Population pharmacokinetic investigation of digoxin in Japanese neonates

OBJECTIVE: To establish the role of patient characteristics in estimating doses of digoxin for neonates using routine therapeutic drug monitoring data. METHOD: The steady-state blood level data (n = 129) after repetitive oral administration in 71 hospitalized neonates were analysed using Nonlinear Mixed Effects Modelling (nonmem), a computer program designed for analysing drug pharmacokinetics in study populations through pooling of data. Analysis of the pharmacokinetics of digoxin was accomplished using a one-compartment open pharmacokinetic model. The effect of a variety of developmental and demographic factors on digoxin disposition was investigated. RESULTS: Estimates generated by nonmem indicated that the clearance of digoxin (CL/F; L/h) was influenced by the demographic variables: total body weight (TBW), gestational age (GA) and neonate clearance factor (trough serum concentration of digoxin; Conc). These influences could be modelled by the equation CL/F = 0.0261 x TBW (kg)0.645 x Conc (ng/mL)(-0.724) x GA (weeks)0.8. The interindividual variability in digoxin clearance was modelled with proportional errors. The estimated coefficient of variation was 7.0%, and the residual variability was 13.1%. CONCLUSION: Clinical application of the model to patient care may permit selection of an appropriate initial maintenance dose, thus enabling the clinician to achieve the desired therapeutic effect. However, the digoxin dosage regimen for the individual patient should be based on a careful appraisal of their clinical need for the drug.     

What value do body weight, age and drug anamnesis have as an index of elevated digoxin level?

A retrospective study of two groups of patients with a different plasma digoxin level (Group A: digoxin greater than or equal to 2 ng/ml, n = 32, Group B: digoxin less than 2 ng/ml, n = 34; total n = 66) showed a significantly lower creatinine clearance (p less than 0.05) in group A. This group also showed a weak correlation between the digoxin level and the length of observation (R = + 0.31, p less than 0.05, n = 29). Furthermore, a weak correlation between digoxin level and the ratio of average daily dosage to creatinine clearance was found for the total sample (R = + 0.30, p less than 0.05, n = 66). Patients treated for less than 7 days and with a higher digoxin level also had a higher dosage and worse renal function (p = 0.05, p = 0.01, respectively). A weak correlation also existed between the digoxin level and creatinine clearance and body weight for the whole sample (R = -0.29, p less than 0.05; R = -0.29, p less than 0.01, respectively; n = 66). The latter correlation was also found within each group. Apart from renal function, the medication taken and body weight seem to be useful variables in predicting impending elevation of the digoxin level. In this study these variables were found to be better suited for the said purpose than the ECG. These conclusions remain to be confirmed by means of a prospective study.     

CORRELATION BETWEEN PREDICTED AND MEASURED DIGOXIN SERUM CONCENTRATIONS

Measurement of digoxin serum concentration can be useful as a direct guide to the dose appropriate to individual patients. Therefore, we have attempted to predict digoxin serum concentration in 62 patients with a wide range of body weight, age and renal function, using creatinine clearance and individual digoxin dose. Creatinine clearance in each patient was determined by the Cockroft and Gault method (1). Digoxin clearance was determined by Scheiner's method (2). Once digoxin clearance was determined, the predicted steady-state serum concentration was calculated using general pharmacokinetic principles. Each patient was on digoxin therapy for at least 1 month. Digoxin serum concentration was measured by the newly developed fluorescence polarization immunoassay (FPIA). A linear regression analysis was performed on the data from the predicted and measured serum level which yielded a slope of 0.9463, intercept of 0.0950 and a correlation coefficient (r) of 0.9600. The method was found to be very useful to predict digoxin serum levels in overdosed and underdosed patients.     

