Population pharmacokinetics of digoxin in Korean patients

AIM: Digoxin possesses a narrow therapeutic index and shows a large inter-patient pharmacokinetic variability. The purpose of this study was to develop a population model for the pharmacokinetics of digoxin in Korean patients. METHODS: Plasma concentrations of digoxin after multiple administration at varying dosing schedules in Korean patients were used for population modeling. Data analysis was performed with the P-Pharm software. The data were best fitted by a one-compartment model. The effect of demographic and clinical factors like sex, age, weight, disease state, and renal function on the pharmacokinetic parameters of digoxin was investigated. RESULTS: The study indicated that the clearance of digoxin was influenced by creatinine clearance, while body weight and creatinine clearance were the covariates for its volume of distribution. The population mean estimates for CL and V were 4.4 l/h and 535 l, respectively. Absorption rate constant was lower in females and in the presence of concomitant drug treatment. CONCLUSION: A population pharmacokinetic model for the digoxin pharmacokinetics in a section of Korean patients was developed. The relationships between the pharmacokinetic parameters and the demographic data and the patient-specific covariates were established.     

The effect of age on digoxin pharmacokinetics in Fischer-344 rats

Digoxin protein binding and pharmacokinetics were studied in 4-, 14-, and 25-month-old male Fischer-344 rats to determine if there were age-dependent changes in digoxin disposition. Serum protein binding did not differ among age groups. The average percentage unbound digoxin for all animals was 61.3 +/- 5.3% (means +/- SD, n = 15). For pharmacokinetic studies, [3H]digoxin and 1 mg/kg unlabeled digoxin were administered as an intravenous bolus dose to animals from each age group. The [3H]digoxin terminal elimination half-life was 2.0, 2.3, and 2.5 hr, respectively. The steady-state volume of distribution in the three age groups was 1.51, 1.49, and 1.27 liters/kg, respectively. Total body clearance for the three age groups was 14.2, 12.1, and 7.5 ml/min/kg, respectively. Analysis of variance of these data followed by Duncan's multiple range test indicated a significant decrease in clearance in the aged rats (25-month-old, p less than 0.05). This age-dependent decrease in clearance suggested that digoxin pharmacokinetics could be a significant factor in age-related alterations in digoxin cardiotoxicity in the rat, as it is in humans, and that the Fischer-344 rat could be a useful model for studies of digoxin pharmacokinetic changes with age.     

Population pharmacokinetics of digoxin in Japanese patients: a 2-compartment pharmacokinetic model.

OBJECTIVE: To clarify the observed variability of digoxin disposition by performing a population pharmacokinetic analysis in a Japanese population. DESIGN: Retrospective analysis of clinical pharmacokinetic data. PATIENTS AND PARTICIPANTS: Data were obtained from 106 patients with heart failure and atrial fibrillation (43 males and 63 females). METHODS: Digoxin concentrations in serum were measured by fluorescence polarisation immunoassay. Population pharmacokinetic analysis was performed using a 2-compartment open pharmacokinetic model with the computer program NONMEM. RESULTS: 246 serum concentrations were obtained. Final pharmacokinetic parameters were: CL (L/h) = (0.036 x TBW + 0.112 x CL(CR)) x 0.77SPI x 0.784CCB, V1 = 1.83 L/kg, V2 = 22.6 L/kg and Q = 0.629 L/h/kg, where CL is total body clearance, V1 and V2 are the apparent volumes of distribution in the central and peripheral compartments, Q is intercompartmental clearance, TBW is total bodyweight (in kg), CL(CR) is creatinine clearance (in ml/min), SPI = 1 for concomitant administration of spironolactone (and zero otherwise) and CCB = 1 for concomitant administration of calcium antagonists (and zero otherwise). Concomitant administration of digoxin and spironolactone resulted in a 23% decrease in digoxin clearance. Concomitant administration of digoxin and calcium antagonists (diltiazem, nicardipine, nifedipine or verapamil) resulted in a 21.6% decrease in digoxin clearance. CONCLUSIONS: The estimated population parameter values may assist clinicians in the individualisation of digoxin dosage regimens.     

