PHARMACOKINETICS-THERAPEUTICS Chn. Pharmacoklnet 28 (6)' 483-493, 1995 0312-5963/95/0006-0483/$05.50/0

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Pharmacokinetic Aspects of Digoxin-Specific Fab Therapy in the Management of Digitalis Toxicity Michael R. Ujhelyil and Sylvie Robert2

1 University of Georgia College of Pharmacy and Medical College of Georgia School of Medicine, Augusta, Georgia, USA

2 Ecole de Pharmacie, Universite Laval, Quebec, Canada

Contents Summary , , , , , , , , , , , , , , , , , , , , . . . . . . 1. Pharmacokinetics of Digoxin-Specific Fab . . . . . . . .

1.1 Pharmacokinetics in Patients with Digoxin Toxicity . 1.2 Pharmacokinetics in Patients with Renal Disease. .

2. Pharmacokinetics of Digoxin During Fab Therapy . . . , 3, Methods of Measuring Digoxin Concentrations During Fab Therapy

3.1 Total Digoxin Concentrations . , , , " , ...... . .... . 3.2 Free Digoxin Concentrations . , ..... . .... .

4. Therapeutic Drug Monitoring of Digoxin Following Administration of Fab 4,1 The Need for Monitoring . . 4.2 Assessing Rebound Toxicity , , " " "" . 4.3 Assessing Fab Dosage ...... . ..... . 4.4 Assessing the Need for Reintroduction of Digoxin 4.5 Assessing the Need for Supplemental Fab

5. Conclusions ...... , . ..... . . ... . . ..

483 485 485 486 488 489 489 489 490 490 490 491 491 491 492

Summary Digoxin intoxication occurs frequently and may require treatment with dig­oxin-specific Fab therapy. Little is known, however, regarding the biological fate of this compound. Pharmacokinetic studies have not been performed in healthy volunteers, but there are limited kinetic data from patients who have received therapy for the treatment of digoxin toxicity. Digoxin-specific Fab is eliminated via renal and nonrenal routes, having a volume of distribution slightly exceeding extracellular volume (0040 Llkg) and an elimination half-life of 16 to 20 hours. Patients with renal impairment and end-stage renal disease have elimination half-life values that are prolonged up to lO-fold in magnitude, while volume of distribution is unaffected. Systemic clearance of digoxin-specific Fab is approx­imately 0.32 ml/min/kg in digoxin-toxic patients with preserved renal function. Renal failure also decreases Fab clearance by up to 75%. Therefore, Fab may reside in the serum of anephric patients for 2 to 3 weeks after administration.

More important is the effect of Fab on the disposition of digoxin. Because digoxin-specific Fab has a stronger digoxin-binding affinity than do biological

484 Ujhelyi & Robert

membranes, it can sequester tissue-bound and intracellular digoxin into the ex­tracellular spaces. This results in a rapid increase in digoxin serum concentrations in the central compartment. Since the majority of digoxin is bound by Fab, it cannot interact with its biological receptor and thus reverses digoxin toxicity.

The pharmacokinetic fate of total digoxin after administration of digoxin-spe­cific Fab follows that of Fab. However, it appears that the elimination half-life of Fab is slightly shorter than that of total digoxin in patients with end-stage renal disease, suggesting that the clearance of Fab is slightly faster than that of total digoxin. Free digoxin concentrations fall rapidly after Fab administration and then rebound upwards within 12 to 24 hours. This rebound in free digoxin con­centrations, however, is delayed by 12 to 130 hours in patients with renal dys­function and end-stage renal disease. Rebound in free digoxin concentrations occurs during the initial phase of the biexponential decline of the serum concen­tration-time profile for digoxin-specific Fab, suggesting that distribution from the vascular spaces is the likely cause. Following the increase, free digoxin con­centrations decline in a manner that is dependent on renal and nonrenal routes of elimination. During this time period it is evident that Fab retains its capability of binding digoxin while it resides in plasma.

There is no evidence to support a dissociation between the Fab-digoxin com­plex over extended periods of time. This was demonstrated in a report where the free fraction of digoxin, in the presence of Fab remained less than the free fraction in the absence of Fab. Recent evidence also supports the role of monitoring free digoxin concentrations in certain patients who received digoxin-specific Fab ther­apy as they are more predictive of the pharmacological activity of digoxin than either total or bound digoxin concentrations. Indeed, free digoxin concentrations correlate with recurrences of digoxin toxicity, the need for supplemental Fab doses, and the efficacy of digoxin therapy initiated during Fab therapy.