The effects of mannitol diuresis on digoxin and phenobarbital handling by the kidney: implications for tubular reabsorption and secretion of the cardiac glycoside

The effect of mannitol diuresis on the renal clearance of digoxin and phenobarbital was studied in dogs. Mannitol diuresis significantly increased the clearance of digoxin and the ratio digoxin: inulin clearances (from 0.7 +/- 0.2 to 1.1 +/- 0.25). The increase in phenobarbital: inulin clearance ratio was significantly higher than the increase in the digoxin: inulin clearance ratio (4.9 fold vs 1.66 fold) (p less than 0.005). Mannitol diuresis did not significantly affect inulin clearance, nor digoxin protein binding during the experimental period while there was a significant increase in PAH clearance. Significant correlations were found between urine flow rate and digoxin renal clearance or digoxin: inulin clearance ratio. The increase in the ratio drug: inulin clearance with diuresis correlated inversely with the initial ratio; animals with more predominant net reabsorption had a higher increase in ratio. These studies suggest that the mannitol-induced increase in digoxin clearance stems from a combination of increased renal blood flow enhancing digoxin secretion, and increased urine flow rate inhibiting its reabsorption. We conclude that urine flow rate and renal blood flow are important determinants of the renal clearance of digoxin, independent of GFR. Any study assessing the effect of pathophysiological states or drug interactions on digoxin renal clearance must control for these factors.     

Population Pharmacokinetics of Digoxin in Duchenne Muscular Dystrophy (DMD) Patients

Routine clinical pharmacokinetic data collected from Duchenne muscular dystrophy (DMD) patients receiving digoxin have been analyzed to evaluate the role of patients' characteristics for estimating dosing regimens. The data were analyzed using NONMEM, a computer program designed for population pharmacokinetic analysis that allows pooling of data. The pharmacokinetic model of digoxin was described using a one-compartment steady-state model. The effect of factors on digoxin clearance was investigated. NONMEM estimates indicate that digoxin clearance was influenced by the variables of body weight and combination with diuretics. The interindividual variability in digoxin clearance was modeled with proportional error with an estimated coefficient of variation of 25%, and the intraindividual variability in digoxin concentration was modeled with equal error with an estimated standard deviation of 0.0828 ng ml(minus sign1). In order to determine whether the population parameters obtained in this study were accurate, we administered digoxin according to individual dosage regimens in four DMD patients, using these values obtained by the Bayesian method. As a result, we found that mean prediction error, which indicates the deviation of prediction accuracy for digoxin concentration in plasma, was small, as were mean absolute prediction error and root mean squared error, showing the accuracy of this prediction method. The dosing method based on clearance values obtained by NONMEM analysis allowed the prediction of the steady-state concentration as a function of maintenance dose with acceptable error for therapeutic drug monitoring.     

Significance of the endogenous digoxin-like substance in infants and mothers

Digoxin serum concentrations were measured by a routine radioimmunoassay in 30 neonates not receiving digoxin; nonetheless, digoxin levels were between 0.17 nM and 1.64nM (means = 0.64nM +/- 0.27 nM). There was a negative correlation between gestational age and concentration of an endogenous digoxin-like substance (EDLS). Neonates less than or equal to 32 wk gestational age had higher levels of EDLS than neonates greater than 32 wk old. EDLS concentrations were compared in 22 mothers and their 24 offspring and were higher in all newborn infants (0.34nM +/- 0.09nM and 0.15nM +/- 0.08nM). EDLS was shown to inhibit Na+-K+-adenosinetriphosphatase activity by measurement of 86Rb uptake in erythrocytes exposed to sera samples from 30 infants in the study. EDLS levels greater than 0.6 ng/ml were associated with lesser 86Rb uptake. Simulation kinetics suggest that the presence of 0.6nM EDLS would lengthen the digoxin t1/2 by 64%, reduce the volume of distribution by 23%, and lower clearance by 53% if the peak "true" digoxin level were 2 ng/ml. EDLS concentrations of 1.5 ng/ml would increase the t1/2 by 207% while reducing the volume of distribution by 43% and clearance by 81%. These considerations cast serious doubts on the validity of currently accepted digoxin kinetics and dosing in preterm infants.     

