Bioavailability Monograph
This monograph is a revision of the digoxin monograph originally published in the January 1975 issue of this Journal. The availability of additional information and studies necessitated publication of this revision.
Digoxin has become the classic example of a drug for which significant bio-inequivalence has been demonstrated among generically equivalent oral dosage forms. Because the drug is widely used in treating life-threatening conditions, and because it has both a low therapeutic index and a bioavailability profile highly sensitive to minor formulation variables, bioequivalency considerations are crucial to drug product selection. Early in 1974, the Food and Drug Administration (FDA) took regulatory measures to eliminate problems of bio-inequivalence among different brands of digoxin tablets by requiring batch certification on the basis of specified dissolution tests. In addition, any company marketing digoxin tablets must submit results of an in vivo comparative bioavailability study performed in crossover design. With these certification procedures in effect , a high and comparable degree of bioavailability for all marketed digoxin products is now claimed by FDA . However, the nature of the drug makes it likely that different brands or lots within a given brand may have significant differences in some aspect of the total bioavailability profile. Therefore, pharmacists should seek and carefully evaluate bioavailability information on digoxin products before selecting them. Moreover, information regarding product reformulations should be provided to pharmacists. The brand should not be changed in a patient already stabilized without reviewing pertinent bioavailability data and consulting the phYSician.
The Drug Entity General Characteristics-Orally administered digoxin is absorbed from the stomach and upper portion of the small intestine. 1 When compared with intravenously administered doses of digoxin, 70-80 percent absorption of digoxin can be expected from oral administration of solution dosage forms or properly formulated tablets.2,3 Prior to the current FDA regUlatory standards for digoxin products, many digoxin tablet formulations were shown to be poorly absorbed, yielding as low as 30 percent absorption based on comparisons with intravenous administration of similar doses. 2,4 However, tablets can be formulated which provide essentially equivalent absorption to solution or elixir dosage forms.3 Peak plasma levels usually occur 60-90 minutes after oral administration, although formulation variables can cause the peak to occur earlier or later. 5,6 Digoxin appears to be absorbed by passive diffusion, indicating that the absorption rate would be proportional to the concentration of free drug at the absorption site.
Vol. NS 17, No. 10, October 1977
Digoxin
Digoxin is 20-30 percent bound to plasma proteins,7 and its biological half-life in normal humans is approximately 36-44 hours. 8,9 Digoxin is metabolized primarily in the liver, but it is also capable of extrahepatic metabolism; from 5 to 15 percent of a normal digoxin dose is excrE..ted in the urine in the form of metabolites. 10 Nearly 35 percent of an administered digoxin dose is excreted unchanged in the urine. 9 ,11,12
Dosage Forms Dosage forms of digoxin must meet USP reqUirements for dissolution, content uniformity and potency relevant to the bioequivalency of digoxin tablets. Certain in vitro dissolution tests correlate with in vivo bioavailability,2,13-15 although some studies 16, 17 also indicate that the USP dissolution procedure and other procedures are not always effective for evaluating bioavailability. Content uniformity generally is a greater problem in tablets that contain a small amount of drug. When dealing with a drug as potent as digoxin, it is particularly important to assure that the content of each tablet is within an acceptable range. Tablet-to-tablet uniformity can be achieved with good manufacturing practices. 18
Analytical Methods In experienced hands, radioimmunoassay is a rapid and precise analytical method with sufficient sensitivity to determine the low blood and urine concentrations after therapeutic doses of digoxin. 16 Kit assays can detect 0.5 ng of digoxin/ml (1 ng = 0.001 j.Lg); other assays can detect 0.2 ng/ml. A new assay 19 can detect 0.05 ng/ml; this assay19 is sufficiently sensitive to permit the measurement of plasma or serum concentrations for up to 96 hours following a single 0.5 mg dose of digoxin.
Bioavailability Literature Survey and Evaluation-Although tablet-to-tablet potency variation had been a recognized problem with digoxin, 20 the 1971 report by Lindenbaum et al. 5 was the first published comparative bioavailability study. The study compared 0.25 mg digoxin tablets-one lot of Burroughs Wellcome digoxin, one lot of Davis-Edwards digoxin and two lots of American Pharmaceutical Co. digoxin. Four normal subjects were used in a randomized crossover design. Single doses (0.5 mg) were given orally after an overnight fast, and serum digoxin levels were determined at 0, 0.5, 1, 1.5, 2, 3 and 5 hours using the radioimmunoassay method. The mean peak serum digoxin levels, which reflect the rate and extent of absorption, varied markedly. The actual values were: Burroughs Wellcome, 2. 1 ng/ml; American Pharmaceutical Co., one lot, 1.4 ng/ml, another lot, 0.30 ng/ml; and Davis-Edwards, 0.50 ng/ml. These peak values were observed at 1.5 hours after drug administration, except for the Burroughs
Wellcome brand for which the peak was observed at 1 hour. Following publication of the study of lindenbaum et al., 5 FDA noted certain deficiencies in the study.20 The major one was that the tablets included in the study had not been subjected to all required USP tests, particularly the content uniformity test of individual tablets. Furthermore, one lot of tablets (the one that resulted in the peak serum level of 0.30 ng/ml) previously had been assayed at the National Center for Drug Analysis and failed to meet the USP content uniformity test. Hence, the product was out of compliance and subject to recall. Another product (the one that gave a peak level of 0.50 ng/ml) was not available for testing, but like the one found out of compliance, it was marketed prior to FDA's voluntary certification program .20 It was pointed out, therefore, that the low serum digoxin levels produced by these tablets could have been due to low tablet potency rather than poor bioavailability. The tablet that achieved the mean 1.4 ng I ml peak serum level and the Burroughs Wellcome brand met USP specifications, and thereJore, the differences in serum levels between these two brands of tablets must be attributed to bioavailability differences. Other possible criticisms of the Lindenbaum et al. 5 study related to the small number of subjects used and the failure to obtain serum levels over a longer period of time. In a later study by Wagner et al.,2 two brands of commercially available 0.25 mg digoxin tablets manufactured in the United States (Burroughs Wellcome and Fougera) were studied in an eight-subject, two-way crossover design using single 0.5 mg doses. Both brands met all USP specifications. The study was carried out for 96 hours (the practical and reasonable time period for comparative digoxin bioavailability studies) and revealed large differences in bioavailability between the two brands. Based on areas under the serum level-time curves (from 0 to 96 hours) , the bioavailability of the Fougera tablets was 55 percent of that observed for the Burroughs Wellcome tablets. Although this work 2 suggested that the ratio of the 0-5 hour areas was essentially the same as the ratio of the 0-96 hour areas (after dose correction) for the two tablets, later investigation 21 showed that the ratio of the dose-corrected AUC O-oo's for the oral solution and the 1-hour intravenous infusion was 100 percent, while the dose-corrected ratio of the 0-96 hour areas was only about 80 percent. This strongly suggests that, at least in some cases, one must eliminate AUC 0-00 (the area appearing in any pharmacokinetic equation) in order to obtain the correct relative efficiency of absorption. By using cumulative urinary excretion to study digoxin bioavailability in four normal volunteers, the relative bioavailability of digoxin from 0.25 mg Burroughs Wellcome tablets was compared to that of an orally
635
Digoxin