Digitalis compounds have a narrow therapeutic range, and continue to be the mainstay of therapy for congestive heart failure and ventricular rate control in patients with atrial fibrillation. There­fore, it is not surprising that digoxin intoxication continues to occur frequently. Probable or con­firmed digoxin toxicity has been reported to occur in 0.9 to 4.6% of patients with congestive heart failure receiving digoxin therapy.[l ·2] Fortunately, the majority of these cases can be managed using supportive care and cessation of digoxin therapy)3] More severe cases, however, may require the ad­ministration of digoxin-specific Fab antibodies (referred to from now on as Fab) as an antidote.

oxin intoxication.[4] Furthermore, Fab became commercially available in the absence of studies describing its pharmacokinetic disposition. Thus, this drug was used by many clinicians without hav­ing knowledge about what dosage to give to pa­tients with liver and/or kidney disease, since the proportion of Fab excreted via renal and nonrenal pathways was unknown. Without data describing the disposition of digoxin following Fab adminis­tration, it has also been questioned whether Fab loses its biological activity in vivo, leading to a reduction over time in the ability of Fab to bind digoxin, and subsequent reintoxication.

Because of this limited information, the man­agement of patients after receiving Fab is an enigma for most clinicians. For example, if toxicity continues or recurs within hours or days after Fab administration, the clinician cannot be certain if

Fab is one of the few drugs that have entered the US market without being studied in a randomised placebo-controlled trial. Fab was approved after ef­ficacy was documented in 63 cases of severe dig-

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Digoxin-Specific Fab Therapy

this is due to: (i) a low neutralising dose of Fab; (ii) faster elimination ofFab than digoxin; or (iii) fac­tors other than digoxin contributing to the patho­logical disturbance. Understanding the pharmaco­kinetics of Fab and its effects on the disposition of digoxin could aid clinicians in their evaluation of the patient. This information may lead clinicians to employ a simple method of measuring free digoxin concentrations, which could ultimately solve the above issues. The objective of this article is to re­view the literature on the pharmacokinetics of Fab and digoxin during Fab therapy in healthy patients and those with compromised renal function, and to describe the quantitative methods, indications and interpretation of total and free digoxin plasma con­centrations during Fab therapy.

1. Pharmacokinetics of Digoxin-Specific Fob

The following section describes the disposition of digoxin-specific immune Fab antibodies. When administered to patients, Fab exists in 2 forms: (i) free of digoxin; or (ii) bound to digoxin. However, in this review we are interested in the disposition of this molecule irrespective of whether or not dig­oxin is bound to Fab. Therefore, we refer to Fab as being digoxin-specific immune Fab molecules without regard to their state of digoxin binding.

Because of concern with serum sickness, there has never been a study to assess the pharmacoki­netic disposition ofFab in healthy volunteers. Data from baboons and dogs indicate that Fab has a larger volume of distribution than its parent IgG molecule, and is renally eliminated via glomerular filtration with an elimination half-life of 5 to 12 hours.[5,6] The plasma concentration-time profile of Fab is biexponential, fitting a classic 2-compart­ment pharmacokinetic model (fig. 1).

1.1 Pharmacokinetics in Patients with Digoxin Toxicity

Pharmacokinetic analysis has been performed in a few patients with digoxin toxicity (n = 6) who participated in a multicentre nonblinded study that used a Fab product manufactured by Burroughs

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c: o

~ C Q) () c: o

<..)

100

10

0.1

• Total digoxin concentrations (1l9/L)

A Free digoxin concentrations (1l9/L)

D Digoxin-specific immune Fab

concentrations (mg/L)

485

0.01 -j,I ..... ,,----,--,----,---,----,---,

o 50 100 150 200 250 300 350

Time (h)

Fig. 1. A representative concentration-time profile of total dig­oxin-specific Fab, total digoxin and free digoxin in a 75-year-old patient with renal insufficiency [serum creatinine of 3091lmol/L (3.5 mg/dl)] who received 120mg of Fab.