Nonparametric population pharmacokinetic analysis of amikacin in neonates, infants, and children

The therapeutic and toxic effects of amikacin are known to depend on its concentration in plasma, but the pharmacokinetics of this drug in neonates, infants, and children and the influences of clinical and biological variables have been only partially assessed. Therapeutic drug monitoring data collected from 155 patients (49 neonates, 77 infants, and 29 children) receiving amikacin were analyzed by a nonparametric population-based approach, the nonparametric maximum-likelihood method. We assessed the effects of gestational and postnatal age, weight, Apgar score, and plasma creatinine and urea concentrations on pharmacokinetic parameters. There is no specific formulation of amikacin for neonates and infants. We therefore used an error model to account for errors due to dilution during preparation of the infusion. The covariates that reduced the variance of clearance from plasma and the volume of distribution by more than 10% were postnatal age (43 and 28%, respectively) and body weight (30.4 and 17.4%, respectively). The expected reduction of clearance was about 10% for the plasma creatinine concentration. The other covariates studied (Apgar scores, plasma urea concentration, gestational age, sex) were found to have little effect. Simulations showed that a smaller percentage of patients had a maximum concentration in plasma/MIC ratio greater than 8 with a regimen of 7.5 mg/kg of body weight twice daily than with a regimen of 15 mg/kg once a day for MICs of 1 to 8 mg/liter.     

新生儿上消化道出血的胃肠外营养支持

【目的】探讨不同营养支持疗法对新生儿上消化道出血患儿的生长发育、临床疗效及合并症发生率的影响。【方法】对 2 2例新生儿上消化道出血患儿 (观察组 )进行胃肠外营养支持 ,与 2 0例对照组比较其生长发育指标 (头围、体重、身长 )、血红蛋白、合并症发生率、平均住院天数等指标的差异。【结果】观察组的头围、体重、血红蛋白增长明显高于对照组 (P <0 .0 1 ;P <0 .0 5 ) ;合并症发生率、平均住院天数明显低于对照组 (P <0 .0 1 ;P <0 .0 5 )。【结论】胃肠外营养对新生儿上消化道出血具有重要的临床支持作用 ,能使患儿在禁食期间得到良好的营养支持 ,尽早康复 ,值得推广。     

Significant factors in predicting sustained ROSC in paediatric patients with traumatic out-of-hospital cardiac arrest admitted to the emergency department

BACKGROUND: Paediatric patients with out-of-hospital cardiac arrest (OHCA) due to trauma pose difficult challenges in resuscitation. Trauma is a major cause of OHCA in children. The aim of this study was to determine which factors were related to predicting a sustained return of spontaneous circulation (ROSC) in paediatric OHCA patients with trauma. METHOD: This retrospective study comprised 115 paediatric patients (56 traumatic and 59 non-traumatic OHCA patients) aged younger than 18 years who had been admitted to the emergency department (ED) from January 2000 to December 2004. We analysed the demographic data and the factors that may have influenced sustained ROSC in the group of OHCA paediatric patients with trauma. The non-trauma group was established as a control group. Survival analysis was used to compare differences in survival rate between trauma and non-trauma OHCA patients. Receiver operating characteristic (ROC) analysis was used to determine the significant in-hospital CPR duration related to sustained ROSC. RESULTS: Initial cardiac rhythm on arrival (P=0.005) and the duration of in-hospital CPR (P<0.001) were significant factors. Patients with PEA or VF had higher rate of sustained ROSC than those with asystole (PEA: P=0.003, VF: P=0.03). In the survival analysis, OHCA children with trauma had a lower chance of survival than non-trauma children as the interval from the scene to the ER increased (P=0.008). Based on the ROC analysis, the cut-off values of in-hospital CPR duration were 25min in OHCA paediatric patients with trauma. CONCLUSION: Several significant factors relating to sustained ROSC were determined in the OHCA paediatric patients with trauma; most importantly, we found that in-hospital CPR may have to be performed for at least 25min to enable a spontaneous circulation to return.     

