Pharmacology 14: 182-190(1976)
Assessment of Methodology in Single-Dose Studies of Digoxin Bioavailability David J. Greenblatt, David W. Dahme, Jan Koch-Weser and Thomas W. Smith The Clinical Pharmacology Unit, Massachusetts General Hospital, Boston, and the Cardiovascular Division, Peter Bent Brigham Hospital, Boston, Mass.
Key Words. Bioavailability • Digitalis glycosides • Digoxin • Pharmacokinetics Abstract. Eight healthy males received 0.75 mg of digoxin by ten modes of administra tion in a single-dose multicrossover bioavailability study. Digoxin concentrations in multiple blood samples drawn after each dose and in six consecutive 24-hour urine collections were used to calculate the areas under the 4-, 8-, and 24-hour serum concentration curve (A-4, A-8, A-24), and the excretion of digoxin during 1 day (U-l ) and 6 days (U-6) following each dose. All five methods of assessment gave very similar information on bioavailability. Individ ual values of A-4 and A-8 were highly correlated (r = 0.973) and had similar variability. A-24 was more variable than A-4 and A-8, and was not as well correlated with either. U-l and U-6 were highly correlated (r = 0.944), and had nearly identical variability which was less than that of any of the area measures. Thus, urinary excretion data provides more reliable and reproducible information about completeness of absorption of digoxin than data based upon serum concentrations. Extending the period of urine collection beyond 1 day or the blood sampling period beyond 4 or 8 h does not enhance the reliability or usefulness of digoxin bioavailability studies.
Received: October 16, 1975.
Downloaded by: University of Connecticut 132.174.250.220 - 5/26/2018 12:13:49 PM
A clear need exists for a reliable and inexpensive method of testing the bioavailability of digoxin preparations. Serum digoxin concentrations and uri nary excretion of digoxin after single and/or multiple doses have been used to evaluate bioavailability in many previous studies. It is not established which method of bioavailability testing provides the necessary information for the least expense and with the least inconvenience to experimental subjects. The present report assesses the relative value of several methods of testing digoxin bioavail ability in single-dose studies.
Greenblatt/Duhme /Koch- Weser/Smith
183
Methods Eight healthy male volunteers, aged 23 to 45 years, participated in a multicrossover study of ten modes of digoxin administration after giving informed consent (3-7). All subjects were free of cardiac or renal disease and had normal values of creatinine clearance. I-'or each trial, 0.75 mg of digoxin (Lanoxin®, Burroughs Wellcome Co.) was administered as a single dose. Venous blood samples were drawn prior to the dose and at 12 points in time after dosing (fig. 1). Six consecutive 24-hour urine collections began at the time of the dose.
Blood sam p le s 0,75 mg
0 10 20 30 £5 min 1h 1.5 2 3
Urine collection ~ 1
- Day 1
8
24 48
J b Day 2 □ - Day 3 □ • Day 4 □ - Day 5 □ - Day 6
Fig. 1. Summary of experimental design.
Table / Digoxin preparation
1-hour in vitro Number dissolution rate, % of trials
Rapid intravenous bolus 1-hour intravenous infusion Intramuscular Elixir (0.05 mg/ml), fasting state Elixir (0.05 mg/ml), postprandial state Tablet 917-1,' fasting state Tablet 474-G,1 fasting state Tablet 991-F,' fasting state Tablet 915-E,‘ fasting state Tablet 915-E,' postprandial state
_
1 Burroughs Wellcome lot number.
— ■ -
> 90 85 65 64 64
10 8 5 14 8 8 8 8 14 8 91 Downloaded by: University of Connecticut 132.174.250.220 - 5/26/2018 12:13:49 PM
Total
-
184
Greenblatt/Duhme/Koch-Weser/Smith
Modes of administration included rapid intravenous bolus, slow intravenous infusion, oral digoxin elixir, and various oral tablet preparations specially formulated to cover a wide range of in vitro dissolution rates (table I). In some cases the same mode of administration was repeated in the same subject. Only five subjects received intramuscular digoxin because it produced severe injection site pain (2). At least 10 days elapsed between trials. Digoxin concentrations in serum and urine were determined by radioimmunoassay (3). Areas under the 4-, 8-, and 24-hour serum digoxin concentration curves (A-4, A-8, A-24) were calculated by the trapezoidal method. 1- and 6-day urinary digoxin excretions (U-l, U-6) were calculated using urinary digoxin concentrations and volumes. Variability in each treatment mean was expressed by calculating the coefficient of variation, equal to 100 times the treatment standard deviation divided by the treatment mean (10). For each method of bioavailability testing, the overall coefficient of variation was calculated by pooling individual values across treatments as if they were standard deviations (7). Linear regression and rank order correlation were used to assess the relation between different methods of bioavailability testing (10).
