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1.
Eur J Pharm Sci ; 167: 105986, 2021 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-34474119

RESUMO

BACKGROUND: Efavirenz is a vital component used to treat HIV-1 infection. Nevertheless, it shows large between-subject variability, which affects both its therapeutic response and adverse effects. OBJECTIVE: To investigate the impact of gene polymorphisms and non-genetic factors on the variability of efavirenz pharmacokinetics and to propose the optimal dose regimens. METHODS: A total of 769 plasma samples from 376 HIV-infected Han Chinese outpatients were collected to develop a population pharmacokinetic model using NONMEM software. The impact of patient demographics, laboratory tests, concomitant medication, and genetic polymorphisms of CYP2B6 and ABCB1 on efavirenz pharmacokinetics were explored. According to the final model, the model-informed dose optimization was conducted. RESULTS: The pharmacokinetics of efavirenz was characterized by a one-compartment model with first-order absorption and elimination. The typical values of the estimated apparent oral clearance, volume of distribution, and absorption rate constant in the final model were 9.44 L/h, 200 L, and 0.727 h - 1, respectively. Efavirenz clearance was significantly influenced by CYP2B6 variants, including rs2099361, rs3745274, and rs2279343, along with albumin and weight. The volume of distribution was affected by albumin and weight. Based on the CYP2B6 polymorphisms of patients, the recommended daily doses of efavirenz were 100 mg for CYP2B6 slow metabolizers, 400 or 600 mg for intermediate metabolizers, and 800 or 1000 mg for extensive metabolizers. CONCLUSIONS: Polymorphisms of CYP2B6, along with albumin and weight, resulted as the predictors of efavirenz pharmacokinetic variability, which could be used in prescribing optimal efavirenz doses.

2.
Eur J Pharm Sci ; 162: 105818, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33771717

RESUMO

BACKGROUND: Little is known about the population pharmacokinetics (PPK) of daptomycin in kidney transplant patients. The present study established a pharmacokinetic model for daptomycin in kidney transplant patients in China and examinee the important factors affecting the pharmacokinetic parameters of daptomycin. METHODS: The study population included 49 kidney transplant patients with 537 daptomycin concentrations. The PPK model of daptomycin was developed using a nonlinear mixed-effects model, a two-compartment structural model, and a mixed residual error model. The stability and predictive ability of the final model were evaluated based on bootstrapping, visual prediction checks and normalized prediction distribution errors. RESULTS: Glomerular filtration rate (GFR) and total body weight significantly affected clearance, and body weight influenced the central volume of distribution. The average clearance of the population was 0.316 L/h, the central volume of distribution was 6.04 L, the intercompartmental clearance was 2.31 L/h, and the peripheral volume of distribution was 2.46 L. Based on the established model and the target of area under curve (AUC0-24h)/minimum inhibition concentration (MIC) ≥666, we developed a recommended dose regimen for kidney transplant patients according to their renal function and weight. The daily doses were 4.0±0.31, 4.7±0.36, 5.1±0.40, 5.5±0.43, 5.8±0.45, and 6.1±0.48 mg/kg when the GFRs were 15, 30, 45, 60, 75, and 90 ml/min/1.73 m2, respectively. CONCLUSION: This study provides a reference for individualized daptomycin administration in kidney transplant recipients, and it is a valuable resource for improving the treatment effect and reducing the toxic effects of daptomycin.


Assuntos
Daptomicina , Transplante de Rim , China , Humanos , Imunossupressores , Modelos Biológicos
3.
Eur J Pharm Sci ; 159: 105729, 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33484815