P-glycoprotein and an unstirred water layer barring digoxin absorption in the vascularly perfused rat small intestine preparation: induction studies with pregnenolone-16alpha-carbonitrile.

Digoxin, a substrate of P-glycoprotein (Pgp) and cytochrome P450 3a (Cyp3a), was used to illustrate the inductive effects of pregnenolone-16alpha-carbonitrile (PCN), a ligand of the pregnane X receptor, on the absorption and disposition of [3H]digoxin in the vascularly perfused rat small intestine preparation. Although increased Cyp3a protein was observed with Western blotting analysis after PCN treatment, metabolism of digoxin to the digoxigenin bis-digitoxoside metabolite in the rat small intestine remained insignificant (<4% dose). PCN pretreatment significantly decreased blood perfusate [3H]digoxin concentrations for both systemic and intraluminal administrations of [3H]digoxin due to increased Pgp levels. The apical secretion by Pgp increased at 90 min with PCN treatment, from 11.2 +/- 5.1% of dose to 20.1 +/- 8.6% of dose after systemic administration of [3H]digoxin; this increase was, however, statistically insignificant (P = 0.13) because of the high variability among preparations. When the composite data for the control and PCN-treated preparations were fit to published physiologically based pharmacokinetic models: the traditional model and the segregated flow model, suboptimal parameters were obtained. The data were further fit to expanded models with a bilayer membrane compartment housing the Pgp adjacent to the apical membrane, or an unstirred water layer (UWL) external to the apical membrane. The models with the UWL yielded improved fits and reasonable parameters associated with digoxin absorption, suggesting that the UWL posed as a barrier for digoxin absorption. Similar results were obtained with the segmental models (the segmental traditional model and the segmental segregated flow model) using the UWL, when heterogeneous distributions of Pgp in the duodenum, jejunum, and ileum were considered.     

Common ATP-binding cassette B1 variants are associated with increased digoxin serum concentration

BACKGROUND AND OBJECTIVE: Digoxin is a known substrate of ATP-binding cassette B1 (ABCB1/MDR1). The results of studies on the association between ABCB1 polymorphisms and digoxin kinetics, however, remain contradictory. Almost all studies were small and involved only single dose kinetics. The goal of this study was to establish ABCB1 genotype effect on digoxin blood concentrations in a large cohort of chronic digoxin users in a general Dutch European population. METHODS: Digoxin users were identified in the Rotterdam Study, a prospective population-based cohort study of individuals aged 55 years and above. Digoxin blood levels were gathered from regional hospitals and laboratories. ABCB1 single nucleotide polymorphisms (SNPs) 1236C-->T, 2677G-->T/A, and 3435C-->T were assessed on peripheral blood DNA using Taqman assays. We studied the association between the ABCB1 genotypes and haplotypes, and digoxin blood levels using linear regression models adjusting for potential confounders. RESULTS: Digoxin serum levels and DNA were available for 195 participants (56.4% women, mean age 79.4 years). All three ABCB1 variants were significantly associated with serum digoxin concentration (0.18-0.21 microg/l per additional T allele). The association was even stronger for the 1236-2677-3435 TTT haplotype allele [0.26 mug/l (95% CI 0.14-0.38)], but absent for other haplotypes (CGC allele considered referent), suggesting an interaction of SNPs in a causal haplotype instead of individual SNP effects. CONCLUSION: We found that the common ABCB1 1236C-->T, 2677G-->T, and 3435C-->T variants and the associated TTT haplotype were associated with higher digoxin serum concentrations in a cohort of elderly European digoxin users in the general population.     