Results Treatment Means Figures 2 and 3 show within-treatment mean (± standard error) values for the five methods o f bioavailability assessment. All five methods yielded very similar information on bioavailability. Rank order and linear regression correla tions among the three mean values based upon serum concentrations, and be tween the two urinary excretion measures, were very close to unity (table II). Correlations between urinary excretion and serum concentration means also were highly significant (table II). The bioavailability of the various preparations has been previously analyzed and is apparent from figures 2 and 3. Intramuscular digoxin was only 8 0-85 %
A-4
A-8
A-24
U-l
Linear regression A-8 A-24 U-l U-6
0.999 0.950 0.980 0.945
0.951 0.960 0.919
0.912 0.843
0.983
Rank order A-8 A-24 U-l U-6
0.988 0.927 0.952 0.879
0.952 0.927 0.855
0.830 0.709
0.952
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Table II. Correlations among treatment means
Bioavailability o f Digoxin
185
Fig. 3. Means (± standard error) of area under the 4-, 8-, and 24-hour serum concentra' tion curve for ten modes of digoxin administration.-------= 4 h ;......... = 8 h ;------- = 24 It.
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Fig. 2. Means (± standard error) of 1- and 6-day urinary digoxin excretion for ten modes of digoxin administration.-------= 1 day;-------- 6 days.
Greenblatt/Duhme/Koch-Weser/Smith
200
¿.00
186
600
800
1.000
Fig. 4. Relation between A-4 and A-8, and between A-4 and A-24, for ten modes of digoxin administration.
Downloaded by: University of Connecticut 132.174.250.220 - 5/26/2018 12:13:49 PM
A re a u n d e r A - h o u r s e ru m concentration curve, ng/ml x min
187
Bioavailability of Digoxin
Table III. Linear regression correlations among individual treatment values
A-8 A-24 U-l U-6
A-4
A-8
A-24
U-l
0.973 0.796 0.805 0.747
0.888 0.734 0.671
0.558 0.502
0.944
absorbed when compared to intravenous infusion (3). Bioavailability of oral digoxin elixir and rapidly dissolving tablet preparations was approximately 65— 70 %, while that of slow dissolution tablets was about 4 5 -5 5 % (3, 5). The rate of digoxin absorption from slow dissolution tablets was reduced when the tab lets were coadministered with food, but postprandial administration did not alter the completeness of digoxin absorption from either tablets or elixir (6). Individual Values Individual values of 1- and 6-day urinary excretion were highly correlated (r = 0.944) regardless of the mode of administration (see fig. 1 of ref. 7). Areas under the 4- and 8-hour serum concentration curves were also highly correlated (r = 0.973), but the correlation of A-24 with A 4 (r = 0.796) and with A-8 (r = 0.888) was not as close (fig. 4). Table III summarizes correlations among individ ual treatment values for all five methods of bioavailability assessment. Variability Table IV shows individual and pooled coefficients of variation for the five methods of bioavailability assessment. The variability of 1- and 6-day urinary excretion data was nearly identical (7). All three measures based upon serum concentrations were more variable than those based upon urinary excretion (table IV, fig. 5). The highest degree of variability was observed in the area under the 24-hour serum concentration curve, for which the pooled coefficient of variation was 29.1 %.
