共查询到20条相似文献,搜索用时 31 毫秒
1.
das Neves J Michiels J Ariën KK Vanham G Amiji M Bahia MF Sarmento B 《Pharmaceutical research》2012,29(6):1468-1484
Purpose
To assess the intracellular delivery, antiretroviral activity and cytotoxicity of poly(??-caprolactone) (PCL) nanoparticles containing the antiretroviral drug dapivirine.Methods
Dapivirine-loaded nanoparticles with different surface properties were produced using three surface modifiers: poloxamer 338 NF (PEO), sodium lauryl sulfate (SLS) and cetyl trimethylammonium bromide (CTAB). The ability of nanoparticles to promote intracellular drug delivery was assessed in different cell types relevant for vaginal HIV transmission/microbicide development. Also, antiretroviral activity of nanoparticles was determined in different cell models, as well as their cytotoxicity.Results
Dapivirine-loaded nanoparticles were readily taken up by different cells, with particular kinetics depending on the cell type and nanoparticles, resulting in enhanced intracellular drug delivery in phagocytic cells. Different nanoparticles showed similar or improved antiviral activity compared to free drug. There was a correlation between increased antiviral activity and increased intracellular drug delivery, particularly when cell models were submitted to a single initial short-course treatment. PEO-PCL and SLS-PCL nanoparticles consistently showed higher selectivity index values than free drug, contrasting with high cytotoxicity of CTAB-PCL.Conclusions
These results provide evidence on the potential of PCL nanoparticles to affect in vitro toxicity and activity of dapivirine, depending on surface engineering. Thus, this formulation approach may be a promising strategy for the development of next generation microbicides. 相似文献2.
Alison P. Joyce Mengmeng Wang Rosemary Lawrence-Henderson Cynthia Filliettaz Sheldon S. Leung Xin Xu Denise M. O’Hara 《Pharmaceutical research》2014,31(7):1823-1833
Purpose
The purpose of this study was to validate the approach of serial sampling from one mouse through ligand binding assay (LBA) quantification of dosed biotherapeutic in diluted whole blood to derive a pharmacokinetic (PK) profile.Methods
This investigation compared PK parameters obtained using serial and composite sampling methods following administration of human IgG monoclonal antibody. The serial sampling technique was established by collecting 10 μL of blood via tail vein at each time point following drug administration. Blood was immediately diluted into buffer followed by analyte quantitation using Gyrolab to derive plasma concentrations. Additional studies were conducted to understand matrix and sampling site effects on drug concentrations.Results
The drug concentration profiles, irrespective of biological matrix, and PK parameters using both sampling methods were not significantly different. There were no sampling site effects on drug concentration measurements except that concentrations were slightly lower in sodium citrated plasma than other matrices.Conclusions
We recommend the application of mouse serial sampling, particularly with limiting drug supply or specialized animal models. Overall the efficiencies gained by serial sampling were 40–80% savings in study cost, animal usage, study length and drug conservation while inter-subject variability across PK parameters was less than 30%. 相似文献3.
Effects of Particle Size and Surface Modification on Cellular Uptake and Biodistribution of Polymeric Nanoparticles for Drug Delivery 总被引:1,自引:0,他引:1
Purpose
To investigate the effects of the particle size and surface coating on the cellular uptake of the polymeric nanoparticles for drug delivery across the physiological drug barrier with emphasis on the gastrointestinal (GI) barrier for oral chemotherapy and the blood–brain barrier (BBB) for imaging and therapy of brain cancer.Methods
Various sizes of commercial fluorescent polystyrene nanoparticles (PS NPs) (viz 20 50, 100, 200 and 500 nm) were modified with the d-α-tocopheryl polyethylene glycol 1,000 succinate (vitamin E TPGS or TPGS). The size, surface charge and surface morphology of PS NPs before and after TPGS modification were characterized. The Caco-2 and MDCK cells were employed as an in vitro model of the GI barrier for oral and the BBB for drug delivery into the central nerve system respectively. The distribution of fluorescent NPs after i.v. administration to rats was analyzed by the high performance liquid chromatography (HPLC).Results
The in vitro investigation showed enhanced cellular uptake efficiency for PS NPs in both of Caco-2 and MDCK cells after TPGS surface coating. In vivo investigation showed that the particle size and surface coating are the two parameters which can dramatically influence the NPs biodistribution after intravenous administration. The TPGS coated NPs of smaller size (< 200 nm) can escape from recognition by the reticuloendothelial system (RES) and thus prolong the half-life of the NPs in the blood system.Conclusions
TPGS-coated PS NPs of 100 and 200 nm sizes have potential to deliver the drug across the GI barrier and the BBB. 相似文献4.
