Pharmacokinetics and Bioavailability of Digoxin Capsules, Solution and Tablets After Single and Multiple Doses
BRIAN L. LLOYD, MB, MRACP DAVID J. GREENBLATT, MD MARCIA D. ALLEN, RN JEROLD S. HARMATZ THOMAS W. SMITH, MD, FACC Boston, Massachusetts
The bioavailability of single doses of dtgoxln capsules (0.4 mg), dlgoxin sokrtlon (0.4 mg) and reference tabtets (0.5 mg) was compared wtth that of single intravenous doses (0.4 mg) of digoxin using measurement of 24 hour urinary excretion and area under the plasma concentration curve. The absolute systemic availabtltty of all three oral preparations was signtficantly less than 100 percent. The bioavallabtltty of capsules and solution was nearly ldentlcal(79 percent and 76 percent, respectively, as assessed with values for area under the concentration curve and 65 percent and 62 percent as m with urtnary excretion values); both forms had greater systemic avallabtltty than the tablet, which had bioavailabt5ty vakres of 50 percent ustng area under the curve and 41 percent using urinary excretion. Capsules and solution also were similar In peak plasma dtgoxin levels achieved (3.7 and 3.1 ng/ml), time of peak concentratlon (0.8 and 0.6 hour after dosage) and apparent first order absorption half-life (11.3 and 10.2 minutes); both capsules and solutlon differed stgntflcantly from tablets (peak level 1.6 ng/ml, time of peak concenkatkx~ 1.2 hours and absorptkn half-5fe 27.1 mtnutes). Single dose findlngs were substantiated when steady state plasma levels and 24 hour urinary excretion values were measured from days 11 through 16 of the period of once daily ingestion. Mean plasma levels (0.70 ng/ml) and urlnary excretion values (45.1 percent of dose) for capsules were nearly identical to those for solution (0.6s ng/ml and 42.5 percent of the dose), and values for both capsules and solution were signlftcantly greater than those for tablets. Withtn- and between-subject variation in bioavailablllty was similar for the three oral preparations. Thus the single dose bioavailability study was predictive of the steady state findings. The btoavailability of digoxin capsules is equivalent to that of a solution and significantly greater than that of a reference tablet formulation.
From the Clinical PharmacologyUnit, fdassadwsettsQeneralHcepttal;andthecerdiovascular Dlvlsion, Deparhwnt of Medicine, Peter Sent Brigham Hospital, Boston, Massachusetts. This study was supported in pert by a grant from Anlw-staw kborawm, MouIt Pmspect, lllinols and by @ants l-H.-18003 (to Dr. Smith) and MK 12279 (to Dr. Qreenblatt and Mr. Harmatz) from the fMofnil Institutt3s of Heafth, Betfwsda, Mwyland.Dr.Lbydwasa Resew& Fellow of ths N&bd IWrt Found&n of Austmfla. Manuswipt rece&ed Novembw 30,1977; revised manuscript received January 30,1978. accepted February 1, 1978. Address for reprints: David J. Greenblatt. MD, Clinical Pharmacology Unit, Massachusetts General Hospital, Boston, Massachusetts 02114.
Achievement of stable and predictable plasma digoxin concentrations during long-term digoxin therapy remains difficult because all currently available oral digoxin preparations are incompletely and variably absorbed from the gastrointestinal tract.’ An optimal fixed dose oral digoxin preparation would have a predictable high level of bioavailability with minimal variation in the extent of absorption within and between subjects. Gelatin capsules containing digoxin in solution reportedly have improved bioavailability and may be a potential replacement for digoxin tablets.28 However, the extent of improved bioavailability of capsules and the issue of whether steady state plasma digoxin levels are less variable than with existing standard preparations have not been settled by previous studies. We investigated the extent and variability of digoxin absorption from the capsule preparation after single and multiple doses in comparison with those of standard reference tablets and solution. July 1978
The Amerfcan Journal of CARDfOLOGV
Volume 42
129
PHARMACDKINETICS
AND BIOAVAILABILITY OF DIGDXIN-LLOYD
ET AL.
