrotic syndrome, and (2) determine whether an appropriate reduction in clofibrate dosage would reduce or eliminate the previously reported toxicity7. 16, 40 while retaining the hypolipidemic effect of the drug in the treatment of hypertriglyceridemia in patients receiving maintenance hemodialysis.
Methods
Patient selection. In the pharmacokinetic study, 5 male patients with long-term renal failure, normal serum albumin, and minimal proteinuria, 5 male subjects with the nephrotic syndrome but normal creatinine clearance, and 8 male subjects with normal renal function were compared (Table I). All medications were stopped 48 hr prior to the administration of clofibrate. No patient was taking drugs that persist for long periods or are known to compete with clofibrate for protein-binding sites, absorption, or metabolism. In the therapeutic trial, 13 nonnephrotic patients on maintenance hemodialysis were selected for treatment with clofibrate based on the following criteria: (I) age- and sex-adjusted plasma triglyceride (TG) in the 95th percentile for a previously described nonuremic population studied in this laboratory23; (2) no history of previous cardiovascular, thromboembolic, peripheral vascular, endocrine, or hepatobiliary disease; (3) not on glucocorticoid therapy; and (4) hemodialysis on a three times per week schedule. Seventeen nonuremic hypertriglyceridemic subjects were chosen as a control group based on the following criteria: (1) plasma TG in the 99th percentile for an agematched control population 23; (2) not on drugs known to compete with clofibrate for proteinbinding sites or metabolism; (3) no history of previous thromboembolic, endocrine, or hepatobiliary disease (4) normal serum albumin levels; (5) not receiving glucocorticoid therapy; and (6) normal renal function. All patients were ambulatory during the study.
Clofibrate toxicity in uremia
Volume 21 Number 3
319
Table II. Hemodialysis patients: Baseline data Duration Pahemodialysis tient Sex Age %IBW (mo)
1 2 3 4 5 6 7 8 9 10 11 12 13
M M M M M M F M F M M M M
Mean SD *Excluding
43 50 35 40 52 30 54 23 45 38 42 27 31 39 10
101 91 115 93 118 93 122 120 132 133 145 126 90 113 18
72
156 36 18 108 60 24 12 24 18 12 30 96 51 45
Mean creatinine (mg/dl)
Albumin (gm/dl)
Age-adjusted TG (percentile)
20.6 10.0 10.8 15.9 12.9 11.4 12.8 18.0 10.8 15.2 17.4 19.8 13.6
4.1 4.4 3.9 3.8 4.5 4.3 4.2 4.5 3.8 4.2 3.6 4.1 4.2
99 99 99 99 97 99 95 99 96 96 95 97 95
Clofibrate treatment (wk) 2-3 gm/wk 11-1.5 gm/wk
4 2 14 5 2 3 3 9 16 4 4* 2
17 25 8 10 9 8 9 10 6 9 19 12 6
Patients 3 and 10.
