国产硫酸氢氯吡格雷在中国健康受试者体内药代动力学和生物等效性研究

目的:研究硫酸氢氯吡格雷在中国健康受试者体内的药代动力学特性并评价其生物等效性.方法:23例中国男性健康受试者随机交叉单剂量口服泰嘉(国产硫酸氢氯比格雷,75mg/片,深圳信立泰药业股份有限公司生产)和波立维(原研厂硫酸氢氯比格雷,75mg/片,杭州赛诺菲-安万特制药有限公司)各150 mg后,采用高效液相色谱-串联质谱法测定血浆中氯吡格雷和氯吡格雷酸的浓度,并进行药代动力学和生物等效性研究.结果:口服泰嘉受试制剂者和波立维参比制剂者血浆中氯吡格雷血药达峰浓度(Cmax)分别为(3.07±3.63)ng/ml和(2.67±2.35)ng/ml;消除半衰期(t1/2)分别为(6.57±3.18)h和(6.96±3.92)h;药物浓度-时间曲线下面积(AUC)0-t分别为(4.75±4.68)ng.h/ml和(4.60±4.20)ng·h/ml.氯吡格雷酸的cmax分别为(6 724±1 899)ng/ml和(6 262±1 968)ng/ml;t1/2分别为(8.77±1.20)h和(10.11±8.99)h;AUC0-t分别为(20 702±5 579)ng·h/ml和(19 817+4 232)ng·h/ml.口服泰嘉受试制剂者相比波立维参比制剂者氯吡格雷和氯吡格雷酸的相对生物利用度分别为(112.8±42.4)%和(107,4±31,6)%.结论:AUC0-t,AUC--∞和cmax经对数转换后,应用方差分析法、双单侧t检验及90%置信区间判断,两种制剂具有生物等效性.     

Pharmacokinetics and Safety of Olmesartan Medoxomil in Combination with Glibenclamide in Healthy Volunteers

Objective. To investigate the pharmacokinetic interactions, safety, and tolerability of the combination of olmesartan medoxomil with glibenclamide. Methods. In an open, three-way crossover, phase I trial, 18 healthy adults entered three randomly ordered, seven-day treatment periods. The three treatments comprised once daily administration of () olmesartan 20 mg, () olmesartan 20 mg plus glibenclamide 3.5 mg, or () glibenclamide 3.5 mg. Results. The combination of olmesartan with glibenclamide did not influence the bioequivalence of the area under the plasma-concentration time curve at steady state during one dosing interval 0 to τ = 24 hours (AUC_ss,τ) or the maximum steady-state concentration (C_ss,max) of both substances. Mean AUC_ss,τ values for olmesartan were 2594.8 ng h/ml for olmesartan alone and 2443.7 ng h/ml in combination with glibenclamide; the corresponding C_ss,max values were 479.3 ng/ml and 462.7 ng/ml, respectively. For glibenclamide, the mean AUC_ss,τ values were 525.7 ng·h/ml for monotherapy and 518.7 ng·h/ml for its combination with olmesartan. The median time to reach C_ss,max (t_max) for glibenclamide was shifted from 2.0 h to 1.0 h when combined with olmesartan, whereas the median t_max values for olmesartan remained unchanged at 1.5 h. During combined treatment with olmesartan plus glibenclamide, no adverse event occurred, and the medications were well tolerated. Conclusion. With the exception of a slight shift of t_max values for glibenclamide, the concomitant administration of olmesartan medoxomil with glibenclamide had no significant effects on the steady-state pharmacokinetics of either agent. This provides the pharmacokinetic rationale for clinical studies to test the combination therapy of patients with hypertension and type-2 diabetes mellitus with both compounds.     

