Pharmacokinetics of propofol when given by intravenous infusion.

We have previously shown with i.v. bolus studies that the elimination of propofol is much slower than previously reported. Now we have studied the implications of this for prolonged i.v. infusion of propofol in seven patients who received continuous infusions of propofol for up to 9 h. Values of elimination half-life ranged from 13.1 to 44.7 h, systemic clearance from 1.02 to 1.63 l h-1 and volume of distribution from 1390 to 3940 l and these were similar to those obtained with bolus administration. The large volume of distribution is consistent with the high octanol/blood partition coefficient, which was found to be 72.0. Despite the very long elimination half-life, blood propofol concentrations appeared to approach steady state within 20 min rather than the 4-5 half-lives normally expected. This is because for this drug, which displays multicompartment pharmacokinetics, the rate of initial rise of blood concentrations is governed primarily by the very short distribution half-life of the drug. Therefore, the long elimination half-life of propofol is probably of little significance in designing infusions regimens, but the lower systemic clearance should be taken into account to avoid unwanted accumulation.     

Pharmacokinetic properties of rithmidazole upon single intravenous introduction

The kinetics of rithmidazole (an imidazobenzimiodazole derivative possessing the properties of I, III, and IV class antiarrhythmics) was studied upon a single intravenous introduction in rats (in a dose of 10 mg/kg) and in healthy male volunteers (300 mg/kg). The drug pharmacokinetics in rat blood plasma was characterized by rapid elimination from the systemic blood flow (drug detected by HPLC only within 6 h); the total plasma clearance was 1.43 liter/(h kg), the terminal half-elimination time was 1.76 h, and the equilibrium distribution volume (2.42 liter/kg) exceeded the total volume of water in the animal organism, which is indicative of a high level of absorption in tissues. The drug is characterized by a low level of binding to blood proteins and erythrocytes. Investigation of the drug distribution between tissues showed evidence of extensive, blood-flow-dependent penetration, with the drug concentration in most tissues exceeding that in the blood plasma. The maximum amounts of rithmidazole were found in the lungs, spleen, liver, and kidneys. The major excretion route for the unchanged drug is via urine and bile, amounting to 10% and approximately 1% of the dose introduced, respectively, determined within 72 h. The results are indicative of a low probability of the hepatoduodenal circulation of the unchanged substance: about 90% of the drug undergo metabolic transformation. The pharmacokinetics of rithmidazole in volunteers was also characterized by rapid elimination from the systemic blood flow; the total plasma clearance was 0.89 liter/(h kg), the terminal half-elimination time was 2.12 h, and the equilibrium distribution volume was 1.66 liter/kg. The obtained results show that the pharmacokinetic profiles of rithmidazole in rats and humans exhibit a similar character, with a high intensity of distribution and elimination processes.     

Clinical pharmacokinetics of dothiepin. Single-dose kinetics in patients and prediction of steady-state concentrations

The pharmacokinetics of dothiepin were evaluated in 9 depressed patients following a single oral dose of 75 mg. Blood and plasma concentrations of dothiepin and 2 major metabolites, northiaden and dothiepin S-oxide, were measured by gas chromatography/mass fragmentography. The mean (+/-SD) peak plasma concentrations of dothiepin were 49 +/- 27 micrograms/L at 3 +/- 1.2h. Mean (+/-SD) estimates of other parameters were as follows: absorption half-life 1.1 +/- 1.1h; distribution half-life 2.2 +/- 0.8 h; elimination half-life 25 +/- 7h; apparent volume of distribution 70 +/- 62 L/kg; and oral clearance 2.1 +/- 1.6 L/kg/h. The mean (+/-SD) peak plasma concentration of dothiepin S-oxide was 125 +/- 43 micrograms/L at 3.5 +/- 1.3h with an elimination half-life of 22 +/- 12 h. The mean peak plasma concentration of northiaden was 6 +/- 3 micrograms/L at 4.5 +/- 1.1h, with an elimination half-life of 31 +/- 12 h. No significant differences were found in pharmacokinetic parameters compared with a previous study in 7 healthy volunteers. When data for the patients and healthy volunteers were combined (n = 16), pharmacokinetic parameters were not found to be affected by age. However, a significant difference was found between males and females for the elimination half-lives of dothiepin and northiaden, and for the apparent volume of distribution of dothiepin. The 24-hour blood/plasma concentrations of dothiepin and dothiepin S-oxide accurately predicted the steady-state concentrations obtained following 4 weeks' treatment with dothiepin 150 mg nocte.     

