514
Br. J. clin. Pharmac. (1976), 3
LETTERS TO THE EDITORS
Ojc _
1.50
CO
2
5
10
15
20
24
20
24
Pretreatment time (h)
.Es C0) a) =L
CO
E
b 30-
-
2 20
C
10
CZoCO L)Cx
5
10
15
Time after dosing (h)
course of anti-inflammatory activity was closely paralleled by the disappearance of the metabolite biphenylyl acetic acid (Figure 2). From studies on the further metabolism of biphenylyl acetic acid in the rat the major urinary excretion product was shown to be the p-OH derivative. Subsequent biological testing of this compound showed it to be only weakly active as an anti-inflammatory agent. It is concluded that the anti-inflammatory activity of BDH 7538 is probably through the metabolite biphenylylacetic acid. I am grateful to Mr D. Barron for furnishing the pharmacological data on BDH 7538 and its metabolites.
R.A. FRANKLIN* BDH (Research) Ltd, Godalming, Surrey.
Figure 2 Time course of (a) anti-inflammatory activity of BHD 7538 and (b) plasma concentrations of the metabolite biphenylyl acetic acid after oral administration of BDH 7538 to the guinea pig.
Received November 10, 1975
References at all times after dosing although the metabolite, biphenylyl acetic acid, was found to be present in substantial amounts. By contrast, plasma from human volunteers who had received the drug contained very little biphenylyl acetic acid < 6.0 ug/ml but much higher levels of the unchanged drug. Further studies in the guinea pig showed that after oral administration of BDH 7538, the time
BARRON, D.I., COPLEY, A.R. & VALLANCE, D.K.
Anti-inflammatory and related properties of 4-(pbiphenylyl)-3-hydroxybutyric acid. Br. J. Pharmac., 33, 396-407. CHEMISTRY AND ENGINEERING NEWS. (1967). New anti-inflammatory drugs. Chem. Eng. News, Feb 13, 10. * Present address: Wyeth Laboratories, Maidenhead. Berkshire
EQUIVALENCE OF LANOXIN TABLETS When prescribing a daily dose of digoxin for an individual patient it is usually assumed that the steady state serum concentration is independent of the number of tablets in which the dose is presented (Dobbs, Mawer, Rodgers, Woodcock & Lucas, 1976). This assumption has proved to be justified in a group of volunteer subjects given the same daily dose of digoxin as different Lanoxin tablet presentations. Six healthy volunteers (three male, three female; ages 28-40years; weight 58-75 kg; creatinine clearance > 90 ml/min) gave informed consent. They each received three 14 day courses of treatment with digoxin (Lanoxin, Wellcome Medical Division). The total daily dose of
0.25 mg was presented as (1) one 0.25 mg tablet,
(2) two 0.125 mg tablets and (3) four 0.0625 mg tablets. The three treatment courses were administered to each subject in a random sequence. The tablets were derived from production batches (2571X, 4674A and 4235S) which were obtained routinely through a hospital pharmacy. Data provided by the manufacturers showed that the dissolution rate for each batch was greater than 95% in 1 hour. The subjects took the daily dose at 10.00 h, approximately 2 h after a light breakfast. Venous blood samples were collected immediately before the dose and 6 h later on days 11, 12, 13 and 14
Br. J. clin. Pharmac. (1976), 3
LETTERS TO THE EDITORS
515
Table 1 (a) Concentrations of digoxin (ng/ml) in serum samples taken from six healthy subjects 6 h after daily doses of 0.25mg on days 11, 12, 13 and 14 of each treatment course
Subject 1 2 3 4 5 6 Mean t s.e.