Pharmacokinetics and Bioequivalence Study of Two Tablet Formulations of Lovastatin in Healthy Volunteers

Lovastatin is a lipid-lowering agent indicated for primary hypercholesterolemia. This study has assessed single-dosing pharmacokinetics of lovastatin and of its main metabolite, lovastatin beta-hydroxyacid, and has compared the pharmacokinetics of two formulations of lovastatin, a test lovastatin generic (LVSG), and a reference (mevinacor 40 MSD) preparation. The pharmacokinetics and bioequivalence of the two formulations of lovastatin were evaluated by a two-way cross-over randomized double blinded study, in 36 healthy volunteers after a single oral dose of 2 × 40 mg per subject. On plasma samples, collected at given intervals of time (0–24h), lovastatin and its main active metabolite were assayed by high pressure liquid chromatography with positive turbo ion spray ionization tandem mass spectrometry detection. The pharmacokinetic parameters, area under the curve total (AUC_t) and to infinity (AUC_inf), peak plasma concentration (C_max), time to attain peak (t_max), and elimination half-life (t_1/2) were determined and analyzed statistically. Only minor differences in the pharmacokinetics of lovastatin and lovastatin hydroxyacid between LVSG and mevinacor were found. Analysis of variance (ANOVA) did not show any significant difference between the two formulations, and 90% confidence intervals fell within the acceptable range for bioequivalence. The tolerability profile was good and comparable for the two formulations of lovastatin. Our study, which was performed with the largest number of subjects compared with those published in literature, indicates the bioequivalence of LVSG and mevinacor tablets. The high inter-subject variability of parameters investigated indicate the need of appropriate sample size in pharmacokinetics studies with lovastatin.     

Pharmacokinetics of Different Formulations of Tioctic (Alpha-Lipoic) Acid in Healthy Volunteers

This study was designed to evaluate in healthy volunteers plasma and cellular (in erythrocytes) of three formulations of alpha-lipoic acid (ALA) available in Italy with different rates of absorption, two with a claimed high absorption rate (Byodinoral 600 QR, Tiocronal 600 HR) and one with a claimed prolonged absorption rate (Tiobec 600 retard). These formulations were compared with the registered ethic formulation of the compound (Thioctacid 600 mg HR), available in Germany. Area under the curve from time 0 to last measured time (AUC_t), peak plasma concentration (C_max) of ALA, and time (T_max ) at which C_max was observed were the plasma kinetic parameters measured. Concentration of ALA at different sampling times was the only parameter assessed for erythrocytes. The AUC_t values were similar for the four formulations of ALA tested. C_max was significantly higher for Byodinoral 600 QR, Tiocronal 600 HR compared to Thioctacid 600 mg HR or Tiobec 600 retard, whereas T_max value was significantly shorter for Byodinoral 600 QR in the order by Tiocronal 600 HR, Thioctacid 600 mg HR, and Tiobec 600 retard. ALA concentrations that accumulated in erytrocytes after the administration of the different formulations of the antioxidant are directly proportional to the plasma levels of each formulation. Because antioxidant capabilities of ALA depend on the glutathione regeneration the compound induces in cells, the most rationale approach for eliciting antioxidant activity at the cellular level is probably in the use of a formulation allowing the compound to reach its target at highest concentrations and in the shortest time.     

Pharmacokinetics of an Anti-Cytomegalovirus Hyperimmunoglobulin after Single Intravenous Administration to Healthy Volunteers

By selecting blood donors with high cytomegalovirus (CMV) antibody titres, a plasma pool was obtained which was used to produce an IgG hyperimmunoglobulin by means of pepsin fractionation. After administration of approximately 100 mg/kg body weight to healthy subjects, the time course both of anti-CMV IgG antibody titres by ELISA and of virus neutralisation (VN) titres was followed for 15 days. Seronegative subjects showed an increase in CMV-IgG antibodies as well as a significant enhancement of VN. The time course of both titres was non-uniform. The decline of both titres was biphasic: CMV-IgG antibodies fell slowly during the first week and remained unchanged thereafter, whereas VN titres decreased markedly faster in the first than in the second week. In seropositive subjects, on the other hand, VN remained unchanged. CMV-IgG antibodies increased by approximately 3 times, followed by a similar biphasic decline as seen in seronegative subjects. Due to the differences between seronegative and seropositive subjects and to the non-uniform time course, no calculations of the elimination rate were feasible.     

