Population pharmacokinetics of ABT-594 in subjects with diabetic peripheral neuropathic pain

What is known and Objective:  ABT‐594 is a non‐opioid, non‐NSAID analgesic. The objective of this work was to characterize the population pharmacokinetics of ABT‐594 in subjects with neuropathic pain. Methods:  Efficacy, safety and pharmacokinetics of ABT‐594 in subjects with painful diabetic polyneuropathy were evaluated in a randomized, double‐blind, placebo‐controlled, parallel‐group, multi‐centre, 7‐week Phase 2 study. Subjects (N = 266) were approximately equally divided into four groups to receive BID regimens of placebo or 150, 225 and 300 μg of ABT‐594. ABT‐594 concentrations were determined from all subjects, whereas a subset of subjects provided intensive pharmacokinetic samples on two occasions. One‐ and two‐compartment models were explored for characterizing plasma ABT‐594 concentration–time profiles. The relative importance of covariates (age, weight, body surface area, creatinine clearance, gender, nicotine use and albumin concentrations) was examined by use of the likelihood ratio test. Model building was accomplished using stepwise forward selection (P < 0·05) and backward elimination (P < 0·005) of covariates. Population analyses were performed using NONMEM. Results and Discussion:  Optimal characterization of the plasma concentration data was achieved using a one‐compartment base model. Creatinine clearance and age were found to be significant covariates in the forward selection process; backward elimination process identified only creatinine clearance as a significant covariate. What is new and Conclusion:  A population pharmacokinetic model was developed to characterize ABT‐594 concentrations in subjects with neuropathic pain. As ABT‐594 is primarily eliminated as unchanged drug in the urine, creatinine clearance and age were significant covariates of clearance with creatinine clearance being the optimal predictor of ABT‐594 clearance.     

Breath analyzer screening of emergency department patients suspected of alcohol intoxication

Background

Acute alcohol intoxication is a frequent cause of emergency department (ED) visits. Evaluating a patient’s alcohol intoxication is commonly based on both a physical examination and determination of blood alcohol concentration (BAC).

Objective

To demonstrate the feasibility and usefulness of using a last-generation infrared breath analyzer as a non-invasive and rapid screening tool for alcohol intoxication in the ED.

Methods

Adult patients suspected of acute alcohol intoxication were prospectively enrolled over 10 days. Breath alcohol concentrations (BrAC) were measured using a handheld infrared breath analyzer. BAC was determined simultaneously by automated enzymatic analysis of a venous blood sample. The relationship between BAC and BrAC values was examined by both linear regression and Bland-Altman analysis.

Results

The study included 54 patients (mean age 40 ± 14 years, sex ratio M/F of 3/1). Breath and blood alcohol concentrations ranged from 0 to 1.44 mg/L and from 0 to 4.40 g/L (0–440 mg/dL), respectively. The mean individual BAC/BrAC ratio was 2615 ± 387, 95% confidence interval 2509–2714, which is 30% higher than the legal ratio in France (2000). The correlation between both measurements was excellent: r = 0.95 (0.92–0.97). Linear regression revealed BAC = 0.026 + 1.29 (BrAC × 2000) and BAC = 0.026 + 0.99 (BrAC × 2615). Mean BAC-BrAC differences and limits of agreement were 0.49 g/L [−0.35, 1.34] (or 49 mg/dL [−35, 134] and 0.01 g/L [−0.68, 0.71] (or 1 mg/dL [−68, 71]), for the 2000 and 2615 ratios, respectively.

Conclusion

The calculated conversion coefficient provided a satisfactory determination of blood alcohol concentration. Breath alcohol testing, using appropriate BAC/BrAC conversion, different from the legal BAC/BrAC, could be a reliable alternative for routine screening and management of alcohol intoxication in the ED.     