5.
Fang Wu Lu Gaohua Ping Zhao Masoud Jamei Shiew-Mei Huang Edward D. Bashaw Sue-Chih Lee 《Pharmaceutical research》2014,31(8):1919-1929
Purpose
The objective of this study is to develop a physiologically-based pharmacokinetic (PBPK) model for each omeprazole enantiomer that accounts for nonlinear PK of the two enantiomers as well as omeprazole racemic drug.Methods
By integrating in vitro, in silico and human PK data, we first developed PBPK models for each enantiomer. Simulation of racemic omeprazole PK was accomplished by combining enantiomer models that allow mutual drug interactions to occur.Results
The established PBPK models for the first time satisfactorily predicted the nonlinear PK of esomeprazole, R-omeprazole and the racemic drug. The modeling exercises revealed that the strong time-dependent inhibition of CYP2C19 by esomeprazole greatly altered the R-omeprazole PK following administration of racemic omeprazole as in contrast to R-omeprazole given alone. When PBPK models incorporated both autoinhibition of each enantiomer and mutual interactions, the ratios between predicted and observed AUC following single and multiple dosing of omeprazole were 0.97 and 0.94, respectively.Conclusions
PBPK models of omeprazole enantiomers and racemic drug were developed. These models can be utilized to assess CYP2C19-mediated drug and genetic interaction potential for omeprazole and esomeprazole. 相似文献6.
Roonak Saadati Simin Dadashzadeh Zahra Abbasian Hoorieh Soleimanjahi 《Pharmaceutical research》2013,30(4):985-995
Purpose
To investigate accelerated blood clearance (ABC) induction upon repeated injections of PLGA-PEG nanoparticles as a commonly used polymeric drug carrier.Methods
Etoposide-loaded PLGA-PEG NPs were developed and administered as the test dose to rats pre-injected with various NP treatments at certain time intervals. Pharmacokinetic parameters of etoposide and production of anti-PEG IgM antibody were evaluated.Results
A notable ABC effect was induced by a wide range of polymer doses (0.1 to 20 mg) of empty NPs, accompanied by IgM secretion. However, a further increase in polymer dose resulted not only in the abrogation of the observed ABC induction but also in distinctly a higher value for AUC of the NPs relative to the control. The data from the PEG-negative group verified the fundamental role of PEG for ABC induction. The first injection of etoposide-containing PEGylated nanoparticles (a cell cycle phase-specific drug) produced a strong ABC phenomenon. Three sequential administrations of etoposide-loaded NPs abolished ABC, although a high level of IgM was still detected, which suggests saturation with insignificant poisoning of immune cells.Conclusion
The presented results demonstrate the importance of clinical evaluations for PLGA-PEG nanocarriers that consider the administration schedule in multiple drug delivery, particularly in cancer chemotherapy. 相似文献7.
Purpose
Flibanserin is being developed for treating hypoactive sexual desire disorder in women; the main side effect is sedation. The analysis objective was to relate flibanserin plasma concentrations with acute sedative effects using a population pharmacokinetic/pharmacodynamic (PK/PD) model.Methods
The population model was developed with NONMEM based on data from 24 healthy volunteers. ??Drowsiness?? was serially assessed by a Visual Analogue Scale (VAS) on a baseline day and after morning oral administration of 100?mg flibanserin together with PK sampling.Results
PK was best described by a three-compartment disposition model and transit compartments accounting for the lag time in absorption. VAS ??drowsiness?? baseline profiles were modeled using linear splines with three breakpoints located at clock times at first and last observation, and at the median of the observation time across subjects. The drug effect followed a sigmoidal EMAX model using predicted effect site concentrations (Ce). The VAS vs. Ce relationship was very steep and effect site and plasma concentration-time profiles were very similar thus suggesting little delay between the occurrence of maximum flibanserin plasma concentrations and drowsiness.Conclusions
At effect site concentrations lower than ??200?ng/mL that are reached approximately 4?h after administration, flibanserin shows hardly any effect on the VAS ??drowsiness?? scale. 相似文献8.