Experimental design. Pharmacokinetic study. All patients were studied after a 12-hr overnight fast. Clofibrate, 1 gm, was ingested and plasma samples were obtained after 0,2,4,8, 12, 14,24,28,32,36, and 48 hr for clofibrate levels. Three of the patients with long-term renal failure were on maintenance hemodialysis. In these patients, clofibrate was administered 40 hr after the completion of the last previous dialysis. Their next dialysis was 48 hr after the administration of the drug. The half-life of total clofibrate in plasma was determined by regression analysis of the logarithm of the clofibrate level from 8 to 28 hr after drug ingestion, the period during which the concentration was related to time in a loglinear fashion. Clofibrate clearance during dialysis was calculated in 2 patients on hemodialysis by the method of Christopher and associates. 12 Therapeutic trial. Four pretreatment fasting venous serum samples were obtained on different days from each dialysis patient for the determination of TG, cholesterol, potassium (K+), and CPK levels. All samples were obtained after a 12-hr overnight fast on the day representing the longest period of time without dialysis. The nonuremic hypertriglyceridemic subjects received 2 gm of clofibrate per day in divided doses and had blood samples drawn
after a 12-hr overnight fast for the determination of clofibrate levels. Based on the pharmacokinetic data (see section in "Results"), 10 dialysis patients (Tables II and III, Patients 1 to 8, 10, and 12) received 2.0 to 3.0 gm/wk of clofibrate in divided doses (1 gm after each dialysis or 500 mg every other day). Weekly serum samples, drawn after a 12-hr fast on the day representing the longest time period without dialysis, were analyzed for CPK, K+ , TG, cholesterol, and clofibrate levels. After 4 ± 2 wk the clofibrate dose was decreased to 1.5 gm/wk (0.5 gm after each dialysis) in 8 patients (Table III, Patients 1 to 3, 5 to 7, 10, and 12) when elevated CPK and clofibrate levels were detected. Two patients (Table II, Patients 4 and 8) withdrew from the study. At this time 3 additional hypertriglyceridemic hemodialysis patients (Table III, Patients 9, 11, and 13) were started on treatment with 1.5 gm/wk (Tables II and III). On this lower dose, serum was analyzed weekly for CPK, clofibrate, K+, TG, and cholesterol levels for the first 4 wk· and then every 2 wk for the remainder of the study (12 ± 6 wk). Anyelevation in CPK or K+ above the normal range or any symptom related to the musculoskeletal or cardiovascular system was presumed to be due to clofibrate toxicity and the medication was stopped. During the study there was no sig-
320
Goldberg et al.
Clinical Pharmacology and Therapeutics
Uremic(S)
60
I I
lG Clofibrote P.O.
+
o
24
12
48
36
HOURS
Fig. 1. Plasma clofibrate concentration and half-life in uremic and normal subjects after a single oral dose of I gm (. = significantly different from control subjects, p < 0.01).
400 ~
c§
2-3 G/WK
~
I~
~
... 300
"
~
~ it
f
~ 200
...
\0
~ ~
100
~
t.--29:!: 21"1. p
Andrew P. Goldberg, M.D., Donald J. Sherrard, M.D., Linda B. Haas, R.N., and John D. Brunzell, M.D. Seattle, Wash. Department of Medicine, University of Washington, and Seattle Veterans Administration Hospital
Patients maintained on chronic hemodialysis are subject to the development of several metabolic abnormalities 21 which may shorten their survival. The frequency of hypertension, carbohydrate intolerance, and hypertriglyceridemia, risk factors for atherosclerosis ,2, 11, 17, 24, 29, 3t, 38, 39, 41 is high in patients on Supported by a grant from Ayerst Laboratories, New York, N. Y., and Grants AM-02456 and HL-18697 from the National Institutes of Health. Part of this work was performed on the Metabolic Ward, Seattle Veterans Administration Hospital, and at the Clinical Research Center, University of Washington Hospital (Public Health Service Grant FR-37). Presented at the annual meeting of the Western Society for Clinical Research, Carmel, Calif., Feb. 6, 1976. Received for pUblication Aug. 20, 1976. Accepted for pUblication Nov. II, 1976. Reprint requests to: John D. Brunzell, M.D., University of Washington Medical Center, Department of Medicine RG-20, Seattle, Wash. 98195.
long-tenn hemodialysis. 2.3.4,9,20-22,27,32,34,35 A premature mortality rate related to atherosclerotic complications, especially myocardial infarction and stroke, has been reported, 20, 22, 32, 34, 35 but the mechanism for the accelerated cardiovascular risk in dialysis patients has not been detennined. It seems warranted that therapeutic intervention be directed at the potentially reversible risk factors for vascular disease that occur in dialysis patients until the specific etiologic factors can be defined. There is evidence suggesting that patients with hypertriglyceridemia are at an increased risk for coronary artery disease. 10, 11, 24, 41 This association appears to apply particularly to patients with diabetes mellitus, 42 chronic renal failure, 20, 22, 32 and with other risk factors for coronary artery disease. 10, 17, 29, 38, 41 The re317
318
Goldberg et al.
