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Absorption of digoxin in children with cystic fibrosis
PEDIATRIC PHARMACOLOGY AND THERAPEUTICS PaulS. Lietman, Edito,
Absorption of digoxin in children with cystic fibrosis The absorption o[digoxin in cystic fibrosis was evaluated in 16 sut~/ects by assessing the relationship between dosage expressed in t*g/kg/day and serum digoxin concentration. The results indicate that the same relationship exists between maintenance dosage and serum levels in these patients and in patients without cystic fibrosis. Thus, no evidence of impaired absopption wasJound.
Arthur a. Moss, M.D., Simon Finkelstein, M.D., Catherine Crudup, B.S., Guillermo A. Young, M.D., Richard R. Dooley, M.D., and Alan B, Osher, M.D., L o s A n g e l e s , Cal([~
COR PULMONALE iS a common complication in cystic fibrosis. 1 Since digoxin is often included in the management of cot pulmonale, the question has been raised whether patients with cystic fibrosis absorb the drug in adequate amounts. Digoxin is a lipid soluble glycoside 2 and cystic fibrosis is characterized by defective fat absorption, which is only partly correctible by pancreatic enzyme supplements. To assess digoxin absorption in this disease, we have measured concentrations o.f serum digoxin in patients with cystic fibrosis and evaluated the relationship between digoxin concentration and dosage. The results were compared to similar data in patients without cystic fibrosis.
MATERIALS AND METHODS Serum digoxin concentrations were determined in 16 patients with severe cystic fibrosis; 11 had been prophylactically digitalized, and five had evidence of heart failure. The age range was 3 to 23 years, with eight patients in the 3- to 14-year age range ( ~ = 9.2 _+ 4), and eight in the 15- to 23-year age range ( ~ = 18.6 + 3). A total of 22 concentrations of serum digoxin were m e a s u r e d in samples o b t a i n e d at least 7 days after From the Departments of Pediatrics and Pathology UCLA School of Medicine. Supported by grangsJ)'om the National Cystic Fibrosis Foundation and the Burt~oughs Wellcome Company, lnc.
digoxin therapy was begun, and 6 to 9 hours after the last dose. All patients were given digoxin in tablet form ( L a n o x i n ) , and, in a d d i t i o n , r e c e i v e d p a n c r e a t i c e n z y m e s (Viokase or Cotazym) with every meal. Eleven patients were digitalized and maintained according to current pediatric practice, 3 and five were digitalized by the "slow method ''4 (no loading dose given). M a i n t e n a n c e digoxin was a d m i n i s t e r e d daily in two divided doses, at breakfast and after dinner. The digoxin assay was performed by the method of Smith and associates s with a few minor modifications as previously described. 6 The data were compared to results obtained at this institution under similar circumstances in a control group consisting of 29 infants and children in the age range 2 months to 14 years, with no evidence of malabsorption. This group consisted of patients with a variety of congenital heart lesions who were treated with digoxin in liquid form (Lanoxin) for congestive heart failure. The regression equations (y = mx + b) and correlation coefficients (r) were computed utilizing the "least square fit" statistic. Serum digoxin concentration was the dependent variable (y) and digoxin maintenance dosage expressed in/,g/kg/day, the independent variable (x). Regression equations, mean serum digoxin concentrations, and standard deviations were computed in cystic fibrosis patients in the age range of 3 to 14 years, and in the cystic fibrosis group as a whole as well as in the control group. The regression slopes were compared
Vol. 86, No. 2, pp. 295-297
296
Moss et al.
The Journal of Pediatrics February 1975
RESULTS
7
6
5-
CYSTIC FIBROSIS
432O'3 Z
W
m O R2 m
o
0
4
8
iO
~
,
20
4 AGE
I" 2"
an Z~
5"
Z
4"
6NONCYSTIC FIBROSIS 7-
8-
Fig. 1. Bar graph showing age frequency distribution of patients with and without cystic fibrosis.