Bioavailability studies should provide the required information about com pleteness and rate of absorption with a minimum of expense, inconvenience, and hazard. Such information usually is much less extensive than that sought in pharmacokinetic investigations designed to elucidate as completely as possible the fate of a drug in the body. The design of a bioavailability study is appropri-
Downloaded by: University of Connecticut 132.174.250.220 - 5/26/2018 12:13:49 PM
Discussion
188
Greenblatt /Duhme /Koch-Weser /Smith Table IV. Treatment coefficients of variation
Urinary excretion
A-4
A-8
A-24
U-l
U-6
IV bolus IV infusion Intramuscular Elixir, fasting Elixir, postprandial Tablet 971-1, fasting Tablet 474-G, fasting Tablet 991-F, fasting Tablet 915-E, fasting Tablet 915-E, postprandial
12.5 10.2 24.5 33.2 25.4 28.6 24.0 19.6 32.5 24.2
15.6 9.7 22.4 33.9 24.7 27.6 21.7 15.7 21.7 25.3
19.8 12.4 29.0 37.9 31.0 28.6 26.9 19.6 35.1 28.0
12.0 6.1 13.0 17.9 23.8 20.3 21.2 25.5 12.6 18.0
8.8 2.2 15.6 14.3 22.1 18.7 13.7 27.0 11.1 28.8
Pooled totals
26.0
23.8
29.1
17.7
17.2
Fig. 5. Overall variability for five methods of bioavailability assessment, expressed as pooled coefficients of variation.
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Area under serum concentration curve
Bioavailability of Digoxin
189
ate when it provides the absorption information that is therapeutically impor tant for the drug formulation studied (9). The present study compared the usefulness and reliability of five methods of assessment of digoxin bioavailability in single-dose studies. The relationship of mean bioavailability values among the various treatments was very similar for all five methods of testing. Variability in measures based on 1- and 6-day urinary excretion was nearly identical, and the individual values were highly correlated. This is consistent with other reports (1, 8), and suggests that 6 days of urine collection add little or nothing to the bioavailability information available from 1 day of collection. Thus the expense and inconvenience of a 6-day collection is seldom justified. All measures of bioavailability based upon serum concentrations were more variable than those based upon urinary excretion. A-4 and A-8 had similar varia tion, and the individual values were closely correlated. A-24 had greater variabil ity than either A-4 or A-8, and individual values of A-24 were not as well correlated with A-4 and with A-8. This is partly explained by the fact that the total 24-hour area is largely dependent upon the serum concentration measured 24 h after the dose. In many instances the 24-hour values were low and thus subject to larger percentage error. In 41 % of all cases the concentration was 0.4 ng/ml or less, and in 17 % it was 0.2 ng/ml or less. Thus, information pro vided by 4 or 8 h of sampling after single doses is equally or more reliable than data derived from 24 h of sampling. Serum concentration measurements clearly are necessary to determine the rate of absorption of digoxin from a given preparation. However, this informa tion is usually of limited interest in bioavailability studies of oral digoxin for mulations, because such preparations are almost always used in chronic therapy. Completeness of absorption from digoxin formulations is indicated more reliably by the urinary excretion of the drug than by its serum concentration. Obviously subjects who can be trusted to provide complete urine collections must be available. Calculation of the area under the serum concentration curve depends less upon reliability of subjects, but multiple blood samples are needed.
This paper was supported in part by grants HL-13008 and HL-14150 from the United States Public Health Service, and by a grant from Burroughs Wellcome Company, and was presented in part at the 76th Annual Meeting of the American Society for Clinical Pharma cology and Therapeutics, Washington, D.C., March 20, 1975. Dr. Koch-Weser was a Bur roughs Wellcome Scholar in Clinical Pharmacology. Dr. Smith is an Established Investigator of the American Heart Association. We are grateful to Ms. Marcia D. Allen for assistance in analysis of data.