Wellcome (,Digibind')J4] In these cases, Fab dis­position was incompletely characterised, and elim­ination half-life values were reported (see table I). In another series of patients with digoxin toxicity with normal renal function (n = 7), the pharmaco­kinetics of Fab were characterised using a product manufactured by Boehringer Mannheim.[7] How­ever, these investigators did not directly measure serum and urinary Fab concentrations, but esti­mated Fab concentrations by using the sum of the estimated digoxin-bound Fab concentrations (bound digoxin concentration x digoxin-binding capacity of Fab), and estimated free Fab concentrations (de­termined by adding 3H-digoxin to serum samples and dialysing the sample). Since the binding capac­ity of Fab is variable because of its poly clonal an­tibody nature, the validity of these pharmacoki­netic values must be questioned. This was evident when negative values of Fab renal clearance were reported in 2 patients.[7] Nevertheless, this study is the most comprehensive analysis of Fab pharma­cokinetics in both healthy and renally impaired in-

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486 Ujhelyi & Robert

Table I. Pharmacokinetic parameters of Fab

Fab source No. of CLCR 11" Vd CLR CLNR CL patients (ml/min) (hours) Ukg (ml/min/kg) (ml/min/kg) (ml/min/kg)

Normal renal function BW(4) 6 NR 16-20 NR NR NR NR BM(7) 7 103±62 14±5.5 0.43 ± 0.12a 0.216±0.10 0.108±0.15 0.324±0.10

Impaired renal function BM(7) 4 38± 16 9.3 ± 3.7 0.36 ± 0.12a 0.14 ±0.07 0.24 ±0.02 0.389 ± 0.11 BW(8) 27 72.5 0.56a NR NR 0.09 BWlg) 19 137 0.33b NR NR 0.089 BW(10) 32 96 0.19b NR NR 0.39

End-stage renal disease BM(11) 1 HD 53 NR 0 0.072 0.072 BWlg) 4 HD 82±23 0.29±0.11b 0 0.049±0.17 0.049±0.17

a Vd during the termina) phase.

b Vd at steady-state.

Abbreviations: BM = Fab from Boehringer Mannheim; BW = Fab from Burroughs Wellcome; CLCR = estimated creatinine clearance; CLR = renal clearance; CLNR = nonrenal clearance; CL = total body clearance; HD = haemodialysis; NR = not reported; Vd = volume of distribution.

dividuals. Pharmacokinetic data from these reports are summarised in table I.

Overall, the volume of distribution of Fab slightly exceeds that of extracellular fluid (0.25 to 0.40 Llkg). Fab is eliminated by renal and nonrenal routes in a two-thirds to one-third proportion, re­spectively, having a terminal elimination half-life ranging from 14 to 20 hours, and a systemic clear­ance of 0.324 mllmin/kg (0.17 to 0.52 mllmin/kg) [0.02 Llhlkg (0.1 to 0.3 Llh/kg)].l4,7]

1 .2 Pharmacokinetics in Patients with Renal Disease

Less is known about the disposition of Fab in patients with severe renal disease. There is a con­cern regarding the disposition of Fab in patients with renal failure because Fab, in this population, may be cleared from the systemic circulation (via metabolism and/or removal by the reticuloendo­thelial system) faster than digoxin. This could re­sult in the release of digoxin from Fab and a poten­tial rebound in digoxin toxicity. Several case reports have tried to verify this hypothesis, includ­ing 2 series of patient cases consisting of 4 and 5 patients with digoxin intoxication and poor renal functionp,8]

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Unfortunately, there are several limitations to these reportsp,8l One limitation is the lack of an accurate measure for glomerular filtration rate. Re­nal dysfunction has been classified by an estimated creatinine clearance value calculated from the Cockcroft and Gault equation.[12l Thus, several pa­tients who were reported to have renal dysfunction had normal serum creatinine values [i.e. <132Ilmol/L (1.5 mg/dl)], and were classified in this manner solely on the basis of age. In one series, the data obtained are severely limited by the short sampling period (<100 hours) in 3 of the 4 patients and, therefore, cannot be considered to provide accurate pharmacokinetic analysis.[8] In another trial, the pharmacokinetic data are limited by an indirect an­alytical method as mentioned aboveP] Regardless, data from these reports are useful, even if the in­formation they provide is limited.