Chloramphenicol Pharmacokinetics in Hospitalized Patients

The apparent body clearance of chloramphenicol was investigated in 21 hospitalized adult patients on 27 occasions. Apparent body clearance was found to be significantly lower (1.99 +/- 1.49 ml/min per kg) in patients with total serum bilirubin concentrations of >1.5 mg/100 ml than in patients with serum bilirubin concentrations of 相似文献   

抚触配合光疗在新生儿高胆红素血症中的应用

目的:探讨抚触配合光疗在新生儿高胆红素血症中的应用效果.方法:依据血清胆红素水平将180例新生儿高胆红素血症患儿分为轻度、中度、重度(A组、B组、C组)三组各60例,各组再随机分为实验组(A1组、B1组、C1组各30例)与对照组(A2组、B2组、C2组各30例),对照组给予蓝光照射治疗与常规护理,实验组在对照组基础上联合抚触.测量并记录治疗后第2、4、6天患儿黄疸指数、哭闹时间,以及患儿每日摄入奶量、大便次数、体重、睡眠时间.结果:治疗后第2、4、6天三组中实验组较对照组患儿黄疸指数降低、哭闹时间减少(P＜0.05,P＜0.01),且三组中实验组较对照组每日摄入奶量多、大便次数多、体重增长快、睡眠时间长(P＜0.01).结论:在蓝光照射治疗同时给予抚触可降低不同程度新生儿高胆红素血症患儿血清胆红素水平,使其摄入奶量多、大便次数多、体重增长快;能提高患儿治疗依从性,促进其神经系统的发育.     

Oral bioavailability of digoxin is enhanced by talinolol: evidence for involvement of intestinal P-glycoprotein

OBJECTIVE: Recent data indicated that disposition of oral digoxin is modulated by intestinal P-glycoprotein. The cardioselective beta-blocker talinolol has been described to be secreted by way of P-glycoprotein into the lumen of the gastrointestinal tract after oral and intravenous administration. We therefore hypothesized that coadministration of digoxin and talinolol may lead to a drug-drug interaction based on a competition for intestinal P-glycoprotein. METHODS: Pharmacokinetics of digoxin (0.5 mg orally), talinolol (30 mg intravenously and 100 mg orally), and digoxin plus talinolol orally, as well as digoxin plus talinolol intravenously, were assessed in five male and five female healthy volunteers (age range, 23 to 30 years; body weight, 60 to 95 kg) in a changeover study with at least a 7-day washout period. Digoxin and talinolol were analyzed by fluorescence polarization immunoassay and HPLC, respectively. RESULTS: Oral coadministration of 100 mg talinolol increased the area under the concentration-time curve (AUC) from 0 to 6 hours and the AUC from 0 to 72 hours of digoxin significantly by 18% and 23%, respectively (5.85+/-1.49 versus 7.22+/-1.29 ng x h/mL and 23.0+/-3.3 versus 27.1+/-3.7 ng x h/mL, for both P<.05) and the maximum serum levels by 45%. Renal clearance and half-life of digoxin remained unchanged. Coinfusion of 30 mg talinolol with oral digoxin had no significant effects on digoxin pharmacokinetics. Digoxin did not affect the disposition of talinolol after both oral and intravenous administration. CONCLUSION: We observed a significantly increased bioavailability of digoxin with oral coadministration of talinolol, which is most likely caused by competition for intestinal P-glycoprotein.     