Simplified approaches to the determination of antipyrine pharmacokinetic parameters.

1. The pharmacokinetics of single intravenous doses of antipyrine were determined in 96 volunteers using multiple (12 or more) plasma antipyrine concentrations measured by high-pressure liquid chromatography during 24-48 h after dosage. These kinetic estimates were compared with those based on: A, the 4 h and 12 h points only; B, the 4 h through 12 h points; C, the 8 h and 24 h points only. 2. Mean clearance values for the complete study (48.0 ml min-1) were nearly identical to abbreviated approaches A, B, and C (49.1, 49.3, and 46.4 ml min-1), and were highly correlated (r = 0.99). 3. Coefficients of variation (CV) between individual clearance values for complete vs abbreviated studies averaged 5.5%, 5.8% and 2.9%, and CVs were less than 15% in 95.8%, 93.7% and 98.9% of subjects, respectively, for methods A, B, and C. 4. Overall mean values of elimination half-life (11.9, 12.1, 12.0 and 12.5 h) and volume of distribution (43.7, 45.1, 45.2, and 44.71) were likewise very similar for complete A, B and C analyses respectively. 5. The best correlation with the complete study was observed for the 8 and 24 h sampling scheme, for which clearance values were within 5% of the reference method in 84% of subjects, and within 10% in 97% of subjects. 6. Antipyrine pharmacokinetic parameters can be estimated with reasonable precision using a simplified two-point blood sampling procedure following a single intravenous dose. Estimates of elimination half-life, volume of distribution and clearance based on 8 h and 24 h data points correlated best with complete pharmacokinetic studies.     

Pharmacokinetics and adverse reactions after a single dose of pentamidine in patients with Trypanosoma gambiense sleeping sickness.

1. Plasma concentrations of pentamidine were measured up to 1-8 months after a single 2 h i.v. infusion of 3.0 to 4.8 mg kg-1 pentamidine isethionate in 11 patients with late stage Trypanosoma gambiense sleeping sickness. 2. Maximum plasma drug concentrations varied between 713 and 2461 nmol 1-1. After termination of infusion, a rapid distribution phase over 10 min was followed by a slower distribution phase and an elimination phase prolonged over weeks to months. 3. The 'terminal' elimination rate constant could be determined in six patients and subsequent kinetic calculations showed a three to fourfold variation in plasma clearance and 'terminal' half-life (median 1126 (range 553-2036) ml min-1 and 265 (107-446) h, respectively). The median apparent volume of distribution (Vss) was 11,850 1. Renal clearance accounted for a median of 11% of total plasma clearance, indicating that metabolism is a major route of pentamidine elimination in man. 4. Side effects were few and mild and a slight or moderate decrease in blood pressure was the most common registered adverse reaction observed in four subjects. 5. The prolonged elimination of pentamidine seems inconsistent with the present recommended dosage regimen of pentamidine for treatment of trypanosomiasis of 7 to 10 parenteral doses given once daily or every second day.     