RESUMO

OBJECTIVE: Pyrotinib, a new oral irreversible pan-ErbB tyrosine kinase inhibitor (TKI), has been approved in China for the treatment of HER2-positive advanced or metastatic breast cancer. This study aimed to conduct a population pharmacokinetics (PK) analysis of pyrotinib and to evaluate the impact of patient characteristics on pyrotinib's PK. METHOD: A total of 1152 samples, provided by 59 adult female patients from two phase I clinical trials, were analyzed by nonlinear mixed-effects modeling. Monte Carlo simulation was conducted to assess impact of covariates on the exposure to pyrotinib. RESULTS: The PK of pyrotinib was adequately described by a one-compartment model with first-order absorption and elimination. Patient's age and total protein levels could affect pyrotinib's apparent volume of distribution, and concomitant use of montmorillonite could decrease the bioavailability of pyrotinib by 50.3%. No PK interactions were observed between capecitabine and pyrotinib. CONCLUSION: In this study, a population PK model of pyrotinib was developed to determine the influence of patient characteristics on the PK of pyrotinib. While patient age and total protein levels can significantly affect the apparent distribution volume of pyrotinib, the magnitude of the impact was limited, thus no dosage adjustment was recommended. Furthermore, concomitant use of montmorillonite for diarrhea needs to be taken with precaution.


Assuntos
Neoplasias da Mama , Acrilamidas , Adulto , Aminoquinolinas , Neoplasias da Mama/tratamento farmacológico , China , Feminino , Humanos , Receptor ErbB-2
4.
Front Pharmacol ; 11: 563967, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33117163

RESUMO

Background: Depending on the renal function of patients and many other influencing factors, studies on vancomycin pharmacokinetics show significant inter- and intra-individual variability. The present study was conducted using a population pharmacokinetics method to investigate the pharmacokinetic parameters and identified their influencing covariates for intravenous vancomycin in adult kidney transplant recipients. Methods: The drug monitoring data included 56 adult renal transplant recipients who received intravenous vancomycin as prophylactic medication. The analysis was performed by a population approach with NONMEM. Data were collected mainly during the first week after transplantation. Monitoring of vancomycin trough concentration in blood was initiated mainly 3-5 days after the initial administration. Results: The one-compartment open model was optimal and adequately described the data. Body weight (WT) and estimated glomerular filtration rate (GFR) were identified as significant covariates of the pharmacokinetic parameters CL and V of intravenous vancomycin in the kidney transplant patients. The typical values of vancomycin CL and V were 2.08 L h-1 and 63.2 L, respectively. A dosage strategy scheme according to model results was also designed. Conclusion: Both WT and GFR of the kidney transplant patients positively influence the pharmacokinetic parameters CL and V for intravenous vancomycin. Our population pharmacokinetic model provides a reference for vancomycin dosage adjustment in kidney transplant recipients.

5.
Zhongguo Dang Dai Er Ke Za Zhi ; 22(1): 12-16, 2020 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-31948518

RESUMO

OBJECTIVE: To evaluate the efficacy and safety of C-reactive protein (CRP)-guided antibiotic treatment strategy for neonates with suspected early-onset sepsis (EOS). METHODS: A total of 428 neonates, with a gestational age of >35 weeks, who were admitted to the Children's Hospital of Chongqing Medical University from February to July, 2019 and were suspected of EOS were enrolled as the observation group. The effect of antibiotic treatment was prospectively observed, and if clinical symptoms were improved and CRP was <10 mg/L in two consecutive tests, discontinuation of antibiotics was considered. A total of 328 neonates (gestational age of >35 weeks) who were admitted to this hospital from February to July, 2018 and were suspected of EOS were enrolled as the control group, and the use of antibiotics was analyzed retrospectively. The two groups were compared in terms of duration of antibiotic treatment, length of hospital stay, incidence rate of repeated infection and clinical outcome. RESULTS: Compared with the control group, the observation group had significantly shorter duration of antibiotic treatment and length of hospital stay (P<0.05). There were no significant differences in the incidence rate of repeated infection and clinical outcome between the two groups (P>0.05). CONCLUSIONS: For neonates with a gestational age of >35 weeks and a suspected diagnosis of EOS, CRP-guided antibiotic treatment strategy can shorten duration of antibiotic treatment and length of hospital stay and does not increase the incidence rate of repeated infection. Therefore, it holds promise for clinical application.


