1 Department of Clinical Pharmacology, University General Hospital of Alicante, Maestro Alonso 109, 03010 Alicante; 2 Department of Internal Medicine, University General Hospital of Alicante, Alicante, Spain
Received 9 January 2002; returned 14 May 2002; revised 1 July 2002; accepted 15 July 2002
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Abstract |
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Keywords: clarithromycin, digoxin, pharmacokinetic interaction, Bayesian
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Introduction |
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Materials and methods |
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Inclusion criteria
Patients older than 65 years treated with a fixed dose of oral digoxin (capsules) for at least 2 weeks before hospital admission, who were treated with oral clarithromycin after hospital admission and who gave informed consent for blood samples to be taken for monitoring of digoxin levels, were included in the study.
Exclusion criteria
Exclusion criteria were: treatment with macrolides during the 2 weeks before hospital admission, hepatic insufficiency, serum bilirubin > 25.7 µmol/L, acute renal insufficiency (serum creatinine > 110 µmol/L), nephrotic syndrome, hypothyroidism, pregnancy or contraindications to macrolides. Patients with serum digoxin concentrations >2 ng/mL on admission were also excluded. Steady-state serum digoxin concentrations were determined on the first day, before administration of the first clarithromycin dose and after 56 days of concomitant treatment with digoxin and clarithromycin. On the first day, blood samples were obtained before the digoxin dose (pre-clarithromycin and digoxin trough serum concentration) and at 6 h after the digoxin and clarithromycin dose. On days 56, a blood sample was obtained at least 6 h after an oral dose of digoxin and another was collected just before the next dose of digoxin (trough serum concentration). Blood samples obtained 6 h after an oral dose of digoxin were named sample 1 and samples collected just before the next dose of digoxin were named sample 2.
On other days serum digoxin concentrations were monitored according to the clinical progress of the patient. When digoxin toxicity was suspected or the serum digoxin concentration in a trough sample exceeded 2 ng/mL the drug was withdrawn. Serum digoxin concentrations were determined using a fluorescence polarization immunoassay (TDX; Abbott Laboratories), with limited cross-reactivity between dihydrodigoxin and digitoxin (DRM).7
A Bayesian approach was used to calculate digoxin pharmacokinetic parameters in every patient with either one or two samples available. Initial systemic clearance (CL) and volume of distribution (Vd) of patients older than 65 years were obtained from the literature: Vd = 4.1 ± 0.9 L/kg, CL = 0.8 ± 0.2 mL/min/kg.8 Absorption was assumed to be first-order with a rate constant of 0.82/h and a bioavailability (F) of 71.5 ± 8.6%.9 A minimization MarquardtLevenberg algorithm with a convergence criterion of 0.001 was used to fit pharmacokinetic parameters to individual data. Pharmacokinetic parameter estimates were determined for every patient using the dosage history and the concentrations measured on the first day of digoxinclarithromycin treatment. Calculated estimates were then combined with the dosage history for 48 days of concomitant treatment to predict concentrations at the times of sampling on days 48. Predicted concentrations were compared with the measured concentrations. Finally, a fit was made for every patient using the dosage history and the concentrations measured after 48 days of digoxinclarithromycin treatment to calculate Vd, CL, elimination rate constant (K) and elimination half-life (t). Gender, age, weight, height, digoxin dosage history, the presence of congestive heart failure, and serum creatinine, were all included in every fit. All calculations were made using the Abbottbase Pharmacokinetic System (version 1.00) software.
All the observations are reported as mean ± standard deviation (S.D.). Vd, CL, K and t statistical differences between groups before and after digoxinclarithromycin treatment were analysed using a paired t-test when data from all patients were available. A P value of <0.05 was considered to indicate statistical significance.
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Results |
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Discussion |
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During hospitalization, four patients began treatment with drugs that could have increased serum digoxin concentrations (spironolactone, which inhibits the excretion of digoxin by the kidney; captopril, by reduction in the loss of digoxin through the renal tubules; verapamil, due to reductions in renal and especially biliary clearance and amiodarone, which reduces both renal and non-renal excretion of digoxin1), but the other three patients did not receive drugs, other than clarithromycin, that could have explained the interaction.
We used a Bayesian approach using initial parameters described in previous studies for patients over 65 years old.10 This approach permitted us to calculate the pharmacokinetic parameters in those patients with only a single digoxin concentration measurement (patients 1 and 5). For all patients, a significant reduction in calculated digoxin clearance was observed after 47 days of concomitant treatment with clarithromycin. Interestingly, patients 6 and 7, treated with amiodarone and verapamil respectively, had digoxin concentrations in sample 1 (67 h post-dose) lower than those in sample 2 (23.524 h post-dose) after 7 days of digoxinclarithromycin treatment and we are unable to offer a definitive explanation for these results. It is possible that changes in the absorption phase (for example, increased bioavailability of the P-glycoprotein substrate digoxin, as has been observed in vivo with erythromycin1,4) and in renal and non-renal elimination could have occurred. However, confirmation of these observations and determination of the reasons for the changes observed in these patients requires a separate pharmacokinetic trial designed specifically to address this.
Patients over 65 years are frequently treated chronically with digoxin. If they receive clarithromycin for respiratory tract infection, the results of this study show that elevated digoxin concentrations may be observed after 57 days of concomitant treatment, but only a relatively small number of patients will develop signs of clinical toxicity (in our study one patient with reduction in renal function). However, we emphasize the need for careful monitoring of serum digoxin concentrations in all elderly patients with normal renal function when treated with clarithromycin, with reduction in digoxin dosage as necessary. In patients with reduced renal function or those receiving other drugs that could impair digoxin clearance, clarithromycin should only be used with caution. The only macrolide that has been reported not to affect serum digoxin levels has been rokitamycin1 and this could be an alternative macrolide to clarithromyin in such patients. However, this would need to be confirmed from clinical trials addressing both its efficacy and potential drug interactions.
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Footnotes |
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References |
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2 . Lindenbaum, J., Rund, D. G., Butler, V. P., Jr, Tse-Eng, D. & Saha, J. R. (1981). Inactivation of digoxin by the gut flora: reversal by antibiotic therapy. New England Journal of Medicine 305, 78994.[Abstract]
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