administered solution (the Burroughs Wellcome parenteral solution) .22 It was observed that digoxin was only 75 percent absorbed from the tablets as compared to the orally administered solution. In another bioavailability study23 involving Burroughs Wellcome digoxin tablets, the absolute bioavailability of a particular lot of 0.25 mg tablets, based on three methods of determination in six normal volunteers, was 62 percent. Huffman et al. 23 suggested that urinary excretion data are a more valid measure of bioavailability of oral digoxin preparations than either steady-state serum digoxin levels or the area under a truncated serum concentration-time curve. But Greenblatt et al. 24 reported that cumulative urinary excretion data are less variable than areas under truncated serum concentration-time curves. However, Stoll and Wagner 14 pointed out that urinary excretion data may be more biased than serum or plasma concentrations because the radioimmunoassay is nonspecific and measures metabolites of digoxin as well as unchanged drug, and one would expect a higher ratio of metabolites to drug in urine than in plasma. Also, Wagner and Ayres 21 reported methods to estimate AUC O-co from serum or plasma concentrations measured at 24, 48, 72 and 96 hours and showed that relative efficiencies of absorption calculated from these areas are more valid. In a later study by Lindenbaum et al., 14 both dissolution tests and serum level studies over 5 or 6 hours were performed using 12 lots of digoxin tablets from eight U.S. companies. Twenty-four-hour urinary digoxin excretion also was measured. The number of subjects used for each of the 12 lots of tablets tested varied from a high of 25 to a low of two. This report 14 listed the lots studied as follows: Burroughs Wellcome '(three lots); Purepac (two lots); and Fougera, Zenith, Davis-Edwards, American Pharmaceutical Co., Premo, West-ward and Lederle (one lot each). According to this report, one lot of the Purepac tablets, the Davis-Edwards tablets and the Fougera tablets were therapeutically ineffective and poorly absorbed. Several bioavailability studies have been reported using digoxin products manufactured and marketed in Europe. Significant variations in bioavailability have been observed between different brands of tablets and even among different lots prepared by the same manufacturer. Reformulation of digoxin tablets in 1971 by The Wellcome Foundation in England (the European counterpart of Burroughs Wellcome) caused a doubling in bioavailability.25.26 It was later shown that the two formulations exhibited pronounced differences in dissolution rate which correlated with differences in bioavailability.27.28 Although these studies 27 .28 indicate variations in bioavailability between brands and among lots of the same brand of digoxin tablets marketed in Europe, at least one study29 which tested three brands of digoxin tablets according to a protocol similar to that
of Lindenbaum et al. 5 (but for different digoxin products) showed no significant differences among the tested products. Analysis of serum level data for 48 hours revealed no significant bioavailability differences between Burroughs Wellcome tablets and 0.25 mg Towne Paulsen tablets in 6 subjects. Another study30 compared 0.25 mg Burroughs Wellcome tablets with 0.25 mg Philips Roxane tablets and showed substantial differences in bioavailability between the specific lots of these brands based on both 8-hour serum data and 9-day cumulative urinary excretion data in 5 subjects.
Regulatory and Compendial Activity In 1970, FDA recalled many brands of digoxin tablets because of failure to meet the USP tablet-to-tablet content uniformity requirements. This test requires that when each of 10 tablets is assayed individually, not less than 9 must be within the limits of 85 to 115 percent of specified potency, and no tablet may be beyOnd the limits of 75 to 125 percent of specified potency. In January 1974, FDA took immediate action to withdraw from the market those digoxin tablets that appeared to possess inadequate bioavailability on the basis of either the USP or FDA dissolution test. 31 To this end, FDA initiated a sampling -program for analyzing batches of digoxin tablets already in the distribution channels to determine if they met the dissolution and other compendial requirements. Products not meeting the dissolution requirements had to be reformulated or they were removed from the market. In addition, some manufacturers are required to submit samples of all new batches of digoxin tablets for analysis and certification by FDA prior to general distribution. Furthermore, in view of the apparently widespread incidence of bio-inequivalence which has been observed among various brands of digoxin tablets, FDA required all manufacturers of oral digoxin products to submit abbreviated new drug applications which show evidence that the products produce adequate bioavailability, using an appropriately designed crossover bioavailability study in human subjects.
Clinical Significance Serum digoxin levels generally correlate with the state of patient digitalization as well as the onset of digoxin toxicity. An early study suggested a relatively constant ratio between serum levels and myocardial digoxin concentration. 32 However, Jusko and Weintraub 33 have demonstrated that a significant correlation exists between myocardium to serum concentration ratios of digoxin and creatinine clearance. This can account for the large variability in tissue to serum ratios which is observed for digoxin, and for the apparent dependence of digoxin distribution on renal function, as well as the fact that plasma digoxin levels do not always discriminate between patients who are toxic (as defined by
636
electrocardiographic criteria) and those who are not. 34 The serum digoxin level that causes a satisfactory therapeutic response or toxicity in one patient is not necessarily the same as that in another patient. The distributions for efficacy and toxicity overlap. Various therapeutic blood level ranges of digoxin have been reported. Smith et al. 35 reported mean values of 1.1 ng/ml (range 0.8-1.6) for nontoxic patients receiving oral doses of 0.25 mg/ day and a mean of 1.4 ng/ml (range 0.9-2.4) for patients receiving 0.5 mg/day. For patients exhibiting digoxin toxicity (e.g., arrhythmias) , an average value of 3.3 ng/ml (range 2.1-8.7) was reported. Marcus et al. 36 studied normal subjects receiving a steady-state oral regimen of 0.5 mg / day and obtained a mean serum level of 1.4 ng / ml at 8 hours after the previous dose. Direct comparison of reported serum levels often is difficult because time of blood sampling is not the same. However, in general, patients responding satisfactorily to digoxin therapy have serum concentrations of 0.6-2 ng/ml while evidence of toxicity begins to appear in many patients when serum digoxin levels reach 3 ng / ml. Essentially all patients with steady-state levels above 3 ng/ml experience toxic effects. Toxicity in pediatric patients usually is not seen until levels exceed 3 to 4 ng/ml. Monitoring serum digoxin levels is felt to be of considerable value in designing appropriate therapeutic regimens for individual patients. 37 The pathological state of the patient influences the clinical seriousness of differences in bioequivalency among different brands of digoxin tablets. In a study30 in which a particular brand of digoxin tablet showed an average of less than half the bioavailability of the innovator product in a single-dose experiment in healthy adults, the test preparation showed even lower availability in patients with congestive heart failure during 4 weeks of chronic dosing. A recent study38 in Israel revealed 15 cases of digoxin intoxication attributable to a particular non-U.S. manufacturer's unannounced formulation change; this generally led to a greater than doubling of plasma levels. FDA has noted that its newest certification mechanisms,31 implemented in 1974, have "assured a high ... and comparable degree of bioavailability for all marketed digoxin products ... "39 Careful adjustment of digoxin doses to the needs of an individual patient still is necessary. Any differences in digoxin bioavailability can be expected to be therapeutically significant because the drug possesses a steep dose-response curve, indicating that the range between ineffective, therapeutic and toxic doses is quite narrow. 22 In the absence of good comparative bioavailability data for two or more chemically equivalent digoxin products, a patient should not be switched from one brand to another once a reasonable therapeutic effect has been achieved with one preparation. Otherwise, either a toxic or
Journal of the American Pharmaceutical Association
nontherapeutic effect may result from a change in the extent of digoxin bioavailability. Furthermore, manufacturers that reformulate digoxin tablets should perform appropriate bioavailability studies to assure that the reformulated product is bioequivalent to the former one. This information should be made available to the medical and pharmaceutical professions.