不同血清成纤维细胞生长因子23水平对腹膜透析患者磷代谢的影响及相关因素分析

目的观察分析不同血清成纤维细胞生长因子（FGF）23水平对腹膜透析患者磷代谢的影响,探讨腹膜透析患者血清FGF23的影响因素。 方法选取重庆医科大学附属成都第二临床学院稳定腹膜透析治疗3个月以上的92例患者,根据患者血清FGF23中位数821 pg/ml,将患者分为低水平组（FGF23<821 pg/ml）和高水平组（FGF23≥821 pg/ml）,比较2组患者饮食蛋白质及磷摄入量、血磷水平、腹膜磷清除率、残肾磷清除率、总磷清除率、血清甲状旁腺素（iPTH）水平、残余肾功能（RRF）;根据透析液肌酐浓度/血浆肌酐浓度值,其中32例患者分为A组（高平均转运＋高转运组）和B组（低平均转运＋低转运组）,比较A、B组患者腹膜转运功能与FGF23的清除。采用多元逐步回归法分析PD患者血FGF23水平的独立影响因素。 结果FGF23高水平组蛋白质和饮食磷摄入量高于低水平组,差异具有统计学意义（P<0.05）;高水平组血磷、iPTH水平高于低水平组,差异具有统计学意义（P<0.05）;高水平组腹膜磷清除、残肾磷清除率、总磷清除率、尿素清除指数、周肌酐清除率较低水平组更低,差异具有统计学意义（P<0.05）。亚组分析显示A组患者FGF23清除率较B组更低,差异具有统计学意义（P=0.044）。多元逐步回归分析显示血磷水平、总磷清除率、Log（iPTH水平）、残肾功能、透析龄是本研究中血清FGF23升高的独立影响因素。 结论血清FGF23更高水平的腹膜透析患者存在总磷清除率更低,饮食磷摄入和血磷水平更高的临床特征;残肾清除磷与腹膜清除磷均影响腹膜透析患者血清FGF23水平,腹膜转运功能高的腹膜透析患者具更低的腹膜FGF23清除率;血磷水平、总磷清除率、Log（iPTH水平）及残肾功能和透析龄是腹膜透析患者血清FGF23水平的独立影响因素。     

Longitudinal assessment of a P-glycoprotein-mediated drug interaction of valspodar on digoxin.

OBJECTIVES: Valspodar is a P-glycoprotein modulator currently under development as a multidrug resistance reversal agent in clinical oncology. A multiple-dose drug interaction study was performed to assess the influence of valspodar on digoxin, a substrate for P-glycoprotein. METHODS: Twelve healthy volunteers received an oral digoxin loading dose of 1 mg on day 1, followed by 0.125 mg once daily to day 11. On day 7, a single oral 400-mg dose of valspodar was given, followed by a regimen of 200 mg twice daily from days 8 to 11. Serial blood samples and urine collections were obtained on days 6, 7, and 11 for digoxin pharmacokinetics and on days 7 and 11 for valspodar pharmacokinetics. On these days, blood pressure, pulse rate, and electrocardiograms were recorded at multiple time points. RESULTS: Coadministration of single-dose valspodar with steady-state digoxin on day 7 yielded an average 76% increase in digoxin AUC and a 62% decrease in digoxin renal clearance (both P = .0001). After a 5-day coadministration period, digoxin AUC increased by an average 211% and apparent total body clearance was decreased by 67% (day 11) compared with steady-state administration of digoxin alone (day 6). Contributing to the change in total body clearance were decreases in both renal clearance (73%) and apparent nonrenal clearance (58%). Both drugs were well tolerated throughout the study. There was no clinically relevant change in the effect of digoxin on vital signs or electrocardiographic parameters when administered with single- or multiple-dose valspodar compared with administration alone in volunteers with healthy cardiovascular systems. CONCLUSIONS: Coadministration of oral valspodar and oral digoxin resulted in a twofold to threefold increase in digoxin systemic exposure. On the basis of these data in healthy volunteers, an initial digoxin dose reduction of 50% would appear to be appropriate when beginning oral valspodar treatment. Throughout the period of coadministration, patients should be carefully monitored for clinical signs of digoxin toxicity in conjunction with digoxin therapeutic drug monitoring. Together, these should serve as the basis for individualized digoxin dose titration.     

Digoxin-like immunoreactivity in serum from neonates and infants reduced by centrifugal ultrafiltration and fluorescence polarization immunoassay