Schaumann et aLl7] were the first to report that renal impairment decreases the renal clearance of Fab by 50% compared with the clearance in pa­tients with normal renal function. However, the re­duction in renal clearance was completely offset by an equally large increase in nonrenal Fab clear­ance. Total systemic Fab clearance and Fab elimi­nation half-life values were, therefore, similar among the patients with and without renal impair-

Ciin. Pharmacokinet. 28 (6) 1995

Digoxin-Specific Fab Therapy

ment. In 2 other case reports [estimated creatinine clearances of 19 and 27 rnl/min (1.14 and 1.62 Llh)], Fab elimination half-life was 3-fold longer and the systemic clearance was 75% lower than in patients with normal renal functionJ8 ,9] In a third case report, only the elimination half-life was doc­umented to be longer in patients with renal im­pairment than that reported in patients with normal renal function, while systemic clearances were re­ported to be similar in both populations.[lO]

Thus, reports by Schaumann et al.[7] and Sin­clair et aUIO] showed that the systemic clearance values of Fab resemble those reported in patients with normal renal function, while reports from Allen et aU8] and Ujhelyi et aP9] documented systemic Fab clearance values to be 75% lower than those reported in patients with normal renal function. Because these small reports involve limited blood sampling (in some cases), use different assay meth­odologies and do not adequately quantify renal function, it is difficult to explain these disparate results. Regardless, these data reveal that renal dysfunction does affect the disposition of Fab by decreasing renal clearance by 50%, decreasing sys­temic clearance up to 75% and increasing elimina­tion half-life by up to lO-foldP-IO]

Volume of distribution of Fab, however, is un­affected by renal dysfunction. The average termi­nal phase volume of distribution (V z) is 0.43 L/kg (0.21 to 0.80 Llkg) in patients with normal renal function, which is similar to the values reported in patients with renal dysfunction.[7] These values are higher than the volume of distribution at steady­state (V ss) in patients with renal disease.[7,8] It is known, however, that V z commonly overpredicts the more appropriate volume of distribution term, V ss . Thus, it appears that moderate and severe renal impairment have no effect on the volume of distri­bution of Fab.

7.2.7 Patients Undergoing Haemofiltration The pharmacokinetic disposition of Fab in pa­

tients undergoing haemofiltration has been inves­tigated in only 5 patients.[9,1l] It is known that Fab is not removed from the systemic circulation by haemodialysis or continuous arteriovenous haemo-

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487

filtration .[13,14] Thus, the data from the 2 reports listed in table I reflect the intrinsic elimination of Fab rather than extracorporeal removal. The sys­temic clearance of Fab in these anephric patients (0.026 to 0.072 mllminlkg) was 4-fold lower than that reported in patients with serum creatinine val­ues less than 133 IlmollL (1.5 mg/dl) and appar­ently normal renal function (mean 0.324 rnlIminlkg; range 0.17 to 0.52 mllmin/kg) [mean 0.02 Llh/kg; range 0.01 to 0.03 Llh/kg]P,9,1l] As expected, these values were also lower than those reported for the patients with renal impairment,l7-11] Be­cause the study patients were anephric, the sys­temic clearance of Fab should be representative of nonrenal routes of elimination, It has been shown by other investigators that Fab is eliminated through nonrenal routes and metabolised by many tissues.[7 ,IS]

As mentioned, Fab cannot be removed from the systemic circulation or extracellular spaces by haemodialysis or continuous arteriovenous haemofiltrationJ13,14] This is probably due to its large molecular size (50 OOOD) which prevents its movement across filter membranes. It is also well established that these dialytic therapies cannot re­move large quantities of digoxin from the body, since the majority of digoxin is distributed into tis­sues. However, it has been shown, in a patient with end-stage renal disease, that plasmapheresis is effective in removing both Fab and the digoxin­bound Fab complexJ13] During a 70-minute treat­ment, Fab serum concentrations dropped by 50% and remained lower than pretreatment values until the next 70-minute plasmapheresis treatment, which also caused a 50% reduction in Fab serum concentrations.[1 3] Based on these findings, the au­thors recommend this procedure for the rapid re­moval of Fab and digoxin in digitalis-intoxicated patients who are anephric. [1 3] However, since there are rarely complications resulting from having Fab and digoxin-Fab complex present in the systemic circulation for prolonged time periods, there is lit­tle rationale to recommend this procedure in all anephric patients receiving Fab therapyJ9]