Criteria for Bioavailability Tests Although FDA has set specific requirements for the marketing of digoxin tablets,32 pharmacists still need to be concerned about bioavailability information on digoxin tablets they dispense, particularly digoxin products of a noninnovator company. The following criteria for bioavailability tests are based on those used by FDA: 1. Tests should be conducted in a three-way crossover design. 2. A minimum of 12 subjects should be used. 3. Subjects should undergo adequate clinical pathological screening, including liver, kidney and hematology function tests and electrocardiograms. 4. When possible, subjects should weigh between 55 and 95 kg. 5. Two weeks should separate the crossover tests. 6. The test product should be compared to: (a) a standard reference tablet product (Burroughs Well come brand of digoxin, Lanoxin) and (b) an aqueous solution administered orally. 7. Data should be in the form of serum level-time profiles and urinary excretion data for 0-24,24-48,48-72 and 72-96 hours. 8. The test should be conducted for a minimum of 5 hours and preferably for 96 hours. 9. Blood level determinations should be made at 0.5, 0.75, 1.0, 1.5,2.0,3.0 and 5 hours and preferably at 12, 24, 48, 72 and 96 hours. 10. Renal clearance of digoxin should be calculated for each subject. 11. AUC 0-00 should be estimated for each subject after each treatment. 12. Relative absorption efficiencies should be calculated for each subject by correcting for changing renal clearances based on the equation developed by Till et al. 4o 13. Plasma levels at each sampling time and the area under the curve should be evaluated according to analysis of variance for a crossover design.
Information Available from Suppliers Bioavailability information was requested by letter from 54 manufacturers and/ or suppliers of digoxin tablets. The following companies did not respond: Approved Pharmaceutical
Vol. NS 17, No. 10, October 1977
Arcum Pharmaceutical Barr Laboratories Barry-Martin Pharmaceutical Blue Cross (Halsey) Blue Line Chemical Bowman Pharmaceutical Carr Drug Columbia Medical Corvit Pharmaceuticals Daniels Pharmaceuticals Davies Rose Hoyt Durst Drug Faraday Laboratories E. Fougera Geneva Drugs Gotham Pharmaceutical Harvey Laboratories ICN Pharmaceutical Generic Division Jenkins Laboratories Kay Pharmacal Ketchum Laboratories Lakeside Laboratories Lannett Lit Drug Midway Medical 0 ' Neal, Jones & Feldman Pen hurst Pharmacal Pharmex Purepac Pharmaceutical Raway Pharmacal Scrip Sherry Pharmaceutical Standex Laboratories. Stanlabs C. O. Truxton Ulmer Pharmacal Vita-Fore Products Winsale Drug Wolins Pharmacal Zenith Laboratories The following four companies indicated that they were only distributors of digoxin tablets manufactured by another company and, therefore, could not provide any bioavailability information: Distributor Manufacturer Consolidated Midland ICN Pharmaceutical H. R. Cenci Laboratories Zenith Laboratories Barr Laboratories H. C. Moore Drug Exchange Zenith Laboratories Robinson Laboratories Zenith Laboratories
Table 1. dose
The follOWing three companies indicated that they no longer distribute or manufacture digoxin tablets: Parke-Davis Stayner Vitarine The following four companies indicated that their products meet compendial requirements including the dissolution test: Geneva Generics Lederle Laboratories Towne Paulsen West-ward
Companies Providing Bioavailability Information Burroughs WeI/come-As the innovator of digoxin, Burroughs Wellcome indicated that it has maintained continued support of digoxin bioavailability studies. Following the initial work of Lindenbaum et al. in 1971,5 which raised the issue of bioavailability with oral digoxin, this company sponsored the studies that correlated in vitro dissolution rates with in vivo bioavailability values. 14 Burroughs Wellcome digoxin is the standard for the comparative bioavailability studies recommended by FDA, and nearly all digoxin bioavailability studies have included a Burroughs Wellcome product. Since publication of the original digoxin monograph, Burroughs Wellcome has supported digoxin availability investigations that resulted in at least seven publications. 41 - 43 These studies evaluated the bioavailability of Burroughs Wellcome digoxin in more than 70 subjects and provided absolute bioavailability data, i.e., efficiency of oral absorption relative to intravenous administration of an identical dose of drug. Based on absolute bioavailability figures from various studies 3,41- 44 using Burroughs Wellcome tablets and elixir, Burroughs Wellcome estimates the average absolute bioavailability of Burroughs Wellcome tablets at 67.7 percent and the average absolute bioavailability of Burroughs Wellcome elixir at 77.2 percent. Philips Roxane-Philips Roxane Laboratories provided bioavailability information on its 0.25 mg digoxin tablets compared to the FDA reference products, an aqueous solution and Burroughs Wellcome tablets, according to the recommendations in the Federal Register. The study involved a seven-way cross-
Mean values of three digoxin preparations using 12 subjects and 0.5 mg
Preparation
Average Area Under Curve a , ng Xhour/ml 0-5 hours 0-72 hours
5. 15 4.22 6.29 5.25
Digoxin 0.25 mg (Philips Roxane) Digoxin 0.25 mg (Burroughs Wellcome) Digoxin solution Mean area of two reference products a Calculated using the trapezoidal rule. b
Standard deviation.
637
(0.80) (2.12) (1.05) (1 .36)
b
17.9 (5.55) 16. 1 (8.73) 27.8 (15.3)
b
Digoxin
over using 12 normal volunteers. Although the total study involved a seven-way crossover, only the following three digoxin products were discussed: 0.25 mg digoxin tablets (Philips Roxane lot 716 1B3); 0.25 mg digoxin tablets (Burroughs Wellcome lot 02251) and 0.5 mg/200 ml digoxin aqueous solution. The tablets were certified to be USP quality. Tables 1-3 summarize the important bioavailability parameters for these three products. The Philips Roxane report indicated that the data presented demonstrate that its tablet meets the Federal Register requirements for bioavailability. The Philips Roxane report also notes that statistical analysis revealed that peak heights, peak times and areas under the curve for the test and reference tablets were not significantly different, but that the test tablet showed significantly higher serum digoxin levels at 30, 45 and 60 minutes and that the reference tablet had a significantly higher serum level at 300 minutes. In spite of the fact that the Philips Roxane report states that the peak heights and times show no significant differences between the two tablets tested (and, by implication, no significant differences in absorption rates) , it is likely that more appropriate statistical analyses might have proved that the differences expressed in Tables 2 and 3 demonstrate the Philips Roxane tablets to be considerably more rapidly ab-
References 1. Doherty, J. E, Perkins, W. H. , and Mitchell, G. K., Arch. Int. Med. 108: 531, 1961 . 2. Wagner, J. G., Christensen, M., Sakmar, E., Blair, D., Yates, J. D., Wallis, P. W., Sedman, A. J., and Stoll, R. G., J. Am. Med. Assoc. 224: 199, 1973. 3. Marcus, F. I., Dickenson, J., Pippen, S., Stafford, M., and Bressler, R., Clin. Pharmacol. Ther. 20: 253 , 1976. 4. Wagner, J. G., Am. Heart J. 88: 133, 1974. 5. Lindenbaum, J. , Mellow, M. H., Blackstone, M. 0., and Butler, U. P., N. Engl. J. Med. 285: 1344, 1971. 6. White, R. J., Chamberlain, D. A., Howard, M., and Smith, T. W., Br. Med. J. 1: 380, 1971. 7. Lukas, D. S., and DeMartino, A. G. , J. Clin. Invest. 48: 1041, 1969. 8. The pharmacological basis of therapeutics, 4th ed., Goodman, L. S., and Gilman, A., editors, The Macmillan Co., New York, New York, 1970, p. 677. 9. Jelliffe, R. W., Ann. Int. Med. 69: 703, 1968. 10. Stoll, R. G., and Wagner, J. G., Clin. Pharmacol. Ther. 17: 117, 1975. 11. St. George, S., Friedman, M., and Ishida, T., J. Clin. Invest. 37: 836, 1958. 12. Doherty, J. E, and Perkins, W. H., Am. Heart J. 63: 528, 1962. 13. Greenblatt, D. S., Duhme, D. W., Koch-Weser, J., and Smith, T. W., Clin. Res. 22: 318A, 1974. 14. Lindenbaum, J., Butler, V. P. , Murphy, J. E, and Cresswell, R. M., Lancet 1: 1215, 1973. 15. Harter, J. G., Skelly, J. P. , and Steers, A. W., Circulation 49: 395, 1974.
