European Journal of Clinical Pharmacology
Europ. J. clin. Pharmacol. 11,329-335 (1977)
© by Springer-Verlag 1977
Distribution and Elimination of Digoxin in Infants G. Wettrell Department of Paediatrics and Clinical Pharmacology, University Hospital, Lund, Sweden
Summary. The distribution and elimination of intravenous digoxin were investigated in seven neonates and infants with heart failure. Serum digoxin concentrations during a 24 h period were determined by radioimmunoassay, using 125I as tracer. The serum values declined biexponentially after the injection and could be fitted to a two-compartment open model by non-linear least-squares regression. The calculated mean half-lives of the distribution (alpha) phase in neonates and infants were 37 and 28 min, respectively. The mean half-life of the elimination (beta) phase in neonates was 44 h, as compared to 19 h in infants. The mean volume of the central compartment and the mean volume of distribution at steady-state were calculated to be 1.3 and 9.91/kg, respectively; no significant differences between neonates and infants were found. The relation between these volumes indicates that digoxin is extensively distributed in tissues. The steady-state distribution volumes of digoxin in neonates and infants exceed those reported in adults. The larger volume of distribution might explain in part why infants with cardiac insufficiency require larger doses of digoxin than adults (on a mg/kg body weight basis) to obtain the same serum concentrations. Elimination of digoxin from the body was slower in neonates than in infants. Key words: Digoxin, pharmacokinetics, two-compartment model, radioimmunoassay, neonates, infants.
dez et al., 1969; Dungan et al., 1972). Recent data on post-mortem tissue concentrations and distribution of digoxin, as determined by 86Rb uptake inhibition assay, also showed that several tissues in the body bind digoxin to about the same extent in both age-groups (Andersson et al., 1975). Although renal elimination of digoxin in infants (> 1 month) was found to be in the same range as in adults (Iisalo and Dahl, 1974; Yanagi et al., 1974), renal elimination in neonates (< 1 month) appeared to be lower (Iisalo and Dahl, 1974; Wettrell et al., 1974; Wettrell and Andersson, 1975). In a recent pharmacokinetic study, age-related differences in distribution and body clearance of digoxin between neonates, infants and children were found (Morselli et al., 1975). Thus, there may be a pharmacokinetic explanation for the recommendation of substantially higher doses (on a mg/kg basis) for infants than adults. In order to further elucidate the fate of digoxin in neonates and infants with heart failure, the pharmacokinetics of its distribution and elimination were investigated. The intravenous serum concentration data were fitted to the equation characterizing a linear two-compartment open model using a digital computer program.
Material and Methods Patients
Despite widespread use of digoxin in infants with cardiac disease, there are few studies of its pharmacokinetics at this age. Previous investigations using tritiated digoxin showed that its tissue distribution and excretion were similar in infants and adults (Hernan-
Seven full-term neonates and infants with a diagnosis of congenital cardiac malformation and congestive heart failure were studied; their clinical details are listed in Table 1. The clinical diagnosis in five patients (no. 3-7) was based on data obtained at cardiac catheterization and angiocardiography. Body surface
330
G. Wettrell: Digoxin in Infants
Table 1. Clinical details of neonates and infants given intravenous digoxin Patient no.
Sex
Age, Weight, kg/ Dosage days surface area, m2 mg
mg/kg b. w.
1 2 3
M F M
2 3 22
3.300/0.19 2.800/0.20 2.700/0.19
0.050 0.038 0.045
0.015 0.014 0.017
4 5 6 7
M M M M
44 52 70 81
3.400/0.22 4.300/0.25 4.550/0.25 4.450/0.26
0.060 0.075 0.075 0.100
0.018 0.017 0.017 0.022
Clinical diagnosis Hyperbilirubinaemia Suspected transposition of the great vessels; asphyxia syndrome Hypoplastic right ventricle; pulmonary valve atresia; patent ductus arteriosus Common A-V canal; Down's syndrome Ventricular septal defect Ventricular septal defect Patent ductus arteriosus
Table 2. Serum concentration and 24-h urine excretion of digoxin in 7 neonates and infants after its intravenous administration Patient
Serum concentration (ng/ml) after (h)
no.
0.5
1
1.5
2
3
3.5
4
8.5 8.2 8.2 7.2 7.0 6.0 10.6
5.2 4.5 4.9 3.6 3.4 2.4 6.2
3.5 3.0 3.2 2.0 2.2 1.9 3.4
2.1 2.3 2.2 1.5 1.7 1.3 2.5
1.7 1.9 1.5 1.0 1.2 1.7
-
-
1.0 -
1.2 1.4 0.8 1.1 0.8 1.7
1
2 3 4 5 6 7
24-h urine excretion,
area was d e t e r m i n e d by a n o m o g r a m f r o m C r a w f o r d et al. (1950). All patients had a b l o o d urea nitrogen concentration within n o r m a l limits.
Drug Administration A commercial p r e p a r a t i o n of digoxin (Lanacrist ® solution for injection, A B D r a c o , Sweden) was used for intravenous administration; the solution contained 250 gg of digoxin per ml, and before injection, it was diluted 1 : 10 with 0 . 9 % saline. E a c h patient received a dose calculated to be one quarter to one third of the digitalizing dose, 0 . 0 5 - 0 . 0 7 m g / k g b. w. at the start of the sampling period. Table 1 lists the individual doses. Digoxin was injected o v e r 2 to 3 rain via a v e n o u s umbilical catheter or scalp vein needle, and the catheter was then flushed with a few ml of 0.9% saline. T h e patients were not fasted.
Blood Samples and Assay B l o o d was o b t a i n e d via an umbilical artery catheter (Patients 1 and 2) or by capillary sampling in E p p e n doff tubes (Patients 3 - 7 ) . B l o o d was collected over a 24 h period after injection of digoxin. T h e duration of the sampling time was d e t e r m i n e d by the clinical con-
5
1.4
-
6
-
1.1 1.0 1.4
8
12
24
volume, ml
per cent of dose
1.2 1.0 1.1 0.6 0.8 0.7 1.I
1.0 0.9 0.8 0.5 0.6 0.5 0.9
1.0 0.8 0.8 0.4 0.5 0.5 0.8
160 162 225 60 374 327 95
13 13 14 6 27 26 15
dition of the patient. F u r t h e r m o r e , although a microm e t h o d was used, the n u m b e r of b l o o d samples were kept as low as possible in view of the age of the patients; Table 2 lists the individual sampling schedules. A 24 h urine was collected in a urine bag (Hollister Inc., U S A ) f r o m the time of digoxin administration. A commercial r a d i o i m m u n o a s s a y kit (Schwarz/ M a n n , O r a n g e b u r g , N e w Y o r k , U S A ) with 125I as tracer was used to m e a s u r e digoxin in serum. T h e m e t h o d has previously b e e n evaluated and f o u n d equal to the 3H-digoxin assay ( T a u b e r t and Shapiro, 1975; Wettrell and A n d e r s s o n , 1975). O n l y a 50 ~tl aliquot of serum was required for a single analysis. T h e serum samples f r o m each patient were run in the same analytical sequence and analysed at least in duplicate. Digoxin concentrations in urine were determ i n e d by an 86Rb u p t a k e inhibition assay (Bertler and Redfors, 1970; Wettrell et al., 1974) and also by the 125I r a d i o i m m u n o a s s a y .