Methods
Solution: 0.4 mg reference standard digoxin dissolved in 2 ml of U.S.P. ethanol and 198 ml of water. The container was rinsed with 40 ml of water, which was also ingested.
Subjects: Twelve healthy male volunteers (Table I) served as experimental subjects after giving informed consent. None had any demonstrable medical disease. Procedure: Each subject received the following four digoxin preparations in random sequence:
TABLE I Pharmacokinetic Case no. 1
Variables After Intravenous Adminlstratlon of Digoxln
Age (yr) 33
3
34 25 28
: 8
3 1; 11 12 Mean SE Comoosite
Tablets: Two 0.25 mg tablets of reference standard digoxin (Lanoxine, Burroughs Wellcome Co., lot no. 022-1, with an in vitro dissolution rate of 75 percent in 1 hour).
29 27
St! 27
29
27.9 fl.O
Weight (kg)
f112a
t112r
(hr)
(hr)
l
80.0 80.9 81.8 84.5 79.5 82.7 85.9 72.7 88.2 88.2 77.3 81.8 77.0 f1.9 77.0
t&w
l
0.05 0.19 0.44 0.32 0.15 0.39 0.41 0.43 0.24 0.08 0.08 0.24 f0.04 0.14
(IitezIkg)
83.01 37.88 10.03 10.19 48.21 11.07 27.70 18.34 9.70 27.73 48.21 27.82 f5.54 19.3
0.85
0.88 0.82 0.71 fO.10 0.81
Clearance (ml/kg per min)
.
l
l
0.128 0.252 0.308 0.501 0.309 0.577 0.821 0.534 0.315 0.179 0.188 0.35 f0.053 0.28
10.95 8.43 4.08 8.77 14.50 7.83 8.79 8.87 3.15 8.75 12.43 8.41 fl.O1 8.72
2.01 2.59 4.88 7.78 3.83 8.17 3.88 4.85 3.74 3.85 3.11 4.35 f0.59 4.47
l
0.42 1.02
(Ilte%kg)
ktdicates that least-squares analysis could not be performed because of outlying data points. SE = star&d error; tuza = distributionhalf-life; tllh = intermediate half-life; tl12@= elimination half-life: Vd = total apparent volume of distribution; VI = volume of central compartment. l
INTRAVENOUS
(0.4
mg)
CAPSULE
(0.4
mg)
c 0.0
SOLUTION
(0.4
4.0
8.0
12.0
24.0
FIGURE 1. Plasma digoxln wn-
0.0
4.0
HOURS
July 1978
20.0
mg) TABLETS
130
16.0
The American Journal d CARDIDLDGY
Volume 42
8.0
12.0
(0.5
18.0
mg)
20.0
24.0
centrations after admintstratfon of ask@edoeeofintreMwwKgdlgoxin and of the three oral dlgoxtn prep aratkxls. Each point Is the meen for all 12 subjects at the time shown (standard errors, omitted fcf clarity, will be provided by the author on request). Also shown are the phsrmacokinetlc functions determined from least-squares regression analysis (see text).
!WARMACOKINfiTICS
TABLE
AND BIOAVAILABILITY OF DIGOXIN-LLOYD
ET AL.
II
Pharmacoklnetlcs d Dlgoxin Absorption From the Three Oral Preparations Capsule(0.4 mg)
Case no.