Population pharmacokinetics of caffeine in healthy male adults using mixed-effects models

Objective: Caffeine has been shown to maintain or improve the performance of individuals, but its pharmacokinetic profile for Asians has not been well characterized. In this study, a population pharmacokinetic model for describing the pharmacokinetics of caffeine in Singapore males was developed. The data were also analysed using non‐compartmental models. Methods: Data gathered from 59 male volunteers, who each ingested a single caffeine capsule in two clinical trials (3 or 5 mg/kg), were analysed via non‐linear mixed‐effects modelling. The participants’ covariates, including age, body weight, and regularity of caffeinated‐beverage consumption or smoking, were analysed in a stepwise fashion to identify their potential influence on caffeine pharmacokinetics. The final pharmacostatistical model was then subjected to stochastic simulation to predict the plasma concentrations of caffeine after oral (204, 340 and 476 mg) dosing regimens (repeated dosing every 6, 8 or 12 h) over a hypothetical 3‐day period. Results: The data were best described by a one‐compartmental model with first‐order absorption and first‐order elimination. Smoking status was an influential covariate for clearance: clearance (mL/min) = 110*SMOKE + 114, where SMOKE was 0 and 1 for the non‐smoker and the smoker respectively. Interoccasion variability was smaller compared to interindividual variability in clearance, volume and absorption rate (27% vs. 33%, 10% vs. 15% and 23% vs. 51% respectively). The extrapolated elimination half‐lives of caffeine in the non‐smokers and the smokers were 4 · 3 ± 1 · 5 and 3 · 0 ± 0 · 7 h respectively. Dosing simulations indicated that dosing regimens of 340 mg (repeated every 8 h) and 476 mg (repeated every 6 h) should achieve population‐averaged caffeine concentrations within the reported beneficial range (4 · 5–9 μg/mL) in the non‐smokers and the smokers respectively over 72 h. Conclusion: The population pharmacokinetic model satisfactorily described the disposition and variability of caffeine in the data. Mixed‐effects modelling showed that the dose of caffeine depended on cigarette smoking status.     

去甲万古霉素群体药动学研究

目的研究去甲万古霉素在感染患者中的群体药动学(PPK)。方法PPK研究在诊断或拟诊为革兰阳性菌感染患者146例中进行,以非线性混合效应模型(NONMEM)程序建立并验证去甲万古霉素PPK模型,根据患者的PPK参数制定给药方案。结果①去甲万古霉素基础药动学模型为线性二房室模型,药动学参数个体间变异为指数模型,个体内变异为加法模型,清除率(CL)、中央室分布容积(V_1)、室间清除率(Q)和周边室分布容积(V_2)的患者个体间变异分别为35.92%、11.40%、0和79.75%,残差误差为3.05mg/L;②患者Ccr值的变化对去甲万古霉素CL的影响不同,当患者肾功能减退时(Ccr≤85 mL/min),CL=2.54×(Ccr/50)~(1.20),当患者肾功能正常时(Ccr>85mL/min),CL=5.66×(WT/60)~(0.52);③患者合并使用利尿药后使去甲万古霉素V_2增大;④老年感染患者(≥65岁)的CL减慢、t_(1/2β)延长,AUC增大。结论肾功能减退和年龄对去甲万古霉素药动学参数有显著影响;根据上述研究结果制定了去甲万古霉素在不同群体患者中的给药方案。     

Population pharmacokinetics of imipenem in burn patients

The interindividual variability of imipenem pharmacokinetic parameters in burn patients suggest that these parameters have to be estimated with a large number of patients. The aim of this study is (i) to estimate these parameters with a population pharmacokinetic approach, and (ii) to test the influence of factors on pharmacokinetics parameters. Data are provided by therapeutic drug monitoring (n = 47,118 samples) and analysed by a nonlinear mixed effect modelling method. Among the tested covariates (age, gender, body weight, height, size of burn and creatinine plasma level) creatinine plasma level affects imipenem pharmacokinetic parameters substantially. The best fit is obtained with a two-compartment model integrating a linear-inverse relationship between imipenem clearance and creatinine plasma level. The estimates of imipenem clearance (16.37 +/- 0.204 L/h) and of the distribution volume of the central compartment (0.376 +/- 0.039 L/kg) are higher in the population of burn patients than the estimates in healthy subjects. This result is connected with high values of glomerule filtration rate and confirms the interest of therapeutic drug monitoring of imipenem in burn patients and particularly for patients with extreme values of creatinine clearance.     

