Pharmacokinetics and bioavailability of digoxin capsules, solution and tablets after single and multiple doses

Pharmacokinetics and bioavailability of digoxin capsules, solution and tablets after single and multiple doses

Pharmacokinetics and Bioavailability of Digoxin Capsules, Solution and Tablets After Single and Multiple Doses BRIAN L. LLOYD, MB, MRACP DAVID J. GRE...

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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; [email protected]= 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 [email protected] 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 [email protected]: 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
6.0,

i

25.0 -

.

~- . =WRLNENO”S

.~

.o

0

CAPSULE

(0.4

mg)

(0.4 mg)

20.0 -

n*

0

x

.

15.0 -

-+-

-4

LG.0 .

IO.0 -

.

.

.

INTRAVENOUS



----F--- ---w--00 x

O. CAPSULE

5.0 -

xx

SOLUTION

-

ii TABLETS

= lNTRNEHOUS (0.4 ms) x = SOL”TlOH (0.4 mg)

l

0.0 -1

40.0

-

4

_________.

50.0 -

x 0

.

. INTRAVE&JS 20.0 -

0.0

xx

0

2.0

4.0

8.0

6.0

li.0

iii.0

7s

A.0

6.0

0

__________ -___---#-00 00 CAPSULE

x ----*---x x ’

i __a!iA~__

x

h

x

10.0 -

SOL:TlON

-

.3

- -

. = ,HTRAvEHO”S 12

TABLETS

(0.5

(0.4 mg) mg)

TAB&S

. 0.0 -1

FIGURE 2. Area under the 24 hour plasma concentration cuve (above) and 24 hov urinary excretion rate of digoxin (below) after a single dose of intravenous dlgoxin and of the three oral digoxin preparations. Individual values and means (* standard error) for all subjects are shown. Values for area under the 24 hour plasma concentration curve after administration of tablets (above) were corrected for the difference in dose.

132

July 1979

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Journal of CARDIOLDGY

Volume 42

1.0

2.0

4.0

6.0

8.0

HOURS

FKiURE 3. Single dose plasma concentration curves for intravenous digoxin in comparison with curves for each of the three oral preparations. Each point is the mean (rt standard error) for all 12 subjects at the time shown.

PWARMACOKlNETlCS AND BIOAVAILABILITY OF DIGOXIN-LLOYD


x 0

:: x

08 0

xx x

CAPSULE (0.4

ms)

A

SOLUTION (0.4

ms)

TABLETS (0.5

m9)

ET AL.

sorption half-life also were significant (F = 4.24, d.f. = 2,26, P <0.05); values of tl/a for capsules and solution were similar (11.3 and 10.2 minutes, respectively), and values for both were smaller than that for tablets (27.1 minutes). The findings strongly suggest that the rate of digoxin absorption from capsules and solution is very similar. However, digoxin is more slowly absorbed from tablets; peak levels are reached later after dosing, and absorption half-life values are longer. For all three preparations there was a lag time between administration and the start of absorption. Single dose bioavailability: Analysis of variance indicated a significant difference among preparations in dose-adjusted values of the 24-hour area under the concentration curve (F = 10.25, d.f. = 3,33, P
The findings indicate that the systemic availability of all oral digoxin preparations was significantly less than 100 percent. The bioavailability of capsules was approximately equivalent to that of the solution, whereas that of the tablet preparation used in this study

x

x x

_____*_____

08 0 0 CAPSULE

xx

x

TABLE III Comparison of Wlthln- and Between-Subject Bloavailabillty*

x

SOLUTION

Variability In

Mode of Administration intravenous Capsule Solutlon Tablets

TABLETS

FIGURE 4. Steady state plasma concentrations (above) and 24 hour urinary excretion rates (below) for the three oral preparations during multiple dose therapy. Each data point is the mean of four to six daily rneas~ements for a given s&ject. The figure shows the across-subject mean (& standard error) of these individual mean values. The urinary excretion data are expressed as percent of dose, thereby taking into account differences in dosages among the preparations.

Single dose AUC (between subjects) Single dose UE (between subjects) Steady state AUC (between subjects) Steady state plasma level (pooled within subjects) Steady state plasma level (between subjects) Steady state UE (pooled within subjects) Steady state UE (between subjects)

28.4

25.9

26.9

45.1

16.0

18.6

33.6

22.7

28.9

24.8

30.2

’ . .

18.7

22.5

20.5

.

