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1.
Ther Drug Monit ; 44(3): 404-413, 2022 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-34629445

RESUMO

BACKGROUND: Teicoplanin is a glycopeptide antibiotic used for the treatment of methicillin-resistant Staphylococcus aureus infections. To ensure successful target attainment, therapeutic drug monitoring-informed dosage adjustment is recommended. However, it relies on the experience of the clinician and the frequency of drug measurements. This study aimed to design a new optimal dosing regimen of teicoplanin with a maintenance dosing strategy for neonates and children based on their physiological characteristics. METHODS: Data from teicoplanin-treated patients (n = 214) were collected from electronic medical records. Covariate analyses were performed using population pharmacokinetic (PK) modeling with 399 serum teicoplanin concentrations from 48 neonates and 166 children. Multiple PK simulations were conducted to explore optimal dosing regimens that would allow control of the trough concentration to the target of 15-30 mg/L quicker than the current standard regimen. RESULTS: Allometrically scaled body weight, postmenstrual age (PMA), renal function, and serum albumin were implemented as substantial covariates for teicoplanin clearance in a two-compartment PK model. Covariate analyses and comprehensive simulation assessments recommended the following modifications to the current regimen: (1) decreased dose for premature babies (PMA ≤28 weeks), (2) decreased dose for children with renal dysfunction, and (3) increased dose for children (0.5-11 years) with an estimated glomerular filtration rate of ≥90 mL/min/1.73 m2. CONCLUSIONS: This study leverages real-world clinical information and proposes new optimal dosing regimens for teicoplanin in neonates and children through PK modeling and simulation analyses, taking into account the age, including PMA, and renal function of patients.


Assuntos
Staphylococcus aureus Resistente à Meticilina , Teicoplanina , Antibacterianos/farmacocinética , Criança , Monitoramento de Medicamentos , Humanos , Recém-Nascido , Método de Monte Carlo , Teicoplanina/farmacocinética
2.
Eur J Clin Pharmacol ; 77(8): 1157-1168, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33527208

RESUMO

PURPOSE: Variability in teicoplanin pharmacokinetics has been explained by multiple factors such as body weight, renal function, and serum albumin level. To improve mechanistic understanding of the causes of variability, a physiologically based pharmacokinetic (PBPK) model can be used as a systematic platform. In this study, a PBPK model of teicoplanin was developed to quantitatively assess the effects of physiological changes due to disease status using virtual populations. METHODS: Predictive performance of the models was evaluated by comparing simulated and observed concentration-time profiles of teicoplanin. Subsequently, sensitivity analyses were conducted to identify potential factors contributing to individual differences in teicoplanin PK. RESULTS: The developed PBPK model generated concentration-time profiles that were comparable to clinical observations in healthy adults, including Caucasians and Japanese, and after single-dose and multiple-dose administration. The predicted PK parameters (i.e., Cmax, AUC, clearance) were within a two-fold range of the observed data in patients with renal impairments as well as healthy adults. Changes in total and unbound teicoplanin concentrations at 72 h, after various dosing regimens (tested 4-14 mg/kg q12h for three doses as a loading dose and then 4-14 mg/kg daily as a maintenance dose), were sensitive to renal function and serum albumin concentrations. CONCLUSION: The PBPK model of teicoplanin provides mechanistic insight into the factors altering its disposition and allows assessments of the theoretical and quantitative impact of individual changes in physiological parameters on its PK even when an actual assessment with adequate sample sizes of patients is challenging.


Assuntos
Antibacterianos/farmacocinética , Modelos Biológicos , Insuficiência Renal/metabolismo , Albumina Sérica/metabolismo , Teicoplanina/farmacocinética , Idoso , Área Sob a Curva , Povo Asiático , Simulação por Computador , Feminino , Taxa de Filtração Glomerular , Humanos , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Gravidade do Paciente , População Branca
3.
Ther Drug Monit ; 38(5): 607-13, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27310200