Population pharmacokinetics and pharmacodynamics of biapenem in paediatric patients

Objective: To develop a population pharmacokinetic model for biapenem in paediatric patients and to use the parameter estimates to assess pharmacodynamic exposure of common bacterial populations. Methods: Biapenem plasma concentrations (n = 125) from 25 paediatric patients were analysed using nonmem . The parameter estimates were used in a Monte Carlo simulation to predict the exposure time during which the drug concentration remains above the minimum inhibitory concentration. Results: A two‐compartment model fitted the data, and creatinine clearance (CL_cr) and total body weight (TBW) were the most significant covariates. The final model was CL (L/h) = 0·0458 × CL_cr, V_c (L) = 0·162 × TBW, Q (L/h) = 2·05, V_p (L) = 1·73, where CL is the clearance, V_c is the volume of distribution of the central compartment, Q is the intercompartmental clearance and V_p is the volume of distribution of the peripheral compartment. Biapenem regimens of 5 mg/kg q8h and 10 mg/kg q8h provided sufficient pharmacodynamic exposures to Pseudomonas aeruginosa and Streptococcus pneumoniae in most typical patient populations. Conclusion: These results better define the pharmacokinetics of biapenem and help in the choice of the appropriate dosage regimens for paediatric.     

Population pharmacokinetics of intravenous valproic acid in Korean patients

OBJECTIVE: To determine population-based pharmacokinetic parameters for intravenous valproic acid, and the factors influencing these parameters, in Korean adults. METHODS: Valproic acid concentrations were obtained using a peak and trough sampling scheme for 102 Korean epileptic patients who were not taking concurrent antiepileptic medication. Three hundred and fifty-four serum concentrations were analysed according to a one-compartment model with a mixed effect modelling method (NONMEM Ver 5.0). The influence of body-weight (kg), height, daily valproic acid dose (mg/day), body mass index (kg/m2), sex, and age on volume of distribution (Vd) and clearance (CL) was assessed in the course of analysis. RESULTS: Vd and CL of valproic acid increased with body-weight. No significant influence of the other screened covariates was observed. The final regression model was: [equation: see text]. Interindividual variabilities (coefficient of variation) for CL and Vd were 32 and 18%, respectively. Residual error including intraindividual variability was 26.7%. CONCLUSION: The current results may be used as a basic reference to optimize drug therapy with intravenous valproic acid. Further research on the paediatric population is necessary to confirm the non-linearity of the relation between body-weight and Vd.     

Population pharmacokinetics of intravenous itraconazole in patients with persistent neutropenic fever

Purpose:  Empirical use of intravenous (IV) itraconazole (ITZ) for febrile neutropenic patients has recently been introduced in Korea. This study was designed to investigate the population pharmacokinetics (PK) of IV-ITZ.
Methods:  Sparse PK data were collected from febrile neutropenic patients undergoing empirical ITZ therapy at 200 mg/day after loading doses. NONMEM (Version. 5·1·1) was used to estimate population PK parameters.
Results:  Forty-two patients were enrolled in the study. Mean population CL and V of IV-ITZ were 10 L/h and 1050 L, respectively. Body weight was the only contributing covariate of CL. The median simulated trough concentration of ITZ after 10 days was predicted to be about 700 ng/mL.
Conclusions:  In this study, we explored the population PK profile of ITZ given in IV formulation. We found that the current dosage regimen of IV-ITZ (200 mg/day) was appropriate to obtain therapeutic trough concentrations for neutropenic patients in Korea.     