*SE Comwsite l
Peak Level @g/ml)
Peak Time (hr after dose)
Lag Time (min)
(min)
l
l
f112a
Solution (0.4 mg)
Tablet (0.5 mg)
Peak Time (hr after dose)
Lag Time (min)
(min)
Peak Time (hr after dose)
3.3 t.: 2:8
0.75 0.5 0.5
11.8 11.5 10.7
11.0 7.2 11.2
2.1 0.8 0.9 1.2
34.3 9.8 1.0
Peak Level @g/ml)
ha
Peak Level (ng/ml)
Lag Time (min)
(min)
0.75 1.5 2.0 1.0
14.4 15.0 13.8
4.2 74.3 31.3
1.0 1.8 1.7
0.75 1.5 1.0
17.4 14.4 11.4
36.8 17.6 7.0
f112a
3.5 3.5 :::
1.0 1.0 0.75
+ 28.2
z.: 2:8
0.75 0.5
14.4 15.0 15.0
2G 19:o 3.5
;::
::;5
1;2 10:8 13.7
S:;
0.75 1.0
1;o
lIj9
42::
00:;5 0.5
12.6
8.5 8.1
2.9 1.3
2.0 1.5
12.0
35.6
2.9 4.2
0.75 0.75
29:8 12.6
0:9 7.8
X:: f.8
0.75 0.5
184:: 9.8
13.1 6.1
2.0 1.6
1.0 0.5
13.8 15.0
31.5 0.7
f :; f0.3 3.4
0.75 0.8 f0.04 0.75
18.1 15.0 f2.4 15.0
12.4 11.3 f3.1 19.8
10.2 4.2 f2.6 7.4
1.6 1.5 f0.2 1.2
1.0 1.2 fO.l
13.9 11.4 ho.6
32.0 27.1 f6.8
1.0
12.4
22.0
l
l l
311 f0.3 2.9
X:: f0.04 0.5
11.9 12.5 f0.8 11.4
l
l
l
l
l
Indicates that least-squares analysis could not be performed because of outlying data points.
Capsules: Two 0.2 mg capsules of digoxin prepared in a liquid-filled soft gelatin capsule (Arnar-Stone Laboratories, lot. no. 746P). Intravenous preparation: 0.4mg of digoxin injection (Lanoxina, lot no. 994-S) diluted with 46.4 ml of sterile 5 percent dextrose in water and infused into an antecubital vein by a constant rate infusion pump over 1 hour. Tablet and capsule preparations were ingested with 240 ml of water. Subjects fasted overnight before each oral dosage trial and abstained from further food or liquid for 4 hours after drug administration. Venous blood samples were drawn through an indwelling catheter, or by venipuncture, before dosage and 0.25,0.5,0.75,1.0,1.5,2.0,2.5,3,4,6,8,12 and 24 hours after digoxin ingestion or the start of infusion. Additional samples were drawn at 65 and 75 minutes after the start of intravenous infusion. A 24 hour urine collection was begun at the time of digoxin administration. After the initial 24 hours of study, each oral preparation was taken daily at 9 AM for 14 additional days. “Steady state” blood samples were collected just before the daily dose on days 11 through 16.Urine was collected in 24 hour periods after doses 11,12,13,14 and 15. After the final dose of each oral preparation, 24 hours of blood sampling was performed as in the case of the initial dose. Subjects remained ambulatory during testing, and at least 14 days elapsed between each trial to permit complete excretion of digoxin from the preceding period. Analysis of plasma and urine: Plasma and urine samples were stored at -20’ C until the time of assay. Digoxin concentrations in plasma and urine were determined with radioimmunoassay as previously described.gJo Analysis of data: Plasma digoxin concentrations after intravenous infusion were analyzed with the computer using iterative nonlinear least-squares regression techniques,11J2 as described in detail elsewhere.13 Data points for individual subjects, as well as for composite points calculated as the across-subject mean plasma concentrations at corresponding points in time, were fitted to bi- or triexponential functions consistent with two- or three-compartment pharmacokinetic models. The functions of best fit were then used to calculate the following pharmacokinetic variable@-is: distribution half-life (ti/sJ, intermediate pi half-life (ti/s,) when appro-
priate, elimination half-life (ti/sg), volume of the central compartment (Vi), total apparent volume of distribution using the area method (V,) and total clearance. After oral administration of digoxin, individual and composite data points were similarly analyzed and fitted to the sum of the smallest number of exponential terms necessary to describe the data adequately. Fitted functions were used to calculate the lag time (tc) elapsing before the start of first order absorption, and the apparent first order absorption half-life (tijs,). In all cases iterative analysis proceeded until the convergence criteria were met or 50 iterative steps were completed. Plasma digoxin concentrations for the 24 hours after the first and last dose of each preparation were used to calculate
the area under the 24 hour plasma concentration curve using the trapezoidal method. Single dose bioavailability was assessed by comparing the area under the plasma concentration curve and the 24 hour urinary excretion values after each preparation, using repeated-measures analyses of variance and the Newman-Keuls test of paired comparisons.17 Relative bioavailabiity of the three oral preparations during long-term therapy was similarly assessed from steady state plasma concentrations and urinary excretion values. Appropriate adjustments were made for differences in oral doses of tablets, capsules and solution. Between- and within-subject variations in the various measures of bioavailability were expressed as coefficients of
variation. The between-subject coefficient of variation for a given mode of treatment was determined as the standard deviation for that treatment divided by the treatment mean, expressed in percent. When multiple measurements were made for the same subjects within a given treatment, an overall within-subject coefficient of variation for that treatment was calculated by weighted pooling of each individual subject’s coefficient of variation.18
Results Single
dose pharmacokinetics:
single dose composite digoxin administration, fit.