5.0O
X
2.5Z O
nI-Z kd r Z
o
(D
2.0X X X
t.5xx
o (D
X
X
Furthermore, the mean serum digoxin concentration obtained in the younger patients with cystic fibrosis (1.1 ng/ml _+ 0.6 SD) on mean digoxin maintenance of 12.4 /xg/kg/day __ 4.0 is almost identical to that obtained in the control group in age range 1 to 14 years. (1.2 ng/ ml _+ 0.7 on a mean digoxin maini~enance of 12.2/xg/kg/ day _+ 4.0). The mean serum digoxin concentration in cystic fibrosis patients 15 to 23 years of age on 0.25 mg daily maintenance dose is 0.5 ng/ml + 0.2. DISCUSSION
oX
x
1.09
I 9
.5-
000
X
9
X9 O
9
--xt--
5
9
~Xo >0,r 9
9 9
la.i 03
p > 0.25).
Xo
X
Z
The age frequency distribution in the cystic fibrosis and control groups is shown in Fig. 1. The age disparity is attributable to the fact that the control group consisted of subjects who generally require digitalis therapy at a much earlier age than patients with cystic fibrosis. The distribution of serum digoxin concentrations as they relate to the maintenance dosage expressed in/xg/ kg/day is illustrated in Fig. 2. The equation obtained by regressing serum concentration against maintenance digoxin dosage in the cystic f i b r o s i s g r o u p as a w h o l e is c o m p u t e d as y = 0.105 x -0.18 where y = serum digoxin concentration and x = digoxin dosage i n / x g / k g / d a y (r = 0.8374). The slope of this regression is significantly different from that o b t a i n e d in the c o n t r o l group (y = 0.122 x -0.32; r = 0.9174) (t =15:2; p (0.005). The regression equation obtained in the cystic fibrosis group 3 to 14 years of age is y = 0.133 x - 0 . 5 8 ( r = 0.8755); the slope o f this r e g r e s s i o n is not significantly different from that o b t a i n e d in the control group (t = 0.539;
10 DIGOXIN
x = Non C/F o : C/F (5-14 yr) 9 = C/F (15-23yr)
2'o
g5 DOSE ( m c g / k g / d e y )
2~
sb
Fig. 2. Distribution of serum digoxin concentrations related to maintenance dosage. (C/F = cystic fibrosis.)
with that obtained for the control group and significance was assessed by the "t-statistic." Eight of the patients in the cystic fibrosis group were in the age range of 15 to 23 years. Since no patients of comparable age were included in the control group, control values for this age category were taken from the results obtained by Brown and Abraham 7 in their study of 6 normal young adults. These investigators also used Burroughs Wellcome & Co. digoxin tablets and the assay method of Smith and associates. 5
T h e results i n d i c a t e that a b s o r p t i o n o f orally administered digoxin tablets is not impaired in patients with cystic fibrosis receiving pancreatic enzymes. W e recognize that because the tablet form o f digoxin (Lanoxin) was used in the study group and the liquid form in the control group, bioavailability of the drug was not strictly comparable since it has been shown that the liquid is more completely absorbed than the tablet. 8 However, if this were an important factor in the present investigation, it would strengthen rather than weaken the conclusion. The unlikely possibility does exist that the preservatives in the two forms of the drug could interact with the pancreatic enzymes in such a way as to make one form preferable over the other, so no definitive statements can be made on the basis of this study regarding absorption of the liquid form. However, in our experience, the vast majority of patients with cystic fibrosis who require digitalis preparations either receive them parent 9 or take them in tablet form.
Volume 86 Number 2
T he observations in this study were not repeated without pancreatic enzymes, since discontinuance of this medication for even a short period of time was not c o n s i d e r e d justified. T h u s , the effect o f pancreatic enzymes on absorption of digoxin was not evaluated. T h e general impression among physicians, who treat cystic fibrosis, that digoxin is poorly absorbed in these patients probably stems from the fact that these subjects are older children, as opposed to the infants with congenital heart disease digitalized because of congestive heart failure. It has been shown that plasma digoxin concentration in infants is significantly higher than in older children, and this negative correlation between age and plasma digoxin concentration arises from the higher dosage per kilogram of body weight customarily used in infants. 9-1~ It does not appear to be due to abSorptive differences since evidence exists that there is no sub s t an t i al difference in a b s o r p t i o n o f digoxin among neonates, infants, and adults. 9,12 The plasma digoxin concentration of 0.5 ng/ml observed in our older patients with cystic fibrosis is identical to that reported by Brown and Abraham 7 in normal young adults on 0.25 mg daily. These values are substantially lower than those r e p o r t e d for hospitalized adults with heart disease, s, 13 Whatever the basis for this difference, it does not appear to be related to absorption. REFERENCES
1. Royce WW: Cot pulmonale in infancy and early childhood. Report on 34 patients with special reference to the
Absorption o f digoxin in cystic fibrosis
2.