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Acknowledgements
Greenblatt/Duhme /Koch- Weser/Smith
190
References
Dr. David J. Greenblatt, Clinical Pharmacology Unit, Massachusetts General Hospital, Boston, MA 02114 (USA)
Downloaded by: University of Connecticut 132.174.250.220 - 5/26/2018 12:13:49 PM
1 Fleckenstein, L.; Kroening, B., and Weintraub, M.: Assessment of the biologic availabil ity of digoxin in man. Clin. Pharmac. Ther. 16: 435 443 (1974). 2 Greenblatt, D.J.; Duhme, D.W., and Koch- Weser, J.: Pain and CPK elevation after intramuscular digoxin. New Engl. J. Med. 288: 689 (1973). 3 Greenblatt, D.J.; Duhme, D.W.; Koch-Weser, J., and Smith, T.W.: Evaluation of digoxin bioavailability in single-dose studies. New Engl. J. Med. 289: 651 -654 (1973). 4 Greenblatt, D.J.; Duhme, D.W.: Koch-Weser, J., and Smith, T.W.: Intravenous digoxin as a bioavailability standard: slow infusion and rapid injection. Clin. Pharmac. Ther. 15: 510-513 (1974). 5 Greenblatt, D.J.; Duhme, D.W.; Koch-Weser, J., and Smith, T.W.: Equivalent bioavail ability from digoxin elixir and rapid-dissolution tablets. J. Am. med. Ass. 229: 1774 — 1776 (1974). 6 Greenblatt, D.J.; Duhme, D.W.; Koch-Weser, J., and Smith, T.W.: Bioavailability of digoxin tablets and elixir in the fasting and postprandial states. Clin. Pharmac. Ther. 16: 444-448 (1974). 7 Greenblatt, D.J.; Duhme, D.W.; Koch-Weser, J., and Smith, T. W.: Comparison of oneand six-day urinary digoxin excretion in single-dose bioavailability studies. Clin. Pharmac. Ther. 16: 813 816 (1974). 8 Huffman, D.H.; Manion, C. V., and Azarnoff D.L.: Intersubject variation in absorption of digoxin in normal volunteers. J. pharm. Sei. 64: 433 - 437 (1975). 9 Koch-Weser, J.: Bioavailability of drugs. New Engl. J. Med. 291: 233-237, 503-506 (197.4). 10 Snedecor, G.W. and Cochran, W.G.: Statistical methods; 6th ed. (Iowa State Univ. Press, Ames 1967).
Assessment of Methodology in Single-Dose Studies of Digoxin Bioavailability David J. Greenblatt, David W. Dahme, Jan Koch-Weser and Thomas W. Smith The Clinical Pharmacology Unit, Massachusetts General Hospital, Boston, and the Cardiovascular Division, Peter Bent Brigham Hospital, Boston, Mass.
Key Words. Bioavailability • Digitalis glycosides • Digoxin • Pharmacokinetics Abstract. Eight healthy males received 0.75 mg of digoxin by ten modes of administra tion in a single-dose multicrossover bioavailability study. Digoxin concentrations in multiple blood samples drawn after each dose and in six consecutive 24-hour urine collections were used to calculate the areas under the 4-, 8-, and 24-hour serum concentration curve (A-4, A-8, A-24), and the excretion of digoxin during 1 day (U-l ) and 6 days (U-6) following each dose. All five methods of assessment gave very similar information on bioavailability. Individ ual values of A-4 and A-8 were highly correlated (r = 0.973) and had similar variability. A-24 was more variable than A-4 and A-8, and was not as well correlated with either. U-l and U-6 were highly correlated (r = 0.944), and had nearly identical variability which was less than that of any of the area measures. Thus, urinary excretion data provides more reliable and reproducible information about completeness of absorption of digoxin than data based upon serum concentrations. Extending the period of urine collection beyond 1 day or the blood sampling period beyond 4 or 8 h does not enhance the reliability or usefulness of digoxin bioavailability studies.
Received: October 16, 1975.
Downloaded by: University of Connecticut 132.174.250.220 - 5/26/2018 12:13:49 PM
A clear need exists for a reliable and inexpensive method of testing the bioavailability of digoxin preparations. Serum digoxin concentrations and uri nary excretion of digoxin after single and/or multiple doses have been used to evaluate bioavailability in many previous studies. It is not established which method of bioavailability testing provides the necessary information for the least expense and with the least inconvenience to experimental subjects. The present report assesses the relative value of several methods of testing digoxin bioavail ability in single-dose studies.