Table 2. Mean peak heights of three digoxin preparations using 12 subjects and 0.5 mg dose Preparation Digoxin 0.25 mg (Philips Roxane) Digoxin 0.25 mg (Burroughs Wellcome) Digoxin solution
Peak Height, ng/ml 2.62 (0.87)
a
1.89 (1.16) 3.39 (0.85)
Table 3. Mean peak times of the three digoxin preparations using 12 subjects and 0.5 mg dose Preparation Digoxin 0.25 mg (Philips Roxane) Digoxin 0.25 mg (Burroughs Wellcome) Digoxin solution
Peak Time, minutes 65 (29)
a
94 (77) 41 (9)
a Standard deviation.
a
sorbed than the Burroughs Wellcome tablets. This is especially likely in view of the fact that th.e statistical analysis reported by Philips Roxane apparently involved data from only three treatments even though the total study involved a seven-way crossover.
Monograph Col/aboratorsDaniel L. Azarnoff, MD, Distinguished Professor of Medicine and Pharmacology, University of Kansas College of Health Sciences, Kansas City, Missouri
This monograph contains information received as of May 31, 1977. Monograph AuthorJohn L. Colaizzi, PhD, Professor of Pharmaceutics and Chairman of the Department, University of Pittsburgh School of Pharmacy, Pittsburgh, Pennsylvania
16. Klink, P. R., Poust, R. I. , Colaizzi, J. L. , and McDonald, R. H., J. Pharm. Sci. 63: 1231, 1974. 17. Ylitalo, P. , Wilen, G., and Lundell, S, J. Pharm. Sci 64: 1264, 1975. 18. Stoll, R. G. , Christensen, M. S., Sakmar, E , and Wagner, J. G., Res. Commun. Chem. Pathol. Pharmacal. 4: 503, 1972. 19. Wagner, J. G., Hallmark, M. R., Sakmar, E., and Ayres, J. W., Steroids, (June) 1977 (in press) . 20. Vitti, T. G., Banes, D., and Byers, T. E, N. Engl. J. Med. 281: 1433, 1971 . 21. Wagner, J. G., and Ayres, J. W., J. Pharmacokinet. Biopharm., 1977 (in press) . 22. Huffman, D. H., and Azarnoff, D. L., J. Am. Med. Assoc. 22: 957, 1972. 23. Huffman, D. H., Manion, C. V., and Azarnoff, D. L., Clin. Pharmacol. Ther. 16: 310, 1974. 24. Greenblatt, D. J., Duhme, D. W. , Koch-Weser, J. , and Smith, T. W., Clin. Pharmacol. Ther. 15: 519, 1974. 25. Harner, J., and Grahame-Smith, D. G., Lancet 2: 325, 1972. 26. Whiting , B. , Rodger, J. C., and Sumner, D. J., Lancet 2: 922, 1972. 27. Steiness, E , Christensen, V., and Johansen, H. , Clin. Pharmacal. Ther. 14: 949, 1973. 28. Fraser, E J., Leach, R. H., Poston, J. W., Bold , A. M., Culank, L. S., and Lipede, A. B. , J. Pharm. Pharmacol. 25: 968, 1973. 29. Hibble, A. G., Isaac, P. , and Grahame-Smith, D. G., Lancet 2: 90, 1972. 30. Fleckenstein, L., Kroening , B., and Weintraub, M , Clin. Pharmacol. Ther. 16: 435, 1974. 31 . Fed. Reg. 39: 2471 (Jan. 22 ) 1974 .
638
Standard deviation.
Lewis B. Sheiner, MD, Assistant Professor of Laboratory Medicine and of Medicine, Department of Clinical Pathology and Laboratory Medicine, University of California, San Francisco, California John G. Wagner, PhD, Professor of Pharmacy and Staff Member, Upjohn Center for Clinical Pharmacology, The University of Michigan, Ann Arbor, Michigan
32. Doherty, J. E , Perkins, W. H., and Flanigan, W. D., Ann. Int. Med. 66: 116, 1967. 33. Jusko, W. J., and Weintraub, M., Clin. Pharmacol. Ther. 16: 449, 1974. 34. Ingelfinger, J. A. , and Goldman, P., N. Engl. J. Med. 294: 867, 1976. 35. Smith, T. W. , Butler, V. P. , and Haber, E., N. Engl. J. Med. 281: 1212, 1969. 36. Marcus, F. I. , Burkhalter, L. , Cuccia, C. , and Kapadia , G. G., Circulation 34: 865 , 1966. 37. Chamberlain, D., Redors, A. , Bertler, A. , Coltart, J., and White, R., Lancet 2: 934, 1971. 38. Danon, A. , Horowitz, J., Ben-lvi, z. , Kaplanski , J. , and Glick, S., Clin. Pharmacol. Ther. 21: 643, 1977. 39 . FDA Drug Bull. 6: 31 , 1966. 40. Till, A. E., Benet, L. l ., and Kwan , K. C., J. Pharmacokinet. Biopharm. 2: 525, 1974. 41 . Greenblatt, D. J., Duhme, D. W., Koch-Weser, J., and Smith, T. W., J. Am. Med. Assoc. 229: 1774, 1974. 42. Huffman, D. H., Manion, C. V., and Azarnoff, D. L. , J. Pharm. Sci. 64: 433, 1975. 43. Mallis, G. I. , Schmidt. D. H., and Lindenbaum, J. Clin. Pharmacol. Ther. 18: 761 , 1975. 44. Greenblatt, D. J., Duhme, D. W., Koch-Weser, J., and Smith, T. W., Conn. Med. 38.' 230, 1974.