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488

1.2.2 Nonrenal Elimination In patients with estimated creatinine clearances

of greater than 65 mllmin (3.9 Llh), approximately 30 to 50% of Fab appears to be eliminated from the systemic circulation through nonrenal routes [0.11 ml/min/kg (0.007 Llh/kg)].l71 The nonrenal or sys­temic clearance of Fab [0.05 ml/min/kg (0.003 Llhlkg)] in anephric patients, however, is approxi­mately 50% lower than the reported nonrenal clear­ance of Fab in patients with normal renal func­tion.£7,9,1l1 It is well established that renal disease can significantly decrease the nonrenal clearance of many drugs.£16] This may also be the case for Fab, although it appears that nonrenal clearance of Fab in patients with mild to moderate renal impair­ment increases to compensate for a decrease in re­nal clearance of Fab.£7] It is possible that the sever­ity of illness in anephric patients may playa role in regulating the nonrenal clearance of Fab, or that the renal clearance values in otherwise healthy patients and those with renal impairment are spurious as a result of the indirect analytical methods used.

In any case, end-stage renal disease will se­verely hinder the elimination of Fab, allowing the drug to remain at molar concentrations, which are still capable of binding digoxin, in the patient's se­rum for weeks. [9] This can significantly complicate patient assessment, making it difficult to decide when the patient can be safely sent home. Further­more, it complicates decisions on how and when to recommence digoxin therapy.

2. Pharmacokinetics of Digoxin During Fab Therapy

Fab reverses digoxin intoxication by altering the pharmacokinetic disposition of the drug. Using an­tigen-antibody principles, Fab has a digoxin-bind­ing affinity of 10-9, which is significantly greater than that of biological membranes, e.g. the Na/K­ATPase pump.[I7-191 These properties give Fab the capability of not only binding digoxin within the extracellular spaces to which Fab is confined, but they also enable Fab to pull digoxin away from its biological binding sites via a concentration gradi­ent of unbound digoxin between the intracellular

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Ujhelyi & Robert

and extracellular spaces.[20-22] Therefore, within minutes of Fab administration there is a 10- to 30-fold increase in the total (bound and free) serum digoxin concentrations as Fab causes a digoxin gra­dient from peripheral tissues into the circulation (fig. 1).[4,7-13,20,23-30] At the same time, there is a

rapid decrease in the free fraction of digoxin in plasma from between 75 and 90% to between 0 and 5%.£4,7-13,20,23-30] Because the majority oftotal dig-

oxin remains bound to Fab, the elimination of total digoxin becomes dependent on the disposition of Fab.[4,7-13,23 ,24] Thus, total digoxin also has a bi­exponential concentration-time profile. The initial phase is representative of free and Fab-bound dig­oxin distributing out of vascular spaces during con­current plasma elimination (fig. 1). The second phase is representative of terminal plasma elimina­tion of total digoxin, which has an elimination half­life ranging between 16 and 30 hours in patients with normal renal function.£7,24]

The elimination half-life of total digoxin in pa­tients with end-stage renal disease ranges from 46 to 330 hours.[9,1\,25,30,311 Furthermore, patients with varying degrees of renal function showed similar elimination half-lives for total digoxin and Fab ranging from 10 to 102 and from 14 to 136 hours, respectively.[8-13,26] The elimination half-life val­ues for total digoxin, however, have been reported to be slightly longer than those for Fab in an aneph­ric population, suggesting that the nonrenal elimi­nation of Fab is slightly faster than digoxin in these patients.[91 Nevertheless, the slightly faster elimi­nation of Fab compared with that of total digoxin has not been shown to significantly affect the dis­position of free digoxin or result in renewed intox­ication due to digoxin.

Fab retains its capability to bind digoxin over the entire period of time it resides in plasma, with no evidence to support that there is dissociation be­tween the Fab-digoxin complex over time.[9] This was demonstrated in a report where the free frac­tion of digoxin in the presence ofFab remained less than 75 to 90% (i.e. the free fraction of digoxin in the absence of Fab).[9,301

Clin. Pharmacokinet. 28 (6) 1995

Digoxin-Specific Fab Therapy

Free digoxin concentrations, on the other hand, fall rapidly after administration of Fab and then increase over time. The rebound increase in free digoxin concentrations peaks approximately 3 to 24 hours after Fab administration in patients with normal renal function and then declines again, but at a slow rate dependent on Fab elimination and renal and nonrenal routes of elimination)4.3o.32] Renal dysfunction delays this peak in free digoxin concentrations by approximately 24 to 96 hours. In anephric patients, the rebound or peak in free dig­oxin concentrations occurs on average 130 hours after Fab administration)8.9,30] The magnitude by which free digoxin concentrations rebound, how­ever, is unaffected by renal function)30]