Pharmacokinetics of Artesunate Alone and in Combination with Sulfadoxine/Pyrimethamine in Healthy Sudanese Volunteers

Artesunate (AS) in combination with sulfadoxine/pyrimethamine (SP) is the first-line therapy for management of uncomplicated Plasmodium falciparum malaria in Sudan. The objective of this study was to assess the potential impact of SP on the pharmacokinetics of AS and its active metabolite, dihydroartemisinin (DHA), in healthy adults. A single-dose, randomized, open-label, crossover study design with a washout period of three weeks was performed with 16 volunteers. After oral administration of AS alone or in combination with SP, T_max values of AS and DHA were significantly prolonged in the combination group (P < 0.05). However, there was no significant effect on the other pharmacokinetic parameters (P > 0.05). The t_1/2 values of AS and DHA were significantly higher in females than in males (P < 0.05). The present findings suggest that co-administration of SP with AS has no clinically relevant impact on the pharmacokinetics of AS or DHA in healthy persons.     

Measuring Plasma Conductivity to Detect Sodium Load in Hemodialysis Patients

Background: Sodium thiosulfate therapy has been proposed for calcific uremic arteriolopathy and nephrogenic systemic fibrosis in hemodialysis patients. The treatment brings 3.7 g (161 mmol) of sodium. How to counterbalance this sodium load was studied.Design, setting, participants, & measurements: Plasma conductivity (Cp) and mass balance index were compared for 20 sessions without thiosulfate and 20 sessions with thiosulfate infusion. Subsequently, the dialysate conductivity was set to 13.8 mS/cm during the entire session. Next, dialysate conductivity was set to 14 mS/cm for the first 3 h and to 13 mS/cm for the last hour of thiosulfate infusion (n = 25).Results: The Cp variation between beginning and end was equal to +0.005 ± 0.13 mS/cm without thiosulfate, +0.24 ± 0.13 mS/cm with thiosulfate, and 14 mS/cm dialysate conductivity (P < 0.001). The decrease in dialysate conductivity at 13.8 mS/cm did not counterbalance the sodium load. The last program adequately compensated the sodium load with a Cp increase of only +0.05 ± 0.14 mS/cm (NS versus without thiosulfate). The total of the dialyzed sodium and the sodium load for this last program was equal to 603 mmol compared with 456 mmol for the sessions without thiosulfate, the difference of 147 mmol being close to the known content of 161 mmol in 25 g of infused thiosulfate.Conclusions: Thiosulfate infusion requires a decrease of dialysate conductivity of −1 mS/cm during the infusion to counterbalance the added 3.7 g (161 mmol) sodium load.Sodium thiosulfate treatment has been proposed to treat calcific uremic arteriolopathy in hemodialysis patients (1–4) and recently for nephrogenic systemic fibrosis (5). The dose is 25 g/1.73 m² per hemodialysis session during the last 60 min. The formulation of sodium thiosulfate is Na₂S₂O₃·(H₂O)₅ and the infusion of this amount of thiosulfate brings a clinically significant sodium load. The calculated sodium load for 25 g of thiosulfate is 3.7 g (161 mmol), corresponding to the amount of sodium contained in 1 L of isotonic sodium chloride infusion.The two patients that underwent the thiosulfate treatment had developed severe calcific uremic arteriolopathy of the extremities. We decided to use sodium thiosulfate at a dose of 25 g per dialysis session. As we started the thiosulfate therapy, we rapidly noticed that the infusion induced a notable increase in plasma conductivity (Figure 1). Hence we recorded the plasma conductivity variation during the dialysis sessions under thiosulfate for the two patients and we modified the dialysate treatment to counterbalance the sodium load.Open in a separate windowFigure 1.Example of a plasma conductivity curve during a dialysis session with thiosulfate infusion during the last hour of dialysis. Dialysate conductivity was kept constant at 14.0 mS/cm.     