Published by
American Pharmaceutical Association 2215 Constitution Ave ., NW Washington , DC 20037
Journal of the American Pharmaceutical Association
This monograph is a revision of the digoxin monograph originally published in the January 1975 issue of this Journal. The availability of additional information and studies necessitated publication of this revision.
Digoxin has become the classic example of a drug for which significant bio-inequivalence has been demonstrated among generically equivalent oral dosage forms. Because the drug is widely used in treating life-threatening conditions, and because it has both a low therapeutic index and a bioavailability profile highly sensitive to minor formulation variables, bioequivalency considerations are crucial to drug product selection. Early in 1974, the Food and Drug Administration (FDA) took regulatory measures to eliminate problems of bio-inequivalence among different brands of digoxin tablets by requiring batch certification on the basis of specified dissolution tests. In addition, any company marketing digoxin tablets must submit results of an in vivo comparative bioavailability study performed in crossover design. With these certification procedures in effect , a high and comparable degree of bioavailability for all marketed digoxin products is now claimed by FDA . However, the nature of the drug makes it likely that different brands or lots within a given brand may have significant differences in some aspect of the total bioavailability profile. Therefore, pharmacists should seek and carefully evaluate bioavailability information on digoxin products before selecting them. Moreover, information regarding product reformulations should be provided to pharmacists. The brand should not be changed in a patient already stabilized without reviewing pertinent bioavailability data and consulting the phYSician.
The Drug Entity General Characteristics-Orally administered digoxin is absorbed from the stomach and upper portion of the small intestine. 1 When compared with intravenously administered doses of digoxin, 70-80 percent absorption of digoxin can be expected from oral administration of solution dosage forms or properly formulated tablets.2,3 Prior to the current FDA regUlatory standards for digoxin products, many digoxin tablet formulations were shown to be poorly absorbed, yielding as low as 30 percent absorption based on comparisons with intravenous administration of similar doses. 2,4 However, tablets can be formulated which provide essentially equivalent absorption to solution or elixir dosage forms.3 Peak plasma levels usually occur 60-90 minutes after oral administration, although formulation variables can cause the peak to occur earlier or later. 5,6 Digoxin appears to be absorbed by passive diffusion, indicating that the absorption rate would be proportional to the concentration of free drug at the absorption site.
Vol. NS 17, No. 10, October 1977
Digoxin
Digoxin is 20-30 percent bound to plasma proteins,7 and its biological half-life in normal humans is approximately 36-44 hours. 8,9 Digoxin is metabolized primarily in the liver, but it is also capable of extrahepatic metabolism; from 5 to 15 percent of a normal digoxin dose is excrE..ted in the urine in the form of metabolites. 10 Nearly 35 percent of an administered digoxin dose is excreted unchanged in the urine. 9 ,11,12
Dosage Forms Dosage forms of digoxin must meet USP reqUirements for dissolution, content uniformity and potency relevant to the bioequivalency of digoxin tablets. Certain in vitro dissolution tests correlate with in vivo bioavailability,2,13-15 although some studies 16, 17 also indicate that the USP dissolution procedure and other procedures are not always effective for evaluating bioavailability. Content uniformity generally is a greater problem in tablets that contain a small amount of drug. When dealing with a drug as potent as digoxin, it is particularly important to assure that the content of each tablet is within an acceptable range. Tablet-to-tablet uniformity can be achieved with good manufacturing practices. 18
Analytical Methods In experienced hands, radioimmunoassay is a rapid and precise analytical method with sufficient sensitivity to determine the low blood and urine concentrations after therapeutic doses of digoxin. 16 Kit assays can detect 0.5 ng of digoxin/ml (1 ng = 0.001 j.Lg); other assays can detect 0.2 ng/ml. A new assay 19 can detect 0.05 ng/ml; this assay19 is sufficiently sensitive to permit the measurement of plasma or serum concentrations for up to 96 hours following a single 0.5 mg dose of digoxin.
Bioavailability Literature Survey and Evaluation-Although tablet-to-tablet potency variation had been a recognized problem with digoxin, 20 the 1971 report by Lindenbaum et al. 5 was the first published comparative bioavailability study. The study compared 0.25 mg digoxin tablets-one lot of Burroughs Wellcome digoxin, one lot of Davis-Edwards digoxin and two lots of American Pharmaceutical Co. digoxin. Four normal subjects were used in a randomized crossover design. Single doses (0.5 mg) were given orally after an overnight fast, and serum digoxin levels were determined at 0, 0.5, 1, 1.5, 2, 3 and 5 hours using the radioimmunoassay method. The mean peak serum digoxin levels, which reflect the rate and extent of absorption, varied markedly. The actual values were: Burroughs Wellcome, 2. 1 ng/ml; American Pharmaceutical Co., one lot, 1.4 ng/ml, another lot, 0.30 ng/ml; and Davis-Edwards, 0.50 ng/ml. These peak values were observed at 1.5 hours after drug administration, except for the Burroughs
Wellcome brand for which the peak was observed at 1 hour. Following publication of the study of lindenbaum et al., 5 FDA noted certain deficiencies in the study.20 The major one was that the tablets included in the study had not been subjected to all required USP tests, particularly the content uniformity test of individual tablets. Furthermore, one lot of tablets (the one that resulted in the peak serum level of 0.30 ng/ml) previously had been assayed at the National Center for Drug Analysis and failed to meet the USP content uniformity test. Hence, the product was out of compliance and subject to recall. Another product (the one that gave a peak level of 0.50 ng/ml) was not available for testing, but like the one found out of compliance, it was marketed prior to FDA's voluntary certification program .20 It was pointed out, therefore, that the low serum digoxin levels produced by these tablets could have been due to low tablet potency rather than poor bioavailability. The tablet that achieved the mean 1.4 ng I ml peak serum level and the Burroughs Wellcome brand met USP specifications, and thereJore, the differences in serum levels between these two brands of tablets must be attributed to bioavailability differences. Other possible criticisms of the Lindenbaum et al. 5 study related to the small number of subjects used and the failure to obtain serum levels over a longer period of time. In a later study by Wagner et al.,2 two brands of commercially available 0.25 mg digoxin tablets manufactured in the United States (Burroughs Wellcome and Fougera) were studied in an eight-subject, two-way crossover design using single 0.5 mg doses. Both brands met all USP specifications. The study was carried out for 96 hours (the practical and reasonable time period for comparative digoxin bioavailability studies) and revealed large differences in bioavailability between the two brands. Based on areas under the serum level-time curves (from 0 to 96 hours) , the bioavailability of the Fougera tablets was 55 percent of that observed for the Burroughs Wellcome tablets. Although this work 2 suggested that the ratio of the 0-5 hour areas was essentially the same as the ratio of the 0-96 hour areas (after dose correction) for the two tablets, later investigation 21 showed that the ratio of the dose-corrected AUC O-oo's for the oral solution and the 1-hour intravenous infusion was 100 percent, while the dose-corrected ratio of the 0-96 hour areas was only about 80 percent. This strongly suggests that, at least in some cases, one must eliminate AUC 0-00 (the area appearing in any pharmacokinetic equation) in order to obtain the correct relative efficiency of absorption. By using cumulative urinary excretion to study digoxin bioavailability in four normal volunteers, the relative bioavailability of digoxin from 0.25 mg Burroughs Wellcome tablets was compared to that of an orally
635
Digoxin
