Studies on the bioavailability of digoxin

The characteristics of the chemical compounds known as the cardiac glycosides are reviewed, with particular reference to the digitalis group. The clinical use of digitalis is outlined from its origins in folk medicine to the present day. It is pointed out that digitalis is in common use in the treatment of heart disease but the ratio is small between the dosage which produces the desired clinical effect and that which causes toxicity. The pharmacokinetics of the most commonly used cardiac glycoside, digoxin, are summarised. Digoxin was one of the first preparations formulated with the use of the mass-production tabletting process and the features of this type of formulation are described. The concepts of bioavailability of drug formulations and its methods of measurement are discussed and the progress of awareness of its clinical relevance is reviewed. A description is given of how difficulty in achieving full digitalisation in a patient suffering from paroxysms of atrial fibrillation led to the realisation that absorption of digoxin in that patient was impaired. Changing the brand of digoxin tablet used by this patient to Lanoxin gave more rapid absorption and higher steady state plasma digoxin concentrations. When the patients' original tablets were ground to a fine powder and administered within a capsule there were further increases in absorption rate and steady state concentrations. Similar results were found in a second patient. However, in a further group of 5 patients with low plasma digoxin concentrations or inadequate control of atrial fibrillation no significant rise in plasma digoxin concentrations were seen after changing to Lanoxin. The plasma digoxin concentrations in a survey of out-patients using Lanoxin and a variety of other brands were lower than those reported a few years earlier in similar patients on equivalent digoxin doses. An explanation of those findings was not apparent until the Burroughs Wellcome Company, manufacturers of Lanoxin, revealed that modications in the production process of Lanoxin were thought to have pronounced effects on bioavailability. In 1972 they announced that a change in production technique a few weeks earlier had doubled the bioavailability of Lanoxin. It became known that an earlier change in 1969 had probably halved Lanoxin bioavailability. The results in the out-patients' survey supported this view of the effect of the 1969 change and suggested that major differences in bioavailability again existed between Lanoxin and many other brands of digoxin tablet. A comparison of 'newer Lanoxin' made since the most recent production change and 'older Lanoxin' manufactured just before this change confirmed that newer Lanoxin gave higher steady state plasma digoxin concentrations and absorption was more rapid. The mean increase in bioavailability was 70%, but individual patients showed marked variation in their response to a change in formulation, with some showing several-fold increases in digoxin concentration. Newer Lanoxin had a much faster in vitro dissolution rate than older Lanoxin, although both had disintegration rates within the limits stipulated by the British Pharmacopoeia. Measurement of the dissolution rate of 15 other brands of digoxin tablet marketed in the United Kingdom showed a wide distribution of values. A trial to compare the bioavailability and clinical efficacy of 7 digoxin brands was carried out in 2 groups of cardiac patients, using steady state plasma digoxin concentration as the measure of bioavailability. This confirmed the difference between older and newer Lanoxin and showed that the bioavailability of the other brands ranged from a bioavailability similar to older Lanoxin to a bioavailability almost equal to the newer Lanoxin, The differences in plasma digoxin concentration were associated with significant differences in the ventricular rate of those patients who had atrial fibrillation. There was a close correlation between bioavailability of these brands and in vitro dissolution rate: there was a correlation coefficient of 0.88 between mean steady state plasma digoxin concentration and the percentage of the dose in solution at 30 minutes. The profile of the relationship between dissolution rate and bioavailability suggested that there might be an upper limit of dissolution rate beyond which no further increase in digoxin absorption would occur. A study was made of newer Lanoxin and 4 formulations designed to provide very rapid in vitro dissolution. Absorption curves showed that these formulations were all rapidly absorbed