Clinical pharmacokinetics of mefloquine

Mefloquine, a quinoline-methanol antimalarial, is effective single dose therapy for all species of malaria infecting humans, including multi-drug-resistant Plasmodium falciparum. It is used both in prophylaxis and treatment. Mefloquine is available either as the hydrochloride salt alone, or in a combined preparation with sulfadoxine and pyrimethamine. There is no parenteral formulation. Several assay methodologies have been developed, but high performance liquid chromatography has been the most used in recent pharmacokinetic studies. These have shown in healthy volunteers that mefloquine is absorbed with a half-life of 1 to 4 hours and a time to peak concentration of 7 to 24 hours (median 16.7 hours). Mean peak blood concentrations have ranged between 50 and 110 (median 83) ng/ml/mg/kg. Estimates of total apparent volume of distribution (Vd/f) have ranged from 13.3 to 40.9 (median 19.2) L/kg, systemic clearance (CL/f) from 0.022 to 0.073 L/h/kg (median 0.026 L/h/kg), and terminal elimination half-life from 13.8 to 40.9 days (median 20 days). Systemic clearance appears to be increased in late pregnancy. In uncomplicated falciparum malaria, peak blood concentrations are 2 to 3 times higher than those in healthy subjects ranging from 112 to 209 (median 144) ng/ml/mg/kg because of contraction in the total apparent volume of distribution. Systemic clearance is usually reduced but elimination rates are increased (possibly because of reduced enterohepatic recycling). Mefloquine absorption appears to be reduced in severe falciparum malaria; plasma protein binding exceeds 98% in both healthy subjects and patients. No important drug interactions have been identified as yet, but the potential for serious interactions with quinine has not been adequately investigated. More studies are needed on the disposition of mefloquine in children.     

Weight related differences in the pharmacokinetics of abacavir in HIV-infected patients

AIM: To study the possible influence of patient characteristics on abacavir pharmacokinetics. METHODS: A population pharmacokinetic model for abacavir was developed using data from 188 adult patients by the use of a nonlinear mixed effects modelling method performed with NONMEM. RESULTS: Abacavir pharmacokinetics was well described by a two-compartment open model with linear absorption and elimination. Typical population estimates for the absorption rate constant (Ka), the apparent central distribution volume (Vc/F), the apparent peripheral distribution volume (Vp/F), the apparent intercompartmental clearance (Q/F) and the apparent plasma clearance (CL/F) were 1.8 h(-1), 75 l, 23.6 l, 10 l h(-1) and 47.5 l h(-1), respectively. Apparent plasma clearance was positively related to bodyweight. Individual Bayesian estimates of CL/F were used to calculate abacavir AUC. The latter decreased from 10.7 +/- 5.0 to 5.7 +/- 1.6 mgh l(-1) when bodyweight increased from 36 to 102 kg. This drop in abacavir exposure could lead to suboptimal treatment for the heaviest patients, as antiviral efficacy of abacavir is known to be related to its AUC. A 400 mg abacavir dose would be necessary to achieve adequate exposure to abacavir in patients weighing more than 60 kg. CONCLUSIONS: The apparent plasma clearance of abacavir was positively related to bodyweight. The efficacy of the current recommended abacavir dosage for patients with high bodyweight should be evaluated in further studies.     

Abacavir pharmacokinetics in human immunodeficiency virus-infected children ranging in age from 1 month to 16 years: a population analysis

Abacavir pharmacokinetics was studied in 105 children by a population approach performed with NONMEM. A 1-compartment open model with linear absorption and elimination adequately described the data. Typical population estimates (percent interindividual variability) of absorption rate constant, apparent distribution volume, and apparent plasma clearance were 1.79 h(-1) (58%), 42.9 L (53%), and 24.3 L/h (30%), respectively. Apparent plasma clearance was positively related to body weight. Individual Bayesian estimates of apparent plasma clearance were used to calculate individual abacavir area under the concentration curve (AUC). For the current weight-based regimen, abacavir exposure was found to be constant throughout the age range of the study, with an overall mean AUC value of 8.5 +/- 2.5 mg x h/L, which is slightly greater than the mean AUC value reported in adults. This study confirms the relevance of the current weight-based abacavir dosage regimen in pediatric patients.     