It appears that when Fab distributes from plasma to extracellular spaces [evident by a 3-fold difference between the volume of distribution of the central compartment (Ve) and Vss], free dig­oxin concentrations increase or rebound upwards (fig. 1))9] Free digoxin concentrations will in­crease or rebound when the molar ratio of the total body load of digoxin to Fab increases beyond the binding capacity of Fab (estimated to be unity based on in vitro studies where 1 nmol of Fab binds 1 nmol of digoxin).[l8] At this point, it is difficult to conclude why renal dysfunction alters the time at which free digoxin concentrations rebound to maximum values, but it is known that this occurs during the a-elimination phase for total digoxin and Fab.[9] Thus, it is likely that renal function al­ters the distribution rate of Fab in relationship to that of total digoxin. This may result in higher dig­oxin plasma concentrations compared with Fab concentrations, and thereby liberate digoxin, in­creasing free digoxin plasma concentrations.

3. Methods of Measuring Digoxin Concentrations During Fab Therapy

3.1 Total Digoxin Concentrations

In a setting of digitalis intoxication, laboratory testing can readily identify patients with toxic se­rum digoxin concentrations by conventional meth­ods such as immunoassay. If the symptomatic

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489

overdosed patient is to receive antidotal therapy with Fab fragments, the pretreatment serum dig­oxin concentration is useful in estimating the initial Fab dosage. However, once Fab has been adminis­tered to the patient, conventional methods of mea­suring digoxin concentrations are no longer valid.

The ability of Fab to interfere with immuno­assays has been well established.[20,28,32-35] To in­terpret serum digoxin concentrations properly in a patient who has received Fab, clinicians must ap­preciate the varied effects that Fab will have upon many of the clinically available assays. Assays that are able to accurately measure total digoxin con­centrations, for example, will show at least a 10-fold increase in digoxin serum concentrations after Fab therapy. [4,7-11 ,28] On the other hand, assays that can measure free concentrations will observe the opposite effects. There are only a few validated assay methodologies that can perform each of the above. To accurately measure total digoxin con­centrations, the assay must denature the Fab pro­tein. This will release all bound digoxin from Fab so that it can interact with, and bind to, the assay antibody for analytical quantitation. There are sev­eral ways by which Fab can be denatured, but the only assay system specifically designed to do this is the Abbott TDx (Abbott Laboratories Diagnostic Division, Irving, Texas, USA»)28.33]

3.2 Free Digoxin Concentrations

Free digoxin concentrations can only be measured by first removing Fab and Fab bound to digoxin from the serum before undertaking the analytical procedures. This is accomplished by ultrafiltrating the serum sample and then analysing the digoxin concentrations of the ultrafiltrate. Fluorescence polarisation immunoassay with ultrafiltration (FPIA-UF) is currently the only immunoassay available for clinical use that is proven to reliably measure free digoxin concentrations in patients af­ter Fab therapy.[28,33,36] This reference assay offers a much shorter turnaround time than that of the equilibrium dialysis process, without sacrificing accuracy. [36] Ultrafiltration is performed using a 'centrifree' micropartition system (Amicon Co.,

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490

Danvers, MA, USA), which has a membrane bar­rier cutoff of 30 OOOD. Fab fragments with a mo­lecular weight of 50 OOOD are thus removed by the ultrafiltration process. Potential interference by digoxin-like immunoreactive substances well known to be elevated in several clinical conditions, including renal failure, is also prevented as these endogenous substances are removed by the centrif­ugal ultrafiltration due to their high degree of pro­tein binding.[37]

Clinical testing has been undertaken to evaluate the reliability and accuracy of widely available dig­oxin immunoassays in determining free digoxin concentrations. The results of in vitro studies have suggested that the Baxter Dade Stratus and the en­zyme-mediated immunoassay, in conjunction with an affinity precolumn (Syvia EMIT), are capable of quantitating free digoxin concentrations in the presence of Fab,l18.33,34] However, the in vivo per­formance of these 2 digoxin immunoassays showed significant bias and prediction errors in determin­ing free digoxin concentrations in Fab-treated pa­tients in comparison with the results obtained by the Abbott TDx FPIA-UF.[28] Clinical monitoring of free digoxin concentrations should therefore rely on an analytical method that uses an ultrafiltra­tion process. This assay method is readily available in many clinical laboratories as it is used to quan­titate free concentrations of other substances such as phenytoin and hormones. The costs associated with the 'centrifree' micropartition system (ap­proximately SUS 1.50 per system) and the addi­tional technician's time required for the centrifuga­tion process are clearly compensated for by the clinical benefits of having reliable free digoxin concentration determinations)37]