July 1978
Figure 1 shows data points for all four modes of together with functions of best
The American Journal of CARDfOLOGY
Volume 42
131
PHARMACOKINETICS
AND
BIOAVAILABILITY
OF DIGDXIN-LLOYD
ET AL.
Disappearance of digoxin from plasma after intravenous infusion was best fitted by two exponential phases in six
subjects and by three exponential phases in five subjects (Table I). In the remaining subject (Case l), a satisfactory fit could not be achieved because of outlying data points. The mean apparent elimination half-life was 27.8 hours, the total volume of distribution 8.4 liters/kg and the total clearance 4.35 ml/min per kg. These values are consistent with data in other reports of intravenous digoxin pharmacokinetics in normal subjects.lg Peak serum digoxin concentrations (in ng/ml) averaged 3.7 after capsule administration, 3.1 after solution, and 1.6
after tablets (Table II). Analyses of variance indicated that the overall difference among preparations was significant (F = 46.5, d.f. = 2,22, P
BRIAN L. LLOYD, MB, MRACP DAVID J. GREENBLATT, MD MARCIA D. ALLEN, RN JEROLD S. HARMATZ THOMAS W. SMITH, MD, FACC Boston, Massachusetts
The bioavailability of single doses of dtgoxln capsules (0.4 mg), dlgoxin sokrtlon (0.4 mg) and reference tabtets (0.5 mg) was compared wtth that of single intravenous doses (0.4 mg) of digoxin using measurement of 24 hour urinary excretion and area under the plasma concentration curve. The absolute systemic availabtltty of all three oral preparations was signtficantly less than 100 percent. The bioavallabtltty of capsules and solution was nearly ldentlcal(79 percent and 76 percent, respectively, as assessed with values for area under the concentration curve and 65 percent and 62 percent as m with urtnary excretion values); both forms had greater systemic avallabtltty than the tablet, which had bioavailabt5ty vakres of 50 percent ustng area under the curve and 41 percent using urinary excretion. Capsules and solution also were similar In peak plasma dtgoxin levels achieved (3.7 and 3.1 ng/ml), time of peak concentratlon (0.8 and 0.6 hour after dosage) and apparent first order absorption half-life (11.3 and 10.2 minutes); both capsules and solutlon differed stgntflcantly from tablets (peak level 1.6 ng/ml, time of peak concenkatkx~ 1.2 hours and absorptkn half-5fe 27.1 mtnutes). Single dose findlngs were substantiated when steady state plasma levels and 24 hour urinary excretion values were measured from days 11 through 16 of the period of once daily ingestion. Mean plasma levels (0.70 ng/ml) and urlnary excretion values (45.1 percent of dose) for capsules were nearly identical to those for solution (0.6s ng/ml and 42.5 percent of the dose), and values for both capsules and solution were signlftcantly greater than those for tablets. Withtn- and between-subject variation in bioavailablllty was similar for the three oral preparations. Thus the single dose bioavailability study was predictive of the steady state findings. The btoavailability of digoxin capsules is equivalent to that of a solution and significantly greater than that of a reference tablet formulation.