Population pharmacokinetic model of carbamazepine derived from routine therapeutic drug monitoring data

The aim of the present study was to develop a population pharmacokinetic model of carbamazepine from routine therapeutic drug monitoring data. Steady-state carbamazepine plasma concentrations determined by homogenous enzyme immunoassay technique, dosing history including cotherapy, schedule of blood sampling, and patients' demographic characteristics were collected retrospectively from patients' chart histories. A one-compartment model was fitted to the data using nonlinear mixed effects modeling. The influence of weight, age, gender, smoking, allergy, carbamazepine daily dose, and cotherapy on clearance (CL/F) was evaluated. Additionally, bioavailability of controlled-release relative to immediate-release tablets was assessed. Two hundred sixty-five patients (423 concentrations) were used to develop a population pharmacokinetic model. The population estimate of CL/F from the base model was 5.14 L/h with interindividual variability of 50.20%. Patients' gender, age, smoking, allergy, cotherapy with lamotrigine and benzodiazepines had no effect on CL/F. Patient weight (WT), daily carbamazepine dose (DCBZ), daily dose of phenobarbitone (DPB) and valproic acid (VPA), when its daily dose exceeded 750 mg, significantly influenced CL/F and were included in the final model:[equation: see text] where VPA is 1 if dose is greater than 750 mg or 0 otherwise. No difference in bioavailability of carbamazepine between controlled- and immediate-release tablets was detected. The model predictions in the validation set had no bias and satisfactory precision. The model can be used for estimation of carbamazepine CL/F in individual patients in the postautoinduction phase and for selection of optimum dosing regimen in routine patient care.     

A simple aid to digoxin prescribing

Summary We have designed a simple nomogram for predicting digoxin dosage and have tested it prospectively in two consecutive studies. These were both conducted in hospital inpatients who were not already taking digoxin but who required drug therapy for atrial tachyarrhythmias and/or cardiac failure. Study I. Sixty-seven patients received digoxin according to the nomogram and 50 completed the ten day course of the study. Fortyone of these patients were eligible for the final analysis. On the tenth day of treatment, 28 patients were within the therapeutic range for plasma digoxin (0.8 to 2.0 ng·ml^–1), 12 were subtherapeutic (<0.8 ng·ml) and one was potentially toxic (>2.0 ng·ml^–1). Study II. Thirty patients completed the second study. Digoxin was prescribed according to the nomogram with the addition of a dosage correction based on the plasma digoxin level on Day 3. On the tenth day of treatment, 24 patients were within the therapeutic range, one in the subtherapeutic and 5 in the potentially toxic.This simple digoxin nomogram, with or without the Day 3 dosage correction, should prove to be a useful aid to prescribing in patients who do not require rapid digitalisation. It is particularly relevant to elderly inpatients with atrial tachyarrhythmias and/or cardiac failure.     

Pharmacoeconomic analysis of osteoporosis treatment with risedronate

Hip fracture is an important and costly problem. Therapy with the bisphosphonate risedronate effectively prevents hip and other fractures among women with established osteoporosis. Risedronate is a first-choice therapy option in the German Guidelines of the Dachverband Osteologie for Osteoporosis according to evidence-based medicine criteria for the treatment of postmenopausal osteoporosis, osteoporosis of the elderly (women aged > 75 years) and glucocorticoid-induced osteoporosis. There are few published economic evaluations of bisphosphonates in Germany. Therefore, an assessment of the cost-effectiveness of risedronate utilizing a state transition Markov model of established postmenopausal osteoporosis based on randomized clinical trial data was developed. Uncertainty underlying model parameters and outcomes was dealt with using traditional sensitivity analysis and stochastic sensitivity analysis to produce quasi-95% Cls. We focused on patients aged 70 years, since this population most closely matches the randomized controlled trial and is typical of osteoporosis patients in Germany. The baseline model was a cohort of 1,000 70-year-old women, who received risedronate for 3 years and were followed up for an overall observation period of 10 years, modelling transitions through estimated health states and evaluating outcomes. Over the 3-year treatment period and 10-year observation period, risedronate dominated the current average basic treatment in Germany. In the risedronate group 33 hip fractures were averted and 32 quality-adjusted life years (QALYs) were gained (discounted values). Risedronate treatment saves costs for German social insurance: the present net value of the associated costs from the perspective of German social insurance is [symbol: see text]10.66 million if risedronate treatment is used versus [symbol: see text]11 million if basic treatment is used. Thus, net savings of [symbol: see text]340,000 for the treatment group per 1,000 treated women were calculated. Furthermore, risedronate treatment is cost effective from the perspective of the statutory health insurance with costs per averted hip fracture in the analyzed population of [symbol: see text]33,856 and cost per QALY gained of [symbol: see text]35,690. Both results demonstrate cost-effectiveness and are far below the accepted threshold level of [symbol: see text]50,000. Based on this analysis, risedronate is a cost-effective treatment for postmenopausal osteoporosis within the German health care system, offering benefits for osteoporotic patients and for budget decision-makers.     