Greenblatt/Duhme /Koch- Weser/Smith
183
Methods Eight healthy male volunteers, aged 23 to 45 years, participated in a multicrossover study of ten modes of digoxin administration after giving informed consent (3-7). All subjects were free of cardiac or renal disease and had normal values of creatinine clearance. I-'or each trial, 0.75 mg of digoxin (Lanoxin®, Burroughs Wellcome Co.) was administered as a single dose. Venous blood samples were drawn prior to the dose and at 12 points in time after dosing (fig. 1). Six consecutive 24-hour urine collections began at the time of the dose.
Blood sam p le s 0,75 mg
0 10 20 30 £5 min 1h 1.5 2 3
Urine collection ~ 1
- Day 1
8
24 48
J b Day 2 □ - Day 3 □ • Day 4 □ - Day 5 □ - Day 6
Fig. 1. Summary of experimental design.
Table / Digoxin preparation
1-hour in vitro Number dissolution rate, % of trials
Rapid intravenous bolus 1-hour intravenous infusion Intramuscular Elixir (0.05 mg/ml), fasting state Elixir (0.05 mg/ml), postprandial state Tablet 917-1,' fasting state Tablet 474-G,1 fasting state Tablet 991-F,' fasting state Tablet 915-E,‘ fasting state Tablet 915-E,' postprandial state
_
1 Burroughs Wellcome lot number.
— ■ -
> 90 85 65 64 64
10 8 5 14 8 8 8 8 14 8 91 Downloaded by: University of Connecticut 132.174.250.220 - 5/26/2018 12:13:49 PM
Total
-
184
Greenblatt/Duhme/Koch-Weser/Smith
Modes of administration included rapid intravenous bolus, slow intravenous infusion, oral digoxin elixir, and various oral tablet preparations specially formulated to cover a wide range of in vitro dissolution rates (table I). In some cases the same mode of administration was repeated in the same subject. Only five subjects received intramuscular digoxin because it produced severe injection site pain (2). At least 10 days elapsed between trials. Digoxin concentrations in serum and urine were determined by radioimmunoassay (3). Areas under the 4-, 8-, and 24-hour serum digoxin concentration curves (A-4, A-8, A-24) were calculated by the trapezoidal method. 1- and 6-day urinary digoxin excretions (U-l, U-6) were calculated using urinary digoxin concentrations and volumes. Variability in each treatment mean was expressed by calculating the coefficient of variation, equal to 100 times the treatment standard deviation divided by the treatment mean (10). For each method of bioavailability testing, the overall coefficient of variation was calculated by pooling individual values across treatments as if they were standard deviations (7). Linear regression and rank order correlation were used to assess the relation between different methods of bioavailability testing (10).
Results Treatment Means Figures 2 and 3 show within-treatment mean (± standard error) values for the five methods o f bioavailability assessment. All five methods yielded very similar information on bioavailability. Rank order and linear regression correla tions among the three mean values based upon serum concentrations, and be tween the two urinary excretion measures, were very close to unity (table II). Correlations between urinary excretion and serum concentration means also were highly significant (table II). The bioavailability of the various preparations has been previously analyzed and is apparent from figures 2 and 3. Intramuscular digoxin was only 8 0-85 %
A-4
A-8
A-24
U-l
Linear regression A-8 A-24 U-l U-6
0.999 0.950 0.980 0.945
0.951 0.960 0.919
0.912 0.843
0.983
Rank order A-8 A-24 U-l U-6
0.988 0.927 0.952 0.879
0.952 0.927 0.855
0.830 0.709
0.952
Downloaded by: University of Connecticut 132.174.250.220 - 5/26/2018 12:13:49 PM
Table II. Correlations among treatment means
Bioavailability o f Digoxin
185
Fig. 3. Means (± standard error) of area under the 4-, 8-, and 24-hour serum concentra' tion curve for ten modes of digoxin administration.-------= 4 h ;......... = 8 h ;------- = 24 It.
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Fig. 2. Means (± standard error) of 1- and 6-day urinary digoxin excretion for ten modes of digoxin administration.-------= 1 day;-------- 6 days.
Greenblatt/Duhme/Koch-Weser/Smith
200
¿.00
186
600
800
1.000
Fig. 4. Relation between A-4 and A-8, and between A-4 and A-24, for ten modes of digoxin administration.