4. Therapeutic Drug Monitoring of Digoxin Following Administration of Fab

4.1 The Need for Monitoring

The feasibility of providing reliable and rapidly available determinations offree digoxin concentra­tions may have several applications in clinical practice. It has been suggested that the release of

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Ujhelyi & Robert

active digoxin from the Fab-digoxin complex after tissue distribution may result in recrudescent tox­icity.[13,20,29,31] Therefore, monitoring of free dig­oxin concentrations may be beneficial in patients with renal failure to identify or prevent rebound toxicity.

Presently, the management of patients treated with Fab is guided solely by clinical findings. Be­cause digoxin bound to Fab is pharmacologically inactive, the free digoxin concentrations are more important predictors of pharmacological activity. Monitoring free digoxin in selected digoxin-toxic patients receiving Fab may be warranted to confirm suspected reintoxication, to as~ess the necessity for and amount of supplemental doses of Fab, and to assess the timing of subsequently required digoxin therapy. A recent report has documented these ben­efits of using free digoxin concentrations for the management of digoxin-toxic patients receiving Fab therapy.l30]

4.2 Assessing Rebound Toxicity

The goal of Fab therapy is to inhibit the toxico­logical and/or pharmacological effects of digoxin by preventing digoxin from interacting with its ef­fector site. Fab accomplishes this by binding dig­oxin, thereby decreasing the availability of free digoxin at the effector site. It can be clinically im­portant to monitor free digoxin concentrations in a select group of patients. In most patients, free dig­oxin concentrations fall rapidly following Fab ther­apy, but then rebound upwards. However, the mag­nitude of this rebound rarely exceeds the therapeutic range of digoxin of 1.0 to 1.5 IJ,g/L (1.28 to 1.92 nmol/L) or causes toxicity. [30] Reports have shown that when free digoxin concentrations rebounded beyond 0.8 IJ,g/L (1.02 nmollL), signs and symptoms of digoxin reintoxication recurred in some patients.[IO,30,36] If signs and symptoms of digoxin toxicity develop early after Fab therapy (12 to 72 hours in patients with normal renal func­tion and 0.5 to 14 days in patients with end-stage renal disease), then obtaining a free digoxin con­centration can assess the possibility of the contrib­utory role of digoxin in the clinical symptoms of

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Digoxin-Specific Fab Therapy

tOXICIty and the need for supplemental Fab doses.[29,38] Several reports dealing with Fab re­administration have been published.l29,39-4I] Un­fortunately, free digoxin concentrations were not measured prospectively in these cases. In one re­port, free digoxin concentrations were analysed retrospectively and revealed that supplemental Fab doses were not needed since free digoxin concen­trations were less than 0.1 j..lg/L (0.l3 nmol/L) at the time of the supplemental doses.[29] Further­more, the low free digoxin concentrations pre­dicted the lack of clinical improvement following supplemental Fab doses. One can assume that monitoring free digoxin concentrations values pro­spectively in these patients may have helped to identify nonresponders to Fab therapy and to pre­vent the readministration of this costly antidote.

4.3 Assessing Fab Dosage

Another reason for the absence of a response or a partial response to Fab therapy may be related to an inadequate Fab dosage. The patient's body­weight is often lacking in an acute setting, poten­tially leading to underestimation of the proper dos­age of Fab. Results from one morbidly obese patient, as well as in patients whose actual body­weight was not available during initial assessment, demonstrated that partial response to Fab treatment was mainly related to the inadequacy of the dosage of FabJ29,40] Also, the short supply of Fab frag­ments available at one centre may be another rea­son to administer suboptimal doses of Fab. Moni­toring of free digoxin concentrations in these subsets of patients can contribute to assessment of Fab response and the need to readminister further antidote.