Development of a Population Pharmacokinetic Model for Taranabant, a Cannibinoid-1 Receptor Inverse Agonist

Taranabant is a cannabinoid-1 receptor inverse agonist developed for the treatment of obesity. A population model was constructed to facilitate the estimation of pharmacokinetic parameters and to identify the influence of selected covariates. Data from 12 phase 1 studies and one phase 2 study were pooled from subjects administered single and multiple oral doses of taranabant ranging from 0.5 to 8 mg. A total of 6,834 taranabant plasma concentrations from 187 healthy and 385 obese subjects were used to develop the population model in NONMEM. A standard covariate analysis using forward selection (α = 0.05) and backward elimination (α = 0.001) was conducted. A three-compartment model with first-order absorption and elimination adequately described plasma taranabant concentrations. The population mean estimates for apparent clearance and apparent steady-state volume of distribution were 25.4 L/h and 2,578 L, respectively. Statistically significant covariate effects were modest in magnitude and not considered clinically relevant (the effects of body mass index (BMI) and creatinine clearance (CrCL) on apparent clearance; BMI, age, CrCL, and gender on apparent volume of the peripheral compartment and age on apparent intercompartmental clearance). The pharmacokinetic profile of taranabant can adequately be described by a three-compartment model with first-order absorption and elimination. Clinical dose adjustment based on covariates effects is not warranted.Key words: NONMEM, obesity, pharmacokinetics, population, taranabant     

The influence of infusion rate on the pharmacokinetics and haemodynamic effects of nisoldipine in man.

1. The pharmacokinetics and haemodynamic effects of nisoldipine on long term i.v. infusion of 2.40 mg and 9.59 mg in 25 h were studied in six healthy subjects. Liver blood flow at 0.8 and 24 h was assessed by measuring indocyanine green (ICG) clearance. 2. After high-dose nisoldipine, systemic clearance was 0.99 +/- 0.16 1 min-1, volume of distribution was 5.8 +/- 1.5 1 kg-1 and elimination half-life was 10.7 +/- 2.4 h. The pharmacokinetic parameters were similar after low-dose nisoldipine. 3. No significant changes in apparent liver blood flow were observed after either high-dose or low-dose nisoldipine. 4. Systolic blood pressure did not change, whereas diastolic blood pressure decreased by approximately 10% during both treatments. Maximal increase in heart rate was approximately 37% at high-dose infusion, whereas this was one half lower during the low-dose regimen. 5. Increased infusion rate results in an unfavourable shift in the haemodynamic effect profile of nisoldipine.     

Effect of food on pharmacokinetics of an inhaled drug: a case study with a VLA-4 antagonist, HMR1031

HMR1031 is a potent and specific antagonist of the integrin VLA-4 (alpha4beta1) binding to vascular cell adhesion molecule-1 (VCAM-1) and fibronectin. HMR1031 is an inhaled drug being developed for the treatment of asthma using an Ultrahaler dry-powder inhalation device. A pharmacoscintigraphic study of HMR1031 suggests a lung deposition of approximately 25% and gastrointestinal tract deposition of approximately 75%. Since oral absorption may be contributing to systemic plasma concentrations, the effect of food on HMR1031 was assessed. This was a single-dose (3 mg), open-label, randomized, two-way crossover (fasted vs. fed) study in 8 healthy male subjects. Blood samples were collected at predose and up to 24 hours postdose. Plasma concentrations were determined by the LC/MS/MS method. HMR1031 was rapidly absorbed, with median tmax values of 1.0 and 0.75 hours under fasted and fed conditions, respectively. Under fasted conditions, mean AUCinfinity and Cmax values were 16.4 ng x h/mL and 4.56 ng/mL, respectively. Under fed conditions, mean AUCinfinity and Cmax values decreased to 11.7 ng x h/mL and 2.81 ng/mL, respectively. The mean terminal elimination half-life (t1/2) for both treatment groups was similar (2.7 h). HMR1031 population estimates of the apparent clearance, apparent volume of distribution, and absorption rate were 225 L/h (4.1% coefficient of variation [CV]), 44.5 L (26% CV), and 0.340 h-1 (7.0% CV), respectively. Food is a significant covariate on clearance. These data suggest that food unexpectedly decreases the systemic exposure of inhaled HMR1031 by approximately 30%, probably due to increased liver blood flow and increased biliary excretion. This decrease in systemic exposure is unlikely to affect the topical effect of the drug but may result in increased variability in plasma pharmacokinetics. The disposition and food effect of HMR1031 can be described using mixed-effect modeling.     