administered solution (the Burroughs Wellcome parenteral solution) .22 It was observed that digoxin was only 75 percent absorbed from the tablets as compared to the orally administered solution. In another bioavailability study23 involving Burroughs Wellcome digoxin tablets, the absolute bioavailability of a particular lot of 0.25 mg tablets, based on three methods of determination in six normal volunteers, was 62 percent. Huffman et al. 23 suggested that urinary excretion data are a more valid measure of bioavailability of oral digoxin preparations than either steady-state serum digoxin levels or the area under a truncated serum concentration-time curve. But Greenblatt et al. 24 reported that cumulative urinary excretion data are less variable than areas under truncated serum concentration-time curves. However, Stoll and Wagner 14 pointed out that urinary excretion data may be more biased than serum or plasma concentrations because the radioimmunoassay is nonspecific and measures metabolites of digoxin as well as unchanged drug, and one would expect a higher ratio of metabolites to drug in urine than in plasma. Also, Wagner and Ayres 21 reported methods to estimate AUC O-co from serum or plasma concentrations measured at 24, 48, 72 and 96 hours and showed that relative efficiencies of absorption calculated from these areas are more valid. In a later study by Lindenbaum et al., 14 both dissolution tests and serum level studies over 5 or 6 hours were performed using 12 lots of digoxin tablets from eight U.S. companies. Twenty-four-hour urinary digoxin excretion also was measured. The number of subjects used for each of the 12 lots of tablets tested varied from a high of 25 to a low of two. This report 14 listed the lots studied as follows: Burroughs Wellcome '(three lots); Purepac (two lots); and Fougera, Zenith, Davis-Edwards, American Pharmaceutical Co., Premo, West-ward and Lederle (one lot each). According to this report, one lot of the Purepac tablets, the Davis-Edwards tablets and the Fougera tablets were therapeutically ineffective and poorly absorbed. Several bioavailability studies have been reported using digoxin products manufactured and marketed in Europe. Significant variations in bioavailability have been observed between different brands of tablets and even among different lots prepared by the same manufacturer. Reformulation of digoxin tablets in 1971 by The Wellcome Foundation in England (the European counterpart of Burroughs Wellcome) caused a doubling in bioavailability.25.26 It was later shown that the two formulations exhibited pronounced differences in dissolution rate which correlated with differences in bioavailability.27.28 Although these studies 27 .28 indicate variations in bioavailability between brands and among lots of the same brand of digoxin tablets marketed in Europe, at least one study29 which tested three brands of digoxin tablets according to a protocol similar to that
of Lindenbaum et al. 5 (but for different digoxin products) showed no significant differences among the tested products. Analysis of serum level data for 48 hours revealed no significant bioavailability differences between Burroughs Wellcome tablets and 0.25 mg Towne Paulsen tablets in 6 subjects. Another study30 compared 0.25 mg Burroughs Wellcome tablets with 0.25 mg Philips Roxane tablets and showed substantial differences in bioavailability between the specific lots of these brands based on both 8-hour serum data and 9-day cumulative urinary excretion data in 5 subjects.
Regulatory and Compendial Activity In 1970, FDA recalled many brands of digoxin tablets because of failure to meet the USP tablet-to-tablet content uniformity requirements. This test requires that when each of 10 tablets is assayed individually, not less than 9 must be within the limits of 85 to 115 percent of specified potency, and no tablet may be beyOnd the limits of 75 to 125 percent of specified potency. In January 1974, FDA took immediate action to withdraw from the market those digoxin tablets that appeared to possess inadequate bioavailability on the basis of either the USP or FDA dissolution test. 31 To this end, FDA initiated a sampling -program for analyzing batches of digoxin tablets already in the distribution channels to determine if they met the dissolution and other compendial requirements. Products not meeting the dissolution requirements had to be reformulated or they were removed from the market. In addition, some manufacturers are required to submit samples of all new batches of digoxin tablets for analysis and certification by FDA prior to general distribution. Furthermore, in view of the apparently widespread incidence of bio-inequivalence which has been observed among various brands of digoxin tablets, FDA required all manufacturers of oral digoxin products to submit abbreviated new drug applications which show evidence that the products produce adequate bioavailability, using an appropriately designed crossover bioavailability study in human subjects.
Clinical Significance Serum digoxin levels generally correlate with the state of patient digitalization as well as the onset of digoxin toxicity. An early study suggested a relatively constant ratio between serum levels and myocardial digoxin concentration. 32 However, Jusko and Weintraub 33 have demonstrated that a significant correlation exists between myocardium to serum concentration ratios of digoxin and creatinine clearance. This can account for the large variability in tissue to serum ratios which is observed for digoxin, and for the apparent dependence of digoxin distribution on renal function, as well as the fact that plasma digoxin levels do not always discriminate between patients who are toxic (as defined by
636
electrocardiographic criteria) and those who are not. 34 The serum digoxin level that causes a satisfactory therapeutic response or toxicity in one patient is not necessarily the same as that in another patient. The distributions for efficacy and toxicity overlap. Various therapeutic blood level ranges of digoxin have been reported. Smith et al. 35 reported mean values of 1.1 ng/ml (range 0.8-1.6) for nontoxic patients receiving oral doses of 0.25 mg/ day and a mean of 1.4 ng/ml (range 0.9-2.4) for patients receiving 0.5 mg/day. For patients exhibiting digoxin toxicity (e.g., arrhythmias) , an average value of 3.3 ng/ml (range 2.1-8.7) was reported. Marcus et al. 36 studied normal subjects receiving a steady-state oral regimen of 0.5 mg / day and obtained a mean serum level of 1.4 ng / ml at 8 hours after the previous dose. Direct comparison of reported serum levels often is difficult because time of blood sampling is not the same. However, in general, patients responding satisfactorily to digoxin therapy have serum concentrations of 0.6-2 ng/ml while evidence of toxicity begins to appear in many patients when serum digoxin levels reach 3 ng / ml. Essentially all patients with steady-state levels above 3 ng/ml experience toxic effects. Toxicity in pediatric patients usually is not seen until levels exceed 3 to 4 ng/ml. Monitoring serum digoxin levels is felt to be of considerable value in designing appropriate therapeutic regimens for individual patients. 37 The pathological state of the patient influences the clinical seriousness of differences in bioequivalency among different brands of digoxin tablets. In a study30 in which a particular brand of digoxin tablet showed an average of less than half the bioavailability of the innovator product in a single-dose experiment in healthy adults, the test preparation showed even lower availability in patients with congestive heart failure during 4 weeks of chronic dosing. A recent study38 in Israel revealed 15 cases of digoxin intoxication attributable to a particular non-U.S. manufacturer's unannounced formulation change; this generally led to a greater than doubling of plasma levels. FDA has noted that its newest certification mechanisms,31 implemented in 1974, have "assured a high ... and comparable degree of bioavailability for all marketed digoxin products ... "39 Careful adjustment of digoxin doses to the needs of an individual patient still is necessary. Any differences in digoxin bioavailability can be expected to be therapeutically significant because the drug possesses a steep dose-response curve, indicating that the range between ineffective, therapeutic and toxic doses is quite narrow. 22 In the absence of good comparative bioavailability data for two or more chemically equivalent digoxin products, a patient should not be switched from one brand to another once a reasonable therapeutic effect has been achieved with one preparation. Otherwise, either a toxic or
Journal of the American Pharmaceutical Association
nontherapeutic effect may result from a change in the extent of digoxin bioavailability. Furthermore, manufacturers that reformulate digoxin tablets should perform appropriate bioavailability studies to assure that the reformulated product is bioequivalent to the former one. This information should be made available to the medical and pharmaceutical professions.