Population pharmacokinetics of cefepime in neonates with severe nosocomial infections

Objective: To define the pharmacokinetic behaviour of cefepime in neonates with severe nosocomial infections using a mixed effects model. Patients and methods: Thirty‐one newborn infants were included in the study; 10 additional infants participated in the validation of the pharmacokinetic model. Cefepime CL and V were determined using an open monocompartmental model with first‐order elimination. The influence of demographic and clinical characteristics on the model was evaluated. The non‐linear mixed effect model (nonmem ) program was used to determine the pharmacokinetic population model. Results: The mean corrected gestational age for infants participating in the construction and validation of the model were 35 and 33 weeks, respectively. Factors included in the final pharmacokinetic model were body surface area (BSA) and calculated CL_CR. The final population model was CL (L/h) = 0·457 BSA (m²) + 0·243 CL_CR (L/h) and V(L) = 4·12 BSA (m²). This model explains 33·3% of the interindividual variability for CL and 12·8% for V. This model was validated in ten neonates with nosocomial infections by assessing the predictive capacity of plasma cefepime concentrations using a priori and Bayesian strategies. Conclusions: The predictive performance of this population model for cefepime plasma concentrations was adequate for clinical purposes and can be used for individualizing cefepime therapy in newborn infants with severe infections. Cefepime plasma concentrations can be predicted based on BSA and calculated CL_CR. Cefepime therapy using a 250 mg/m² dose administered every 12 h is adequate to achieve plasma concentrations greater than 8 μg/mL during more than 60% of the dosing interval and is expected to be effective in the treatment of bloodstream infections caused by most gram negative organisms in newborn infants. A dose of 550 mg/m² would be required for the treatment of infections caused by Pseudomonas sp.     

Differences in the single-oral-dose pharmacokinetics and urinary excretion of paracetamol and its conjugates between Hong Kong Chinese and Caucasian subjects

BACKGROUND AND OBJECTIVES: The present study was conducted to determine if ethnic differences exist for single oral dose pharmacokinetics of paracetamol and its conjugates between Hong Kong Chinese and Caucasian subjects. METHODS: Twenty healthy Chinese (n = 11) and Caucasian (n = 9) subjects, aged 21-44 years, 11 male and nine female, were given oral paracetamol syrup 20 mg/kg, following an overnight fast. Paracetamol and its metabolites (glucuronide, sulphate, cysteine and mercapturic acid conjugates) were measured in serial plasma samples (0.25, 0.5, 0.75, 1.0, 1.5, 2, 3,...,12, 24 h) and urine collections (0-24 h) by high-performance liquid chromatography. RESULTS: In Chinese subjects, the (mean range) peak plasma concentration of paracetamol was 23.8 mug/mL (17.9-32.3) and time to attain this peak 0.66 h (0.5-0.75). This was lower (P < 0.015) at 18.7 microg/mL (14.4-22.9) and achieved later (P < 0.033) at 1.06 h (0.5-2.0) in Caucasians. In Chinese subjects, plasma levels of glucuronide were lower, sulphate higher and cysteine conjugates significantly lower than in Caucasians (P < 0.05). Chinese subjects excreted 6% more sulphate and 5% less glucuronide. They also excreted significantly less mercapturic acid conjugates (P < 0.001). DISCUSSION AND CONCLUSION: Chinese subjects show more rapid absorption of paracetamol, a tendency to produce less glucuronide but more sulphate conjugates and reduced production of cysteine and mercapturic acid conjugates. The latter may help to protect against hepatotoxicity following paracetamol overdose.     

The pharmacokinetics of fluconazole in healthy Chinese adult volunteers: influence of ethnicity and gender