22.6

31.6

26.3

21.6

23.3

19.9

14.6

17.1

24.5

.

Expressed as coefficient of variation (in percent). AUC = area under the plasma concentration curve; UE = urinary excretion.

July 1978

l

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Volume 42

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PHARMACOKINETICS AN0 BIOAVAIIABILITY

o.o* 0.0

OF DIGOXIN-LLOYD

ET AL.

I;.0

4.0

2.0

0.0

1

21.0

0.0

HOURS

0

x 0

-----a---A

SOLUTION CAPSULE

FIGURE 5. Above, plasma digoxin concentration during the final steady state dosage interval. Each point is the mean for all subjects at the times shown. Below, area under the 24 hour plasma concentration curve during the final dosags interval at steady state. Individual values and mean (k standard error) for all 12 subjects are shown.

TABLETS (DOSE-CO~G~ECTED)

was substantially or capsules.

less than that of either the solution

Steady-state bioavailability: Mean steady state serum digosin concentrations (in ng/ml) based upon four to six measurements in each subject in each treatment condition were: 0.70 for capsules, 0.69 for solution and 0.69 for tablets (Fig. 4). After correction for dose, the overall difference among treatments was significant (F = 10.04, d.f. = 2,22, P
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July 1979

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Volume 42

Figure 5 shows the composite serum concentration curves for all three oral preparations during the steady state dosage interval. The area under the 24 hour concentration curve at

steady state, after correction for dose, differed significantly among preparations(F = 24.75,d.f. = 2,22,P
Betweenand within-subject coefficients of variation: Table III summarizes the coefficients of variation for all modes of treatment. For the two single

PHARMACDKINETICS AND BIOAVAILABILITY OF DIGOXIN-LLOYD ET AL.

dose measures of bioavailability, intravenous digoxin and oral capsules had approximately equal coefficients of variation, which were less than or equal to those of the solution and tablet preparations. For steady state plasma levels and urinary excretion of digoxin, withinand between-subject coefficients of variation for capsules also were less than or equivalent to those of solution and tablets. For all three treatments, betweensubject coefficient of variation values for steady state plasma levels were higher than within-subject values. This was also the case for steady state urinary excretion during treatment with tablets. However, within-subject coefficients of variation for urinary excretion during the capsule and solution treatments exceeded betweensubject values. Discussion All currently available formulations of digoxin used for oral administration (tablets, elixir) are variably and incompletely absorbed from the gastrointestinal tract.l One approach to formulation of oral digoxin preparations with improved bioavailability has been the development of gelatin capsules containing a digoxin solution. Studies of these capsules suggest that the bioavailability of this digoxin preparation is greater and more consistent than that of tablets and possibly of oral digoxin solution.2-8 As is customary in current studies of digoxin bioavailability,2*sJ3Js we utilized a slow intravenous infusion as the reference standard for 100 percent systemic availability. Because values for area under the concentration curve and urinary excretion of digoxin after a given intravenous dose are influenced by the rate of infusion,z*so our estimates of absolute systemic availability of oral digoxin preparations apply specifically to the 1 hour intravenous infusion standard. On the basis of this reference system, our findings from the single dose study indicate that the systemic availability

of the capsule preparation is significantly less than 100 percent. Furthermore, the rate and completeness of digoxin absorption from capsules were essentially identical to those of a standard digoxin solution. This was evident from comparison of values for areas under the plasma concentration curve or 24 hour urinary excretion of digoxin after single doses, as well as from steady state plasma digoxin levels and urinary excretion values on several consecutive days during long-term therapy. Other reports2p6,s have suggested that absorption of the capsule preparation approaches 100 percent completeness and is greater than that of even an oral solution. In any case, it is clear that the bioavailability of digoxin capsules exceeds that of a standard reference tablet.s-s Finally, one study21 suggested that between-subject variability in steady state serum digoxin levels was less during treatment with capsules than with tablets. However, our findings and those of most other investigators2Jv5-s do not demonstrate a striking or consistent difference among oral preparations in within- or between-subject coefficients of variation of systemic availability after either single or multiple doses. Peak plasma digoxin levels after ingestion of the various oral preparations tended to be highest with the capsules. Anecdotal reports22 and other suggestions23 have associated high peak digoxin levels with the occurrence of transient cardiac arrhythmias, but systematic experimental study has revealed no such associations.24 The clinical implications of the high peak digoxin concentrations after ingestion of capsules require further study. Acknowledgement We are grateful for the collaboration of Dr. Dean S. MacLaughlin (supported in part by U.S. Public Health Service Grant GM-23430 to the Boston Collaborative Drug Surveillance Program) and the editorial assistance of Ms. Ann Werner.