Intravenously administered digoxin in patients with acute atrial fibrillation: a population pharmacokinetic/pharmacodynamic analysis based on the Digitalis in Acute Atrial Fibrillation trial

OBJECTIVE: Atrial fibrillation is commonly treated with intravenously administered digoxin. The main objective of this study was to investigate the relationship between plasma concentration of digoxin and heart rate. SUBJECTS AND METHODS: Plasma concentrations of digoxin were analysed in 105 patients allocated to digoxin therapy in the Digitalis in Acute Atrial Fibrillation (DAAF) trial. A pharmacokinetic/pharmacodynamic (PK/PD) model for the relationship among digoxin dose, plasma concentration and heart rate in patients remaining in atrial fibrillation was constructed using non-linear, mixed-effect modelling. One hundred and twenty-two placebo-treated patients were included as a control group. In 56 patients, one late sample at 16 h after the first dose of digoxin was obtained while in 49 patients an early sample at 0.25-0.5 h and a late sample 16 h after the first dose were obtained. Heart rate was measured at 0, 2, 6, 12 and 16 h after inclusion, with data from 98, 89, 67, 56 and 53 patients available at each time point, respectively. RESULTS: A two-compartment model best described the time course of digoxin concentrations in plasma. Digoxin and creatinine clearance correlated strongly and mean plasma concentration of digoxin at 16 h was within recommended levels (1.6+/-1.0 nM). The decrease in heart rate in placebo-treated patients was, on average, 0.5 beats/min (bpm) per hour. In patients on digoxin, a linear relationship between the estimated digoxin concentration at the effect site and the drop-in heart rate was found. The half-life for the digoxin distribution to the effect compartment was approximately 3.8 h. The degree of reduction was related to the initial heart rate and patients with higher heart rate had a more pronounced decrease. The model predicted that a digoxin concentration of 1 nM at the effect site reduces heart rate by 9.4%. CONCLUSION: A PK/PD model for the relationship between the plasma concentration of digoxin, the estimated concentration at the effect site and the reduction in heart rate during atrial fibrillation could be defined using a population pharmacokinetic approach. Our data indicate that a more aggressive dosing regimen of digoxin may be more effective in terms of heart rate reduction.     

No pharmacokinetic or pharmacodynamic interaction between digoxin and the oral direct thrombin inhibitor ximelagatran in healthy volunteers

The interaction potential of digoxin and ximelagatran, an oral direct thrombin inhibitor being developed for the prevention and treatment of thromboembolic disease, was investigated in this randomized, double-blind, 2-way crossover study. On 2 separate occasions, healthy female and male volunteers (n = 16) received ximelagatran 36 mg or placebo twice daily for 8 days separated by a 4- to 14-day washout period. All volunteers received a single oral dose of digoxin 0.5 mg on day 4 of both study periods. No interaction between ximelagatran and digoxin was detected in the pharmaco-kinetic parameters (using a 90% confidence interval [CI] of least squares mean estimate ratios), including melagatran (the active form of ximelagatran) AUC(tau) and C(max) and digoxin AUC(t) and C(max). Digoxin did not alter the melagatran-induced prolongation of the activated partial thromboplastin time, and both drugs were well tolerated when administered in combination. In conclusion, no pharmacokinetic or pharmacodynamic interaction between digoxin and ximelagatran was observed in this study.     