Downloaded by: University of Connecticut 132.174.250.220 - 5/26/2018 12:13:49 PM
A re a u n d e r A - h o u r s e ru m concentration curve, ng/ml x min
187
Bioavailability of Digoxin
Table III. Linear regression correlations among individual treatment values
A-8 A-24 U-l U-6
A-4
A-8
A-24
U-l
0.973 0.796 0.805 0.747
0.888 0.734 0.671
0.558 0.502
0.944
absorbed when compared to intravenous infusion (3). Bioavailability of oral digoxin elixir and rapidly dissolving tablet preparations was approximately 65— 70 %, while that of slow dissolution tablets was about 4 5 -5 5 % (3, 5). The rate of digoxin absorption from slow dissolution tablets was reduced when the tab lets were coadministered with food, but postprandial administration did not alter the completeness of digoxin absorption from either tablets or elixir (6). Individual Values Individual values of 1- and 6-day urinary excretion were highly correlated (r = 0.944) regardless of the mode of administration (see fig. 1 of ref. 7). Areas under the 4- and 8-hour serum concentration curves were also highly correlated (r = 0.973), but the correlation of A-24 with A 4 (r = 0.796) and with A-8 (r = 0.888) was not as close (fig. 4). Table III summarizes correlations among individ ual treatment values for all five methods of bioavailability assessment. Variability Table IV shows individual and pooled coefficients of variation for the five methods of bioavailability assessment. The variability of 1- and 6-day urinary excretion data was nearly identical (7). All three measures based upon serum concentrations were more variable than those based upon urinary excretion (table IV, fig. 5). The highest degree of variability was observed in the area under the 24-hour serum concentration curve, for which the pooled coefficient of variation was 29.1 %.
Bioavailability studies should provide the required information about com pleteness and rate of absorption with a minimum of expense, inconvenience, and hazard. Such information usually is much less extensive than that sought in pharmacokinetic investigations designed to elucidate as completely as possible the fate of a drug in the body. The design of a bioavailability study is appropri-
Downloaded by: University of Connecticut 132.174.250.220 - 5/26/2018 12:13:49 PM
Discussion
188
Greenblatt /Duhme /Koch-Weser /Smith Table IV. Treatment coefficients of variation
Urinary excretion
A-4
A-8
A-24
U-l
U-6
IV bolus IV infusion Intramuscular Elixir, fasting Elixir, postprandial Tablet 971-1, fasting Tablet 474-G, fasting Tablet 991-F, fasting Tablet 915-E, fasting Tablet 915-E, postprandial
12.5 10.2 24.5 33.2 25.4 28.6 24.0 19.6 32.5 24.2
15.6 9.7 22.4 33.9 24.7 27.6 21.7 15.7 21.7 25.3
19.8 12.4 29.0 37.9 31.0 28.6 26.9 19.6 35.1 28.0
12.0 6.1 13.0 17.9 23.8 20.3 21.2 25.5 12.6 18.0
8.8 2.2 15.6 14.3 22.1 18.7 13.7 27.0 11.1 28.8
Pooled totals
26.0
23.8
29.1
17.7
17.2
Fig. 5. Overall variability for five methods of bioavailability assessment, expressed as pooled coefficients of variation.