Tablet presentation Two 0.125mg
One 0.25mg
0.43 0.78 0.58 0.67 0.67 0.77
0.34 0.69 0.63 0.69 0.44 0.70
0.55 0.76 0.61 0.59 0.77 0.63 0.63 ± 0.02
0.52 0.63 0.57 0.59 0.72 0.74
0.64 0.77 0.45 0.69 0.45 0.65
0.66 0.76 0.45 0.91 0.62 0.85 0.69 ±
0.54 0.67 0.76 1.05 0.56 0.71 0.02
FourO.0625mg
0.73 0.68 0.58 0.79 0.77 0.77 0.79 0.57 0.63 0.68 0.70 0.60 0.80 0.77 0.62 0.76 0.70 0.61 0.52 0.57 - 0.73 0.50 0.69 0.67 ± 0.02
0.62 0.82 0.58 0.77 0.73 -
mean
(b) Urinary excretion of digoxin (,g/24 h) by six healthy subjects, given daily doses of 0.25 mg, on days 11 and 14 of each treatment course Subject
One 0.25mg
1 2 3 4 5 6 Mean ± s.e. mean
102 85 149 116 92 131 91 115 118 131 137 111 115 ± 7
of each treatment course. Two 24 h urine collections were made between days 11 and 14. Aliquots of serum and urine were stored at -30 C until the day of assay. Samples from each subject were analysed within a single assay (Lanoxitest ,B, Wellcome Reagents Ltd) to avoid confounding differences due to presentations with differences due to between assay variation. The estimated within assay coefficient of variation was 15% at a concentration of 0.5 ng/ml and 10% at 0.8 ng/ml. The measured digoxin contents of (a) 6 h serum (ng/ml) and (b) urine (gg/24 h) are shown in Table 1. Analysis of variance showed no significant differences (P> 0.1) between the presentations with respect to 6 h serum concentration or 24 h urine excretion. The before dose serum concentrations corresponding with presentations (1), (2) and (3) were 0.47 ±0.02, 0.53 ± 0.02 and 0.47 ± 0.02 ng/ml respectively. It is concluded that the studied batches of the three different Lanoxin tablets were equivalent with respect to the bioavailability of digoxin. We are grateful to Mr J. W. Poston (Clinical Department), Mr J. McCrerie and Mr A. Sabey
Tablet presentation Two 0.125mg Four 0.0625mg 101 143 145 216 94 129 118 131 138 121 134 ± 8
122 136 191 137 154 95 136 ±
143 133 119 141 122 134 7
(Central Analytical Laboratories), at the Wellcome Foundation Ltd, for their advice and co-operation. Our thanks also go to the volunteers who kindly gave their time to help in this study.
The work was supported by a project grant from the Medical Research Council to Professor G.E. Mawer for the study of factors influencing the drug dosage requirements of individual patients. SYLVIA M. DOBBS, E. MARGARET RODGERS & B.G. WOODCOCK Department of Pharmacology, Materia Medica and Therapeutics, University of Manchester, Manchester M13 9PT Received January 8, 1976
References DOBBS, S.M., MAWER, G.E., RODGERS, E.M., WOODCOCK, B.G. & LUCAS, S.B. (1976). Can maintenance digoxin dose requirements be predicted? Br. J. clin.
Pharmac., 3, 231-237.
Br. J. clin. Pharmac. (1976), 3
LETTERS TO THE EDITORS
Ojc _
1.50
CO
2
5
10
15
20
24
20
24
Pretreatment time (h)
.Es C0) a) =L
CO
E
b 30-
-
2 20
C
10
CZoCO L)Cx
5
10
15
Time after dosing (h)
course of anti-inflammatory activity was closely paralleled by the disappearance of the metabolite biphenylyl acetic acid (Figure 2). From studies on the further metabolism of biphenylyl acetic acid in the rat the major urinary excretion product was shown to be the p-OH derivative. Subsequent biological testing of this compound showed it to be only weakly active as an anti-inflammatory agent. It is concluded that the anti-inflammatory activity of BDH 7538 is probably through the metabolite biphenylylacetic acid. I am grateful to Mr D. Barron for furnishing the pharmacological data on BDH 7538 and its metabolites.
R.A. FRANKLIN* BDH (Research) Ltd, Godalming, Surrey.
Figure 2 Time course of (a) anti-inflammatory activity of BHD 7538 and (b) plasma concentrations of the metabolite biphenylyl acetic acid after oral administration of BDH 7538 to the guinea pig.
Received November 10, 1975
References at all times after dosing although the metabolite, biphenylyl acetic acid, was found to be present in substantial amounts. By contrast, plasma from human volunteers who had received the drug contained very little biphenylyl acetic acid < 6.0 ug/ml but much higher levels of the unchanged drug. Further studies in the guinea pig showed that after oral administration of BDH 7538, the time
BARRON, D.I., COPLEY, A.R. & VALLANCE, D.K.