Modelling the influence of MDR1 polymorphism on digoxin pharmacokinetic parameters

Objectives Digoxin is a well-known probe for the activity of P-glycoprotein. The objective of this work was to apply different methods for covariate selection in non-linear mixed-effect models to study the relationship between the pharmacokinetic parameters of digoxin and the genotype for two major exons located on the multi-drug-resistance 1 (MDR1) gene coding for P-glycoprotein. Methods Thirty-two healthy volunteers were recruited in three pharmacokinetic drug interaction studies. The data after a single oral administration of digoxin alone were pooled. All subjects were genotyped for the MDR1 C3435T and G2677T/A genotypes. The concentration-time profile of digoxin was established using 12–16 blood samples taken between 15 min and 72 h after administration. We modelled the pharmacokinetics of digoxin using non-linear mixed-effect models. Parameter estimation was performed using the stochastic approximation EM method (SAEM). We used three methods to select the covariate model: selection from a full model using Wald tests, forward inclusion using the log-likelihood ratio test and model selection using the Bayesian Information Criterion. Results The three covariate inclusion methods led to the same final model. Carriers of two T alleles for the C3435T polymorphism in exon 26 of MDR1 had a lower apparent volume of distribution than carriers of a C allele. The only other covariate effect was a shorter absorption time-lag in women. Conclusion The apparent volume of distribution of digoxin is lower in TT subjects, probably reflecting differences in bioavailability. Non-linear mixed-effect models can be useful for detecting the influence of covariates on pharmacokinetic parameters.     

Elimination kinetics of ethanol in pregnant women

To evaluate the pharmacokinetics of ethanol in the early second trimester of pregnancy, ethanol concentrations simultaneously measured in the maternal blood (EtOH-MB) and in the amniotic fluid (EtOH-AF) of six pregnant women were obtained from a previous study in which a single ethanol dose of 300mgkg(-1) body weight was administered orally. For maternal blood ethanol concentration, the kinetic equation was: [Formula: see text] where k(12) and k(21) are, respectively, the rate constant of ethanol transfer from either the central compartment to the peripheral compartment or vice versa; [Formula: see text] is the maximal velocity for ethanol oxidation; and [Formula: see text] is the concentration at which half of the maximal rate of ethanol elimination is reached. The maximum concentration of EtOH in AF was 60% lower than in MB ( [Formula: see text] ). However, the AUC(0-3.5h) in AF was only 16% lower than the value for MB ( [Formula: see text] ). The k(12) ( [Formula: see text] h(-1)) was almost twice faster than k(21) ( [Formula: see text] h(-1)). The [Formula: see text] was [Formula: see text] microgml(-1)h(-1) and [Formula: see text] was [Formula: see text] microgml(-1). Our results imply that in the early second trimester, ethanol metabolism is fast. However, ethanol clearance from the AF is slower than ethanol clearance in MB. This process is widely variable, and our findings may partially explain the wide variability of ethanol's toxic effects on the fetus.     

饮食对地高辛药动学的影响研究

目的研究饮食对健康受试者单剂量口服地高辛(DIG)片血药浓度的影响。方法 20名男性健康志愿者随机分为2组,每组10人,试验开始前一晚禁食10h,晨起后口服地高辛片0.25mg,另一组在进食后5min口服地高辛片0.25mg。经1周清洗期后,两组交叉试验。采用化学发光法测定人血浆中地高辛的浓度,采用3p97软件计算药动学参数并比较进食或空腹对药动学的影响。结果空腹和进食后服用地高辛片,血浆地高辛药物tmax分别为(6.33±0.60)h、(7.13±1.32)h,Cmax分别为(1.82±0.045)ng/ml、(1.81±0.039)ng/ml,AUC0-12分别为(19.47±7.34)ng/(h·ml)、(20.65±7.95)ng/(h·ml),t1/2z分别为(6.45±0.76)h、(7.01±0.87)h,MRT0-12分别为(8.43±2.34)h、(9.13±3.27)h。上述药动学参数经t检验无统计学意义(P>0.05)。结论空腹喝进食后服用地高辛片,其各药动学参数无显著性差异,可认为进食对本药在男性健康人体内的代谢无影响。     