We evaluated the TDx Digoxin II (Abbott) modified procedure for interference from digoxin-like immunoreactive factors (DLIF) in pediatric patients. The effectiveness of centrifugal ultrafiltration as a means of removing DLIF interference from the serum of such patients was assessed. We used sera from 40 patients who had not received digoxin, whom we divided into two age groups: 30 neonates (less than 34 days postpartum) and 10 infants (younger than six months). Digoxin-like immunoreactivity was detected in 34 of 41 (83%) neonatal specimens (range 0.2-1.0 micrograms/L) and 16 of 25 (60%) infants' specimens (range 0.2-1.3 micrograms/L). Centrifugal ultrafiltration of serum specimens from these patients reduced but did not eliminate the DLIF interference in some specimens. A comparison of concentrations of DLIF in serum with various other patients' characteristics demonstrated a strong correlation (r = 0.915; P = 0.0001) between DLIF and serum bilirubin in the infants. Apparent digoxin concentrations from 19 serum and serum ultrafiltrate samples collected from 13 patients (four neonates and nine infants) who were treated with digoxin showed a good correlation (r = 0.97); however, the serum samples showed a positive bias of 0.39 microgram/L. We conclude that the TDx Digoxin II modified procedure is still subject to considerable DLIF interference in these two pediatric populations. This interference can be reduced in some serum specimens, but cannot be eliminated completely as others reported.     

Comparison of four digoxin immunoassays with respect to interference from digoxin-like immunoreactive factors

Objectives: Comparison of a new monoclonal digoxin assay with three polyclonal digoxin assays for their cross-reactivity to digoxinlike immunoreactive factors (DLIF) and digoxin metabolites.

Design and Methods: Sixty-:six nondigitalized patient samples from 5 different groups: neonates, women in 3rd trimester pregnancy, and patients with liver or renal diseases, or undergoing organ transplants, and 139 samples from digoxin-treated patients of 4 categories (hospital sick, liver, renal, and outpatients) were compared in 4 different digoxin assays: (a) ACS™ Digoxin (ACS) developed for the automated chemiluminescent Ciba Corning ACS 180^® system, (b) Baxter Stratus™ (Stratus, a fluoroimmunoassay), (c) Ciba-Corning Magic^TM (Magic, a radioimmunoassay), and (d) an in-house radioimmunoassay (RIA). The ACS^TM and RIA were also compared for their cross-reactivity to four principal digoxin metabolites.

Results and Conclusion: Among the nondigitalized specimens, no significant DLIF interference was found for all 4 assays among the pregnant women or liver and transplant patients. However, the neonates registered high DLIF interference with Magic™ and RIA, but none for ACS™ or Stratus™. DLIF interference in renal samples was highest in the Magic assay and lowest in RIA. Among the specimens with digoxin, a higher number of discrepant samples were found from the sick patients than from outpatients. In 75% of such discrepant samples, the ACS™ result was less than other assay results, suggesting DLIF as the probable cause. The two assays differed most in their cross-reactivity to the deglycated metabolites, digoxigenin and its mono-digitoxoside.     

Digoxin pharmacokinetics: role of renal failure in dosage regimen design.

Radioimmunoassayed serum concentration and urinary excretion data for digoxin from azotemic patients were characterized using a 2-compartment open model. Urinary excretion rates of digoxin as well as serum concentration data are needed to accurately characterize the disposition of the drug. Seven patients with renal failure showed highly variable steady-state volumes of distribution (V-ss-D equals 195 to 489 liters/1.73 m-minus2) and t1/2beta values (1.5 to 5.2 days). This variability is a major limiting factor in the use of dosage regimen nomograms that assume a constant V-ss-D and a rigorous relationship between t1/2beta and creatinine clearance (Cl-CR). Body clearance (Cl-B) is a parameter that is affected by both elimination and distribution of drugs. A linear relationship between Cl-B and renal clearance of digoxin or Cl-CR was found and was used to develop a model-independent approach to calculation of maintenance doses of digoxin. Several methods for calculating steady-state serum concentrations of digoxin (C-ss-p) were compared with actual measurements obtained in 16 chronically medicated patients. Optimum computation of C-ss-p is obtained by use of digoxin renal and body clearances. Variability in the digoxin:creatinine renal clearance ratio is the major limiting factor in prediction of digoxin dosage regimens.     