Huali Wu Jeffrey R. Infante Vicki L. Keedy Suzanne F. Jones Emily Chan Johanna C. Bendell Wooin Lee Beth A. Zamboni Satoshi Ikeda Hiroshi Kodaira Mace L. Rothenberg Howard A. Burris III William C. Zamboni 《European journal of clinical pharmacology》2013,69(12):2073-2081
Purpose
To investigate pharmacokinetics (PK) of encapsulated CPT-11, released CPT-11 and the active metabolite SN-38 following administration of IHL-305 and to identify factors that may influence IHL-305 PK.Methods
Plasma samples from 39 patients with solid tumors were collected in a phase I study. IHL-305 was administered as a 1 h IV infusion with doses ranging from 3.5 to 210 mg/m2. Plasma concentrations of encapsulated CPT-11, released CPT-11 and SN-38 were used to develop a population PK model using NONMEM®.Results
PK of encapsulated CPT-11 was described by 1-compartment model with nonlinear clearance and PK of released CPT-11 was described by a 1-compartment model with linear clearance for all patients. PK of the active metabolite SN-38 was described by a 2-compartment model with linear clearance for all patients. Covariate analysis revealed that gender was a significant covariate for volume of distribution of encapsulated CPT-11. Vencap in male patients is 1.5-fold higher compared with female patients.Conclusions
The developed population PK modeling approach is useful to predict PK exposures of encapsulated and released drug and can be applied to the more than 300 other nanoparticle formulations of anticancer agents that are currently in development. The effect of gender on PK of IHL-305 needs to be further evaluated. 相似文献9.
Purpose
To create poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs), where a drug-encapsulating NP core is covered with polyethylene glycol (PEG) in a normal condition but exposes a cell-interactive TAT-modified surface in an environment rich in matrix metalloproteinases (MMPs).Methods
PLGA NPs were modified with TAT peptide (PLGA-pDA-TAT NPs) or dual-modified with TAT peptide and a conjugate of PEG and MMP-substrate peptide (peritumorally activatable NPs, PANPs) via dopamine polymerization. Cellular uptake of fluorescently labeled NPs was observed with or without a pre-treatment of MMP-2 by confocal microscopy and flow cytometry. NPs loaded with paclitaxel (PTX) were tested against SKOV-3 ovarian cancer cells to evaluate the contribution of surface modification to cellular delivery of PTX.Results
While the size and morphology did not significantly change due to the modification, NPs modified with dopamine polymerization were recognized by their dark color. TAT-containing NPs (PLGA-pDA-TAT NPs and PANPs) showed changes in surface charge, indicative of effective conjugation of TAT peptide on the surface. PLGA-pDA-TAT NPs and MMP-2-pre-treated PANPs showed relatively good cellular uptake compared to PLGA NPs, MMP-2-non-treated PANPs, and NPs with non-cleavable PEG. After 3 h treatment with cells, PTX loaded in cell-interactive NPs showed greater toxicity than non-interactive ones as the former could enter cells during the incubation period. However, due to the initial burst drug release, the difference was not as clear as microscopic observation.Conclusions
PEGylated polymeric NPs that could expose cell-interactive surface in response to MMP-2 were successfully created by dual modification of PLGA NPs using dopamine polymerization. 相似文献10.
Purpose
To understand the relationship between the risk of opioid-related gastrointestinal adverse effects (AEs) and exposure to tapentadol and oxycodone as well as its active metabolite, oxymorphone, using pharmacokinetic/pharmacodynamic models.Methods
The analysis was based on a study in patients with moderate-to-severe pain following bunionectomy. Population PK modeling was conducted to estimate population PK parameters for tapentadol, oxycodone, and oxymorphone. Time to AEs was analyzed using Cox proportional-hazards models.Results
Risk of nausea, vomiting, and constipation significantly increased with exposure to tapentadol or oxycodone/oxymorphone. However, elevated risk per drug exposure of AEs for tapentadol was ~3?C4 times lower than that of oxycodone, while elevated AE risk per drug exposure of oxycodone was ~60 times lower than that for oxymorphone, consistent with reported in vitro receptor binding affinities for these compounds. Simulations show that AE incidence following administration of tapentadol IR is lower than that following oxycodone IR intake within the investigated range of analgesic noninferiority dose ratios.Conclusions
This PK/PD analysis supports the clinical findings of reduced nausea, vomiting and constipation reported by patients treated with tapentadol, compared to patients treated with oxycodone. 相似文献11.