Pharmacokinetics of xamoterol after intravenous and oral administration to patients with chronic heart failure

Summary The pharmacokinetics of xamoterol, a -adrenergic partial agonist under clinical evaluation for the treatment of mild to moderate heart failure, have been studied in 8 cardiac failure patients (NYHA Class II) of mean age 62 years.After i.v. dosing, the elimination half-life was 7.4±0.4 h, the total body clearance was 228±30 ml·min^–1 and the volume of distribution at steady-state was 56±91. 72.5±4.3% of the dose was recovered unchanged in urine. After the oral dose, the absolute bioavailability of xamoterol was shown to be 5.9%. Peak plasma concentrations occurred 1 to 2.5 h after the oral dose. The apparent elimination half-life was significantly longer after oral doses (16±2 h) compared to that observed after an intravenous dose. Renal clearance of xamoterol exceeded glomerular filtration rate as measured by creatinine clearance.The pharmacokinetics of xamoterol in cardiac failure patients with good renal function (creatinine clearance >90 ml·min^–1) were similar to published data in young healthy male volunteers.     

中国患者异丙酚群体药代动力学(英文)

目的:用NONMEN程序分析中国患者群体药代动力学,并定量研究性别、年龄和体重对异丙酚药代参数的影响。方法:研究了76例择期手术的患者(男37例、女39例、年 龄19-77岁、体重39-86kg),共收集1459个血液标本。用NONMEN方法分析清除率和分布容积的个体间变异以及年龄、体重和性别的影响。结果:可用三室模型模拟异丙酚的药代动力学参数。体重可影响异丙酚的中央室、浅外周室和深外周室的清除率以及中央室的分布容积,而浅外周室和深外周室的分布容积保持不变。体重60kg的成人的上述药代参数的估计值分别为:1.56L/min、0.737L/min、0.360L/min、12.1L、43L、213L。老人随年龄的增大而清除率和中央室的分布容积减少。结论:中国人的异丙酚的药代动力学可用标准三室模型描述,年龄和体重可影响模型参数。因此根据患者的个体药代参数可改善靶控输注的精密度。     

The effect of fenfluramine on disposition and rate of antipyrine elimination.

The effect of fenfluramine, administered orally in a daily dose of 1 mg/kg for 40 days, on the disposition and rate of elimination of antipyrine was studied in 15 obese patients. Although the plasma half-life of antipyrine was unchanged, the apparent volume of distribution (1/kg) fell by 11.6% (p less than 0.001) and the plasma metabolic clearance rate (1/kg/h) of antipyrine was reduced by 14.1% (p less than 0.01). No correlation occurred between change in clearance, on the one hand, and change in patient weight or apparent volume of distribution of antipyrine, on the other. In vitro drug-metabolizing enzyme activity in the rat was measured using rate of aminopyrine and hexobarbital metabolism as indices. Fenfluramine inhibited the metabolism of both substrates. It is concluded that fenfluramine can diminish the rate of elimination of drugs which are extensively metabolized by reduction of microsomal enzyme activity. Also, drug clearance may be diminished by reduction of apparent volume of distribution.     

Nonparametric expectation maximisation (NPEM) population pharmacokinetic analysis of caffeine disposition from sparse data in adult caucasians: systemic caffeine clearance as a biomarker for cytochrome P450 1A2 activity

OBJECTIVE: To explore the ability of the nonparametric expectation maximisation (NPEM) method of population pharmacokinetic modelling to deal with sparse data in estimating systemic caffeine clearance for monitoring and evaluation of cytochrome P450 (CYP) 1A2 activity. DESIGN AND PARTICIPANTS: Nonblind, single-dose clinical investigation in 34 non-related adult Bulgarian Caucasians (18 women and 16 men, aged between 18 and 62 years) with normal and reduced renal function. METHODS: Each participant received oral caffeine 3 mg/kg. Two blood samples per individual were taken according to the protocol for measuring caffeine plasma concentrations. A total of 67 measured concentrations were used to obtain NPEM estimates of caffeine clearance. Paraxanthine/caffeine plasma ratios were calculated and correlated with clearance estimates. Graphical methods and tests for normality were applied and parametric and nonparametric statistical tests were used for comparison. RESULTS: NPEM median estimates of caffeine absorption and elimination rate constants, k(a) = 4.54 h(-1) and k(el) = 0.139 h(-1), as well as of fractional volume of distribution and plasma clearance, V(S1) = 0.58 L/kg and CL(S1) = 0.057 L/h/kg, agreed well with reported values from more 'data rich' studies. Significant correlations were observed between paraxanthine/caffeine ratios at 3, 8 and 10 hours and clearance (Spearman rank correlation coefficients, r(s), >0.74, p 相似文献   

