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.     

Population pharmacokinetics of digoxin in pediatric patients

Digoxin pharmacokinetics were studied in a pediatric population with an age range of 6 days to 1 year using the population pharmacokinetic approach. Digoxin data were analyzed by mixed-effects modeling according to a one-compartment steady-state pharmacokinetic model using NONMEM software. The final model selected for the population prediction of digoxin clearance in pediatric patients was as follows: [equation: see text] Individual empirical Bayesian estimates were generated on the basis of the population estimates and were used to correlate the optimum dose of digoxin and patient age according to the following equation: [equation: see text] This equation and its derived nomogram may be used for the initial dosing of digoxin in children aged between 0 and 1 year. The use of this nomogram in routine monitoring requires further pharmacokinetic and clinical validation.     

Population pharmacokinetics of haloperidol using routine clinical pharmacokinetic data in Japanese patients

OBJECTIVE: To clarify the observed variability of haloperidol disposition in patients with psychiatric disorders. DESIGN: Retrospective population pharmacokinetic study. PARTICIPANTS: 218 Japanese patients aged 16 to 82 years who provided 391 serum haloperidol concentrations. METHODS: Routine clinical pharmacokinetic data gathered from patients receiving haloperidol were analysed to estimate population pharmacokinetic parameters with the nonlinear mixed effects model (NONMEM) computer program. RESULTS: The final pharmacokinetic model was CL = 42.4 * (TBW/60)(0.655) * 0.814(AGE> or = 55) * (DOSE/200)(0.236) * 1.32(ANTIEP) and Vd = 34.4 * TBW * 0.336( AGE> or = 65), where CL is total body clearance (L/h), Vd is apparent volume of distribution (L), TBW is total bodyweight (kg), DOSE is daily dosage (microg/kg/day), ANTIEP = 1 for concomitant administration of antiepileptic drugs (phenobarbital, phenytoin or carbamazepine) and 0 otherwise, AGE > or = 55 = 1 for patient aged 55 years or over and 0 otherwise, and AGE > or = 65 = 1 for patient aged 65 years or over and 0 otherwise. Concomitant administration of haloperidol and antiepileptic drugs resulted in a 32% increase in haloperidol clearance. Patients aged 55 years or over showed an 18.6% reduction in clearance, and elderly patients aged 65 years or over showed a 66.4% reduction in apparent volume of distribution. Inclusion of terms for the concomitant administration of haloperidol and antiparkinsonian drugs (amantadine, bromocriptine, biperiden, trihexyphenidyl or mazaticol) or cytochrome P450 (CYP) 2D6 substrates (levomepromazine, perphenazine, thioridazine, amitriptyline or clomipramine) did not significantly improve the estimate of haloperidol clearance. CONCLUSION: Application of the findings in this study to patient care may permit selection of an appropriate initial maintenance dosage to achieve target haloperidol serum concentrations, thus enabling the clinician to achieve the desired therapeutic effect.     

老年心衰患者口服地高辛群体药动学模型的建立

目的:应用非线性混合效应模型计算国人老年心衰患者口服地高辛(digxion)群体药动学参数,以促进个体化给药。方法:采用荧光偏振免疫法(FPIA)测定84例老年患者120例次地高辛的血清浓度并收集相关临床指标,运用NONMEM软件建立群体药动学模型。结果:地高辛的药动学符合一室线性开放模型,固定效应参数中,体质量、剂量、血肌酐及尿素氮对参数有影响。最终回归模型中地高辛血药浓度估算值与实测浓度间线性关系良好。结论:用群体药动学模型分析常规监测数据可为老年患者个体化给药提供依据。     

Population pharmacokinetic model of digoxin in older Chinese patients and its application in clinical practice

Aim:

To establish a population pharmacokinetic (PPK) model of digoxin in older Chinese patients to provide a reference for individual medication in clinical practice.

Methods:

Serum concentrations of digoxin and clinically related data including gender, age, weight (WT), serum creatinine (Cr), alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN), albumin (ALB), and co-administration were retrospectively collected from 119 older patients taking digoxin orally for more than 7 d. NONMEM software was used to get PPK parameter values, to set up a final model, and to assess the models in clinical practice.

Results:

Spironolactone (SPI), WT, and Cr markedly affected the clearance rate of digoxin. The final model formula is Cl/F=5.9×[1–0.412×SPI]×[1–0.0101×(WT–62.9)]×[1–0.0012×(Cr–126.8)] (L/h); Ka=1.63 (h⁻¹); V_d/F=550 (L). The population estimates for Cl/F and V_d/F were 5.9 L/h and 550 L, respectively. The interindividual variabilities (CV) were 49.0% for Cl/F and 94.3% for V_d/F. The residual variability (SD) between observed and predicted concentrations was 0.365 μg/L. The difference between the objective function value and the primitive function value was less than 3.84 (P>0.05) by intra-validation. Clinical applications indicated that the percent of difference between the predicted concentrations estimated by the PPK final model and the observed concentrations were −4.3%–+25%. Correlation analysis displayed that there was a linear correlation between observated and predicted values (y=1.35x+0.39, r=0.9639, P<0.0001).