Objective: The purpose of the present study was to investigate and compare the influence of ethnicity (including Han, Mongolian, Korean, Hui and Uygur) and gender on the pharmacokinetics of fluconazole in healthy adult volunteers after administration of 200‐mg fluconazole tablet. Methods: Ten healthy subjects (five males and five females) of each ethnicity were recruited and given a single 200‐mg dose of fluconazole in tablet form. Blood samples were obtained before dosing and at various predetermined time points after administration up to 96 h. Drug levels were measured by high‐performance liquid chromatography. The blood concentration–time profiles were analyzed using a non‐compartmental approach to estimate the absorption parameters (AUC_(0–96), C_max and t_max), the distribution parameter (V_d) and the disposition parameters (t_1/2 and CL). Results: Ethnicity did not affect the parameter estimates, but gender did. However, the gender differences in pharmacokinetic parameter could be accounted for by differences in weight. There was a high linear correlation between weight and ln C_max, ln AUC (ln means natural logarithmic transformation), V_d and CL. Conclusions: Ethnicity (Chinese Han, Mongolian, Korean, Hui and Uygur) influences the pharmacokinetics of fluconazole tablet. However, there were statistically significant gender differences in AUC, C_max, V_d and CL. But these could be accounted for by weight differences. If fluconazole dose‐adjustment is deemed necessary, this can be done on a weight basis rather than gender basis.     

The individual variation in pharmacokinetics and pharmacodynamics of furosemide in young normal male subjects

Abstract. Following a 24 h control period in the ward 80 mg furosemide was injected intravenously to ten young healthy, male volunteers. The serum clearance of furosemide (Cl_s) was between 140 and 201 ml min^-1 and on the average the renal clearance was 66% of Cl_s. During the initial 30 min period a maximum additional excretion rate of sodium of 3·3 mmol min^-1 was reached at an excretion rate of 0·8 mg furosemide min^-1. A marked initial drop in creatinine clearance (Cl_cr) was noted and Cl_{cr(24 h)} showed an average decrease of 12% after the drug administration. The serum concentration of potassium was decreased at 1 and 2 h after the injection and of sodium from 2 h and on. The concentration of albumin in serum increased by 3% ( P < 0·05) already after 5 min. After 2 h a maximum increase of 14% was reached. After 8 min diastolic blood pressure was increased by 13% ( P < 0·05), whereas systolic blood pressure reached a significant decrease gradually (7% after 3 h).     

Effects of Paeoniae Radix, a traditional Chinese medicine, on the pharmacokinetics of phenytoin

BACKGROUND: Phenytoin (PHT), one of the most widely prescribed antiepileptic drugs, has been reported to be associated with numerous drug-drug interactions. However, there are far fewer reports about the pharmacokinetic interactions between PHT and traditional Chinese medicines (TCMs). Paeoniae Radix (PR), one of the well-known TCMs, is used as an adjunct in some epileptic patients. OBJECTIVE: In the present work, we studied the influences of PR on the pharmacokinetics of PHT in rats to identify the possible interactions between PR and PHT. METHOD: A single dose of PHT (100 mg/kg) alone or in combination with PR extract (300 mg/kg) was administered by gavage to male SD rats. Serial blood samples of PHT were obtained for up to 24 h post-administration and measured by high-performance liquid-chromatography. The free (unbound) plasma concentrations of PHT were determined by fluorescence polarization immunoassay. The plasma concentrations were used to construct pharmacokinetic profiles by plotting drug concentration-time curves. All data were subsequently processed by the computer program WINNONLIN. Statistical comparisons of pharmacokinetic parameters were performed with the unpaired Student t-test. RESULTS: The mean maximum plasma concentration of PHT was attained 2 h after oral administration of PHT alone and 4-6 h after oral administration of PHT in combination with PR. The plasma level of PHT declined with a half-life of 5.38 h after PHT alone and 4.03 h after PHT and PR given together. No statistically significant differences were obtained in most of the pharmacokinetic parameters (Cmax, AUC, t1/2, MRT and CL/F) and protein binding rates of PHT between the two treatments. However, significant differences in Tmax and Vd/F between groups were noted. CONCLUSION: The significant increase in Tmax indicated that simultaneous oral administration of PR delayed the absorption of PHT. The delayed absorption of PHT might lead to its slow onset of clinical effect. There were no significant differences in Cmax, AUC, t1/2, MRT and CL/F of PHT between the two groups, showing that PR could not significantly affect the extent of absorption, metabolism and elimination of PHT. No significant difference in protein binding rate was found, indicating that PR might not significantly alter the protein binding of PHT. While a significant decrease in Vd/F was noted, the mechanism underlying the apparently decreased Vd/F of PHT influenced by PR needs further study.     