Clinical Pharmacology and Therapeutics
Table I. Clofibrate kinetics: Patient data Age (yr)
Serum creatinine (mg/dl)
Uremic group (N = 5) 44 ± 12 11.7 ± 3.6* Nephrotic group (N = 5) 48 ± 7 1.3 ± 0.1
Creatinine clearance (mlimin)
3.9 ± 100
4.8*
± 24
Nonuremic control group (N = 8) 47 ± 9 1.2 ± 0.2 98 ± 20
Serum albumin (gm/dl)
Plasma clofibrate half-life (hr)
3.8 ± 0.3
109.6 ± 35.9*
2.3 ± 0.5*
8.7 ±
4.0 ± 0.4
16.5 ±
3.5t 4.7
Protein excretion (gm/day)
1.3 ±
0.8
13.2 ± 11.9*
o
*p < 0.00 I compared with nonuremic control subjects. tp < 0.01 compared with nonuremic subjects.
sults obtained from the relevant intervention trials 14 , 15, 36. 37 undertaken' to evaluate the efficacy of lipid-lowering drugs or dietary modification in the prevention of new events of coronary artery disease have been equivocal and inconclusive. l The importance of lowering plasma triglycerides in hyperlipidemic patients therefore remains to be proved. Clofibrate effectively lowers plasma triglyceride levels in nonuremic hypertriglyceridemi~ patients. 5. 13. 26. 33 Most patients with normal renal function tolerate clofibrate without difficultyY' 26. 33 On the other hand, an acute manifestation of clofibrate toxicity, severe myositis and elevated creatine phosphokinase (CPK) levels has been reported in patients with varying degrees of chronic renal failure,16. 40 the nephrotic syndrome,7 and normal renal function. 30. 43. 44 In nonuremic patients the reason for this syndrome is not apparent, but its presence suggests the necessity for the measurement of CPK, in addition to other tests, during clofibrate therapy. 18. 19 Gugler and associates 25 have documented the importance of the kidney in the metabolism of clofibrate, but no kinetic data for clofibrate has been reported in severe uremia. This study was designed to: (I) determine the rate of plasma clofibrate disappearance in patients with long-term renal failure and patients with the nephrotic syndrome, and (2) determine whether an appropriate reduction in clofibrate dosage would reduce or eliminate the previously reported toxicity7. 16, 40 while retaining the hypolipidemic effect of the drug in the treatment of hypertriglyceridemia in patients receiving maintenance hemodialysis.
Methods
Patient selection. In the pharmacokinetic study, 5 male patients with long-term renal failure, normal serum albumin, and minimal proteinuria, 5 male subjects with the nephrotic syndrome but normal creatinine clearance, and 8 male subjects with normal renal function were compared (Table I). All medications were stopped 48 hr prior to the administration of clofibrate. No patient was taking drugs that persist for long periods or are known to compete with clofibrate for protein-binding sites, absorption, or metabolism. In the therapeutic trial, 13 nonnephrotic patients on maintenance hemodialysis were selected for treatment with clofibrate based on the following criteria: (I) age- and sex-adjusted plasma triglyceride (TG) in the 95th percentile for a previously described nonuremic population studied in this laboratory23; (2) no history of previous cardiovascular, thromboembolic, peripheral vascular, endocrine, or hepatobiliary disease; (3) not on glucocorticoid therapy; and (4) hemodialysis on a three times per week schedule. Seventeen nonuremic hypertriglyceridemic subjects were chosen as a control group based on the following criteria: (1) plasma TG in the 99th percentile for an agematched control population 23; (2) not on drugs known to compete with clofibrate for proteinbinding sites or metabolism; (3) no history of previous thromboembolic, endocrine, or hepatobiliary disease (4) normal serum albumin levels; (5) not receiving glucocorticoid therapy; and (6) normal renal function. All patients were ambulatory during the study.