Criteria for Bioavailability Tests Although FDA has set specific requirements for the marketing of digoxin tablets,32 pharmacists still need to be concerned about bioavailability information on digoxin tablets they dispense, particularly digoxin products of a noninnovator company. The following criteria for bioavailability tests are based on those used by FDA: 1. Tests should be conducted in a three-way crossover design. 2. A minimum of 12 subjects should be used. 3. Subjects should undergo adequate clinical pathological screening, including liver, kidney and hematology function tests and electrocardiograms. 4. When possible, subjects should weigh between 55 and 95 kg. 5. Two weeks should separate the crossover tests. 6. The test product should be compared to: (a) a standard reference tablet product (Burroughs Well come brand of digoxin, Lanoxin) and (b) an aqueous solution administered orally. 7. Data should be in the form of serum level-time profiles and urinary excretion data for 0-24,24-48,48-72 and 72-96 hours. 8. The test should be conducted for a minimum of 5 hours and preferably for 96 hours. 9. Blood level determinations should be made at 0.5, 0.75, 1.0, 1.5,2.0,3.0 and 5 hours and preferably at 12, 24, 48, 72 and 96 hours. 10. Renal clearance of digoxin should be calculated for each subject. 11. AUC 0-00 should be estimated for each subject after each treatment. 12. Relative absorption efficiencies should be calculated for each subject by correcting for changing renal clearances based on the equation developed by Till et al. 4o 13. Plasma levels at each sampling time and the area under the curve should be evaluated according to analysis of variance for a crossover design.
Information Available from Suppliers Bioavailability information was requested by letter from 54 manufacturers and/ or suppliers of digoxin tablets. The following companies did not respond: Approved Pharmaceutical
Vol. NS 17, No. 10, October 1977
Arcum Pharmaceutical Barr Laboratories Barry-Martin Pharmaceutical Blue Cross (Halsey) Blue Line Chemical Bowman Pharmaceutical Carr Drug Columbia Medical Corvit Pharmaceuticals Daniels Pharmaceuticals Davies Rose Hoyt Durst Drug Faraday Laboratories E. Fougera Geneva Drugs Gotham Pharmaceutical Harvey Laboratories ICN Pharmaceutical Generic Division Jenkins Laboratories Kay Pharmacal Ketchum Laboratories Lakeside Laboratories Lannett Lit Drug Midway Medical 0 ' Neal, Jones & Feldman Pen hurst Pharmacal Pharmex Purepac Pharmaceutical Raway Pharmacal Scrip Sherry Pharmaceutical Standex Laboratories. Stanlabs C. O. Truxton Ulmer Pharmacal Vita-Fore Products Winsale Drug Wolins Pharmacal Zenith Laboratories The following four companies indicated that they were only distributors of digoxin tablets manufactured by another company and, therefore, could not provide any bioavailability information: Distributor Manufacturer Consolidated Midland ICN Pharmaceutical H. R. Cenci Laboratories Zenith Laboratories Barr Laboratories H. C. Moore Drug Exchange Zenith Laboratories Robinson Laboratories Zenith Laboratories
Table 1. dose
The follOWing three companies indicated that they no longer distribute or manufacture digoxin tablets: Parke-Davis Stayner Vitarine The following four companies indicated that their products meet compendial requirements including the dissolution test: Geneva Generics Lederle Laboratories Towne Paulsen West-ward
Companies Providing Bioavailability Information Burroughs WeI/come-As the innovator of digoxin, Burroughs Wellcome indicated that it has maintained continued support of digoxin bioavailability studies. Following the initial work of Lindenbaum et al. in 1971,5 which raised the issue of bioavailability with oral digoxin, this company sponsored the studies that correlated in vitro dissolution rates with in vivo bioavailability values. 14 Burroughs Wellcome digoxin is the standard for the comparative bioavailability studies recommended by FDA, and nearly all digoxin bioavailability studies have included a Burroughs Wellcome product. Since publication of the original digoxin monograph, Burroughs Wellcome has supported digoxin availability investigations that resulted in at least seven publications. 41 - 43 These studies evaluated the bioavailability of Burroughs Wellcome digoxin in more than 70 subjects and provided absolute bioavailability data, i.e., efficiency of oral absorption relative to intravenous administration of an identical dose of drug. Based on absolute bioavailability figures from various studies 3,41- 44 using Burroughs Wellcome tablets and elixir, Burroughs Wellcome estimates the average absolute bioavailability of Burroughs Wellcome tablets at 67.7 percent and the average absolute bioavailability of Burroughs Wellcome elixir at 77.2 percent. Philips Roxane-Philips Roxane Laboratories provided bioavailability information on its 0.25 mg digoxin tablets compared to the FDA reference products, an aqueous solution and Burroughs Wellcome tablets, according to the recommendations in the Federal Register. The study involved a seven-way cross-
Mean values of three digoxin preparations using 12 subjects and 0.5 mg
Preparation
Average Area Under Curve a , ng Xhour/ml 0-5 hours 0-72 hours
5. 15 4.22 6.29 5.25
Digoxin 0.25 mg (Philips Roxane) Digoxin 0.25 mg (Burroughs Wellcome) Digoxin solution Mean area of two reference products a Calculated using the trapezoidal rule. b
Standard deviation.