健康志愿者和胃食管反流病患者食管动力的性别差异

背景：食管动力受多种因素影响，性别因素对食管动力的影响尚不清楚。目的：探讨健康志愿者、非糜烂性反流病（NERD）和反流性食管炎（RE）患者食管动力的性别差异。方法：83例健康志愿者以及具有典型胃食管反流症状的NERD患者196例和RE患者104例纳入本研究。受试者行食管测压，测定下食管括约肌压力（LESP）和食管体部运动功能（包括食管体部各段蠕动收缩波幅、蠕动波传导速度和湿咽成功率）。结果：RE组男性患者比例显著高于NERD组（69．2％对43．4％，P〈0．05）。健康对照组和NERD组男性基础LESP较女性显著降低（P〈0．05），男性健康志愿者食管体部近端蠕动收缩波幅显著低于女性（P〈0．05），男性RE患者湿咽成功率显著低于女性患者（P〈0．05）。男性NERD患者LESP降低发生率显著高于女性患者（45．9％对29．7％，P〈0．05），男性RE患者食管体部运动功能障碍发生率显著高于女性患者（68．1％对46．9％，P〈0．05）。结论：无论是胃食管反流病（GERD）患者还是健康志愿者，男性的食管动力均较女性差，男性性别是GERD发病的危险因素之一。     

Dialyzability and Pharmacokinetics of Sitafloxacin Following Multiple Oral Dosing in Infected Hemodialysis Patients

The pharmacokinetics and dialyzability of oral sitafloxacin, a newly available quinolone, in infected intermittent hemodialysis patients have not been reported previously. Seven infected maintenance hemodialysis patients lacking residual renal function were enrolled. Sitafloxacin (50 mg after hemodialysis on the first day, on the next day and 4 h before scheduled hemodialysis session on the 3rd day) was orally administered. On the 3rd day, blood was taken from arterial and venous sides before and 2 and 4 h after session initiation. Another sampling was performed 1 h after the session and on the 5^th day of the study. Pharmacokinetic parameters and dialyzability of sitafloxacin were evaluated. All patients exhibited improved symptoms without major problems. Drug concentrations in all arterial samples were above the MIC of targeted bacteria. Dialyzer clearance and elimination fraction were 49.9 ± 0.9 mL/min per m² and 53.3 ± 2.1%, respectively. Apparent half‐life during dialysis session was significantly shorter than that after the session (4.0 ± 0.4 and 46.5 ± 3.6 h, during and after the session, respectively). Dialyzer clearance was positively correlated with urea reduction ratio and negatively correlated with serum albumin concentration. About 23% of the drug in the body was removed by dialysis. Rebound of the drug concentration after the dialysis was not seen. Oral dosing of this drug at 50 mg daily in maintenance hemodialysis patients provides a safe drug concentration compatible with that of healthy subjects orally receiving 100 mg daily. Because a significant amount of the drug was removed, administration might be undertaken after the dialysis session.     

Gentamicin as Empirical Treatment in Hemodialysis Patients: Safety,Pharmacokinetics, and Pharmacodynamics

The aim of this study was to describe the safety profile and pharmacokinetic/pharmacodynamic parameters in end‐stage renal disease patients who received gentamicin as empirical treatment in catheter‐related bacteremia when they showed infection signs, regardless of the timing of the next HD. Patients received gentamicin 3 mg/kg before blood culture extraction when they showed infection signs and regardless of the timing of next hemodialysis session. Serum concentrations were collected after the gentamicin administration (peak level) and before the next HD (trough level). Toxicities and adverse drug events were registered. The main pharmacokinetic/pharmacodynamic goal for Gram‐negative infections was peak:minimum inhibitory concentration (MIC) ≥10. Sixteen patients were included. Nephrotoxicity was not assessed in this population, and no ototoxicity was found. According to microbial isolation and gentamicin susceptibility, the value of peak:MIC was 5.4 ± 2.0. The administration of gentamicin in these conditions was safe. Estimated pharmacokinetic values were consistent with previous studies and appropriate according to peak:MIC goal for Gram‐negative organisms with MIC ≤1 mg/L.     