Xingrong Liu Ying C. Ou Jun Zhang Ago Ahene Douglas Clark Su-Chun Hsieh Matthew Cooper Changhua Ji 《Pharmaceutical research》2014,31(3):809-818
Purpose
This study was to characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of a chimeric protein, CD4-anchoring bi-functional fusion inhibitor (CD4-BFFI), in monkeys and assess the feasibility for HIV-1 treatment in humans.Methods
The serum concentrations of CD4-BFFI and CD4 receptors were determined and modeled using a target-mediated drug disposition (TMDD) model following intravenous administration of 1 or 10 mg/kg in monkeys. In vitro CD4 internalization was examined in human peripheral blood mononuclear cells.Results
Noncompartmental analysis showed a decrease in clearance (1.35 to 0.563 mL/h/kg) and an increase in half-lives (35 to 50 h) with increasing doses. Dose-dependent CD4 occupancy was observed. The TMDD model reasonably captured the PK/PD profiles and suggested greater degradation rate constant for the free CD4 than the bound CD4. In vitro assay showed CD4-BFFI did not reduce the internalization of cell surface CD4. The simulated serum concentrations of CD4-BFFI were 20-fold above its in vitro IC50 for HIV-1 at 3 mg/kg weekly or biweekly following subcutaneous administration in humans.Conclusions
The TMDD modeling and in vitro CD4 internalization study indicate that CD4-BFFI does not induce CD4 internalization and CD4-BFFI short half-life is likely due to normal CD4 internalization. The simulated human PK supports CD4-BFFI as a promising anti-HIV-1 agent. 相似文献12.
Purpose
The objective of this study was to develop a custom-tailored polymeric drug delivery system for paclitaxel, employing a novel biodegradable block co-polymer (P), intended to be intravenously administered, capable of improving therapeutic index of the drug and devoid of the adverse effect of an uncontrolled release.Methods
Paclitaxel loaded nanoparticles (PTX-NPs) were prepared by a modified nanoprecipitation method and emulsification-solvent evaporation method. Our approach involves a focusing on the formulation parameters that can be modified in order to obtain completely customized NPs in terms of size, zeta-potential, drug content and release profile. The biocompatibility and anti-proliferative efficiency of PTX-NPs against glioblastoma cell line were evaluated in vitro by MTS.Results
All formulations showed spherical nanometric (<200 nm), monodisperse (~0.1), Poly (Ethylene Glycol) (PEG)-coated and negatively charged particles. Selected NPs revealed higher PTX content (up to 24%) in comparison with polyester-based NPs. The release behaviour of PTX from the developed NPs exhibited an approximately first-order profile, without initial burst and characterized by a slow and constant release. Hydrophobic character of the NPs can be set in order to achieve a slower and more controlled release for a prolonged period of time. PTX-NPs were hemocompatible and had significant in vitro anti-tumoral activity against human primary glioblastoma cell line (U-87 MG); cytotoxicity was in time- and drug concentration- dependent manner.Conclusions
The developed drug delivery system proved to be suitable for intravenous administration. NPs characteristics can be customized to obtain high PTX loaded NPs that can improve therapeutic index and avoid an uncontrolled release. 相似文献13.
Alexander Bauer Martin J. Wolfsegger 《European journal of clinical pharmacology》2014,70(12):1465-1470
Purpose
Estimating pharmacokinetic parameters in the presence of an endogenous concentration is not straightforward as cross-reactivity in the analytical methodology prevents differentiation between endogenous and dose-related exogenous concentrations. This article proposes a novel intuitive modeling approach which adequately adjusts for the endogenous concentration.Methods
Monte Carlo simulations were carried out based on a two-compartment population pharmacokinetic (PK) model fitted to real data following intravenous administration. A constant and a proportional error model were assumed. The performance of the novel model and the method of straightforward subtraction of the observed baseline concentration from post-dose concentrations were compared in terms of terminal half-life, area under the curve from 0 to infinity, and mean residence time.Results
Mean bias in PK parameters was up to 4.5 times better with the novel model assuming a constant error model and up to 6.5 times better assuming a proportional error model.Conclusions
The simulation study indicates that this novel modeling approach results in less biased and more accurate PK estimates than straightforward subtraction of the observed baseline concentration and overcomes the limitations of previously published approaches. 相似文献14.