Pharmacokinetic Model A semilogarithmic plot of s e r u m c o n c e n t r a t i o n versus time for Patient 2 is d e m o n s t r a t e d in Fig. 1. T h e o t h e r patients had similar serum c o n c e n t r a t i o n curves. T h e
G. Wettrell: Digoxin in Infants
331
biexponential behaviour of the disposition curve indicated that two exponential functions are required for satisfactory fit to the data. It was also found that any compartmental model used to fit the present data had to contain a minimum of two compartments. Therefore, the serum data for digoxin were described by use of a two-compartment open model (Riegelman et al., 1968). The rate constants k12, k21, kel in the two-compartment open model and the initial concentration of the central compartment (C1°) were estimated from the experimental data by a non-linear least-squares program LISPID (kindly supplied by K. J. Astr6m, Dept. of Automatic Control, Institute of Technology, Lund, Sweden) on a Univac 1108 computer. In the leastsquares analysis differences between the model and actual measurements were weighted by the reciprocal of the variance of the measurement errors. The latter varied with the absolute value of the concentration and were determined by making 10 measurements on test samples of known concentrations. When the parameters of the compartment model and the initial dose are known, it is possible to compute the volumes of distribution. It is also possible to simulate the model to obtain the time courses of the amounts of drug in the compartments; such a simulation is shown in Fig. 2. The simulations were done with an interactive simulation language SIMNON.
Analysis of Pharmacokinetic Parameters
(gq. 1)
where D is the dose given (as a bolus injection) and C1° the estimated serum concentration at zero time obtained from the non-linear equation. The total volume of distribution at steady-state, Vdss, can be obtained from the following equation (Riggs, 1963) V d ss ~-
( e l 2 q- k21) k21
• V 1
8: 6. 4"
1'
0.i 0
2 4 6 8
1'2
;6
2'0
2'4
Time,h
Fig. 1. Semilogarithmic plot of observed (*) and computer fitted (o) serum concentrations of digoxin for 24 h after its rapid intravenous injection in Patient 2 1.0-
0 1D
0.8.
= 0.6"
/
0
"-.0.~ o~ F
o
~
18
1~
2'o
2'5
Time s h
Fig. 2. Simulation of distribution and elimination of digoxin during 24 h after intravenous injection in Patient 2. A = amount in central compartment, B = amount in peripheral compartment and C = amount of digoxin eliminated
drug elimination processes (Jusko and Gibaldi, 1972), was determined from the equation C1B = V 1 ' kel = V d f i " fi
(Eq. 4)
(Eq. 2)
After steady-state is attained, the volume of distribution, determined as Vail, relates the total amount of drug in the body to the drug concentration in the serum at all times during the second exponential phase, i. e. the fl-slope (Gibaldi et al., 1969). This volume is obtained from the equation Vd/~ ~--Re, - Vl/]~
ng/ml
0.0
The volume of the central compartment (V1) was calculated from the equation D V 1 = C1°
Digoxin, 10.
(Eq. 3)
Body clearance, CIB, corresponding to the sum of all
Prediction of Steady-State Serum Concentration
of Digoxin Basic parameters estimated from a single-dose study can be used to predict the average blood concentration during a multiple-dose regimen (Wagner et al., 1965). Presuming first-order kinetics in the two-compartment model, the mean steady-state concentration, Css, of a drug is a function of the availability, F, the maintenance dose, D, the disposition rate con-
G. Wettrell:Digoxinin Infants
332 stant,/3, the apparent volume of distribution, Vdfi, and the dose interval, T (Wagner et al., 1965). Css =
F •D (Eq. 5) fi" Vdfl" T Numerical values for the parameters in equation 5 were obtained from average data in previous studies and from calculated values obtained in the present study. Thus, bioavailability (F) of digoxin elixir (Lanoxin ® paediatric solution, Burroughs-Wellcome Ltd., United Kingdom) in neonates and infants was estimated to be ~ipproximately 0.75 (Wettrell and Andersson, 1975). Maintenance doses (D) in neonates and infants were based on the prevailing oral dose schedule for digoxin elixir (Wettrell et al., 1974) for which the dosing interval (T) is 12 h.
Results
Serum Concentration and Urinary Excretion of Digoxin Individual serum concentrations of digoxin during the first 24 h after intravenous administration are listed in Table 2. All the patients showed a biexponential decline. A rapid fall in serum concentration was observed during the first 2 h, followed by slow disappearance during the succeeding hours. Four of the patients (nos. 2, 3, 6 and 7) showed a slight deviation from the anticipated serum concentration curves between the 3rd and 8th h after injection. A semilogarithmic plot of the observed serum digoxin concentrations versus time in Patient 2, shown in Fig. 1, as well as the least-squares fitted values, and the fit appear adequate. Urinary excretion of digoxin during the first 24 h after intravenous administration in Patients 5 and 6 was found to be 27 and 26 per cent of the given dose, respectively. The 24 h urine collections from these patients were believed to be complete (continuous supervision); the collection of the other urine specimens might have been incomplete, particularly those from Patients 4 and 7. In Patients 5 and 6 the amount of digoxin excreted in urine was found to be less than half the daily total elimination calculated on the basis of the pharmacokinetic parameters.
Pharmacokinetic Parameters The results of the pharmacokinetic analyses are shown in Tables 3 and 4. There was extensive distribution of digoxin to the peripheral compartment, as indicated by an average volume of distribution at steady-state, VdSs,of 9.91/kg compared to the average volume of the
central compartment, V1 of 1.3 1/kg. The half-lives of the distribution (alpha) phase ranged from 0.44 to 0.69 h. There is an illustration of the simulation of the time course of distribution based on available pharmacokinetic parameters in Fig. 2. The rapid disappearance of digoxin from the central compartment might be due mainly to an increase in the peripheral compartment rather than elimination of the glycoside. During the elimination (beta) phase, the mean volume of distribution, Vail, was calculated to be 12.1 1/kg. The half-lives corresponding to this phase ranged from 13.6 to 57.8 h. The elimination, calculated as clearance from the body, C1B, varied between 57 and 268 ml/min/1.73 m2; individual values are listed in Table 4. There seemed to be slow elimination of digoxin from the body during the first month of life. Serum digoxin concentration was measured in some of the patients (nos. 3-7) under steady-state conditions. The relationship between serum concentrations determined after several days of maintenance therapy and those predicted by Equation 5 is shown in Table 4.