From the Clinical PharmacologyUnit, fdassadwsettsQeneralHcepttal;andthecerdiovascular Dlvlsion, Deparhwnt of Medicine, Peter Sent Brigham Hospital, Boston, Massachusetts. This study was supported in pert by a grant from Anlw-staw kborawm, MouIt Pmspect, lllinols and by @ants l-H.-18003 (to Dr. Smith) and MK 12279 (to Dr. Qreenblatt and Mr. Harmatz) from the fMofnil Institutt3s of Heafth, Betfwsda, Mwyland.Dr.Lbydwasa Resew& Fellow of ths N&bd IWrt Found&n of Austmfla. Manuswipt rece&ed Novembw 30,1977; revised manuscript received January 30,1978. accepted February 1, 1978. Address for reprints: David J. Greenblatt. MD, Clinical Pharmacology Unit, Massachusetts General Hospital, Boston, Massachusetts 02114.
Achievement of stable and predictable plasma digoxin concentrations during long-term digoxin therapy remains difficult because all currently available oral digoxin preparations are incompletely and variably absorbed from the gastrointestinal tract.’ An optimal fixed dose oral digoxin preparation would have a predictable high level of bioavailability with minimal variation in the extent of absorption within and between subjects. Gelatin capsules containing digoxin in solution reportedly have improved bioavailability and may be a potential replacement for digoxin tablets.28 However, the extent of improved bioavailability of capsules and the issue of whether steady state plasma digoxin levels are less variable than with existing standard preparations have not been settled by previous studies. We investigated the extent and variability of digoxin absorption from the capsule preparation after single and multiple doses in comparison with those of standard reference tablets and solution. July 1978
The Amerfcan Journal of CARDfOLOGV
Volume 42
129
PHARMACDKINETICS
AND BIOAVAILABILITY OF DIGDXIN-LLOYD
ET AL.
Methods
Solution: 0.4 mg reference standard digoxin dissolved in 2 ml of U.S.P. ethanol and 198 ml of water. The container was rinsed with 40 ml of water, which was also ingested.
Subjects: Twelve healthy male volunteers (Table I) served as experimental subjects after giving informed consent. None had any demonstrable medical disease. Procedure: Each subject received the following four digoxin preparations in random sequence:
TABLE I Pharmacokinetic Case no. 1
Variables After Intravenous Adminlstratlon of Digoxln
Age (yr) 33
3
34 25 28
: 8
3 1; 11 12 Mean SE Comoosite
Tablets: Two 0.25 mg tablets of reference standard digoxin (Lanoxine, Burroughs Wellcome Co., lot no. 022-1, with an in vitro dissolution rate of 75 percent in 1 hour).
29 27
St! 27
29
27.9 fl.O
Weight (kg)
f112a
t112r
(hr)
(hr)
l
80.0 80.9 81.8 84.5 79.5 82.7 85.9 72.7 88.2 88.2 77.3 81.8 77.0 f1.9 77.0
t&w
l
0.05 0.19 0.44 0.32 0.15 0.39 0.41 0.43 0.24 0.08 0.08 0.24 f0.04 0.14
(IitezIkg)
83.01 37.88 10.03 10.19 48.21 11.07 27.70 18.34 9.70 27.73 48.21 27.82 f5.54 19.3
0.85
0.88 0.82 0.71 fO.10 0.81
Clearance (ml/kg per min)
.