Yu-Jin Jin Ubonvan Termsarasab Seung-Hak Ko Jae-Seong Shim Saeho Chong Suk-Jae Chung Chang-Koo Shim Hyun-Jong Cho Dae-Duk Kim 《Pharmaceutical research》2012,29(12):3443-3454
Purpose
Hyaluronic acid-ceramide (HACE)-based nanoparticles (NPs) were developed for the targeted delivery of doxorubicin (DOX), and their antitumor efficacy for melanoma was evaluated.Methods
DOX-loaded HACE-based self-assembled NPs were prepared and their physicochemical properties were characterized. The in vitro cytotoxicity of HACE was measured using an MTS-based assay. The cellular uptake efficiency of DOX into mouse melanoma B16F10 cells was assessed by confocal laser scanning microscopy and flow cytometry. Tumor growth and body weight were monitored after the intratumoral and intravenous injection of DOX-loaded NPs into a B16F10 tumor-bearing mouse model.Results
DOX-loaded NPs, with a mean diameter of ~110?nm, a narrow size distribution, and high drug entrapment efficiency, were prepared. A sustained DOX release pattern was shown, and drug release was enhanced at pH 5.5 compared with pH 7.4. The cytotoxicity of HACE to B16F10 cells was negligible. It was assumed that DOX was taken up into the B16F10 cells through receptor-mediated endocytosis. A significant inhibitory effect was observed on tumor growth, without any serious changes in body weight, after the injection of DOX-loaded NPs into the B16F10 tumor-bearing mouse model.Conclusions
DOX-loaded HACE-based NPs were successfully developed and their antitumor efficacy against B16F10 tumors was demonstrated. 相似文献15.
Purpose
The lack of effective delivery vehicles impedes in vivo applications of siRNA. The trimethyl chitosan-cysteine (TC) nanoparticles (NPs) were developed for in vivo delivery of tumor necrosis factor α (TNF-α) siRNA via oral gavage and intraperitoneal injection.Methods
The nanoparticles formulated from TC conjugate of 100, 200, and 500 kDa were prepared through ionic gelation with sodium tripolyphosphate, termed as TC100 NPs, TC200 NPs, and TC500 NPs, respectively. They were evaluated in terms of stability, siRNA protection, cellular uptake and TNF-α knockdown in peritoneal exudates macrophage cells (PECs), and in vivo TNF-α silencing in acute hepatic injury mice.Results
TC100 NPs exhibited poor stability in simulated physiological environment compared to TC200 NPs and TC500 NPs. Compared to TC500 NPs, TC200 NPs could significantly enhance in vitro and in vivo cellular uptake by PECs and facilitate cytoplasmic siRNA release, resulting in high in vitro and in vivo TNF-α knockdown. Superior TNF-α suppressing level was obtained with TC200 NPs via oral gavage rather than intraperitoneal injection.Conclusions
The efficacies of in vivo TNF-α silencing were related to the molecular weight of TC conjugate and the administration route, which would assist in the rational design of siRNA vehicles. 相似文献16.
Purpose
The present investigation aimed at brain targeting of sumatriptan succinate (SS) for its optimal therapeutic effect in migraine through nanoparticulate drug delivery system using poly (butyl cyanoacrylate) (PBCA) and bovine serum albumin linked with apolipoprotein E3 (BSA-ApoE).Method
The study involved formulation optimization of PBCA nanoparticles (NPs) using central composite design for achieving minimum particle size, maximum entrapment efficiency along with sustained drug release. SS incorporated in BSA-ApoE NPs (S-AA-NP) were prepared by desolvation technique and compared with SS loaded polysorbate 80 coated optimized PBCA NPs (FPopt) in terms of their brain uptake potential, upon oral administration in male Wistar rats. The NPs were characterized by FTIR, thermal, powder XRD and TEM analysis.Results
The in vivo studies of FPopt and S-AA-NP on male Wistar rats demonstrated a fairly high brain/plasma drug ratio of 9.45 and 12.67 respectively 2 h post oral drug administration. The behavioural studies on male Swiss albino mice affirmed the enhanced anti-migraine potential of S-AA-NP than FPopt (P?<?0.001).Conclusion
The results of this work, therefore, indicate that BSA-ApoE NPs are significantly better than polysorbate 80 coated PBCA NPs for brain targeting of SS (P?<?0.05) and also offer an improved therapeutic strategy for migraine management.17.