4.4 Assessing the Need for Reintroduction of Digoxin

A complication of Fab therapy is the loss of the therapeutic effect of digoxin. Canine studies have shown that the administration of Fab in digoxin­toxic dogs reversed the inotropic actions of digoxin over a 12- to 36-hour time period.l42] In a series of patients, reversal of the therapeutic effect of dig-

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491

oxin occurred within 24 to 48 hours of administra­tion of Fab in 5 of 14 patients.[29] Four of the 5 patients developed a rapid ventricular response when atrial fibrillation re-established itself as the underlying rhythm 24 to 48 hours following Fab therapy. The other patient developed worsening congestive heart failure symptoms 24 hours fol­lowing Fab therapy. Therefore, after reversal of signs and symptoms of digoxin toxicity, many cli­nicians have to recommence digoxin therapy to control the underlying disease when other pharma­cological options are not acceptable.

Digoxin therapy can be safely administered 48 to 72 hours after Fab administration in patients with normal renal function, and therapy can be monitored using standard clinical immunoassays. In patients with renal dysfunction, Fab may be present in the serum for weeks, making it difficult to reinitiate therapy without monitoring free dig­oxin concentrations. A recent report describes this problem in an anephric patient who received Fab for digoxin-induced third degree heart block.[43] The patient reverted back to atrial fibrillation with a symptomatic rapid ventricular response 24 hours after administration of Fab. Digoxin therapy was subsequently reinitiated, although serum concen­trations for both total digoxin and Fab were ex­tremely high. Free digoxin concentrations at the time of the arrhythmia, however, were well below the therapeutic range. Reinitiation of digoxin ther­apy (0.25mg of intravenous digoxin) in this patient resulted in a large increase in the free concentration of digoxin from 0.6 to 2.54 j..lg/L (0.77 to 3.25 nmol/L) and a therapeutic response was reported. The subsequent concentrations of free digoxin were maintained above 1.0 j..lg/L (1.28 nmol/L) with administration of oral digoxin 0.125mg every other day, which resulted in adequate rhythm con­trol (ventricular rate 60 to 88 beats/minute).

4.5 Assessing the Need for Supplemental Fab

In other cases, monitoring free digoxin concen­trations could circumvent or dictate the adminis­tration of supplemental Fab doses to patients who

Clin. Pharmacokinet. 28 (6) 1995

492

have signs and symptoms of digoxin reintoxication early after the initial dose of FabPO,38] If free dig­oxin concentrations at this time are greater than 1.0 to 1.51 Ilg/L(1.28 to 1.93nmollL),oneshouldcon­sider the possibility of reintoxication and the pos­sible need for administration of more Fab, while low digoxin concentrations will aid the clinician in ruling out digoxin as a cause for the signs and symptoms of apparent toxicity. It should be re­membered, however, that free digoxin concentra­tions reflect 125% of total concentrations with re­gard to generally understood concentration versus effect relationships. This is because the efficacy and toxicity of digoxin is based upon total digoxin concentrations: free concentrations are 20 to 25% lower than total concentrations, since digoxin is 20 to 25% bound to serum proteinsJ44] Furthermore, free digoxin concentration monitoring may reduce hospital stays since there have been cases where attending physicians refuse to discharge patients (who are admitted with a diagnosis of digoxin tox­icity) if they continue to have high and unreliable total digoxin concentrations after Fab therapy.[29]

5. Conclusions

Fab administration significantly alters the dis­position of digoxin. Therefore, monitoring total digoxin concentrations can no longer predict effi­cacy or toxicity. On the other hand, recent evidence suggests that free serum digoxin concentrations are more valuable in predicting the pharmacological activity of digoxin during Fab therapy.

Patients with normal renal function quickly eliminate Fab and digoxin bound to Fab, and rarely require the use of free digoxin concentration mon­itoring. Patients with end-stage renal disease, how­ever, eliminate Fab and digoxin very slowly. These patients have been shown to have recurrences of digoxin toxicity that correlate to a rebound in free serum digoxin concentrations several days after administration ofFab. These patients will also need free digoxin concentration monitoring if digoxin therapy is going to be reinitiated soon after admin­istration of Fab.

© Adis International limited, All rights reserved,

Ujhe/yi & Robert

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Correspondence and reprints; Dr Michael R. Ujhelyi, University of Georgia College of Pharmacy and Medical College of Georgia School of Medicine, Augusta; GA 30912, USA.

Clin. Pharmacokinet. 28 (6) 1995