637
(0.80) (2.12) (1.05) (1 .36)
b
17.9 (5.55) 16. 1 (8.73) 27.8 (15.3)
b
Digoxin
over using 12 normal volunteers. Although the total study involved a seven-way crossover, only the following three digoxin products were discussed: 0.25 mg digoxin tablets (Philips Roxane lot 716 1B3); 0.25 mg digoxin tablets (Burroughs Wellcome lot 02251) and 0.5 mg/200 ml digoxin aqueous solution. The tablets were certified to be USP quality. Tables 1-3 summarize the important bioavailability parameters for these three products. The Philips Roxane report indicated that the data presented demonstrate that its tablet meets the Federal Register requirements for bioavailability. The Philips Roxane report also notes that statistical analysis revealed that peak heights, peak times and areas under the curve for the test and reference tablets were not significantly different, but that the test tablet showed significantly higher serum digoxin levels at 30, 45 and 60 minutes and that the reference tablet had a significantly higher serum level at 300 minutes. In spite of the fact that the Philips Roxane report states that the peak heights and times show no significant differences between the two tablets tested (and, by implication, no significant differences in absorption rates) , it is likely that more appropriate statistical analyses might have proved that the differences expressed in Tables 2 and 3 demonstrate the Philips Roxane tablets to be considerably more rapidly ab-
References 1. Doherty, J. E, Perkins, W. H. , and Mitchell, G. K., Arch. Int. Med. 108: 531, 1961 . 2. Wagner, J. G., Christensen, M., Sakmar, E., Blair, D., Yates, J. D., Wallis, P. W., Sedman, A. J., and Stoll, R. G., J. Am. Med. Assoc. 224: 199, 1973. 3. Marcus, F. I., Dickenson, J., Pippen, S., Stafford, M., and Bressler, R., Clin. Pharmacol. Ther. 20: 253 , 1976. 4. Wagner, J. G., Am. Heart J. 88: 133, 1974. 5. Lindenbaum, J. , Mellow, M. H., Blackstone, M. 0., and Butler, U. P., N. Engl. J. Med. 285: 1344, 1971. 6. White, R. J., Chamberlain, D. A., Howard, M., and Smith, T. W., Br. Med. J. 1: 380, 1971. 7. Lukas, D. S., and DeMartino, A. G. , J. Clin. Invest. 48: 1041, 1969. 8. The pharmacological basis of therapeutics, 4th ed., Goodman, L. S., and Gilman, A., editors, The Macmillan Co., New York, New York, 1970, p. 677. 9. Jelliffe, R. W., Ann. Int. Med. 69: 703, 1968. 10. Stoll, R. G., and Wagner, J. G., Clin. Pharmacol. Ther. 17: 117, 1975. 11. St. George, S., Friedman, M., and Ishida, T., J. Clin. Invest. 37: 836, 1958. 12. Doherty, J. E, and Perkins, W. H., Am. Heart J. 63: 528, 1962. 13. Greenblatt, D. S., Duhme, D. W., Koch-Weser, J., and Smith, T. W., Clin. Res. 22: 318A, 1974. 14. Lindenbaum, J., Butler, V. P. , Murphy, J. E, and Cresswell, R. M., Lancet 1: 1215, 1973. 15. Harter, J. G., Skelly, J. P. , and Steers, A. W., Circulation 49: 395, 1974.
Table 2. Mean peak heights of three digoxin preparations using 12 subjects and 0.5 mg dose Preparation Digoxin 0.25 mg (Philips Roxane) Digoxin 0.25 mg (Burroughs Wellcome) Digoxin solution
Peak Height, ng/ml 2.62 (0.87)
a
1.89 (1.16) 3.39 (0.85)
Table 3. Mean peak times of the three digoxin preparations using 12 subjects and 0.5 mg dose Preparation Digoxin 0.25 mg (Philips Roxane) Digoxin 0.25 mg (Burroughs Wellcome) Digoxin solution
Peak Time, minutes 65 (29)
a
94 (77) 41 (9)
a Standard deviation.
a
sorbed than the Burroughs Wellcome tablets. This is especially likely in view of the fact that th.e statistical analysis reported by Philips Roxane apparently involved data from only three treatments even though the total study involved a seven-way crossover.
Monograph Col/aboratorsDaniel L. Azarnoff, MD, Distinguished Professor of Medicine and Pharmacology, University of Kansas College of Health Sciences, Kansas City, Missouri
This monograph contains information received as of May 31, 1977. Monograph AuthorJohn L. Colaizzi, PhD, Professor of Pharmaceutics and Chairman of the Department, University of Pittsburgh School of Pharmacy, Pittsburgh, Pennsylvania
16. Klink, P. R., Poust, R. I. , Colaizzi, J. L. , and McDonald, R. H., J. Pharm. Sci. 63: 1231, 1974. 17. Ylitalo, P. , Wilen, G., and Lundell, S, J. Pharm. Sci 64: 1264, 1975. 18. Stoll, R. G. , Christensen, M. S., Sakmar, E , and Wagner, J. G., Res. Commun. Chem. Pathol. Pharmacal. 4: 503, 1972. 19. Wagner, J. G., Hallmark, M. R., Sakmar, E., and Ayres, J. W., Steroids, (June) 1977 (in press) . 20. Vitti, T. G., Banes, D., and Byers, T. E, N. Engl. J. Med. 281: 1433, 1971 . 21. Wagner, J. G., and Ayres, J. W., J. Pharmacokinet. Biopharm., 1977 (in press) . 22. Huffman, D. H., and Azarnoff, D. L., J. Am. Med. Assoc. 22: 957, 1972. 23. Huffman, D. H., Manion, C. V., and Azarnoff, D. L., Clin. Pharmacol. Ther. 16: 310, 1974. 24. Greenblatt, D. J., Duhme, D. W. , Koch-Weser, J. , and Smith, T. W., Clin. Pharmacol. Ther. 15: 519, 1974. 25. Harner, J., and Grahame-Smith, D. G., Lancet 2: 325, 1972. 26. Whiting , B. , Rodger, J. C., and Sumner, D. J., Lancet 2: 922, 1972. 27. Steiness, E , Christensen, V., and Johansen, H. , Clin. Pharmacal. Ther. 14: 949, 1973. 28. Fraser, E J., Leach, R. H., Poston, J. W., Bold , A. M., Culank, L. S., and Lipede, A. B. , J. Pharm. Pharmacol. 25: 968, 1973. 29. Hibble, A. G., Isaac, P. , and Grahame-Smith, D. G., Lancet 2: 90, 1972. 30. Fleckenstein, L., Kroening , B., and Weintraub, M , Clin. Pharmacol. Ther. 16: 435, 1974. 31 . Fed. Reg. 39: 2471 (Jan. 22 ) 1974 .
638
Standard deviation.
Lewis B. Sheiner, MD, Assistant Professor of Laboratory Medicine and of Medicine, Department of Clinical Pathology and Laboratory Medicine, University of California, San Francisco, California John G. Wagner, PhD, Professor of Pharmacy and Staff Member, Upjohn Center for Clinical Pharmacology, The University of Michigan, Ann Arbor, Michigan
32. Doherty, J. E , Perkins, W. H., and Flanigan, W. D., Ann. Int. Med. 66: 116, 1967. 33. Jusko, W. J., and Weintraub, M., Clin. Pharmacol. Ther. 16: 449, 1974. 34. Ingelfinger, J. A. , and Goldman, P., N. Engl. J. Med. 294: 867, 1976. 35. Smith, T. W. , Butler, V. P. , and Haber, E., N. Engl. J. Med. 281: 1212, 1969. 36. Marcus, F. I. , Burkhalter, L. , Cuccia, C. , and Kapadia , G. G., Circulation 34: 865 , 1966. 37. Chamberlain, D., Redors, A. , Bertler, A. , Coltart, J., and White, R., Lancet 2: 934, 1971. 38. Danon, A. , Horowitz, J., Ben-lvi, z. , Kaplanski , J. , and Glick, S., Clin. Pharmacol. Ther. 21: 643, 1977. 39 . FDA Drug Bull. 6: 31 , 1966. 40. Till, A. E., Benet, L. l ., and Kwan , K. C., J. Pharmacokinet. Biopharm. 2: 525, 1974. 41 . Greenblatt, D. J., Duhme, D. W., Koch-Weser, J., and Smith, T. W., J. Am. Med. Assoc. 229: 1774, 1974. 42. Huffman, D. H., Manion, C. V., and Azarnoff, D. L. , J. Pharm. Sci. 64: 433, 1975. 43. Mallis, G. I. , Schmidt. D. H., and Lindenbaum, J. Clin. Pharmacol. Ther. 18: 761 , 1975. 44. Greenblatt, D. J., Duhme, D. W., Koch-Weser, J., and Smith, T. W., Conn. Med. 38.' 230, 1974.
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