Conclusion:

The PPK final model of digoxin in older Chinese patients can be established using the NONMEM software, which can be applied in clinical practice.     

Population pharmacokinetic analysis of fexofenadine in Japanese pediatric patients

A population pharmacokinetic analysis was conducted to characterize the pharmacokinetics of fexofenadine in Japanese pediatric patients (6 months through 16 years) with perennial allergic rhinitis or atopic dermatitis. The dataset was composed of 515 patients (including 109 adults), for a total of 1,080 concentration–time points. The analysis was performed with NONMEM using the SAEM method. Several structural models and residual error models were evaluated. The relationship between the individual estimates and the potential covariates was then investigated: demographic and pathophysiologic characteristics were tested as potential model covariates (forward selection method). The qualification of the model was performed using visual predictive check and bootstrap. A two-compartment disposition model with first-order absorption best fitted the data. The inter-individual variability was modeled through an exponential error model for all parameters (except for ka for which no inter-individual term could be estimated), while a proportional error model was used to model the residual variability. The final model included two covariates on elimination clearance and one on the intercompartmental clearance. CL/F was related to BSA and patient’s age (expressed in months) Q/F was also related to BSA. Once the model was correctly qualified, exposure parameters such as C_max and AUC_τ were computed and compared between each age sub-group and between Japanese and Caucasians patients. These comparisons did not reveal any major difference (less than 50 %) between subgroups.     

Population pharmacokinetic analysis of micafungin in Japanese patients with fungal infections

The object of this analysis was to develop a population pharmacokinetic model of micafungin, a new anti-fungal agent of the echinocandin class, to optimize dosing in Japanese patients with fungal infections. Population pharmacokinetics parameters were determined using NONMEM based on pharmacokinetic data from 198 subjects in seven clinical studies, comprising four phase I, two phase II and one pediatric phase III study. The healthy subjects received intravenous infusion of 2.5-150 mg micafungin. Adult and pediatric patients, age range of 8 month to 15 yeras old, were received 25-150 mg and 1-6 mg/kg daily, respectively. A total of 1825 micafungin plasma samples were available for this analysis. Two-compartment pharmacokinetic model was adopted. The clearance of micafungin was influenced by body weight in children and platelet counts (PLT). However the PLT accounted for less than 20% of the variation of micafungin clearance in Japanese subjects. In conclusions, body weight is the primary covariate factor in pediatric patients. The dose adjustment by body weight would be required only pediatric patients for the micafungin therapy in Japanese patients with fungal infection.     

Differential pharmacokinetics of digoxin in elderly patients

Digoxin remains one of the most commonly prescribed of all cardiac medications. The main indications for digoxin usage include atrial fibrillation and heart failure; both these conditions are more prevalent in older patients. Given the aging population and the increasing incidence of heart failure we would expect prescribing of digoxin to remain as frequent or to even increase in older patients. Older patients are also more likely to develop toxicity and diagnosis of digoxin toxicity can be difficult in this group. Numerous components contribute to the development of toxicity in older patients, ranging from aging-related changes in renal function or body mass to polypharmacy and possible interactions with digoxin. It is therefore important to understand how the pharmacokinetics of digoxin may be altered in the older population. Application of basic pharmacological principles may be helpful in anticipating these problems. This review describes the pharmacokinetics of digoxin, the changes in pharmacokinetics with increasing age and how concomitant disease states or drug interactions may affect the pharmacokinetics of digoxin. Greater knowledge about the causes and prevention of digoxin toxicity should further reduce the morbidity and mortality arising from digoxin toxicity, especially in the elderly population.     

Population pharmacokinetic and exposure-response analyses of guanfacine in Japanese pediatric ADHD patients

Guanfacine hydrochloride extended-release tablet (GXR) is approved for child and adolescent patients with attention-deficit/hyperactivity disorder (ADHD). The aims of this study were to develop a population pharmacokinetic model of guanfacine after administration of GXR and to evaluate factors influencing the pharmacokinetics of guanfacine in pediatric ADHD patients. A population pharmacokinetic analysis was performed using 3231 plasma concentration data items of guanfacine for pediatric ADHD patients aged 6–17 years obtained from clinical studies in Japan and the US. In addition, the relationship of the ADHD Rating Scale IV (ADHD RS-IV, efficacy endpoint) total score with exposure to guanfacine was assessed for Japanese pediatric ADHD patients. A one-compartment model with first-order absorption and lag time well described the plasma concentration data of guanfacine in pediatric ADHD patients. Body weight was selected as a covariate of apparent total body clearance and apparent volume of distribution. There was no pharmacokinetic difference between Japanese and non-Japanese pediatric ADHD patients. The results suggested a tendency of exposure-dependent reduction in the ADHD RS-IV total score, whereas the reduction was observed even at low plasma exposure levels compared with the placebo group.     