Pharmacokinetics of tinidazole in chronic renal failure and in patients on haemodialysis.

The pharmacokinetics of tinidazole after infusion (800 mg in 15 min) were studied in 12 patients with chronic renal failure (RI) and in five patients undergoing regular dialysis treatment (RD). Tinidazole elimination plasma half-life was 15.09 +/- 0.68 h (mean +/- s.e. mean) (RI) and 12.9 +/- 1.0 h after dialysis (RD), but there was a significant decrease in half-life during dialysis (4.25 +/- 0.43 h) P less than 0.001). The apparent volume of distribution (0.64 +/- 0.03 l/kg) was equal to extra and intracellular water volume and tinidazole was little bound to plasma protein (8%). There was a slight sex difference in apparent volume of distribution between male patients (0.70 +/- 0.09 l/kg) and female patients (0.59 +/- 0.10 l/kg) (P = 0.07), but as body clearance decreases in the same order, there was no modification of plasma half-life. In renal failure, pharmacokinetics of tinidazole were not disturbed because no correlation between half-life, body clearance and creatinine clearance occurred; urine elimination was about 7% of administered dose. Plasma clearance during dialysis was 49.9 +/- 3.2 ml/min and about 43% of the available drug was eliminated during the 6 h dialysis procedure. These results suggest that an additional half-dose infusion should be given after the end of dialysis in patients undergoing regular dialysis treatment.     

Propofol: assay and regional mass balance in the sheep

1. Pharmacokinetic data for propofol, a new intravenous anaesthetic agent, indicate that there may be extensive extrahepatic clearance. This was investigated during intravenous infusions of propofol in adult merino ewes with chronic intravascular cannulae using a newly developed simple and rapid assay for propofol in blood and other biological samples. 2. The assay was based on organic solvent extraction of pH 4.5 buffered blood, urine or tissue homogenate, followed by reverse-phase h.p.l.c. with fluorescence detection. 3. A mean total body clearance of propofol of 3.15 l/min, (SD 0.87 l/min; n = 8) was found, consistent with a high hepatic extraction ratio (overall mean 0.87, SD 0.19; n = 8) and clearance (overall mean 1.12, SD 0.25 l/min; n = 7). The difference between total and hepatic clearances consisted principally of pulmonary clearance, but its extent was variable. 4. Other regional pharmacokinetic data were consistent with propofol distribution into muscle and brain tissues and propofol 'production' by the kidney, probably from a propofol metabolite formed elsewhere. 5. If these data are confirmed in humans then clinical pharmacokinetic data so far derived from peripheral venous blood sampling will require re-evaluation.     

Pharmacokinetics of sotalol during pregnancy

Summary Sotalol, a beta-adrenoceptor blocking drug, was administered to 6 healthy pregnant volunteers between 32–36 weeks gestation and when at least 6 weeks post-partum. On both occasions, each volunteer was given sotalol 100 mg intravenously and 400 mg orally in randomised order with at least a 1 week washout period between. Plasma samples were analysed for sotalol using a fluorometric method and the pharmacokinetic profiles investigated. The systemic clearance of sotalol was significantly greater in the antenatal period (2.4±0.3 ml/min/kg) than in the post-natal phase (1.5±0.1 ml/min/kg). The apparent volume of distribution was similar in the two periods: the elimination half-life was 6.6±0.6h ante-natally and 9.3±0.7h post-natally after intravenous drug but the trend for faster elimination was not significant. The elimination half-life after oral administration (about 10h) and bioavailability (about 90%) were not altered significantly by pregnancy. It is suggested that the more rapid clearance of sotalol in pregnancy may be due to increases in renal plasma flow and glomerular filtration rate.     