Discussion
The results of this study indicate that the pharmacokinetics of digoxin in paediatric patients can be characterized by a linear two-compartment open model. This model has previously been used in disposition studies of digoxin in adults (Dengler et al., 1973; Reuning et al., 1973; Nyberg et al., 1974; Koup et al., 1975 a). Some of the patients showed a deviation from the expected, biexponential serum concentration curve, probably due to enterohepatic cycling (Nyberg et al., 1974; Koup et al., 1975 a). The deviation, however, was small and transient in relation to the total time course of digoxin disposition. Digoxin appeared to be rapidly distributed in the body. Thus the calculated half-life of the alpha phase (range 26 to 41 rain), which mainly represents distribution from the central to the peripheral compart•ment, was short. This finding agrees with results in neonates and infants reported by Morselli et al. (1975). Similar half-life values have been found for the distribution of tritiated digoxin in paediatric patients (Dungan et al., 1972). The large volume of the central compartment compared to the plasma volume in this age group (Friis-Hansen, 1971) indicates that digoxin in plasma rapidly equilibrates with highly perfused organs. The mean value of the volume was somewhat higher in neonates and infants than has been previously reported in adults (Dengler et al., 1973; Nyberg et al., 1974). The steady-state volume of distribution was
G. Wettrell: Digoxin in Infants
333
Table 3. Pharmacokinetic parameters according to the two-compartment open model after iv. digoxin (C1°, k12, k21, and ke~_+standard deviation of the estimate) Patient no.
C1° (ng/ml)
a (h-l)
/3 (h-')
k12 (h-l)
k21 (h-l)
kei (h-l)
VI (l/kg)
Va/~ (1/kg)
Vass (1/kg)
1
15.1 _+1.6 10.8 -+1.2 12.8 _+1.4 12.6 _+1.6 12.9 _+1.8 11.3 -+1.7 17.6 -+2.1
1.30
0.012
1.05__+0.08
0.12+0.01
0.13__+0.03
1.0
11.3
9.8
1.00
0.017
0.76_+0.07
0.12_+0.01
0.14_+0.03
1.3
10.5
9.3
1.15
0.021
0.86-_+0.07
0.13_+0.01
0.19_+0.03
1.3
11.5
9.9
1.44
0.042
0.91_+0.07
0.14_+0.02
0.43-+0.08
1.4
14.3
10.4
1.58
0.051
1.03_+0.11
0.20_+0.02
0.40_+0.06
1.4
10.6
8.3
1.78
0.036
1.30-+0.14
0.20_+0.02
0.32_+0.06
1.5
13.1
10.9
1.27
0.025
0.91-+0.08
0.13_+0.01
0.26_+0.04
1.3
13.2
11.1
2 3 4 5 6 7
Table 4. Pharmacokinetic parameters and comparison of predicted and measured serum concentrations of digoxin in seven neonates and infants with heart failure Patient no.
1 2 3 4 5 6 7
(Tm)a a
(T1/2)/3a (h)
Body clearance of digoxin, C1B (ml/min/l.73 m 2)
Predicted serum concentration of digoxin at steadystate, Cs~ (ng/ml)
Measured serum concentration of digoxin at steadystate, (ng/ml)
(h)
0.54 0.69 0.60 0.48 0.44 0.39 0.55
57.8 40.8 33.0 16.5 13.6 19.3 27.7
68 72 57 268 267 248 162
2.8 2.3 1.7 0.9 0.9 1.0 1.5
1.4 1.5 0.8 1.5 1.6
0.693 a
T1/2c¢
_
T1/Zfl
--
0.693
/3
much larger than the total body water (Friis-Hansen, 1971), which means that digoxin is extensively distributed and bound to additional tissues. The steadystate distribution volume in neonates and infants exceeded the value found in adults (Reuning et al., Nyberg et al., 1974; Koup et al., 1975 a). A still higher mean value of apparent volume of distribution in infants than in the present study was recently reported (Morselli et al., 1975). The larger volume of distribution in neonates and infants might be due to increased tissue binding of digoxin in these age-groups, although no significant difference between infants and adults in the digoxin content of several tissues was found during maintenance therapy (Andersson et al., 1975). A further reason for the quantitative differences in volume of
distribution between infants and adults could be changes with age in body composition. The larger volume of extracellular fluid in neonates and infants, however, can only contribute slightly to the increased volume of distribution, as digoxin is mainly bound to tissues. The plasma protein binding of digoxin in neonates is low and in the same range as in adults (Lukas and Martino, 1969; Koup et al., 1975 b; Gorodischer et al., 1974). Therefore, this parameter cannot account for the difference between the paediatric and adult patients in the volume of distribution of digoxin. The reason for the age difference is unclear but might be attributable in part to increased tissue binding and in part to age-related changes in body composition (extracellular fluid volume, and ratio tissue weight/body weight).
334
The elimination of digoxin, calculated as the halflife of the beta phase, was longer in neonates (mean value, 44 h) than in infants (mean value, 19 h); similar results were found by Morselli et al. (1975). The present values in infants were shorter than those reported by Hernandez et al. (1969), but were in agreement with findings of Dungan et al. (1972). Elimination of digoxin, calculated as body clearance, was also found to change with age. Thus, clearance of the glycoside from the body was slower during the first month of life (mean value, 65 ml/min/1.73 m 2) than during the following months (mean value, 236 ml/min/1.73 m2). Similar age-related differences between neonates and infants have been demonstrated in a study of the renal clearance of digoxin (Wettrell et al., 1974). The total elimination seemed to be higher in infants than in adults. However, it should be noted that elimination measured as body clearance might be influenced by the larger distribution volume found in infants. Moreover, the relatively short sampling period (24 h) might have contributed in some patients to what was only an approximate calculation of the elimination (/3) phase. It has also been demonstrated that calculations of elimination half-life based only on serum concentrations of digoxin could lead to lower values than those based both on serum and urine glycoside concentrations (Koup et al, 1975 a and b). Therefore, the elimination half-life in some patients might have been too short giving the impression of increased elimination. The predicted steady-state serum concentration in some of the patients (nos 4 and 6) was lower than that actually measured (Table 4). This finding to some extent, can be explained by use of the approximate calculation of the elimination phase. Considering the wide individual variation in the pharmacokinetic parameters in neonates and infants with heart failure, the value of these calculations for predictive clinical purposes seems to be limited. The amount of digoxin excreted in urine compared to total elimination calculated from the pharmacokinetic parameters suggested non-renal elimination of considerable magnitude in certain patients. Despite a possible overestimate of total elimination, the finding suggests an alternative route of removal of the glycoside from the body, for example by metabolism and biliary excretion. In healthy adults, about 25 per cent of the total elimination of digoxin was estimated to be non-renal (Koup et al., 1975 a). In a previous study in paediatric patients using tritiated digoxin, Dungan et al. (1972) found that the mean excretion in urine and faeces in the 24 h after an intravenous injection was only 32 per cent; however, intersubject variation was wide (19-47 per cent). It was suggested that the extent of metabolism was
G. Wettrell: Digoxin in Infants
greater than was implied by the given data (Dungan et al., 1972). Metabolic degradation of digoxin in infants, greater than that currently accepted, has recently been discussed by Morselli et al. (1975). Therefore, further studies of elimination by different routes in the paediatric age groups appears desirable.