Purpose
In pharmacokinetic (PK)/pharmacodynamic (PD) modelling and simulations (M&S), omitting dropouts can cause inaccuracies in parameter estimation and clinical trial simulations (CTS). This study examines the impact of different imputation methods for missing data on the interpretation of model results, as well as develops a selection model (where dropout and efficacy are jointly modelled) for use in CTS.Methods
Missing data were imputed using single and multiple imputation and pattern mixtures methods for a previously reported duloxetine PK/PD model. The probability of dropout was described in the selection model and CTS was conducted with a hypothetical drug to examine the impact of dropout on trial results.Results
The study completion rate was 75% and dropouts were not random. Model parameters obtained with different imputation methods were mostly within 40% (range 0 to 63%) compared to the model without dropouts. CTS showed 0.3 points lower median pain scores and 3% lower coefficient of variation over the 12-week simulations when dropout was included.Conclusions
Missing data had little impact on the original population PK/PD analyses. Sensitivity analyses for dropouts should be conducted in M&S exercises. The utility of selection models in CTS was explored via a hypothetical case study. 相似文献18.
Purpose
The aim of this work was to evaluate in vivo poly(lactide)-d-α-tocopheryl polyethylene glycol 1,000 succinate nanoparticles (PLA–TPGS NPs) for controlled and sustained small molecule drug chemotherapy.Methods
The drug-loaded PLA–TPGS NPs were prepared by the dialysis method. Particle size, surface morphology and surface chemistry, in vitro drug release and cellular uptake of NPs were characterized. In vitro and in vivo therapeutic effects of the nanoparticle formulation were evaluated in comparison with Taxol®.Results
The PLA–TPGS NP formulation exhibited significant advantages in in vivo pharmacokinetics and xenograft tumor model versus the PLGA NP formulation and the pristine drug. Compared with Taxol®, the PLA–TPGS NP formulation achieved 27.4-fold longer half-life in circulation, 1.6-fold larger area-under-the-curve (AUC) with no portion located above the maximum tolerance concentration level. For the first time in the literature, one shot for 240 h chemotherapy was achieved in comparison with only 22 h chemotherapy for Taxol® at the same 10 mg/kg paclitaxel dose. Xenograft tumor model further confirmed the advantages of the NP formulation versus Taxol®.Conclusions
The PLA–TPGS NP formulation can realize a way of controlled and sustained drug release for more than 10 days, which relieves one of the two major concerns on cancer nanotechnology, i.e. feasibility. 相似文献19.
V. Guy-Viterbo A. Scohy R. K. Verbeeck R. Reding P. Wallemacq Flora Tshinanu Musuamba 《European journal of clinical pharmacology》2013,69(8):1533-1542
Purposes
Tacrolimus (TAC) is the most widely used immunosuppressant for the prevention of acute rejection after solid organ transplantation. Its pharmacokinetics (PK) show considerable variability, making TAC a good candidate for therapeutic drug monitoring (TDM). The principal aim of the study was to describe the PK of TAC in pediatric patients during the first year after transplantation.Methods
Routine TDM trough levels of TAC were obtained from 42 pediatric liver allograft recipients during the first year after transplantation. A population PK model was developed using nonlinear mixed-effects modeling to describe TAC PK during this period and to explain the observed variability by means of patients’ demographics, biochemical test results and physiological characteristics.Results
The PK of TAC were best described by a two-compartment model with first-order elimination. Apparent volumes of the central compartment, intercomparmental clearance and maximum blood clearance estimates were 253 L, 115 L/day and 314 L/day, respectively. The absorption first-order rate and volume of peripheral compartment were fixed to 4.5 h-1 and 100 L, respectively. While hematocrit levels, time after transplantation and bodyweight influenced TAC clearance, bodyweight was the only covariate retained on volume of distribution.Conclusions
We developed a TAC population PK model in pediatrics covering the first year after liver transplantation that may serve as a tool for TAC dose individualization as part of TDM. 相似文献20.