Digoxin intoxication: the relationship of clinical presentation to serum digoxin concentration

A radioimmunoassay for serum digoxin concentration has been used to study the interrelationships of circulating levels of the drug and various factors in the clinical setting in 48 hospitalized patients with cardiac rhythm disturbances due to digoxin intoxication. 131 patients on maintenance doses of digoxin without toxicity and 48 patients with equivocal evidence of digoxin excess were also studied and compared with the toxic group.Patients with cardiac rhythm disturbances due to digoxin intoxication tended to be older and to have diminished renal function compared with the nontoxic group; body weight, serum potassium concentration, underlying cardiac rhythm, and nature of cardiac disease were not significantly different for the groups as a whole. Despite comparable mean daily digoxin dosages, digoxin intoxicated patients had a mean serum digoxin concentration of 3.7 +/-1.0 (SD) ng/ml, while nontoxic patients had a mean level of 1.4 +/-0.7 ng/ml (P < 0.001), 90% of patients without evidence of toxicity had serum digoxin concentrations of 2.0 ng/ml or less, while 87% of the toxic group had levels above 2.0; the range of overlap between the two groups extended from 1.6 to 3.0 ng/ml. Patients with atrioventricular block as their principal toxic manifestation had a significantly lower mean serum digoxin concentration than those in whom ectopic impulse formation was the chief rhythm disturbance.Patients with equivocal evidence of digoxin excess had received comparable daily maintenance doses of digoxin but had a mean serum concentration of 1.9 +/-0.8 ng/ml, intermediate between those of the nontoxic (P < 0.005) and toxic (P < 0.001) groups. Renal function as judged by mean blood urea nitrogen concentration was also intermediate.The data indicate that knowledge of the serum digoxin concentration, weighed in the clinical context, is useful in the management of patients receiving this drug.     

Quinidine reduces biliary clearance of digoxin in man

Quinidine is known to reduce the renal clearance of digoxin, but this effect does not completely explain the influence of quinidine on the total clearance of digoxin. We therefore studied the effect of quinidine administration on biliary clearance of digoxin in five patients with atrial fibrillation. Biliary clearance of digoxin under steady state conditions before and during treatment with quinidine was investigated using a duodenal-marker-perfusion technique. Quinidine caused an average 42% (range 21-65%, P less than 0.02) reduction of the measured biliary clearance of digoxin. We conclude that the biliary effect adds to the previously demonstrated inhibitory effect of quinidine on the renal clearance of digoxin and helps to explain the decrease in total clearance of the drug. This is the first demonstration in man of a pharmacokinetic drug interaction at the level of biliary excretion.     

Apixaban after hip or knee arthroplasty versus enoxaparin: efficacy and safety in key clinical subgroups

Background: New oral anticoagulants for thromboprophylaxis after hip or knee arthroplasty have been given as fixed‐dose regimens. Objective: To evaluate the consistency of the antithrombotic efficacy and bleeding risk of apixaban 2.5 mg twice daily compared with enoxaparin 40 mg once daily after knee or hip arthroplasty across the clinical characteristics of age, gender, body weight, body mass index (BMI) and creatinine clearance. Methods: The pooled results of the ADVANCE‐2 (knee arthroplasty) and ‐3 (hip arthroplasty) randomized trials were used to evaluate if treatment had a statistically significantly different effect (P < 0.10) on major venous thromboembolism (VTE) and bleeding for the characteristics of age, gender, body weight, BMI and creatinine clearance. Both univariate analysis and multivariate logistic regression were used. Results: Univariate analyses identified statistically significant interactions for age and major VTE (P = 0.09); for both age (P = 0.07) and body weight (P = 0.07) and the outcome of major bleeding; and for creatinine clearance (P = 0.03) and the composite outcome of major and clinically relevant non‐major bleeding. Estimates of these possible differences were not precise, with wide 95% confidence intervals (CIs) that included a zero difference for several subgroups. Multivariate logistic regression analysis did not detect a statistically significant interaction for any outcomes. Conclusions: This analysis found no convincing evidence that age, weight, gender, BMI or creatinine clearance influenced the balance of benefit to risk for apixaban compared with enoxaparin. Because only 5% of patients had a creatinine clearance between 30 and 50 mL min^?1, further data are needed in such patients.