Acknowledgements. I thank Prof. K. J. ~str6m, Dept. of Automatic Control, Institute of Technology, Lund, Sweden, for his stimulating assistance in the pharmacokinetic calculations. I am indebted to Miss Siv Karlson for skilful technical assistance and to Miss Anne Nilsson for excellent secretarial work. Grants from the Swedish Medical Research Council (project no. 14X-2829) and from the Swedish National Association against Heart and Chest Diseases supported the investigation.
References Andersson, K.-E., Bertler, A., Wettrell, G.: Post-mortem distribution and tissue concentrations of digoxin in infants and children. Actapaediat. scand. 64, 497-504 (1975) Bertler, A., Redfors, A.: An improved method of estimating digoxin in human plasma. Clin. Pharmacot. Ther. 11, 665-673 (1970) Crawford, J. D., Terry, M. E., Rourke, G. M.: Simplification of drug dosage calculation by application of the surface area principle. Pediatrics 5, 783-790 (1950) Dengler, H.J., Bodem, G., Wirth, K.: Pharmacokinetic and metabolic studies with Lanatoside C, a- and ~acetyldigoxin and digoxin in man. Proc. 5th Int. Cong. Pharmacology. San Francisco, 1972, vol. 3, pp 112-126. Basel: Karger 1973 Dungan, W.T., Doherty, J.E., Harvey, C., Char, F., Dalrymple, G. W.: Tritiated digoxin XVIII: Studies in infants and children. Circulation 46, 983-988 (1972) Friis-Hansen, B.: Body composition during growth. Pediatrics 47, 264-274 (1971) Gibaldi, M., Nagashima, R., Levy, G.: Relationship between drug concentration in plasma or serum and amount of drug in the body. J. pharm. Sci. 58, 193-197 (1969) Gorodischer, R., Krasner, J., Yaffe, S. J.: Serum protein binding of digoxin in newborn infants. Research Comm. chem. Path. Pharmacol. 9, 387-390 (1974) Hernandez, A., Bruton, R. M., Pagtakhan, R. D., Goldring, D. J.: Pharmacodynamics of 3H-digoxin in infants. Pediatrics 44, 418-427 (1969) Iisalo, E., Dahl, M.: Serum levels and renal excretion of digoxin during maintenance therapy in children. Acta paediat, scand. 63, 699-704 (1974) Jusko, W. J., Gibaldi, M.: Effects of change in elimination on various parameters of the two-compartment open model. J. pharm. Sci. 61, 1270-1273 (1972) Koup, J.R., Greenblatt, D.J., Jusko, W.J., Smith, T.W., KochWeser, J.: Pharmacokinetics of digoxin in normal subjects after intravenous bolus and infusion doses. J. Pharmacokin. Biopharm. 3, 181-192 (1975 a) Koup, J.R., Jusko, W.J., Elwood, C.M., Kohli, R.K.: Digoxin pharmacokinetics. Role of renal failure in dosage regimen design. Clin. Pharmacol. Ther. 18, 9-21 (1975 b) Lukas, D.S., De Martino, A.G.: Binding of digitoxin and some
G. Wettrell: Digoxin in Infants related cardenolides to human plasma proteins. J. clin. Invest. 48, 1041-1053 (1969) Morselli, P.L., Assael, B.M., Gomeni, R., Mandelli, M., Marini, A., Reali, E., Visconti, U., Sereni, F.: Digoxin pharmacokinetics during human development. Basic and therapeutic aspects of perinatal pharmacology (ed. Morselli, L., Garattini, S. and F. Sereni), p. 377-392, New York: Raven Press 1975 Nyberg, L., Andersson, K.-E., Bertler, ~.: Bioavailability of digoxin from tablets. II. Radioimmunoassay and disposition pharmacokinetics of digoxin after intravenous administration. Acta pharm, suecia 11, 459-470 (1974) Reuning, R. H., Sams, R. A., Notari, R. E.: Role of pharmaeokinetics in drug dosage adjustment. I. Pharmacologic effect kinetics and apparent volume of distribution of digoxin. J. clin. Pharmacol. 13, 127-141 (1973) Riegelman, S., Loo, I. C. K., Rowland, M.: Shortcomings in pharmacokinetic analyses by conceiving the body to exhibit properties of a single compartment. J. pharm. Sci. 57, 117-123 (1968) Riggs, D. S.: The mathematical approach to physiological problems, p. 193-220, Baltimore, Maryland: Williams and Wilkins 1963 Taubert, K., Shapiro, W.: Serum digoxin levels using an l~SI-labelled antigen: Validation of method and observations on cardiac patients. Amer. Heart J. 89, 79-86 (1975)
335 Wagner, J.G., Northam, I.T., Alway, C.D., Carpenter, O.S.: Blood levels of drug at the equilibrium state after multiple dosing. Nature (Lond.) 207, 1301-1302 (1965) Wettrell, G., Andersson, K.-E., Bertler, ~., Lundstr6m, N.R.: Concentrations of digoxin in plasma and urine in neonates, infants and children with heart disease. Acta paediat, seand. 63, 705-710 (1974) Wettrell, G., Andersson, K.-E.: Absorption of digoxin in infants. Europ. J. clin. Pharmacol. 9, 49-55 (1975) Yanagi, R., Kim, W.P., Krasula, R, W., Soyka, L.F., Hastreiter, A.R.: Urinary excretion of digoxin in infants and children. Circulation 49-50, (Suppl. 3) abs No. 484, 1974 Received." January 30, 1976, and in revised form: November 2, 1976, accepted." November 18, 1976 Dr. G. Wettrell Dept. of Paediatrics and Clinical Pharmacology University Hospital S-221 85 Lund Sweden
Europ. J. clin. Pharmacol. 11,329-335 (1977)
© by Springer-Verlag 1977
Distribution and Elimination of Digoxin in Infants G. Wettrell Department of Paediatrics and Clinical Pharmacology, University Hospital, Lund, Sweden
Summary. The distribution and elimination of intravenous digoxin were investigated in seven neonates and infants with heart failure. Serum digoxin concentrations during a 24 h period were determined by radioimmunoassay, using 125I as tracer. The serum values declined biexponentially after the injection and could be fitted to a two-compartment open model by non-linear least-squares regression. The calculated mean half-lives of the distribution (alpha) phase in neonates and infants were 37 and 28 min, respectively. The mean half-life of the elimination (beta) phase in neonates was 44 h, as compared to 19 h in infants. The mean volume of the central compartment and the mean volume of distribution at steady-state were calculated to be 1.3 and 9.91/kg, respectively; no significant differences between neonates and infants were found. The relation between these volumes indicates that digoxin is extensively distributed in tissues. The steady-state distribution volumes of digoxin in neonates and infants exceed those reported in adults. The larger volume of distribution might explain in part why infants with cardiac insufficiency require larger doses of digoxin than adults (on a mg/kg body weight basis) to obtain the same serum concentrations. Elimination of digoxin from the body was slower in neonates than in infants. Key words: Digoxin, pharmacokinetics, two-compartment model, radioimmunoassay, neonates, infants.