Cardiac Effects of Water Immersion in Healthy Volunteers

To evaluate cardiac chamber size and ejection fraction during head-out immersion of patients in the semisitting position in neutral temperature water bath, 12 volunteers were studied using transthoracic echocardiography (TTE). In this open, controlled, prospective clinical study, left ventricular end-systolic, end-diastolic volumes, and ejection fraction were measured in 12 adult awake healthy volunteers using TTE with the patient in a semisitting position pre-, during, and postimmersion in the Dornier extracorporeal shock wave lithotriptor water bath at 35°C. Left ventricular end-diastolic volume significantly increased from an average of 96.0 ± 10.8 to 130 ± 19 cm³, P < 0.0001 and left ventricular end-systolic volume increased from an average 38.9 ± 6.9 to 45.2 ± 8.0 cm³, P < 0.01. Left ventricular ejection fraction increased significantly from control to water immersion from 0.59 ± 0.1% to 0.65 ± 0.1% (P < 0.001). The results of this study demonstrate that water immersion in normal healthy volunteers significantly increases both left ventricular diastolic and systolic volume, and that there is a significant increase in left ventricular ejection fraction after water immersion, (e.g., bathing, lithotripsy). While this increased cardiac filling is well-tolerated in most patients, it may not be well-tolerated in some patients who have limited cardiac reserve, including patients with heart failure.     

Evidence-Based Medicine and the Problem of Healthy Volunteers

Healthy controls are subjects without the disease being studied but may have other conditions indirectly affecting outcome. In the present epidemics of obesity a few subjects with undiagnosed nonalcoholic fatty liver disease enter clinical studies as controls, producing biased results. Stricter selection criteria should be considered to prevent this risk.     

Absorption of Food Cobalamins Assessed by the Double-Isotope Method in Healthy Volunteers and in Patients with Chronic Diarrhoea

To make a food preparation containing radioactively labelled cobalamins, rabbits were given repeated injections with ⁵⁷Co-labelled cyanocobalamin. The liver was removed, homogenized, and fried for 1 min or boiled for 30 min. Of the radioactivity in the fried homogenate 41.7% was recovered in the centrifuged supernatant compared with 50.8% in the boiled homogenate. The radioactivity in the supernatants had a molecular size close to that of free ⁵⁷Co-labelled cyanocobalamin. Forty-two per cent of the radioactivity in the whole homogenate had been incorporated into 5-deoxyadenosyl-, 10% into methyl-, and 16.5% into hydroxy-cobalamin. To assess the validity of a double-isotope method for measuring the intestinal absorption of doses of the ⁵⁷Co-labelled liver cobalamins, ⁵¹CrCl₃ was used as a non-absorbable marker. In 14 healthy volunteers the correlation coefficient between the absorption measured by the double-isotope technique and the faecal excretion test was highly significant (r = 0.96, p < 0.005), and there was only a small variation in the ⁵⁷Co/⁵¹Cr ratio in successive stool collections. In 11 patients with chronic diarrhoea there was a significant correlation between the absorption measured by the double-isotope technique and the faecal excretion test (r = 0.92, p < 0.005), but in some patients there was considerable variation in the ⁵⁷Co/⁵¹Cr ratio in successive stool collections.     

Cryptosporidium muris: Infectivity and Illness in Healthy Adult Volunteers

Although Cryptosporidium parvum and C. hominis cause the majority of human cryptosporidiosis cases, other Cryptosporidium species are also capable of infecting humans, particularly when individuals are immunocompromised. Ten C. muris cases have been reported, primarily in human immunodeficiency virus (HIV) -positive patients with diarrhea. However, asymptomatic cases were reported in two HIV-negative children, and in another case, age and immune status were not described. This study examines the infectivity of C. muris in six healthy adults. Volunteers were challenged with 10⁵ C. muris oocysts and monitored for 6 weeks for infection and/or illness. All six patients became infected. Two patients experienced a self-limited diarrheal illness. Total oocysts shed during the study ranged from 6.7 × 10⁶ to 4.1 × 10⁸, and the number was slightly higher in volunteers with diarrhea (2.8 × 10⁸) than asymptomatic shedders (4.4 × 10⁷). C. muris-infected subjects shed oocysts longer than occurred with other species studied in healthy volunteers. Three volunteers shed oocysts for 7 months. Physical examinations were normal, with no reported recurrence of diarrhea or other gastrointestinal complaints. Two persistent shedders were treated with nitazoxanide, and the infection was resolved. Thus, healthy adults are susceptible to C. muris, which can cause mild diarrhea and result in persistent, asymptomatic infection.     