Clofibrate toxicity in uremia
Volume 21 Number 3
319
Table II. Hemodialysis patients: Baseline data Duration Pahemodialysis tient Sex Age %IBW (mo)
1 2 3 4 5 6 7 8 9 10 11 12 13
M M M M M M F M F M M M M
Mean SD *Excluding
43 50 35 40 52 30 54 23 45 38 42 27 31 39 10
101 91 115 93 118 93 122 120 132 133 145 126 90 113 18
72
156 36 18 108 60 24 12 24 18 12 30 96 51 45
Mean creatinine (mg/dl)
Albumin (gm/dl)
Age-adjusted TG (percentile)
20.6 10.0 10.8 15.9 12.9 11.4 12.8 18.0 10.8 15.2 17.4 19.8 13.6
4.1 4.4 3.9 3.8 4.5 4.3 4.2 4.5 3.8 4.2 3.6 4.1 4.2
99 99 99 99 97 99 95 99 96 96 95 97 95
Clofibrate treatment (wk) 2-3 gm/wk 11-1.5 gm/wk
4 2 14 5 2 3 3 9 16 4 4* 2
17 25 8 10 9 8 9 10 6 9 19 12 6
Patients 3 and 10.
Experimental design. Pharmacokinetic study. All patients were studied after a 12-hr overnight fast. Clofibrate, 1 gm, was ingested and plasma samples were obtained after 0,2,4,8, 12, 14,24,28,32,36, and 48 hr for clofibrate levels. Three of the patients with long-term renal failure were on maintenance hemodialysis. In these patients, clofibrate was administered 40 hr after the completion of the last previous dialysis. Their next dialysis was 48 hr after the administration of the drug. The half-life of total clofibrate in plasma was determined by regression analysis of the logarithm of the clofibrate level from 8 to 28 hr after drug ingestion, the period during which the concentration was related to time in a loglinear fashion. Clofibrate clearance during dialysis was calculated in 2 patients on hemodialysis by the method of Christopher and associates. 12 Therapeutic trial. Four pretreatment fasting venous serum samples were obtained on different days from each dialysis patient for the determination of TG, cholesterol, potassium (K+), and CPK levels. All samples were obtained after a 12-hr overnight fast on the day representing the longest period of time without dialysis. The nonuremic hypertriglyceridemic subjects received 2 gm of clofibrate per day in divided doses and had blood samples drawn
after a 12-hr overnight fast for the determination of clofibrate levels. Based on the pharmacokinetic data (see section in "Results"), 10 dialysis patients (Tables II and III, Patients 1 to 8, 10, and 12) received 2.0 to 3.0 gm/wk of clofibrate in divided doses (1 gm after each dialysis or 500 mg every other day). Weekly serum samples, drawn after a 12-hr fast on the day representing the longest time period without dialysis, were analyzed for CPK, K+ , TG, cholesterol, and clofibrate levels. After 4 ± 2 wk the clofibrate dose was decreased to 1.5 gm/wk (0.5 gm after each dialysis) in 8 patients (Table III, Patients 1 to 3, 5 to 7, 10, and 12) when elevated CPK and clofibrate levels were detected. Two patients (Table II, Patients 4 and 8) withdrew from the study. At this time 3 additional hypertriglyceridemic hemodialysis patients (Table III, Patients 9, 11, and 13) were started on treatment with 1.5 gm/wk (Tables II and III). On this lower dose, serum was analyzed weekly for CPK, clofibrate, K+, TG, and cholesterol levels for the first 4 wk· and then every 2 wk for the remainder of the study (12 ± 6 wk). Anyelevation in CPK or K+ above the normal range or any symptom related to the musculoskeletal or cardiovascular system was presumed to be due to clofibrate toxicity and the medication was stopped. During the study there was no sig-
320
Goldberg et al.
Clinical Pharmacology and Therapeutics
Uremic(S)
60
I I
lG Clofibrote P.O.
+
o
24
12
48
36
HOURS
Fig. 1. Plasma clofibrate concentration and half-life in uremic and normal subjects after a single oral dose of I gm (. = significantly different from control subjects, p < 0.01).
400 ~
c§
2-3 G/WK
~
I~
~
... 300
"
~
~ it
f
~ 200
...
\0
~ ~
100
~
t.--29:!: 21"1. p
