Pharmacokinetics and Bioavailability of Digoxin Capsules, Solution and Tablets After Single and Multiple Doses BRIAN L. LLOYD, MB, MRACP DAVID J. GREENBLATT, MD MARCIA D. ALLEN, RN JEROLD S. HARMATZ THOMAS W. SMITH, MD, FACC zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA Boston, Massac huse tts From the Clinical Pharmacology Unit, fdassa- dwsettsQeneralHcepttal;andthecerdiovascular Dlvlsion, Deparhwnt of Medicine, Peter Sent Brigham Hospital, Boston, Massachusetts. This study was supported in pert by a grant from Anlw-staw kborawm, MouIt Pmspect, lllinols and by @ants l-H.-18003 (to Dr. Smith) and MK 12279 (to Dr. Qreenblatt and Mr. Harmatz) from the fMofnil Institutt3s of Heafth, Betfwsda, Mwyland.Dr.Lbydwasa Resew& Fellow of ths N&bd IWrt Found&n of Austmfla. Manuswipt rece&ed Novembw 30,1977; revised manuscript received January 30,1978. accepted February 1, 1978. Address for reprints: David J. Greenblatt. MD, Clinical Pharmacology Unit, Massachusetts General Hospital, Boston, Massachusetts 02114. The bioavailability of single doses of dtgoxln capsules (0.4 mg), dlgoxin sokrtlon (0.4 mg) and reference tabtets (0.5 mg) was compared wtth that of single intravenous doses (0.4 mg) of digoxin using measurement of 24 hour urinary excretion and area under the plasma concentration curve. The absolute systemic availabtltty of all three oral preparations was sig- ntficantly less than 100 percent. The bioavallabtltty of capsules and so- lution was nearly ldentlcal(79 percent and 76 percent, respectively, as assessed with values for area under the concentration curve and 65 percent and 62 percent as m with urtnary excretion values); both forms had greater systemic avallabtltty than the tablet, which had bio- availabt5ty vakres of 50 percent ustng area under the curve and 41 percent using urinary excretion. Capsules and solution also were similar In peak plasma dtgoxin levels achieved (3.7 and 3.1 ng/ml), time of peak con- centratlon (0.8 and 0.6 hour after dosage) and apparent first order ab- sorption half-life (11.3 and 10.2 minutes); both capsules and solutlon differed stgntflcantly from tablets (peak level 1.6 ng/ml, time of peak concenkatkx~ 1.2 hours and absorptkn half-5fe 27.1 mtnutes). Single dose findlngs were substantiated when steady state plasma levels and 24 hour urinary excretion values were measured from days 11 through 16 of the period of once daily ingestion. Mean plasma levels (0.70 ng/ml) and url- nary excretion values (45.1 percent of dose) for capsules were nearly identical to those for solution (0.6s ng/ml and 42.5 percent of the dose), and values for both capsules and solution were signlftcantly greater than those for tablets. Withtn- and between-subject variation in bioavailablllty was similar for the three oral preparations. Thus the single dose bio- availability study was predictive of the steady state findings. The bto- availability of digoxin capsules is equivalent to that of a solution and significantly greater than that of a reference tablet formulation. Achievement of stable and predictable plasma digoxin concentrations during long-term digoxin therapy remains difficult because all currently available oral digoxin preparations are incompletely and variably ab- sorbed from the gastrointestinal tract.’ An optimal fixed dose oral di- goxin preparation would have a predictable high level of bioavailability with minimal variation in the extent of absorption within and between subjects. Gelatin capsules containing digoxin in solution reportedly have improved bioavailability and may be a potential replacement for digoxin tablets.28 However, the extent of improved bioavailability of capsules and the issue of whether steady state plasma digoxin levels are less variable than with existing standard preparations have not been settled by previous studies. We investigated the extent and variability of digoxin absorption from the capsule preparation after single and multiple doses in comparison with those of standard reference tablets and solution. July 1978 The Amerfcan Journal of CARDfOLOGV Volume 42 129