Impact of Dialysate Sodium Concentration Lowering on Home Blood Pressure Variability in Hemodialysis Patients

Blood pressure variability is an independent risk factor for mortality and cardiovascular events in hemodialysis patients. Dialysate sodium concentration may not only have effects on blood pressure but also on blood pressure variability. We investigated whether dialysate sodium concentration lowering could decrease home blood pressure variability in hemodialysis patients. Forty‐three hemodialysis patients at their dry weight assessed by bioimpedance methods with pre‐dialysis serum sodium >136 mmol/L were recruited. Firstly, patients underwent a 1‐month standard dialysis with dialysate sodium concentration of 138 mmol/L, and then the dialysate sodium concentration was decreased to 136 mmol/L for 8 weeks. Home blood pressure was assessed on waking up and at bedtime for 1 week. Coefficient of variation was used to define home blood pressure variability. After the intervention, whole‐day systolic blood pressure variability decreased from 5.7 ± 2.6% to 4.3 ± 1.7% and evening systolic blood pressure variability decreased from 7.9 ± 4.1% to 6.2 ± 3.1%. Morning systolic blood pressure variability had a reduction from 7.8 ± 2.4% to 5.9 ± 3.3% but did not achieve statistical significance (P = 0.077). Whole‐day, morning and evening systolic blood pressure were decreased significantly. Less changes were observed in diastolic blood pressure parameters. Interdialytic weight gain mildly but significantly decreased. Volume parameters, dietary sodium intake and incidence of adverse events were similar throughout the study period. Lowering dialysate sodium concentration could improve home blood pressure variability among hemodialysis patients who had achieved their dry weight.     

Variability in Sublingual Microvessel Density and Flow Measurements in Healthy Volunteers

Objectives: As sublingual microvascular indices are increasingly heralded as new resuscitation end‐points, better population data are required to power clinical studies. This paper describes improved methods to quantify sublingual microvessel flow and density in images obtained by sidestream dark field (SDF) technology in healthy volunteers, including vessels under 10 μm in diameter. Materials and Methods: Measurements of sublingual capillary density and flow were obtained by recording three 15‐second images in 20 healthy volunteeers over three days. Two independent observers quantified capillary density by using two methods: total vessel length (mm/mm²) and counting (number/mm). Both intraoral and temporal variabilities within subject and observer reproducibilities were determined by using coefficients of variability and reproducibility indices. Results: For small (1–10 μm), medium (11–20 μm), and large (21–50 μm) diameter, mean vessel density with standard deviations (SDs) in volunteers was 21.3(±4.9), 5.2 (±1.2), and 2.7 (±0.9) mm/mm², respectively. Also, 94.0±1.4% of small vessels, 94.5±1.4% of medium vessels, and 94.5±4.0% of large vessels had continuous perfusion. Within subjects, the means of all measurements over three days varied less than 13, 22, and 35% in small, medium, and large vessels, respectively. Interobserver reproducibility was good, especially for capillary (1–10 μm) density and flow measurements. Conclusions: Our methods of microvessel flow and density quantification have low observer variability and confirm the stability of microcirculatory measurements over time. These results facilitate the development of SDF‐acquired sublingual microvascular indices as feasible microperfusion markers in shock resuscitation.     

Electrogastrography Before and After a High-Caloric,Liquid Test Meal in Healthy Volunteers and Patients with Severe Functional Dyspepsia