dez et al., 1969; Dungan et al., 1972). Recent data on post-mortem tissue concentrations and distribution of digoxin, as determined by 86Rb uptake inhibition assay, also showed that several tissues in the body bind digoxin to about the same extent in both age-groups (Andersson et al., 1975). Although renal elimination of digoxin in infants (> 1 month) was found to be in the same range as in adults (Iisalo and Dahl, 1974; Yanagi et al., 1974), renal elimination in neonates (< 1 month) appeared to be lower (Iisalo and Dahl, 1974; Wettrell et al., 1974; Wettrell and Andersson, 1975). In a recent pharmacokinetic study, age-related differences in distribution and body clearance of digoxin between neonates, infants and children were found (Morselli et al., 1975). Thus, there may be a pharmacokinetic explanation for the recommendation of substantially higher doses (on a mg/kg basis) for infants than adults. In order to further elucidate the fate of digoxin in neonates and infants with heart failure, the pharmacokinetics of its distribution and elimination were investigated. The intravenous serum concentration data were fitted to the equation characterizing a linear two-compartment open model using a digital computer program.
Material and Methods Patients
Despite widespread use of digoxin in infants with cardiac disease, there are few studies of its pharmacokinetics at this age. Previous investigations using tritiated digoxin showed that its tissue distribution and excretion were similar in infants and adults (Hernan-
Seven full-term neonates and infants with a diagnosis of congenital cardiac malformation and congestive heart failure were studied; their clinical details are listed in Table 1. The clinical diagnosis in five patients (no. 3-7) was based on data obtained at cardiac catheterization and angiocardiography. Body surface
330
G. Wettrell: Digoxin in Infants
Table 1. Clinical details of neonates and infants given intravenous digoxin Patient no.
Sex
Age, Weight, kg/ Dosage days surface area, m2 mg
mg/kg b. w.
1 2 3
M F M
2 3 22
3.300/0.19 2.800/0.20 2.700/0.19
0.050 0.038 0.045
0.015 0.014 0.017
4 5 6 7
M M M M
44 52 70 81
3.400/0.22 4.300/0.25 4.550/0.25 4.450/0.26
0.060 0.075 0.075 0.100
0.018 0.017 0.017 0.022
Clinical diagnosis Hyperbilirubinaemia Suspected transposition of the great vessels; asphyxia syndrome Hypoplastic right ventricle; pulmonary valve atresia; patent ductus arteriosus Common A-V canal; Down's syndrome Ventricular septal defect Ventricular septal defect Patent ductus arteriosus
Table 2. Serum concentration and 24-h urine excretion of digoxin in 7 neonates and infants after its intravenous administration Patient
Serum concentration (ng/ml) after (h)
no.
0.5
1
1.5
2
3
3.5
4
8.5 8.2 8.2 7.2 7.0 6.0 10.6
5.2 4.5 4.9 3.6 3.4 2.4 6.2
3.5 3.0 3.2 2.0 2.2 1.9 3.4
2.1 2.3 2.2 1.5 1.7 1.3 2.5
1.7 1.9 1.5 1.0 1.2 1.7
-
-
1.0 -
1.2 1.4 0.8 1.1 0.8 1.7
1
2 3 4 5 6 7
24-h urine excretion,
area was d e t e r m i n e d by a n o m o g r a m f r o m C r a w f o r d et al. (1950). All patients had a b l o o d urea nitrogen concentration within n o r m a l limits.
Drug Administration A commercial p r e p a r a t i o n of digoxin (Lanacrist ® solution for injection, A B D r a c o , Sweden) was used for intravenous administration; the solution contained 250 gg of digoxin per ml, and before injection, it was diluted 1 : 10 with 0 . 9 % saline. E a c h patient received a dose calculated to be one quarter to one third of the digitalizing dose, 0 . 0 5 - 0 . 0 7 m g / k g b. w. at the start of the sampling period. Table 1 lists the individual doses. Digoxin was injected o v e r 2 to 3 rain via a v e n o u s umbilical catheter or scalp vein needle, and the catheter was then flushed with a few ml of 0.9% saline. T h e patients were not fasted.
Blood Samples and Assay B l o o d was o b t a i n e d via an umbilical artery catheter (Patients 1 and 2) or by capillary sampling in E p p e n doff tubes (Patients 3 - 7 ) . B l o o d was collected over a 24 h period after injection of digoxin. T h e duration of the sampling time was d e t e r m i n e d by the clinical con-
5
1.4
-
6
-
1.1 1.0 1.4
8
12
24
volume, ml
per cent of dose
1.2 1.0 1.1 0.6 0.8 0.7 1.I
1.0 0.9 0.8 0.5 0.6 0.5 0.9
1.0 0.8 0.8 0.4 0.5 0.5 0.8
160 162 225 60 374 327 95
13 13 14 6 27 26 15
dition of the patient. F u r t h e r m o r e , although a microm e t h o d was used, the n u m b e r of b l o o d samples were kept as low as possible in view of the age of the patients; Table 2 lists the individual sampling schedules. A 24 h urine was collected in a urine bag (Hollister Inc., U S A ) f r o m the time of digoxin administration. A commercial r a d i o i m m u n o a s s a y kit (Schwarz/ M a n n , O r a n g e b u r g , N e w Y o r k , U S A ) with 125I as tracer was used to m e a s u r e digoxin in serum. T h e m e t h o d has previously b e e n evaluated and f o u n d equal to the 3H-digoxin assay ( T a u b e r t and Shapiro, 1975; Wettrell and A n d e r s s o n , 1975). O n l y a 50 ~tl aliquot of serum was required for a single analysis. T h e serum samples f r o m each patient were run in the same analytical sequence and analysed at least in duplicate. Digoxin concentrations in urine were determ i n e d by an 86Rb u p t a k e inhibition assay (Bertler and Redfors, 1970; Wettrell et al., 1974) and also by the 125I r a d i o i m m u n o a s s a y .