References 1. 2.

3.

4.

5.

6. 7. a.

Gt’aWHaM DJ,smfthNV, Koch-Weaer

J: Bioavailabilii of drugs: the dfgoxin dilemma. Clin Pharmacokin 1:36-51, 1976 Marcus FI, Mckemon J, PippIn S, et al: Digoxin bioavailability: formulations and rates of infusions. Clin Pharmacol Ther 20: 253-259,1976 GhKti P, CaWnwzo 0, Madem 0, et al: Bioavailabilky of digoxin in a new soluble pharmaceutical formulation in capsules. J Pharm Sci 66:267-269, 1977 Johnron BP, SrMh Q, French J: The comparability of dosage regimens of Lanoxin tablets and lanoxicaps. Br J Clin Pharmacol 4:209-211,1977 MaIlk Q, &hmlUl DH, Lbbdenbaum Jr Superior bioavailability of digoxln solution in capsules. Clin Pharmacol Ther 18:761-766, 1976 Johnron BP, Bye C, Jone8 G, ei al: A completely absorbed oral preparation of digoxin. Clin Pharmacol Ther 19:746-751, 1976 LMeebaum Jr Greater bioavailabilii of digoxin solution in capsules. Clin Pharmacol Ther 21:278-282, 1977 BIdon PF: A comparison of the bioavailability of digoxin in capsule, tablet, and solution taken orally with intravenous digoxin. J

Clin Pharmacol 16:461-467, 1976 9. Smith lW, Butler VP, Haber E: Determination of therapeutic and toxic serum concentrations by radioimmunoassay. N Engl J Med 261:1212-1216,1969 10. Greenblatt DJ, Duhma DW, Koch-Weser J, et al: Evaluation of digoxin bioavailability in single-dose studies. N Engl J Med 289: 651-654,1973 11. Usanis RA: NLIN-Nonlinear Least Squares Estimation of Parameters (Library Services Series Document no. LSR-089-1). Research Triangle Park, North Carolina, Triangle Universities Computation Center, 1972 12. Marcfuardt DW: An algorithm for least-squares estimation of non&ear parameters. JSoc Ind Appl Math ?1:431-441, 1963 13. Greenbfatt DJ. Pfeffer HJ, O&s HR. et al: Pharmacokinetics of quintdine in humans after fntravenous, intramuscular and oral administration. J Pharmacol Exp Ther 202:365-378, 1977 14. Greanbfait DJ, KocfwWeeer Jr Clinical pharmacoklnetics. N Engl J Med 293:702-705,964970, 1975 15. W+erJf%F w%nantals of Cllnical pharmacokinetics. Hamilton, Illinois, Drug Intelligence Publications, 1975

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PHARMACOKINETICS AN0 BIOAVAILABILITY OF DIGOXIN-LLOYD ET AL.

16. Glbakli M, Per&r D: Pharmacokinetics. New York, Marcel Dekker, 1975 17. Snedecor GW, Co&ran WO: Statistical Methods. Ames, Iowa, University of Iowa Press, 1967 16. Greenblati DJ, Duhme DW, Koch-Weser J, et al: Comparison of one- and six-day urinary digoxin excretion in single-dose bioavailability studies. Clin Pharmacol Ther 16:813-816, 1974 19. llsalo E: Clinical pharmacokinetics of digoxin. Clin Pharmacokin 2:1-16, 1977 20. Greenblati DJ, Duhme DW, Koch-Weser J, et al: Intravenous digoxin as a bioavailabilii standard: slow infusion and rapid injection.

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Clin Pharmacol Ther 15510~513, 2 1.

1974

[email protected] EM, Gob&e SM, Kenyon WI, et al: Evaluation of digoxin

capsules In outpatients. Br Med J 3:234-235, 1977 22. Mamlnem V, RebnI P, Pa&kale E: Transient cardiac arrhythmias after single daily maintenance doses of digoxin. Clin Pharmacol Ther 20:266-268,1976 23. Harter JO, Bkelly JP, Steers AW: Digoxin-the regulatory viewpoint. Circulation 49:395-398, 1974 24. Chapple DJ, Hughes R, Johnson BF: The relationship between cardlotoxicity and plasma dlgoxln concentration in cunscious dogs. Br J Pharmacol57:23-27, 1976