Assuntos
Antibacterianos/uso terapêutico , Sepse , Proteína C-Reativa , Idade Gestacional , Humanos , Recém-Nascido , Estudos Retrospectivos , Sepse/tratamento farmacológico
6.
Front Pharmacol ; 9: 603, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29997498

RESUMO

The main goal of our study was to characterize the population pharmacokinetics of vancomycin in critically ill Chinese neonates to develop a pharmacokinetic model and investigate factors that have significant influences on the pharmacokinetics of vancomycin in this population. The study population consisted of 80 neonates in the neonatal intensive care unit (ICU) from which 165 trough and peak concentrations of vancomycin were obtained. Nonlinear mixed effect modeling was used to develop a population pharmacokinetic model for vancomycin. The stability and predictive ability of the final model were evaluated based on diagnostic plots, normalized prediction distribution errors and the bootstrap method. Serum creatinine (Scr) and body weight were significant covariates on the clearance of vancomycin. The average clearance was 0.309 L/h for a neonate with Scr of 23.3 µmol/L and body weight of 2.9 kg. No obvious ethnic differences in the clearance of vancomycin were found relative to the earlier studies of Caucasian neonates. Moreover, the established model indicated that in patients with a greater renal clearance status, especially Scr < 15 µmol/L, current guideline recommendations would likely not achieve therapeutic area under the concentration-time curve over 24 h/minimum inhibitory concentration (AUC24h/MIC) ≥ 400. The exceptions to this are British National Formulary (2016-2017), Blue Book (2016) and Neofax (2017). Recommended dose regimens for neonates with different Scr levels and postmenstrual ages were estimated based on Monte Carlo simulations and the established model. These findings will be valuable for developing individualized dosage regimens in the neonatal ICU setting.

7.
J Gen Virol ; 85(Pt 7): 2023-2034, 2004 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-15218188

RESUMO

Full-length sequences of the Epstein-Barr virus (EBV) gene for latent membrane protein (LMP)-1 from 22 nasopharyngeal carcinoma (NPC) biopsy specimens and 18 non-neoplastic counterparts (NPI) were determined. Relative to the B95-8 strain, the amino acid sequences of the toxic-signal and transformation domains were changed variably in NPC and NPI specimens; in contrast, no change was observed in the NF-kappaB (nuclear factor kappaB) activation domain. HLA typing revealed that 47 % of NPC and 31 % of NPI specimens were HLA A2-positive. A major A2-restricted epitope within LMP-1 (residues 125-133) was analysed. At residue 126, a change of L-->F was detected in 91 % (20/22) of NPC and 67 % (12/18) of NPI specimens. In addition, a deletion at residue 126 was detected in one NPC sample from Taiwan. At residue 129, a change of M-->I was observed in all samples, regardless of whether they were NPC or NPI. The changes in this peptide between NPC and NPI specimens, including mutation and deletion, are statistically significant (P<0.05). A recent report indicated that this variant sequence is recognized poorly by epitope-specific T cells. Genotyping results indicated that 96 % of NPC and 67 % of NPI samples carried a type A virus. By scanning the entire sequence of LMP-1, eight distinct patterns were identified. Detailed examination of these patterns revealed that type A strains are more prevalent in NPC than in NPI specimens and are marked by the loss of an XhoI site, the presence of a 30 bp deletion and the presence of a mutated, A2-restricted, T cell target epitope sequence. These results suggest that an EBV strain carrying an HLA A2-restricted 'epitope-loss variant' of LMP-1 is prevalent in NPC in southern China and Taiwan.


Assuntos
Antígeno HLA-A2/genética , Herpesvirus Humano 4/genética , Neoplasias Nasofaríngeas/patologia , Neoplasias Nasofaríngeas/virologia , Proteínas da Matriz Viral/química , Sequência de Aminoácidos , Substituição de Aminoácidos , Sequência de Bases , China , Primers do DNA , Epitopos/genética , Variação Genética , Herpesvirus Humano 4/isolamento & purificação , Humanos , Complexo Principal de Histocompatibilidade/genética , NF-kappa B/metabolismo , Fragmentos de Peptídeos/química , Reação em Cadeia da Polimerase , Mapeamento por Restrição , Taiwan
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