Pharmacokinetic Model A semilogarithmic plot of s e r u m c o n c e n t r a t i o n versus time for Patient 2 is d e m o n s t r a t e d in Fig. 1. T h e o t h e r patients had similar serum c o n c e n t r a t i o n curves. T h e
G. Wettrell: Digoxin in Infants
331
biexponential behaviour of the disposition curve indicated that two exponential functions are required for satisfactory fit to the data. It was also found that any compartmental model used to fit the present data had to contain a minimum of two compartments. Therefore, the serum data for digoxin were described by use of a two-compartment open model (Riegelman et al., 1968). The rate constants k12, k21, kel in the two-compartment open model and the initial concentration of the central compartment (C1°) were estimated from the experimental data by a non-linear least-squares program LISPID (kindly supplied by K. J. Astr6m, Dept. of Automatic Control, Institute of Technology, Lund, Sweden) on a Univac 1108 computer. In the leastsquares analysis differences between the model and actual measurements were weighted by the reciprocal of the variance of the measurement errors. The latter varied with the absolute value of the concentration and were determined by making 10 measurements on test samples of known concentrations. When the parameters of the compartment model and the initial dose are known, it is possible to compute the volumes of distribution. It is also possible to simulate the model to obtain the time courses of the amounts of drug in the compartments; such a simulation is shown in Fig. 2. The simulations were done with an interactive simulation language SIMNON.
Analysis of Pharmacokinetic Parameters
(gq. 1)
where D is the dose given (as a bolus injection) and C1° the estimated serum concentration at zero time obtained from the non-linear equation. The total volume of distribution at steady-state, Vdss, can be obtained from the following equation (Riggs, 1963) V d ss ~-
( e l 2 q- k21) k21
• V 1
8: 6. 4"
1'
0.i 0
2 4 6 8
1'2
;6
2'0
2'4
Time,h
Fig. 1. Semilogarithmic plot of observed (*) and computer fitted (o) serum concentrations of digoxin for 24 h after its rapid intravenous injection in Patient 2 1.0-
0 1D
0.8.
= 0.6"
/
0
"-.0.~ o~ F
o
~
18
1~
2'o
2'5
Time s h
Fig. 2. Simulation of distribution and elimination of digoxin during 24 h after intravenous injection in Patient 2. A = amount in central compartment, B = amount in peripheral compartment and C = amount of digoxin eliminated
drug elimination processes (Jusko and Gibaldi, 1972), was determined from the equation C1B = V 1 ' kel = V d f i " fi
(Eq. 4)
(Eq. 2)
After steady-state is attained, the volume of distribution, determined as Vail, relates the total amount of drug in the body to the drug concentration in the serum at all times during the second exponential phase, i. e. the fl-slope (Gibaldi et al., 1969). This volume is obtained from the equation Vd/~ ~--Re, - Vl/]~
ng/ml
0.0
The volume of the central compartment (V1) was calculated from the equation D V 1 = C1°
Digoxin, 10.
(Eq. 3)
Body clearance, CIB, corresponding to the sum of all
Prediction of Steady-State Serum Concentration
of Digoxin Basic parameters estimated from a single-dose study can be used to predict the average blood concentration during a multiple-dose regimen (Wagner et al., 1965). Presuming first-order kinetics in the two-compartment model, the mean steady-state concentration, Css, of a drug is a function of the availability, F, the maintenance dose, D, the disposition rate con-
G. Wettrell:Digoxinin Infants
332 stant,/3, the apparent volume of distribution, Vdfi, and the dose interval, T (Wagner et al., 1965). Css =
F •D (Eq. 5) fi" Vdfl" T Numerical values for the parameters in equation 5 were obtained from average data in previous studies and from calculated values obtained in the present study. Thus, bioavailability (F) of digoxin elixir (Lanoxin ® paediatric solution, Burroughs-Wellcome Ltd., United Kingdom) in neonates and infants was estimated to be ~ipproximately 0.75 (Wettrell and Andersson, 1975). Maintenance doses (D) in neonates and infants were based on the prevailing oral dose schedule for digoxin elixir (Wettrell et al., 1974) for which the dosing interval (T) is 12 h.
Results
Serum Concentration and Urinary Excretion of Digoxin Individual serum concentrations of digoxin during the first 24 h after intravenous administration are listed in Table 2. All the patients showed a biexponential decline. A rapid fall in serum concentration was observed during the first 2 h, followed by slow disappearance during the succeeding hours. Four of the patients (nos. 2, 3, 6 and 7) showed a slight deviation from the anticipated serum concentration curves between the 3rd and 8th h after injection. A semilogarithmic plot of the observed serum digoxin concentrations versus time in Patient 2, shown in Fig. 1, as well as the least-squares fitted values, and the fit appear adequate. Urinary excretion of digoxin during the first 24 h after intravenous administration in Patients 5 and 6 was found to be 27 and 26 per cent of the given dose, respectively. The 24 h urine collections from these patients were believed to be complete (continuous supervision); the collection of the other urine specimens might have been incomplete, particularly those from Patients 4 and 7. In Patients 5 and 6 the amount of digoxin excreted in urine was found to be less than half the daily total elimination calculated on the basis of the pharmacokinetic parameters.
Pharmacokinetic Parameters The results of the pharmacokinetic analyses are shown in Tables 3 and 4. There was extensive distribution of digoxin to the peripheral compartment, as indicated by an average volume of distribution at steady-state, VdSs,of 9.91/kg compared to the average volume of the
central compartment, V1 of 1.3 1/kg. The half-lives of the distribution (alpha) phase ranged from 0.44 to 0.69 h. There is an illustration of the simulation of the time course of distribution based on available pharmacokinetic parameters in Fig. 2. The rapid disappearance of digoxin from the central compartment might be due mainly to an increase in the peripheral compartment rather than elimination of the glycoside. During the elimination (beta) phase, the mean volume of distribution, Vail, was calculated to be 12.1 1/kg. The half-lives corresponding to this phase ranged from 13.6 to 57.8 h. The elimination, calculated as clearance from the body, C1B, varied between 57 and 268 ml/min/1.73 m2; individual values are listed in Table 4. There seemed to be slow elimination of digoxin from the body during the first month of life. Serum digoxin concentration was measured in some of the patients (nos. 3-7) under steady-state conditions. The relationship between serum concentrations determined after several days of maintenance therapy and those predicted by Equation 5 is shown in Table 4.