l
l
0.128 0.252 0.308 0.501 0.309 0.577 0.821 0.534 0.315 0.179 0.188 0.35 f0.053 0.28
10.95 8.43 4.08 8.77 14.50 7.83 8.79 8.87 3.15 8.75 12.43 8.41 fl.O1 8.72
2.01 2.59 4.88 7.78 3.83 8.17 3.88 4.85 3.74 3.85 3.11 4.35 f0.59 4.47
l
0.42 1.02
(Ilte%kg)
ktdicates that least-squares analysis could not be performed because of outlying data points. SE = star&d error; tuza = distributionhalf-life; tllh = intermediate half-life; tl12@= elimination half-life: Vd = total apparent volume of distribution; VI = volume of central compartment. l
INTRAVENOUS
(0.4
mg)
CAPSULE
(0.4
mg)
c 0.0
SOLUTION
(0.4
4.0
8.0
12.0
24.0
FIGURE 1. Plasma digoxln wn-
0.0
4.0
HOURS
July 1978
20.0
mg) TABLETS
130
16.0
The American Journal d CARDIDLDGY
Volume 42
8.0
12.0
(0.5
18.0
mg)
20.0
24.0
centrations after admintstratfon of ask@edoeeofintreMwwKgdlgoxin and of the three oral dlgoxtn prep aratkxls. Each point Is the meen for all 12 subjects at the time shown (standard errors, omitted fcf clarity, will be provided by the author on request). Also shown are the phsrmacokinetlc functions determined from least-squares regression analysis (see text).
!WARMACOKINfiTICS
TABLE
AND BIOAVAILABILITY OF DIGOXIN-LLOYD
ET AL.
II
Pharmacoklnetlcs d Dlgoxin Absorption From the Three Oral Preparations Capsule(0.4 mg)
Case no.
*SE Comwsite l
Peak Level @g/ml)
Peak Time (hr after dose)
Lag Time (min)
(min)
l
l
f112a
Solution (0.4 mg)
Tablet (0.5 mg)
Peak Time (hr after dose)
Lag Time (min)
(min)
Peak Time (hr after dose)
3.3 t.: 2:8
0.75 0.5 0.5
11.8 11.5 10.7
11.0 7.2 11.2
2.1 0.8 0.9 1.2
34.3 9.8 1.0
Peak Level @g/ml)
ha
Peak Level (ng/ml)
Lag Time (min)
(min)
0.75 1.5 2.0 1.0
14.4 15.0 13.8
4.2 74.3 31.3
1.0 1.8 1.7
0.75 1.5 1.0
17.4 14.4 11.4
36.8 17.6 7.0
f112a
3.5 3.5 :::
1.0 1.0 0.75
+ 28.2
z.: 2:8
0.75 0.5
14.4 15.0 15.0
2G 19:o 3.5
;::
::;5
1;2 10:8 13.7
S:;
0.75 1.0
1;o
lIj9
42::
00:;5 0.5
12.6
8.5 8.1
2.9 1.3
2.0 1.5
12.0
35.6
2.9 4.2
0.75 0.75
29:8 12.6
0:9 7.8
X:: f.8
0.75 0.5
184:: 9.8
13.1 6.1
2.0 1.6
1.0 0.5
13.8 15.0
31.5 0.7
f :; f0.3 3.4
0.75 0.8 f0.04 0.75
18.1 15.0 f2.4 15.0
12.4 11.3 f3.1 19.8
10.2 4.2 f2.6 7.4
1.6 1.5 f0.2 1.2
1.0 1.2 fO.l
13.9 11.4 ho.6
32.0 27.1 f6.8
1.0
12.4
22.0
l
l l
311 f0.3 2.9
X:: f0.04 0.5
11.9 12.5 f0.8 11.4
l
l
l
l
l
Indicates that least-squares analysis could not be performed because of outlying data points.