Pharmacokinetics and tissue concentrations of ceftazidime in burn patients

Summary The pharmacokinetics and tissue concentrations of ceftazidime have been investigated in 8 patients with severe burns (20–80% of body surface area) undergoing skin transplantation 2 to 21 days after injury. Two prophylactic doses of ceftazidime were administered as 1 g i.v. bolus injections with an 8 h interval. Blood, urine, burn blister fluid and tissue were frequently sampled and drug concentrations were analyzed by HPLC. The kinetics of ceftazidime was the same after each dose.In these patients the pharmacokinetics of ceftazidime was greatly altered from that in other patients and there was much interindividual variation. The mean ceftazidime elimination half-life, apparent volume of distribution and total clearance were: 2.7 h, 30.91 (0.38 l·kg^–1) and 139 ml·min^–1, respectively. A linear correlation was found between creatinine clearance and the renal clearance of the ceftazidime, the mean values being 108 and 95 ml·min^–1, respectively. No correlation was found between creatinine clearance and the total clearance of ceftazidime. The mean percentage urine recovery was 69% of the dose. Tissue and burn blister fluid concentrations were above the MIC, and ranged from 40.0 to 3.1 mg·kg^–1. A substantial increase in the apparent volume of distribution and non-renal clearance of ceftazidime was observed, probably due to increased capillary permeability and drug loss through the wound surface replacement of prior to surgery and subsequently to lost and blood fluid.     

Sirolimus population pharmacokinetic/pharmacogenetic analysis and bayesian modelling in kidney transplant recipients

OBJECTIVES: The objectives of the present study were: (i) to analyse the population pharmacokinetics of sirolimus in renal transplant recipients co-administered mycophenolate mofetil, but no calcineurin inhibitor over the first 3 months post-transplantation and study the influence of different potential covariates, including genetic polymorphisms of cytochrome P450 (CYP) metabolic enzymes and active transporters, on pharmacokinetic parameters; and (ii) to develop a Bayesian estimator able to reliably estimate the individual pharmacokinetic parameters and exposure indices in this population. METHODS: Twenty-two adult renal transplant patients treated with sirolimus participated in this study. Ninety concentration-time profiles (938 sirolimus whole blood samples) were collected at days 7 and 14, and months 1 and 3 post-transplantation. The population pharmacokinetic study was conducted using the nonlinear mixed effects model software, NONMEM, and validated using both the bootstrap and the cross-validation approaches. Finally, a Bayesian estimator based on a limited sampling strategy was built using the post hoc option. RESULTS: A two-compartment open model with first-order elimination and Erlang's distribution (to describe the absorption phase) best fitted the data. The mean pharmacokinetic parameter estimates were 5.25 h(-1), 218L and 292L for the transfer rate constant, the apparent volume of the central and peripheral compartments, respectively. The CYP3A5*1/*3 polymorphism significantly influenced the apparent oral clearance: mean oral clearance = 14.1 L/h for CYP3A5 non expressers (CYP3A5*3/*3 genotype) versus 28.3 L/h for CYP3A5 expressers (CYP3A5*1/*3 and *1/*1 genotypes). The standard errors of all the parameter estimates were <15%. Maximum a posteriori Bayesian forecasting allowed accurate prediction of sirolimus area under the concentration-time curve from 0 to 24 hours using a combination of only three sampling times (0, 1 and 3 hours post-dose), with a non-significant bias of -2.1% (range -22.2% to +25.9%), and a good precision (root mean square error = 10.3%). This combination is also easy to implement in clinical practice. CONCLUSION: This study presents an accurate population pharmacokinetic model showing the significant influence of the CYP3A5*1/*3 polymorphism on sirolimus apparent oral clearance, and a Bayesian estimator accurately predicting sirolimus pharmacokinetics in patients co-administered mycophenolate mofetil, but no calcineurin inhibitor.