Discussion
The results of this study indicate that the pharmacokinetics of digoxin in paediatric patients can be characterized by a linear two-compartment open model. This model has previously been used in disposition studies of digoxin in adults (Dengler et al., 1973; Reuning et al., 1973; Nyberg et al., 1974; Koup et al., 1975 a). Some of the patients showed a deviation from the expected, biexponential serum concentration curve, probably due to enterohepatic cycling (Nyberg et al., 1974; Koup et al., 1975 a). The deviation, however, was small and transient in relation to the total time course of digoxin disposition. Digoxin appeared to be rapidly distributed in the body. Thus the calculated half-life of the alpha phase (range 26 to 41 rain), which mainly represents distribution from the central to the peripheral compart•ment, was short. This finding agrees with results in neonates and infants reported by Morselli et al. (1975). Similar half-life values have been found for the distribution of tritiated digoxin in paediatric patients (Dungan et al., 1972). The large volume of the central compartment compared to the plasma volume in this age group (Friis-Hansen, 1971) indicates that digoxin in plasma rapidly equilibrates with highly perfused organs. The mean value of the volume was somewhat higher in neonates and infants than has been previously reported in adults (Dengler et al., 1973; Nyberg et al., 1974). The steady-state volume of distribution was
G. Wettrell: Digoxin in Infants
333
Table 3. Pharmacokinetic parameters according to the two-compartment open model after iv. digoxin (C1°, k12, k21, and ke~_+standard deviation of the estimate) Patient no.
C1° (ng/ml)
a (h-l)
/3 (h-')
k12 (h-l)
k21 (h-l)
kei (h-l)
VI (l/kg)
Va/~ (1/kg)
Vass (1/kg)
1
15.1 _+1.6 10.8 -+1.2 12.8 _+1.4 12.6 _+1.6 12.9 _+1.8 11.3 -+1.7 17.6 -+2.1
1.30
0.012
1.05__+0.08
0.12+0.01
0.13__+0.03
1.0
11.3
9.8
1.00
0.017
0.76_+0.07
0.12_+0.01
0.14_+0.03
1.3
10.5
9.3
1.15
0.021
0.86-_+0.07
0.13_+0.01
0.19_+0.03
1.3
11.5
9.9
1.44
0.042
0.91_+0.07
0.14_+0.02
0.43-+0.08
1.4
14.3
10.4
1.58
0.051
1.03_+0.11
0.20_+0.02
0.40_+0.06
1.4
10.6
8.3
1.78
0.036
1.30-+0.14
0.20_+0.02
0.32_+0.06
1.5
13.1
10.9
1.27
0.025
0.91-+0.08
0.13_+0.01
0.26_+0.04
1.3
13.2
11.1
2 3 4 5 6 7
Table 4. Pharmacokinetic parameters and comparison of predicted and measured serum concentrations of digoxin in seven neonates and infants with heart failure Patient no.
1 2 3 4 5 6 7
(Tm)a a
(T1/2)/3a (h)
Body clearance of digoxin, C1B (ml/min/l.73 m 2)
Predicted serum concentration of digoxin at steadystate, Cs~ (ng/ml)
Measured serum concentration of digoxin at steadystate, (ng/ml)
(h)
0.54 0.69 0.60 0.48 0.44 0.39 0.55
57.8 40.8 33.0 16.5 13.6 19.3 27.7
68 72 57 268 267 248 162
2.8 2.3 1.7 0.9 0.9 1.0 1.5
1.4 1.5 0.8 1.5 1.6
0.693 a
T1/2c¢
_
T1/Zfl
--
0.693
/3
much larger than the total body water (Friis-Hansen, 1971), which means that digoxin is extensively distributed and bound to additional tissues. The steadystate distribution volume in neonates and infants exceeded the value found in adults (Reuning et al., Nyberg et al., 1974; Koup et al., 1975 a). A still higher mean value of apparent volume of distribution in infants than in the present study was recently reported (Morselli et al., 1975). The larger volume of distribution in neonates and infants might be due to increased tissue binding of digoxin in these age-groups, although no significant difference between infants and adults in the digoxin content of several tissues was found during maintenance therapy (Andersson et al., 1975). A further reason for the quantitative differences in volume of
distribution between infants and adults could be changes with age in body composition. The larger volume of extracellular fluid in neonates and infants, however, can only contribute slightly to the increased volume of distribution, as digoxin is mainly bound to tissues. The plasma protein binding of digoxin in neonates is low and in the same range as in adults (Lukas and Martino, 1969; Koup et al., 1975 b; Gorodischer et al., 1974). Therefore, this parameter cannot account for the difference between the paediatric and adult patients in the volume of distribution of digoxin. The reason for the age difference is unclear but might be attributable in part to increased tissue binding and in part to age-related changes in body composition (extracellular fluid volume, and ratio tissue weight/body weight).
334
The elimination of digoxin, calculated as the halflife of the beta phase, was longer in neonates (mean value, 44 h) than in infants (mean value, 19 h); similar results were found by Morselli et al. (1975). The present values in infants were shorter than those reported by Hernandez et al. (1969), but were in agreement with findings of Dungan et al. (1972). Elimination of digoxin, calculated as body clearance, was also found to change with age. Thus, clearance of the glycoside from the body was slower during the first month of life (mean value, 65 ml/min/1.73 m 2) than during the following months (mean value, 236 ml/min/1.73 m2). Similar age-related differences between neonates and infants have been demonstrated in a study of the renal clearance of digoxin (Wettrell et al., 1974). The total elimination seemed to be higher in infants than in adults. However, it should be noted that elimination measured as body clearance might be influenced by the larger distribution volume found in infants. Moreover, the relatively short sampling period (24 h) might have contributed in some patients to what was only an approximate calculation of the elimination (/3) phase. It has also been demonstrated that calculations of elimination half-life based only on serum concentrations of digoxin could lead to lower values than those based both on serum and urine glycoside concentrations (Koup et al, 1975 a and b). Therefore, the elimination half-life in some patients might have been too short giving the impression of increased elimination. The predicted steady-state serum concentration in some of the patients (nos 4 and 6) was lower than that actually measured (Table 4). This finding to some extent, can be explained by use of the approximate calculation of the elimination phase. Considering the wide individual variation in the pharmacokinetic parameters in neonates and infants with heart failure, the value of these calculations for predictive clinical purposes seems to be limited. The amount of digoxin excreted in urine compared to total elimination calculated from the pharmacokinetic parameters suggested non-renal elimination of considerable magnitude in certain patients. Despite a possible overestimate of total elimination, the finding suggests an alternative route of removal of the glycoside from the body, for example by metabolism and biliary excretion. In healthy adults, about 25 per cent of the total elimination of digoxin was estimated to be non-renal (Koup et al., 1975 a). In a previous study in paediatric patients using tritiated digoxin, Dungan et al. (1972) found that the mean excretion in urine and faeces in the 24 h after an intravenous injection was only 32 per cent; however, intersubject variation was wide (19-47 per cent). It was suggested that the extent of metabolism was
G. Wettrell: Digoxin in Infants
greater than was implied by the given data (Dungan et al., 1972). Metabolic degradation of digoxin in infants, greater than that currently accepted, has recently been discussed by Morselli et al. (1975). Therefore, further studies of elimination by different routes in the paediatric age groups appears desirable.
