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Determination of Digoxin Clearance in Japanese Elderly Patients for Optimization of Drug Therapy

A Population Pharmacokinetics Analysis Using Nonlinear Mixed-Effects Modelling

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Abstract

Background: Optimal use of digoxin in the elderly population requires information about the drug’s pharmacokinetics and the influence of various factors on the drug’s disposition. However, because of sampling restrictions, it is often difficult to perform traditional pharmacokinetic studies in elderly patients.

Objective: This study was conducted to determine the apparent total clearance of digoxin from serum after oral administration (CL/F) and to establish the role of patient characteristics in estimating doses of digoxin for elderly patients (age ≥65 years), using routine therapeutic drug monitoring data.

Methods: Analyses of the pharmacokinetics of digoxin were conducted using the nonlinear mixed-effects modelling (NONMEM®) software, a computer program designed to analyse pharmacokinetics in study populations by allowing pooling of data. Steady-state data (140 observations) obtained by routine therapeutic drug monitoring following repeated oral administration of digoxin in 94 hospitalized elderly patients (age ≥65 years) were analysed to establish the role of patient characteristics in estimating doses of digoxin for elderly patients.

Results: Estimates generated by NONMEM® indicated that digoxin CL/F was influenced by the demographic variables of total bodyweight (TBW), serum creatinine (SCr), age (AGE), presence of congestive heart failure (CHF), concomitant administration of the calcium channel antagonists (calcium channel blockers [CCBs]: verapamil, diltiazem or nifedipine), sex (SEX) and elderly clearance factor (trough serum concentration of digoxin; [Ctrough]^θ). The full version of the final NONMEM® model was CL/F[L/h]=(0.588 × TBW [kg])^(0.189) × SCr[mg/dL]^(−0.163) × (AGE [years]/65)^(−0.152) × 0.957^(CCB) × 0.941^(CHF) × 0.965^(SEX) × Ctrough [ng/mL]^ (−0.180), where CCB is 1 for concomitant administration of a CCB and is 0 otherwise; CHF is 1 for patients with CHF and is 0 otherwise; SEX is 0 for male and is 1 for female; and the elderly clearance factor Ctrough −0.180 is 1 for digoxin Ctrough <1.7ng/mL.

Conclusions: We developed a new model for elderly patient dosing of digoxin with good predictive performance. Clinical application of the findings of the present study to patient care may permit selection of an appropriate initial digoxin maintenance dose, thus enabling the clinician to achieve a desired therapeutic effect. However, the digoxin dosage regimen should be based on an appraisal of the individual patient’s clinical need for the drug.

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Acknowledgements

No sources of funding were used to assist in the conduct of this study. The authors have no conflicts of interest that are directly relevant to the content of this study.

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Authors and Affiliations

  1. Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka, Japan

    Miho Yukawa, Hirohito Ikeda & Hatsumi Aki

  2. Laboratory of Evidence-Based Pharmacotherapy, Daiichi University of Pharmacy, 22-1 Tamagawa-Cho, Minami-Ku, Fukuoka, 815-8511, Japan

    Eiji Yukawa & Takako Takiguchi

  3. Department of Pharmacy, Yufuin Kosei-Nenkin Hospital, Yufu, Japan

    Fumihiro Suematsu

  4. Department of Hospital Pharmacy, Kyushu Kosei-Nenkin Hospital, Kitakyushu, Japan

    Masao Mimemoto

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  1. Miho Yukawa
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  2. Eiji Yukawa
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  3. Fumihiro Suematsu
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  4. Takako Takiguchi
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  5. Hirohito Ikeda
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  6. Hatsumi Aki
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  7. Masao Mimemoto
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Correspondence to Eiji Yukawa.

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Yukawa, M., Yukawa, E., Suematsu, F. et al. Determination of Digoxin Clearance in Japanese Elderly Patients for Optimization of Drug Therapy. Drugs Aging 28, 831–841 (2011). https://doi.org/10.2165/11594230-000000000-00000

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  • DOI: https://doi.org/10.2165/11594230-000000000-00000

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