Combination of long-acting furosemide and instant-acting amiloride: pharmacokinetics and pharmacodynamics in human subjects

Summary— The pharmacokinetics and pharmacodynamics of the combination of amiloride (2 times 2.5 mg) and long-acting furosemide (2 times 10 mg) were compared with amiloride (5 mg) and furosemide (20 mg) in 12 healthy male volunteers aged 26.2 ± 1.6 years and weighing 68.8 ± 6.2 kg, after random order administration. Furosemide and amiloride plasma or urine concentrations were determined by HPLC with fluorimetric detection. The rate of absorption ( t _max = 3 h) and the bioavailability of the two diuretics were not significantly modified by their combination. Furosemide plasma half-life was 2.77 ± 1.04 h after the combination treatment and 2.76 ± 0.98 h alone, amiloride plasma half-life was respectively 15.7 ± 4.6 h and 14.6 ± 3.7 h. The urinary elimination of furosemide was significantly higher in the 2–4 h interval in the combination treatment, accompanying its delayed maximum effect of diuresis. A synergistic effect was observed after the combination administration of the two diuretics; between the 2nd and the 8th hour, the sodium elimination was significantly increased ( P < 0.01) and the potassium excretion was significantly decreased ( P = 0.05). After a single dose, no modification of plasma or erythrocyte magnesium levels was observed. This study shows that the combination of the two drugs entails a synergy of their activities which does not involve pharmacokinetic changes.     

Population pharmacokinetics and pharmacodynamics of meropenem in Japanese pediatric patients

The aims of this study were to develop a population pharmacokinetic model for meropenem in Japanese pediatric patients, and to use this model to assess the pharmacodynamics of meropenem regimens against common bacterial populations. Pharmacokinetic data were pooled from nine separate studies (229 plasma samples and 61 urine samples from 40 infected children), modeled using the NONMEM program, and used for a pharmacodynamic simulation to estimate the probabilities of attaining the bactericidal target (40% of the time above the MIC for the bacterium). In the final population pharmacokinetic model, body weight (BW, kg) was the most significant covariate: Cl_r (l/h) = 0.254 × BW, Cl_nr (l/h) = 3.45, V _c (l) = 0.272 × BW, Q (l/h) = 1.65, and V _p (l) = 0.228 × BW, where Cl_r and Cl_nr are the renal and non-renal clearances, V _p and V _c are the volumes of distribution of the central and peripheral compartments, and Q is the intercompartmental (central–peripheral) clearance. In most typical patients (BW = 10, 20, and 30 kg), the approved regimens of 10–40 mg/kg, three times a day (0.5-h infusions), achieved a target attainment probability of >80% against Escherichia coli, Streptococcus pneumoniae, methicillin-susceptible Staphylococcus aureus, Haemophilus influenzae, and Pseudomonas aeruginosa isolates. The results of this study provide a better understanding of the pharmacokinetics and pharmacodynamics of meropenem in Japanese pediatric patients.     

Population pharmacokinetics of ketanserin in pre-eclamptic patients and its association with antihypertensive response

Ketanserin is an antihypertensive drug that is increasingly being used parenterally in the treatment of pre-eclampsia. Because of lack of efficacy in a substantial part of our pre-eclamptic patients, we determined the plasma concentrations of ketanserin in 51 pre-eclamptic patients. Population pharmacokinetic parameters were assessed using the iterative two-stage Bayesian population procedure. The influence of individual pharmacokinetic parameters on antihypertensive response, expressed as the attainment of a diastolic blood pressure 相似文献   

Population Pharmacokinetics Study of Nemonoxacin Among Chinese Patients With Moderate Hepatic Impairment

Purpose

Nemonoxacin is a novel C-8-methoxy nonfluorinated quinolone that has been approved for the treatment of community-acquired pneumonia (CAP) in adults. The goals of this study were to evaluate the pharmacokinetic (PK) and population PK parameters of nemonoxacin and to provide the appropriate dose adjustment recommendations for patients with hepatic impairment.