Background: The cutaneous recording of gastric electric rhythm, so-called electrogastrography (EGG), has been purported as a non-invasive method for studying patients with functional dyspepsia and unexplained nausea and vomiting. The aims of this study were to determine normal values for EGG characteristics before and after a liquid, high-caloric test meal and to investigate whether EGG could discriminate between patients with functional dyspepsia and normal controls. Methods: In studying 20 healthy volunteers and 10 patients with functional dyspepsia, we recorded gastric electrical activity during the 30 min before and after a liquid 1.0-1.5 kcal/ml test meal. Satiety before and after the meal was estimated on a 10-point scale. EGG was analysed regarding dominant frequency, instability of the dominant frequency, power ratio and percentage activity in the normal frequency range. Results: The mean ( ± s ) caloric intake in patients with functional dyspepsia (286 ± 160 kcal) was significantly lower ( P < 0.001) than in healthy volunteers (610 ± 211 kcal). The patients reported a more pronounced feeling of satiety before the test meal (5.6 ± 3.2) compared to healthy volunteers (3.6 ± 1.2, P < 0.05), but at the end of the test meal there was no difference in satiety (7.9 ± 2.5 versus 7.7 ± 1.0). However, none of the EGG parameters showed any difference between patients and healthy volunteers. Conclusions: EGG before and after a high-caloric test meal showed large variation in healthy subjects and seemed to be of little value for differentiating between healthy individuals and patients with functional dyspepsia.     

Pharmacokinetics and Pharmacodynamics of Intensified versus Standard Dosing of Mycophenolate Sodium in Renal Transplant Patients

Background and objectives: Adequate early mycophenolic acid (MPA) exposure is an important determinant for effective rejection prophylaxis. This pharmacokinetic study investigated whether an intensified dosing regimen of enteric-coated mycophenolate sodium (EC-MPS) could achieve higher mycophenolic acid (MPA) exposure early after transplantation versus a standard dosing regimen.Design, setting, participants, & measurements: De novo kidney transplant recipients (n = 75) who were treated with basiliximab induction and cyclosporine were randomly assigned to receive EC-MPS as either standard dosing (1440 mg/d; n = 37) or intensified dosing (days 0 through 14: 2880 mg/d; days 15 through 42: 2160 mg/d; followed by 1440 mg/d; n = 38). Full 12-hour pharmacokinetic and pharmacodynamic profiles were taken at six time points during the first 3 months. Exploratory analysis of inosine monophosphate dehydrogenase (IMPDH) activity was also performed for better understanding of the pharmacokinetic–pharmacodynamic relationship between MPA exposure and IMPDH activity in the early posttransplantation period. Preliminary efficacy parameters, safety, and tolerability were assessed.Results: Exposure to MPA was significantly higher on days 3 and 10 after transplantation in the intensified versus standard EC-MPS group, with 52.9 versus 22.2% (P < 0.05) of patients reaching MPA exposure >40 mg/h per L in the first week. The intensified regimen resulted in significantly lower IMPDH activity on day 3 after transplantation, and the overall safety was comparable for both groups.Conclusions: These pharmacokinetic and safety data support further research on the hypothesis that early adequate MPA exposure could improve clinical outcome.The combination of mycophenolic acid (MPA), given as mycophenolate mofetil (MMF) or enteric-coated mycophenolate sodium (EC-MPS), with steroids and calcineurin inhibitors (either cyclosporine A [CsA] or tacrolimus) has become standard immunosuppressive therapy worldwide. MMF and EC-MPS have a similar efficacy and safety profile (1,2) but differ in their pharmacokinetic characteristics (3).A large number of retrospective and prospective studies support the hypothesis that adequate early MPA exposure is an important determinant for effective rejection prophylaxis (4–13). Whereas the majority of tacrolimus-treated patients achieve adequate MPA exposure early after transplantation (13,14), studies have demonstrated that approximately 50% of patients who are treated with CsA and standard MPA dosages are underexposed (4,7,12,13). Larger initial MMF dosages (up to 4 g/d) have been suggested early after transplantation for achievement of sufficient MPA exposure in combination with CsA (13,15,16).There are only limited data on the pharmacokinetics, safety, and efficacy of higher (>3 g/d) MMF dosages (4,5,17), and data on higher EC-MPS dosages are lacking. The aim of this pilot study was to investigate the feasibility and safety of achieving target MPA exposure levels (≥40 mg/h per L), measured as area under time-concentration curve (AUC), using an intensified EC-MPS dosing regimen, compared with a standard dosing regimen, in de novo CsA-treated renal transplant patients. In addition, an exploratory analysis of inosine-monophosphate dehydrogenase (IMPDH) activity was performed for better understanding of the pharmacokinetic–pharmacodynamic relationship between MPA exposure and IMPDH activity early after transplantation.