地高辛中毒病人的临床药物动力学变化

本文对81例心衰病人的地高辛（DG）临床药物动力学资料进行研究，探讨中毒病人与非中毒病ADG临床药物动力学的差异及影响因素。结果中毒组病人的DG药物动力学参数与非中毒组病人存在极显著性差异（P＜0．01）、CL减少37．9％，Vd减少8．3％，T1／2延长43．5％，K减少1／3；给药剂量也应较非中毒病人减少40％，才能确保用药安全。中毒组病人年龄显著高于非中毒病人（P＜0．01），提示DG中毒多发生于老年心衰病人。而中毒组病人的肾功能显著低于非中毒病人（P＜0．01）。相关分析显示，年龄与肾功能、心功能、CL和Vd相关极为显著（P＜0．01），肾功能与DG药物动力学参数、心功能存在显著相关。     

Assay of cardiotonic steroids based on a 2-compartment model]

In an attempt to develop an assay method for cardiotonic steroids (CS), a two compartment model was applied to the whole dog. As representative CS, g-strophanthin, digoxin and digoxigenin were infused continuously to the animal, and the minimal cardiotonic, irregularity and lethal doses were determined, together with indices K1 and K2, representing the rate of uptake and elimination, respectively, of these compounds into and out of a specific site within the myocardium. The order of cardiotonic potency was: g-strophanthin greater than digoxin greater than digoxigenin. The indices K1 (and K2) were the greatest with digoxigenin )digoxigenin), the second greatest with g-strophanthin (digoxin) and the smallest with digoxin (g-strophanthin). The order of the margin of safety as a ratio between the minimal irregularity and the minimal cardiotonic doses was: digoxin greather than g-strrophanthin greather than lethal and the minimal cardiotonic doses. The cardiotonic, irregularity and lethal doses obtained in the present study coincided well with the values obtained in the canine heart-lung preparations, thus lending further support to the idea that effects of the CS appear when the substances accumulated to a definite amount at a specific site within the myocardium.     

Population pharmacokinetics of duloxetine in Japanese pediatric patients with major depressive disorder

The objectives of this analysis were to characterize the pharmacokinetics of duloxetine in Japanese pediatric patients aged 9–17 years with major depressive disorder (MDD) and to explore potential intrinsic factors affecting its pharmacokinetics. A population pharmacokinetic (PK) model was developed with plasma steady-state duloxetine concentrations from Japanese pediatric patients with MDD in an open-label long-term extension trial in Japan (ClinicalTrials.gov Identifier: NCT03395353). Duloxetine pharmacokinetics in Japanese pediatric patients was well described by a one-compartment model with first-order absorption. The population mean estimates of CL/F and V/F of duloxetine were 81.4 L/h and 1170 L, respectively. Patient intrinsic factors were assessed for their potential influence on duloxetine apparent clearance (CL/F). Only sex was identified as a statistically significant covariate of duloxetine CL/F. Duloxetine pharmacokinetic parameters and model-predicted duloxetine concentrations at steady state in the Japanese pediatric population were compared with those in Japanese adults. The mean duloxetine CL/F in pediatrics is slightly higher than adults, it is, however, expected that comparable steady-state duloxetine exposure in pediatric patients can be achieved with the approved dose regimen for adults. The population PK model provides useful information to understand the pharmacokinetic characteristics of duloxetine for Japanese pediatric patients with MDD.ClinicalTrials.gov identifierNCT03395353     

Population pharmacokinetics of clinafloxacin in healthy volunteers and patients with infections: experience with heterogeneous pharmacokinetic data

OBJECTIVE: Clinafloxacin is a new fluoroquinolone antibacterial with inhibitory activity against aerobic, anaerobic and atypical bacterial pathogens. The objectives of this study are to evaluate the pharmacokinetics of clinafloxacin in healthy volunteers and patients with infections and to describe our experience with mixed-effects modelling using heterogeneous pharmacokinetic data. DESIGN AND SETTING: Retrospective analysis of data from phase I to III trials. PATIENTS AND PARTICIPANTS: 204 healthy volunteers and 221 patients with infections. METHODS: Nonlinear mixed-effects modelling (MEM) was used to evaluate 3437 clinafloxacin plasma concentrations collected in 15 phase I to III trials. Models were developed separately for the healthy volunteers and patients, and then for the combined study population. RESULTS: The phase I data were best described with a 2-compartment linear model with first-order absorption. The absorption lag-time and absorption rate constant were 0.24h and 1.17h(-1), respectively. The volumes of distribution were found to be nonlinear functions of body surface area. Estimated creatinine clearance was the most important covariate for systemic clearance (CL). Interoccasion variability (IOV) in CL was observed in the patients in the phase II trial. In the combined study population, the variability in CL was best described by a model including IOV and distinct variabilities for healthy volunteers and patients. CONCLUSION: MEM was useful for evaluating data collected during different phases of drug development for this new fluoroquinolone agent.     