3.
4.
5.
6.
7.
8. 9.
10. 11. 12.
13.
297
occurrence of pulmonary heart disease in cystic fibrosis of the pancreas, Pediatrics 8:255, 1951. White WF; and Griswold O: Absorption rate studies of orally administered cardiac glycosides in cats, J Am Pharmacol Assoc 41:42, 1952. Gellis SS and Kagan BM, editors: Current pediatric therapy, ed 6, Philadelphia, 1973, WB Saunders, Company, p 137. Marcus FI, Burkhalter L, Cuccia C, et al.: Administration of tritiated digoxin with and without a loading dose. A metabolic study, Circulation 34:865, 1966. Smith TW, Butler VP Jr, and Haber E: Determination of therapeutic and toxic serum digoxin concerttration by radioimmunoassay, N Engl J Med 281:1212, 1969. Fogelman AM, LaMont JT, Finkelstein S, et al.: Fallibility of plasma digoxin in differentiating toxic from nontoxic patients, Lancet 2:727, 1971. Brown DD, and Abraham GN: Plasma digoxin levels in normal human volunteers following chronic oral and intramuscular administration, J Lab Clin Med 82:201, 1973. Huffman DH, and Azarnoff DL: Absorption of orally given digoxin preparations, JAMA 222"957, 1972. Rogers MC, Willerson JT, Goldblatt A, et al.: Serum digoxin concentrations in the human fetus, neonate, and infant, N Engl J Med 287:1010, 1972. O'Malley K, Coleman EN, Doig WB, et al.: Plasma digoxin levels in infants, Arch Dis Child 48:55, 1973. Hayes CJ, Butler VP Jr, and Gersony WM: Serum digoxin studies in infants and children, Pediatrics 52:561, 1973. Hernandez A, Burton RM, Pagtaklan RD, et at.: Pharmacodynamics of 3H-Digoxin in infants, Pediatrics 44:418, 1969. Belier GA, Smith TW, Abelmann WH, et al.: Digitalis intoxication. A prospective clinical study with serum level correlations, N Engt J Med 284:989, 1971.
Absorption of digoxin in children with cystic fibrosis The absorption o[digoxin in cystic fibrosis was evaluated in 16 sut~/ects by assessing the relationship between dosage expressed in t*g/kg/day and serum digoxin concentration. The results indicate that the same relationship exists between maintenance dosage and serum levels in these patients and in patients without cystic fibrosis. Thus, no evidence of impaired absopption wasJound.
Arthur a. Moss, M.D., Simon Finkelstein, M.D., Catherine Crudup, B.S., Guillermo A. Young, M.D., Richard R. Dooley, M.D., and Alan B, Osher, M.D., L o s A n g e l e s , Cal([~
COR PULMONALE iS a common complication in cystic fibrosis. 1 Since digoxin is often included in the management of cot pulmonale, the question has been raised whether patients with cystic fibrosis absorb the drug in adequate amounts. Digoxin is a lipid soluble glycoside 2 and cystic fibrosis is characterized by defective fat absorption, which is only partly correctible by pancreatic enzyme supplements. To assess digoxin absorption in this disease, we have measured concentrations o.f serum digoxin in patients with cystic fibrosis and evaluated the relationship between digoxin concentration and dosage. The results were compared to similar data in patients without cystic fibrosis.
MATERIALS AND METHODS Serum digoxin concentrations were determined in 16 patients with severe cystic fibrosis; 11 had been prophylactically digitalized, and five had evidence of heart failure. The age range was 3 to 23 years, with eight patients in the 3- to 14-year age range ( ~ = 9.2 _+ 4), and eight in the 15- to 23-year age range ( ~ = 18.6 + 3). A total of 22 concentrations of serum digoxin were m e a s u r e d in samples o b t a i n e d at least 7 days after From the Departments of Pediatrics and Pathology UCLA School of Medicine. Supported by grangsJ)'om the National Cystic Fibrosis Foundation and the Burt~oughs Wellcome Company, lnc.