地高辛血药浓度超出安全限值风险预测模型的建立与评估

目的：探讨地高辛血药浓度超出安全限值（2.0 ng·mL^-1）的影响因素并构建相关风险预测模型,为地高辛的安全合理用药提供参考。方法：回顾性分析2019年1月至2020年12月安徽医科大学附属六安医院服用地高辛进行治疗并接受血药浓度监测的153例住院患者的临床资料,将所纳入患者按地高辛血药浓度监测值分为达标组（0.5 ng·mL^-1≤血药浓度值≤2.0 ng·mL^-1）和超限组（血药浓度值>2.0 ng·mL^-1）,对两组患者的性别、年龄、体质指数（BMI）、肾损害情况、日均服药剂量,合并用药情况采用Logistic回归分析筛选地高辛血药浓度超出安全限值的独立影响因素,根据筛选出的独立影响因素建立列线图预测模型,并对该模型进行评估。结果：患者的性别（OR=0.379,95% CI：0.244~0.589）、肾损害情况（OR=0.252,95% CI：0.162~0.391）、日均服药剂量（OR=0.438,95% CI：0.279~0.689）、合用促胃动力药（OR=1.975,95% CI：1.294~3.013）、合用抗菌药物（OR=0.471,95% CI：0.299~0.741）,合用β受体阻滞剂（OR=0.454,95% CI：0.277~0.642）以及合用芪苈强心胶囊（OR=0.096,95% CI：0.026~0.353）是地高辛血药浓度超出安全限值的独立影响因素。根据所筛选出的7项独立影响因素,建立了地高辛血药浓度超出安全限值的列线图预测模型,该模型的C-index指数为0.742,表明该列线图模型具有较好的区分度,对该模型进行验证后发现预测值和观察值基本一致,表明该列线图预测模型具有较好的一致性。结论：本研究通过筛选出地高辛血药浓度超出安全限值的独立影响因素建立了能够预测其相关风险的列线图模型,该列线图有着良好的区分度及一致性,具有较高的临床应用价值,对甄别洋地黄中毒高风险人群,提前准备应对方案有着较为重要的指导意义。     

Effect of Chinese medicines Chan Su and Lu-Shen-Wan on serum digoxin measurement by Digoxin III, a new digoxin immunoassay

Chan Su and Lu-Shen-Wan are Chinese medicines that crossreact with digoxin immunoassays. Recently, Abbott Laboratories released a new digoxin immunoassay, Digoxin III. We studied potential interference of Chan Su and Lu-Shen-Wan with the Digoxin III assay by comparing results obtained by using Digoxin II and fluorescence polarization immunoassay, also manufactured by Abbott Laboratories. Aliquots of a drug-free serum pool were supplemented with aqueous extract of Chan Su or Lu-Shen-Wan and apparent digoxin concentrations were measured using all three digoxin assays. Significant crossreactivity of Chan Su and Lu-Shen-Wan was observed with the new Digoxin III assay. Moreover, when mice were fed with Chan Su or Lu-Shen-Wan, significant apparent digoxin concentrations were also observed in the sera of mice using the Digoxin III assay indicating that such interferences are also present in vivo. When serum pools prepared from patients receiving digoxin were further supplemented with Chan Su or Lu-Shen-Wan extract, falsely elevated digoxin values were observed with both Digoxin III and fluorescence polarization immunoassay, but digoxin values were falsely lowered using the Digoxin II assay. For example, when one aliquot of Digoxin Serum Pool 1 containing 0.94 ng/mL of digoxin was supplemented with 5.0 microg/mL of Chan Su extract, the digoxin concentration was falsely elevated to 6.60 ng/mL as measured by the Digoxin III assay and 6.99 as measured by the fluorescence polarization immunoassay assay. In contrast, the observed digoxin value was falsely lowered to 0.72 ng/mL using the Digoxin II assay. Interference of Chan Su and Lu-Shen-Wan in the Digoxin III assay cannot be eliminated by monitoring free digoxin concentrations. Digibind neutralizes digoxin-like immunoreactive components of Chan Su and such effect can be monitored by measuring apparent free digoxin concentrations using the Digoxin III assay. We conclude the both Chan Su and Lu-Shen-Wan significantly interfere with serum digoxin measurements by the new Digoxin III assay.     