Population pharmacokinetic analysis of letrozole in Japanese postmenopausal women

Purpose  

Letrozole is an orally active aromatase inhibitor for the treatment of breast cancer. The objectives of this study were to examine the pharmacokinetic profile of letrozole in Japanese subjects and to identify factors that influence variability in the pharmacokinetics of letrozole using population pharmacokinetic (PPK) analysis.     

Population pharmacokinetics of gentamicin in neonates using a nonlinear, mixed-effects model.

The population pharmacokinetics of gentamicin in neonates was determined using a nonlinear, mixed-effects model (NONMEM). The final regression equations derived to estimate clearance (Cl) and volume of distribution (Vd) were Cl = 0.120 * (WT/2.4)1.36 L/hr and Vd = 0.429 * (WT) L. The interindividual variability (% CV) for clearance was 26.2% and for volume of distribution 15.9%. Intraindividual variability was 11.0%. In a separate group of 30 neonates, the predictive ability of the NONMEM-generated population variables was compared to the predictions from a standard two-stage population analysis. The trough concentrations predicted using NONMEM-generated parameters were significantly less biased and more precise; there were no significant differences between the methods in predicting peaks. NONMEM is a useful tool for determining population pharmacokinetics and appears to be consistent across populations using routine clinical data and limited observation.     

Evaluation of a computerized digoxin pharmacokinetic consultation service

A pharmacy-conducted digoxin pharmacokinetic consultation service was implemented to determine the influence of the service on patient serum digoxin concentrations. Changes in digoxin dosages and serum levels during a three-week period were compared with a three-week control period in which the consultation was not offered. Of 47 patients evaluated, there was no statistically significant (P > 0.05) difference between the control and the study group in terms of population variables. The study group receiving pharmacokinetic consultations showed a significantly greater (P > 0.05) number of dosage changes resulting in therapeutic serum drug levels than did the control group whose physicians received a report of serum drug level by itself. The number of patients with steady-state serum digoxin levels in the therapeutic range of 1-2 ng/ml increased from 45.5% to 80% as a result of the clinical pharmacokinetic consultations. This study demonstrated that a pharmacy-based clinical pharmacokinetic consultation service can provide potential benefits to the patient by aiding clinicians in optimizing serum drug concentrations.     

Population pharmacokinetics of ceftriaxone in critically ill septic patients: a reappraisal

AIMS

To investigate the population pharmacokinetics of ceftriaxone in critically ill patients suffering from sepsis, severe sepsis or septic shock.

METHODS

Blood samples were collected at preselected times in 54 adult patients suffering from sepsis, severe sepsis or septic shock in order to determine ceftriaxone concentrations using high-performance liquid chromatography-ultraviolet detection. The pharmacokinetics of ceftriaxone were assessed on two separate occasions for each patient: on the second day of ceftriaxone therapy and 48 h after catecholamine withdrawal in patients with septic shock, or on the fifth day in patients with sepsis. The population pharmacokinetics of ceftriaxone were studied using nonlinear mixed effects modelling.

RESULTS

The population estimates (interindividual variability; coefficient of variation) for ceftriaxone pharmacokinetics were: a clearance of 0.88 l h⁻¹ (49%), a mean half-life of 9.6 h (range 0.83–28.6 h) and a total volume of distribution of 19.5 l (range 6.48–35.2 l). The total volume of distribution was higher than that generally found in healthy individuals and increased with the severity of sepsis. However, the only covariate influencing the ceftriaxone pharmacokinetics was creatinine clearance. Dosage simulations showed that the risk of ceftriaxone concentrations dropping below the minimum inhibitory concentration threshold was low.

CONCLUSIONS

Despite the wide interpatient variability of ceftriaxone pharmacokinetic parameters, our results revealed that increasing the ceftriaxone dosage when treating critically ill patients is unnecessary. The risk of ceftriaxone concentrations dropping below the minimum inhibitory concentration threshold is limited to patients with high glomerular filtration rates or infections with high minimum inhibitory concentration pathogens (>1 mg l⁻¹).