digoxin therapy was begun, and 6 to 9 hours after the last dose. All patients were given digoxin in tablet form ( L a n o x i n ) , and, in a d d i t i o n , r e c e i v e d p a n c r e a t i c e n z y m e s (Viokase or Cotazym) with every meal. Eleven patients were digitalized and maintained according to current pediatric practice, 3 and five were digitalized by the "slow method ''4 (no loading dose given). M a i n t e n a n c e digoxin was a d m i n i s t e r e d daily in two divided doses, at breakfast and after dinner. The digoxin assay was performed by the method of Smith and associates s with a few minor modifications as previously described. 6 The data were compared to results obtained at this institution under similar circumstances in a control group consisting of 29 infants and children in the age range 2 months to 14 years, with no evidence of malabsorption. This group consisted of patients with a variety of congenital heart lesions who were treated with digoxin in liquid form (Lanoxin) for congestive heart failure. The regression equations (y = mx + b) and correlation coefficients (r) were computed utilizing the "least square fit" statistic. Serum digoxin concentration was the dependent variable (y) and digoxin maintenance dosage expressed in/,g/kg/day, the independent variable (x). Regression equations, mean serum digoxin concentrations, and standard deviations were computed in cystic fibrosis patients in the age range of 3 to 14 years, and in the cystic fibrosis group as a whole as well as in the control group. The regression slopes were compared
Vol. 86, No. 2, pp. 295-297
296
Moss et al.
The Journal of Pediatrics February 1975
RESULTS
7
6
5-
CYSTIC FIBROSIS
432O'3 Z
W
m O R2 m
o
0
4
8
iO
~
,
20
4 AGE
I" 2"
an Z~
5"
Z
4"
6NONCYSTIC FIBROSIS 7-
8-
Fig. 1. Bar graph showing age frequency distribution of patients with and without cystic fibrosis.
5.0O
X
2.5Z O
nI-Z kd r Z
o
(D
2.0X X X
t.5xx
o (D
X
X
Furthermore, the mean serum digoxin concentration obtained in the younger patients with cystic fibrosis (1.1 ng/ml _+ 0.6 SD) on mean digoxin maintenance of 12.4 /xg/kg/day __ 4.0 is almost identical to that obtained in the control group in age range 1 to 14 years. (1.2 ng/ ml _+ 0.7 on a mean digoxin maini~enance of 12.2/xg/kg/ day _+ 4.0). The mean serum digoxin concentration in cystic fibrosis patients 15 to 23 years of age on 0.25 mg daily maintenance dose is 0.5 ng/ml + 0.2. DISCUSSION
oX
x
1.09
I 9
.5-
000
X
9
X9 O
9
--xt--
5
9
~Xo >0,r 9
9 9
la.i 03
p > 0.25).
Xo
X
Z
The age frequency distribution in the cystic fibrosis and control groups is shown in Fig. 1. The age disparity is attributable to the fact that the control group consisted of subjects who generally require digitalis therapy at a much earlier age than patients with cystic fibrosis. The distribution of serum digoxin concentrations as they relate to the maintenance dosage expressed in/xg/ kg/day is illustrated in Fig. 2. The equation obtained by regressing serum concentration against maintenance digoxin dosage in the cystic f i b r o s i s g r o u p as a w h o l e is c o m p u t e d as y = 0.105 x -0.18 where y = serum digoxin concentration and x = digoxin dosage i n / x g / k g / d a y (r = 0.8374). The slope of this regression is significantly different from that o b t a i n e d in the c o n t r o l group (y = 0.122 x -0.32; r = 0.9174) (t =15:2; p (0.005). The regression equation obtained in the cystic fibrosis group 3 to 14 years of age is y = 0.133 x - 0 . 5 8 ( r = 0.8755); the slope o f this r e g r e s s i o n is not significantly different from that o b t a i n e d in the control group (t = 0.539;
10 DIGOXIN
x = Non C/F o : C/F (5-14 yr) 9 = C/F (15-23yr)
2'o
g5 DOSE ( m c g / k g / d e y )
2~
sb
Fig. 2. Distribution of serum digoxin concentrations related to maintenance dosage. (C/F = cystic fibrosis.)