Pharmacokinetics of intravenously administered digoxin and histopathological picture in rabbits with experimental bile duct obstruction.

This study aimed to examine the effect of obstructive cholestasis on the pharmacokinetics of digoxin. Eighteen male rabbits were randomly ascribed to the two study groups: the sham-operated control group and the examined group - with common and cystic bile duct ligations. Digoxin was administered intravenously as a single dose of 0.02 mg/kg, and blood samples were withdrawn for up to 24 h. Digoxin concentrations were determined by the FPIA method. The pharmacokinetic parameters were calculated using a noncompartmental analysis. During the whole observation period the blood serum concentrations of digoxin were statistically higher in animals with obstructive cholestasis versus the controls. A significant increase in the area under the plasma concentration-time curve, decrease in the total body clearance and in the volume of distribution on the 6th day after the bile ducts ligation as compared to the sham-operated controls, were observed. The obtained results suggest an impaired elimination of digoxin in obstructive cholestasis in rabbits.     

Serum cystatin C is not a better marker of creatinine or digoxin clearance than serum creatinine

AIMS: To assess whether cystatin C, a new serum marker of renal function, is a better index of creatinine or digoxin clearance than serum creatinine in older people. METHODS: Twenty-two volunteers over the age of 65 years (mean 73 +/- 5) were recruited from a healthy elderly volunteer database. None of the volunteers was taking digoxin or other medication known to interfere with digoxin kinetics or assay. Digoxin was infused at a dose of 7-10 microg kg(-1) and blood samples were taken over the following 48 h and assayed for serum digoxin. Serum cystatin C, creatinine and creatinine clearance were measured and a calculated creatinine clearance was estimated using the Cockcroft Gault formula. Digoxin clearance was calculated using a pharmacokinetic software package. All values were log transformed to normalize their distribution. RESULTS: Of the 22 volunteers enrolled into the study, 18 completed the study. Serum cystatin C ranged between 0.72 and 1.89 mg l(-1) and serum creatinine ranged from 69.6 to 153.9 micromol l(-1). Measured creatinine clearance ranged from 38 to 123 ml min(-1) and calculated creatinine clearance from 29.5 to 88.0 ml min(-1). Digoxin clearance ranged from 51.0 to 103.5 ml min(-1). Cystatin C correlated extremely well with creatinine (r=0.93, P<0.001, 95% CI 0.82, 0.97) and with creatinine clearance (r=0.67, P=0.002, 95% CI 0.3, 0.87). Neither serum cystatin C nor serum creatinine correlated with digoxin clearance (r=0.25, P=0.31, 95% CI -0.25, 0.64 and r=0.44, P=0.068, 95% CI -0.03, 0.75, respectively). Measured creatinine clearance, however, did correlate well with digoxin clearance (r=0.55, P=0.018, 95% CI 0.11, 0.81). CONCLUSIONS: Serum cystatin C and serum creatinine show very similar correlations with creatinine and digoxin clearances. Serum cystatin C does not offer any advantages in this respect. It remains to be seen whether cystatin C offers any advantage over creatinine in elderly people in other respects.     