Capsules: Two 0.2 mg capsules of digoxin prepared in a liquid-filled soft gelatin capsule (Arnar-Stone Laboratories, lot. no. 746P). Intravenous preparation: 0.4mg of digoxin injection (Lanoxina, lot no. 994-S) diluted with 46.4 ml of sterile 5 percent dextrose in water and infused into an antecubital vein by a constant rate infusion pump over 1 hour. Tablet and capsule preparations were ingested with 240 ml of water. Subjects fasted overnight before each oral dosage trial and abstained from further food or liquid for 4 hours after drug administration. Venous blood samples were drawn through an indwelling catheter, or by venipuncture, before dosage and 0.25,0.5,0.75,1.0,1.5,2.0,2.5,3,4,6,8,12 and 24 hours after digoxin ingestion or the start of infusion. Additional samples were drawn at 65 and 75 minutes after the start of intravenous infusion. A 24 hour urine collection was begun at the time of digoxin administration. After the initial 24 hours of study, each oral preparation was taken daily at 9 AM for 14 additional days. “Steady state” blood samples were collected just before the daily dose on days 11 through 16.Urine was collected in 24 hour periods after doses 11,12,13,14 and 15. After the final dose of each oral preparation, 24 hours of blood sampling was performed as in the case of the initial dose. Subjects remained ambulatory during testing, and at least 14 days elapsed between each trial to permit complete excretion of digoxin from the preceding period. Analysis of plasma and urine: Plasma and urine samples were stored at -20’ C until the time of assay. Digoxin concentrations in plasma and urine were determined with radioimmunoassay as previously described.gJo Analysis of data: Plasma digoxin concentrations after intravenous infusion were analyzed with the computer using iterative nonlinear least-squares regression techniques,11J2 as described in detail elsewhere.13 Data points for individual subjects, as well as for composite points calculated as the across-subject mean plasma concentrations at corresponding points in time, were fitted to bi- or triexponential functions consistent with two- or three-compartment pharmacokinetic models. The functions of best fit were then used to calculate the following pharmacokinetic variable@-is: distribution half-life (ti/sJ, intermediate pi half-life (ti/s,) when appro-
priate, elimination half-life (ti/sg), volume of the central compartment (Vi), total apparent volume of distribution using the area method (V,) and total clearance. After oral administration of digoxin, individual and composite data points were similarly analyzed and fitted to the sum of the smallest number of exponential terms necessary to describe the data adequately. Fitted functions were used to calculate the lag time (tc) elapsing before the start of first order absorption, and the apparent first order absorption half-life (tijs,). In all cases iterative analysis proceeded until the convergence criteria were met or 50 iterative steps were completed. Plasma digoxin concentrations for the 24 hours after the first and last dose of each preparation were used to calculate
the area under the 24 hour plasma concentration curve using the trapezoidal method. Single dose bioavailability was assessed by comparing the area under the plasma concentration curve and the 24 hour urinary excretion values after each preparation, using repeated-measures analyses of variance and the Newman-Keuls test of paired comparisons.17 Relative bioavailabiity of the three oral preparations during long-term therapy was similarly assessed from steady state plasma concentrations and urinary excretion values. Appropriate adjustments were made for differences in oral doses of tablets, capsules and solution. Between- and within-subject variations in the various measures of bioavailability were expressed as coefficients of
variation. The between-subject coefficient of variation for a given mode of treatment was determined as the standard deviation for that treatment divided by the treatment mean, expressed in percent. When multiple measurements were made for the same subjects within a given treatment, an overall within-subject coefficient of variation for that treatment was calculated by weighted pooling of each individual subject’s coefficient of variation.18
Results Single
dose pharmacokinetics:
single dose composite digoxin administration, fit.
July 1978
Figure 1 shows data points for all four modes of together with functions of best
The American Journal of CARDfOLOGY
Volume 42
131
PHARMACOKINETICS
AND
BIOAVAILABILITY
OF DIGDXIN-LLOYD
ET AL.
Disappearance of digoxin from plasma after intravenous infusion was best fitted by two exponential phases in six
subjects and by three exponential phases in five subjects (Table I). In the remaining subject (Case l), a satisfactory fit could not be achieved because of outlying data points. The mean apparent elimination half-life was 27.8 hours, the total volume of distribution 8.4 liters/kg and the total clearance 4.35 ml/min per kg. These values are consistent with data in other reports of intravenous digoxin pharmacokinetics in normal subjects.lg Peak serum digoxin concentrations (in ng/ml) averaged 3.7 after capsule administration, 3.1 after solution, and 1.6
after tablets (Table II). Analyses of variance indicated that the overall difference among preparations was significant (F = 46.5, d.f. = 2,22, P