with that obtained for the control group and significance was assessed by the "t-statistic." Eight of the patients in the cystic fibrosis group were in the age range of 15 to 23 years. Since no patients of comparable age were included in the control group, control values for this age category were taken from the results obtained by Brown and Abraham 7 in their study of 6 normal young adults. These investigators also used Burroughs Wellcome & Co. digoxin tablets and the assay method of Smith and associates. 5
T h e results i n d i c a t e that a b s o r p t i o n o f orally administered digoxin tablets is not impaired in patients with cystic fibrosis receiving pancreatic enzymes. W e recognize that because the tablet form o f digoxin (Lanoxin) was used in the study group and the liquid form in the control group, bioavailability of the drug was not strictly comparable since it has been shown that the liquid is more completely absorbed than the tablet. 8 However, if this were an important factor in the present investigation, it would strengthen rather than weaken the conclusion. The unlikely possibility does exist that the preservatives in the two forms of the drug could interact with the pancreatic enzymes in such a way as to make one form preferable over the other, so no definitive statements can be made on the basis of this study regarding absorption of the liquid form. However, in our experience, the vast majority of patients with cystic fibrosis who require digitalis preparations either receive them parent 9 or take them in tablet form.
Volume 86 Number 2
T he observations in this study were not repeated without pancreatic enzymes, since discontinuance of this medication for even a short period of time was not c o n s i d e r e d justified. T h u s , the effect o f pancreatic enzymes on absorption of digoxin was not evaluated. T h e general impression among physicians, who treat cystic fibrosis, that digoxin is poorly absorbed in these patients probably stems from the fact that these subjects are older children, as opposed to the infants with congenital heart disease digitalized because of congestive heart failure. It has been shown that plasma digoxin concentration in infants is significantly higher than in older children, and this negative correlation between age and plasma digoxin concentration arises from the higher dosage per kilogram of body weight customarily used in infants. 9-1~ It does not appear to be due to abSorptive differences since evidence exists that there is no sub s t an t i al difference in a b s o r p t i o n o f digoxin among neonates, infants, and adults. 9,12 The plasma digoxin concentration of 0.5 ng/ml observed in our older patients with cystic fibrosis is identical to that reported by Brown and Abraham 7 in normal young adults on 0.25 mg daily. These values are substantially lower than those r e p o r t e d for hospitalized adults with heart disease, s, 13 Whatever the basis for this difference, it does not appear to be related to absorption. REFERENCES
1. Royce WW: Cot pulmonale in infancy and early childhood. Report on 34 patients with special reference to the
Absorption o f digoxin in cystic fibrosis
2.
3.
4.
5.
6.
7.
8. 9.
10. 11. 12.
13.
297
occurrence of pulmonary heart disease in cystic fibrosis of the pancreas, Pediatrics 8:255, 1951. White WF; and Griswold O: Absorption rate studies of orally administered cardiac glycosides in cats, J Am Pharmacol Assoc 41:42, 1952. Gellis SS and Kagan BM, editors: Current pediatric therapy, ed 6, Philadelphia, 1973, WB Saunders, Company, p 137. Marcus FI, Burkhalter L, Cuccia C, et al.: Administration of tritiated digoxin with and without a loading dose. A metabolic study, Circulation 34:865, 1966. Smith TW, Butler VP Jr, and Haber E: Determination of therapeutic and toxic serum digoxin concerttration by radioimmunoassay, N Engl J Med 281:1212, 1969. Fogelman AM, LaMont JT, Finkelstein S, et al.: Fallibility of plasma digoxin in differentiating toxic from nontoxic patients, Lancet 2:727, 1971. Brown DD, and Abraham GN: Plasma digoxin levels in normal human volunteers following chronic oral and intramuscular administration, J Lab Clin Med 82:201, 1973. Huffman DH, and Azarnoff DL: Absorption of orally given digoxin preparations, JAMA 222"957, 1972. Rogers MC, Willerson JT, Goldblatt A, et al.: Serum digoxin concentrations in the human fetus, neonate, and infant, N Engl J Med 287:1010, 1972. O'Malley K, Coleman EN, Doig WB, et al.: Plasma digoxin levels in infants, Arch Dis Child 48:55, 1973. Hayes CJ, Butler VP Jr, and Gersony WM: Serum digoxin studies in infants and children, Pediatrics 52:561, 1973. Hernandez A, Burton RM, Pagtaklan RD, et at.: Pharmacodynamics of 3H-Digoxin in infants, Pediatrics 44:418, 1969. Belier GA, Smith TW, Abelmann WH, et al.: Digitalis intoxication. A prospective clinical study with serum level correlations, N Engt J Med 284:989, 1971.