Effect of exenatide on the steady-state pharmacokinetics of digoxin

This open-label study investigated the effect of exenatide coadministration on the steady-state plasma pharmacokinetics of digoxin. A total of 21 healthy male subjects received digoxin (day 1, 0.5 mg twice daily; days 2-12, 0.25 mg once daily) and exenatide (days 8-12, 10 microg twice daily). Digoxin plasma and urine concentrations were measured on days 7 and 12. Exenatide coadministration did not change the overall 24-hour steady-state digoxin exposure (AUCtau,ss) and Cmin,ss but caused a 17% decrease in mean plasma digoxin Cmax,ss (1.40 to 1.16 ng/mL) and an increase in digoxin tmax,ss (median increase, 2.5 hours). Although the decrease in digoxin Cmax,ss was statistically significant, peak concentrations were within the therapeutic concentration range in all subjects. Digoxin urinary pharmacokinetic parameters were not altered. Gastrointestinal symptoms, the most common adverse effects of exenatide, decreased over time. Exenatide administration does not cause any changes in digoxin steady-state pharmacokinetics that would be expected to have clinical sequelae; thus, dosage adjustment does not appear warranted, based on pharmacokinetic considerations.     

Influence of coadministration on the pharmacokinetics of azimilide dihydrochloride and digoxin

The influence of coadministration on digoxin and azimilide pharmacokinetics/pharmacodynamics was assessed in a randomized, 3-way crossover study in 18 healthy men. Serial blood and urine samples were obtained for azimilide and digoxin quantitation. Treatment effects on pharmacokinetics were assessed using analysis of variance. The relationship between azimilide blood concentrations and QT(c) prolongation was characterized by an E(max) model. Effects of coadministration on pharmacodynamics were assessed using a mechanistic-based inhibition model. Azimilide pharmacokinetics was unaffected by digoxin, except for a 36% increase in CL(r) (P = .0325), with no change in CL(o). Digoxin pharmacokinetics was unaffected by azimilide, except for a 21% increase in C(max) (P = .0176) and a 10% increase in AUC(tau) (P = .0121). Digoxin coadministration increased the apparent EC(50) with no effect on E(max), consistent with competitive inhibition (K(i) = 0.899 ng/mL). The pharmacokinetic and pharmacodynamic changes observed upon coadministration were small and are not expected to be clinically important.     

Predictive performance study of two digoxin assays in subjects with various degrees of renal function

This prospective study was conducted to compare the predictive performance of fluorescence polarization immunoassay (FPIA, Abbott TDx Digoxin II) and radioimmunoassay (RIA, Kallestad Labs) with combined low-pressure liquid chromatography/RIA (LPLC/RIA) digoxin assay in measuring 15-17 serum digoxin concentrations (SDC) obtained after a single 10 microg/kg intravenous digoxin dose in patients with various degrees of renal function and at different SDC ranges. Eighteen men and women were stratified into 3 age- and gender-matched groups based upon renal function [N = 6 in each, group I (Cl(cr) < 10 mL/min), group II (Cl(cr) = 10-50 mL/min), and group III (Cl(cr) > 50 mL/min)]. Serum digoxin concentrations were measured at time zero; at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, and 12 hours; and at 2, 3, 4, and 5-7 days after the digoxin dose, using the three different digoxin assays. TDx Digoxin II was unbiased [mean error -0.09 (95% CI -0.19, 0.01)] and RIA biased [mean error -0.29 (95% CI -0.36, -0.21)] to over-predict SDC by 14.2%. In group I patients, the analysis revealed a bias to over-predict SDC by 6.0% for TDx Digoxin II [mean error -0.16 (95% CI -0.29, -0.07)] and an unbiased performance by RIA. In groups II and III, both TDx Digoxin II and RIA showed biased performance, the mean magnitude of bias was low (< 20%). For intermediate SDC range (> 0.5 ng/mL and < or = 3.0 ng/mL), TDx Digoxin II was unbiased in predicting SDC, whereas RIA was biased to under-predict SDC [mean error 0.13 (95% CI 0.10, 0.16)] by 9.9%. The magnitude of bias observed in all cases was less than 20%. Both assays, TDx Digoxin II and RIA, imprecisely measured SDC for all samples combined, different groups and SDC ranges. In all time-paired samples, TDx Digoxin II (FPIA) performed better than the RIA. In conclusion, the magnitude of bias observed with either assay at different groups and SDC ranges was not likely to be clinically relevant. Therefore, either assay may be used to measure SDC in clinical practice.