Acknowledgements. I thank Prof. K. J. ~str6m, Dept. of Automatic Control, Institute of Technology, Lund, Sweden, for his stimulating assistance in the pharmacokinetic calculations. I am indebted to Miss Siv Karlson for skilful technical assistance and to Miss Anne Nilsson for excellent secretarial work. Grants from the Swedish Medical Research Council (project no. 14X-2829) and from the Swedish National Association against Heart and Chest Diseases supported the investigation.
References Andersson, K.-E., Bertler, A., Wettrell, G.: Post-mortem distribution and tissue concentrations of digoxin in infants and children. Actapaediat. scand. 64, 497-504 (1975) Bertler, A., Redfors, A.: An improved method of estimating digoxin in human plasma. Clin. Pharmacot. Ther. 11, 665-673 (1970) Crawford, J. D., Terry, M. E., Rourke, G. M.: Simplification of drug dosage calculation by application of the surface area principle. Pediatrics 5, 783-790 (1950) Dengler, H.J., Bodem, G., Wirth, K.: Pharmacokinetic and metabolic studies with Lanatoside C, a- and ~acetyldigoxin and digoxin in man. Proc. 5th Int. Cong. Pharmacology. San Francisco, 1972, vol. 3, pp 112-126. Basel: Karger 1973 Dungan, W.T., Doherty, J.E., Harvey, C., Char, F., Dalrymple, G. W.: Tritiated digoxin XVIII: Studies in infants and children. Circulation 46, 983-988 (1972) Friis-Hansen, B.: Body composition during growth. Pediatrics 47, 264-274 (1971) Gibaldi, M., Nagashima, R., Levy, G.: Relationship between drug concentration in plasma or serum and amount of drug in the body. J. pharm. Sci. 58, 193-197 (1969) Gorodischer, R., Krasner, J., Yaffe, S. J.: Serum protein binding of digoxin in newborn infants. Research Comm. chem. Path. Pharmacol. 9, 387-390 (1974) Hernandez, A., Bruton, R. M., Pagtakhan, R. D., Goldring, D. J.: Pharmacodynamics of 3H-digoxin in infants. Pediatrics 44, 418-427 (1969) Iisalo, E., Dahl, M.: Serum levels and renal excretion of digoxin during maintenance therapy in children. Acta paediat, scand. 63, 699-704 (1974) Jusko, W. J., Gibaldi, M.: Effects of change in elimination on various parameters of the two-compartment open model. J. pharm. Sci. 61, 1270-1273 (1972) Koup, J.R., Greenblatt, D.J., Jusko, W.J., Smith, T.W., KochWeser, J.: Pharmacokinetics of digoxin in normal subjects after intravenous bolus and infusion doses. J. Pharmacokin. Biopharm. 3, 181-192 (1975 a) Koup, J.R., Jusko, W.J., Elwood, C.M., Kohli, R.K.: Digoxin pharmacokinetics. Role of renal failure in dosage regimen design. Clin. Pharmacol. Ther. 18, 9-21 (1975 b) Lukas, D.S., De Martino, A.G.: Binding of digitoxin and some
G. Wettrell: Digoxin in Infants related cardenolides to human plasma proteins. J. clin. Invest. 48, 1041-1053 (1969) Morselli, P.L., Assael, B.M., Gomeni, R., Mandelli, M., Marini, A., Reali, E., Visconti, U., Sereni, F.: Digoxin pharmacokinetics during human development. Basic and therapeutic aspects of perinatal pharmacology (ed. Morselli, L., Garattini, S. and F. Sereni), p. 377-392, New York: Raven Press 1975 Nyberg, L., Andersson, K.-E., Bertler, ~.: Bioavailability of digoxin from tablets. II. Radioimmunoassay and disposition pharmacokinetics of digoxin after intravenous administration. Acta pharm, suecia 11, 459-470 (1974) Reuning, R. H., Sams, R. A., Notari, R. E.: Role of pharmaeokinetics in drug dosage adjustment. I. Pharmacologic effect kinetics and apparent volume of distribution of digoxin. J. clin. Pharmacol. 13, 127-141 (1973) Riegelman, S., Loo, I. C. K., Rowland, M.: Shortcomings in pharmacokinetic analyses by conceiving the body to exhibit properties of a single compartment. J. pharm. Sci. 57, 117-123 (1968) Riggs, D. S.: The mathematical approach to physiological problems, p. 193-220, Baltimore, Maryland: Williams and Wilkins 1963 Taubert, K., Shapiro, W.: Serum digoxin levels using an l~SI-labelled antigen: Validation of method and observations on cardiac patients. Amer. Heart J. 89, 79-86 (1975)
335 Wagner, J.G., Northam, I.T., Alway, C.D., Carpenter, O.S.: Blood levels of drug at the equilibrium state after multiple dosing. Nature (Lond.) 207, 1301-1302 (1965) Wettrell, G., Andersson, K.-E., Bertler, ~., Lundstr6m, N.R.: Concentrations of digoxin in plasma and urine in neonates, infants and children with heart disease. Acta paediat, seand. 63, 705-710 (1974) Wettrell, G., Andersson, K.-E.: Absorption of digoxin in infants. Europ. J. clin. Pharmacol. 9, 49-55 (1975) Yanagi, R., Kim, W.P., Krasula, R, W., Soyka, L.F., Hastreiter, A.R.: Urinary excretion of digoxin in infants and children. Circulation 49-50, (Suppl. 3) abs No. 484, 1974 Received." January 30, 1976, and in revised form: November 2, 1976, accepted." November 18, 1976 Dr. G. Wettrell Dept. of Paediatrics and Clinical Pharmacology University Hospital S-221 85 Lund Sweden