Downloaded by: University of Connecticut 132.174.250.220 - 5/26/2018 12:13:49 PM
Area under serum concentration curve
Bioavailability of Digoxin
189
ate when it provides the absorption information that is therapeutically impor tant for the drug formulation studied (9). The present study compared the usefulness and reliability of five methods of assessment of digoxin bioavailability in single-dose studies. The relationship of mean bioavailability values among the various treatments was very similar for all five methods of testing. Variability in measures based on 1- and 6-day urinary excretion was nearly identical, and the individual values were highly correlated. This is consistent with other reports (1, 8), and suggests that 6 days of urine collection add little or nothing to the bioavailability information available from 1 day of collection. Thus the expense and inconvenience of a 6-day collection is seldom justified. All measures of bioavailability based upon serum concentrations were more variable than those based upon urinary excretion. A-4 and A-8 had similar varia tion, and the individual values were closely correlated. A-24 had greater variabil ity than either A-4 or A-8, and individual values of A-24 were not as well correlated with A-4 and with A-8. This is partly explained by the fact that the total 24-hour area is largely dependent upon the serum concentration measured 24 h after the dose. In many instances the 24-hour values were low and thus subject to larger percentage error. In 41 % of all cases the concentration was 0.4 ng/ml or less, and in 17 % it was 0.2 ng/ml or less. Thus, information pro vided by 4 or 8 h of sampling after single doses is equally or more reliable than data derived from 24 h of sampling. Serum concentration measurements clearly are necessary to determine the rate of absorption of digoxin from a given preparation. However, this informa tion is usually of limited interest in bioavailability studies of oral digoxin for mulations, because such preparations are almost always used in chronic therapy. Completeness of absorption from digoxin formulations is indicated more reliably by the urinary excretion of the drug than by its serum concentration. Obviously subjects who can be trusted to provide complete urine collections must be available. Calculation of the area under the serum concentration curve depends less upon reliability of subjects, but multiple blood samples are needed.
This paper was supported in part by grants HL-13008 and HL-14150 from the United States Public Health Service, and by a grant from Burroughs Wellcome Company, and was presented in part at the 76th Annual Meeting of the American Society for Clinical Pharma cology and Therapeutics, Washington, D.C., March 20, 1975. Dr. Koch-Weser was a Bur roughs Wellcome Scholar in Clinical Pharmacology. Dr. Smith is an Established Investigator of the American Heart Association. We are grateful to Ms. Marcia D. Allen for assistance in analysis of data.
Downloaded by: University of Connecticut 132.174.250.220 - 5/26/2018 12:13:49 PM
Acknowledgements
Greenblatt/Duhme /Koch- Weser/Smith
190
References
Dr. David J. Greenblatt, Clinical Pharmacology Unit, Massachusetts General Hospital, Boston, MA 02114 (USA)
Downloaded by: University of Connecticut 132.174.250.220 - 5/26/2018 12:13:49 PM
1 Fleckenstein, L.; Kroening, B., and Weintraub, M.: Assessment of the biologic availabil ity of digoxin in man. Clin. Pharmac. Ther. 16: 435 443 (1974). 2 Greenblatt, D.J.; Duhme, D.W., and Koch- Weser, J.: Pain and CPK elevation after intramuscular digoxin. New Engl. J. Med. 288: 689 (1973). 3 Greenblatt, D.J.; Duhme, D.W.; Koch-Weser, J., and Smith, T.W.: Evaluation of digoxin bioavailability in single-dose studies. New Engl. J. Med. 289: 651 -654 (1973). 4 Greenblatt, D.J.; Duhme, D.W.: Koch-Weser, J., and Smith, T.W.: Intravenous digoxin as a bioavailability standard: slow infusion and rapid injection. Clin. Pharmac. Ther. 15: 510-513 (1974). 5 Greenblatt, D.J.; Duhme, D.W.; Koch-Weser, J., and Smith, T.W.: Equivalent bioavail ability from digoxin elixir and rapid-dissolution tablets. J. Am. med. Ass. 229: 1774 — 1776 (1974). 6 Greenblatt, D.J.; Duhme, D.W.; Koch-Weser, J., and Smith, T.W.: Bioavailability of digoxin tablets and elixir in the fasting and postprandial states. Clin. Pharmac. Ther. 16: 444-448 (1974). 7 Greenblatt, D.J.; Duhme, D.W.; Koch-Weser, J., and Smith, T. W.: Comparison of oneand six-day urinary digoxin excretion in single-dose bioavailability studies. Clin. Pharmac. Ther. 16: 813 816 (1974). 8 Huffman, D.H.; Manion, C. V., and Azarnoff D.L.: Intersubject variation in absorption of digoxin in normal volunteers. J. pharm. Sei. 64: 433 - 437 (1975). 9 Koch-Weser, J.: Bioavailability of drugs. New Engl. J. Med. 291: 233-237, 503-506 (197.4). 10 Snedecor, G.W. and Cochran, W.G.: Statistical methods; 6th ed. (Iowa State Univ. Press, Ames 1967).