Anti-inflammatory and related properties of 4-(pbiphenylyl)-3-hydroxybutyric acid. Br. J. Pharmac., 33, 396-407. CHEMISTRY AND ENGINEERING NEWS. (1967). New anti-inflammatory drugs. Chem. Eng. News, Feb 13, 10. * Present address: Wyeth Laboratories, Maidenhead. Berkshire
EQUIVALENCE OF LANOXIN TABLETS When prescribing a daily dose of digoxin for an individual patient it is usually assumed that the steady state serum concentration is independent of the number of tablets in which the dose is presented (Dobbs, Mawer, Rodgers, Woodcock & Lucas, 1976). This assumption has proved to be justified in a group of volunteer subjects given the same daily dose of digoxin as different Lanoxin tablet presentations. Six healthy volunteers (three male, three female; ages 28-40years; weight 58-75 kg; creatinine clearance > 90 ml/min) gave informed consent. They each received three 14 day courses of treatment with digoxin (Lanoxin, Wellcome Medical Division). The total daily dose of
0.25 mg was presented as (1) one 0.25 mg tablet,
(2) two 0.125 mg tablets and (3) four 0.0625 mg tablets. The three treatment courses were administered to each subject in a random sequence. The tablets were derived from production batches (2571X, 4674A and 4235S) which were obtained routinely through a hospital pharmacy. Data provided by the manufacturers showed that the dissolution rate for each batch was greater than 95% in 1 hour. The subjects took the daily dose at 10.00 h, approximately 2 h after a light breakfast. Venous blood samples were collected immediately before the dose and 6 h later on days 11, 12, 13 and 14
Br. J. clin. Pharmac. (1976), 3
LETTERS TO THE EDITORS
515
Table 1 (a) Concentrations of digoxin (ng/ml) in serum samples taken from six healthy subjects 6 h after daily doses of 0.25mg on days 11, 12, 13 and 14 of each treatment course
Subject 1 2 3 4 5 6 Mean t s.e.
Tablet presentation Two 0.125mg
One 0.25mg
0.43 0.78 0.58 0.67 0.67 0.77
0.34 0.69 0.63 0.69 0.44 0.70
0.55 0.76 0.61 0.59 0.77 0.63 0.63 ± 0.02
0.52 0.63 0.57 0.59 0.72 0.74
0.64 0.77 0.45 0.69 0.45 0.65
0.66 0.76 0.45 0.91 0.62 0.85 0.69 ±
0.54 0.67 0.76 1.05 0.56 0.71 0.02
FourO.0625mg
0.73 0.68 0.58 0.79 0.77 0.77 0.79 0.57 0.63 0.68 0.70 0.60 0.80 0.77 0.62 0.76 0.70 0.61 0.52 0.57 - 0.73 0.50 0.69 0.67 ± 0.02
0.62 0.82 0.58 0.77 0.73 -
mean
(b) Urinary excretion of digoxin (,g/24 h) by six healthy subjects, given daily doses of 0.25 mg, on days 11 and 14 of each treatment course Subject
One 0.25mg
1 2 3 4 5 6 Mean ± s.e. mean
102 85 149 116 92 131 91 115 118 131 137 111 115 ± 7
of each treatment course. Two 24 h urine collections were made between days 11 and 14. Aliquots of serum and urine were stored at -30 C until the day of assay. Samples from each subject were analysed within a single assay (Lanoxitest ,B, Wellcome Reagents Ltd) to avoid confounding differences due to presentations with differences due to between assay variation. The estimated within assay coefficient of variation was 15% at a concentration of 0.5 ng/ml and 10% at 0.8 ng/ml. The measured digoxin contents of (a) 6 h serum (ng/ml) and (b) urine (gg/24 h) are shown in Table 1. Analysis of variance showed no significant differences (P> 0.1) between the presentations with respect to 6 h serum concentration or 24 h urine excretion. The before dose serum concentrations corresponding with presentations (1), (2) and (3) were 0.47 ±0.02, 0.53 ± 0.02 and 0.47 ± 0.02 ng/ml respectively. It is concluded that the studied batches of the three different Lanoxin tablets were equivalent with respect to the bioavailability of digoxin. We are grateful to Mr J. W. Poston (Clinical Department), Mr J. McCrerie and Mr A. Sabey
Tablet presentation Two 0.125mg Four 0.0625mg 101 143 145 216 94 129 118 131 138 121 134 ± 8
122 136 191 137 154 95 136 ±
143 133 119 141 122 134 7
(Central Analytical Laboratories), at the Wellcome Foundation Ltd, for their advice and co-operation. Our thanks also go to the volunteers who kindly gave their time to help in this study.
The work was supported by a project grant from the Medical Research Council to Professor G.E. Mawer for the study of factors influencing the drug dosage requirements of individual patients. SYLVIA M. DOBBS, E. MARGARET RODGERS & B.G. WOODCOCK Department of Pharmacology, Materia Medica and Therapeutics, University of Manchester, Manchester M13 9PT Received January 8, 1976
References DOBBS, S.M., MAWER, G.E., RODGERS, E.M., WOODCOCK, B.G. & LUCAS, S.B. (1976). Can maintenance digoxin dose requirements be predicted? Br. J. clin.
Pharmac., 3, 231-237.