RESUMO

BACKGROUND: Sirolimus is a mammalian target of rapamycin inhibitor that is being used to prevent organ rejection in kidney transplant patients often in combination with calcineurin inhibitors (CNIs; cyclosporine and tacrolimus). All 3 drugs are metabolized primarily by CYP3As. Clinical drug-drug interaction (DDI) studies of cyclosporine on sirolimus pharmacokinetics have been reported; however, there are a few clinical DDI data related to tacrolimus. METHODS: In vitro inhibition assay with sirolimus were conducted using recombinant CYP3As and human microsomes in the presence and absence of CNIs. Sirolimus concentrations were determined by validated high-performance liquid chromatography-tandem mass spectrometry (LC/MS-MS) assay. The DDI risk in terms of increase in sirolimus area under the curve (AUC) was evaluated by a mechanistic model using in vitro inhibition data and published pharmacokinetic parameters of CNIs. RESULTS: Both CNIs showed similar inhibitory effects on sirolimus metabolism in human liver and intestinal microsomes. Cyclosporine predominantly inhibited CYP3A4 (half maximal inhibitory concentration = 0.71 µM) rather than CYP3A5 (>5 µM), whereas tacrolimus showed similar inhibition for CYP3A4 (0.29 µM) and CYP3A5 (0.41 µM). The predicted increase in AUC of sirolimus during the coadministration of cyclosporine was 3.9-fold, which was comparable to the observed clinical data (3.3-fold) in healthy volunteers. Sirolimus AUC was estimated to a 2.8- to 3.2-fold increase during the coadministration of tacrolimus, based on the reported Cmax values and doses of tacrolimus in kidney transplant patients. In addition, exploratory sensitivity analysis indicated that the predicted increase in sirolimus AUC was sensitive to the free fraction of cyclosporine but not to the free fraction of tacrolimus. CONCLUSIONS: This study suggests that tacrolimus has a lower clinical DDI risk potential affecting sirolimus pharmacokinetics compared with cyclosporine in kidney transplant patients.


Assuntos
Interações Medicamentosas , Transplante de Rim , Sirolimo/farmacocinética , Tacrolimo/farmacologia , Ciclosporina/farmacologia , Citocromo P-450 CYP3A/efeitos dos fármacos , Inibidores do Citocromo P-450 CYP3A/farmacologia , Humanos , Imunossupressores/farmacocinética , Técnicas In Vitro , Microssomos/efeitos dos fármacos , Microssomos/metabolismo , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Medição de Risco
4.
Curr Drug Metab ; 11(8): 678-85, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20973757

RESUMO

The attrition rate in drug development is being reduced by continuous advances in science and technology introduced by various academic institutions and pharmaceutical companies. This has been certainly noticeable in reducing the frequency with which unfavorable absorption, distribution, metabolism, and elimination (ADME) characteristics of any candidate drug causes failure in clinical development. Nonetheless, it is important that the objectives in reducing attrition during later stages of development are matched by information generated in the earliest stage of discovery. In this review, we summarize the methodologies employed during the early stages of drug discovery and discuss new findings in the areas of (1) drug metabolism enzymes, (2) the contribution of cytochrome P450 enzymes (P450, CYP) to hepatic metabolism, (3) prediction of hepatic intrinsic clearance, (4) reaction phenotyping, and (5) the metabolic differences between highly homologous enzymes such as CYP3A4 and CYP3A5. The total contribution of P450 and UDP-glucuronosyltransferases to drug metabolism is reported to be more than 80%; therefore, glucuronidation is increasingly recognized as an important clearance pathway in addition to that of P450 enzymes. When estimating the contribution of P450, interpreting the results of inhibition studies using a single P450 inhibitor can lead to false conclusions. For instance, 1-aminobenzotriazole and SKF-525A have a varying range of IC(50) values for inhibition of drug exidation-reaction by different CYP450 enzymes. There are disparities between methodologies at early stage drug discovery and late stage development. For example, although the drug depletion approach for the prediction of hepatic intrinsic clearance may not be desirable at late stages of development, it is suitable at the early drug discovery stage since kinetic characterization and measurement of specific drug metabolites are not required. Data from protein binding assays in plasma and/or liver microsomes is an integral part to predicting hepatic clearance; therefore, the prediction methods for protein binding have been addressed in terms of automation and in silico prediction. The approach to reaction phenotyping using recombinant P450 microsome data are reviewed as this approach enables combining the drug depletion method with appropriate scaling factors to predict clearance values. CYP3A enzymes have broad substrate specificities and are responsible for the oxidative metabolism of more than 50% of clinically used drugs. Although CYP3A4 is the most abundant CYP3A isoform in adult human liver, CYP3A5 may contribute more to CYP3A-mediated drug oxidation by human liver microsomes than CYP3A4 does, especially in Japanese subjects, who typically have a relatively high frequency of genetic CYP3A5 expression. Lack of efficacy and presence of serious side effects in some sub-group of patients remain the biggest sources of drug failure at late stage of drug development. Advances in appreciation of inter-individual variabilities in ADME, by creation of virtual individuals and use of appropriate information from early discovery may lead to a better anticipation of variable clinical and toxicological outcome following administration of any new drug candidate. Thus may also help with dosing strategies which minimize the potential side effects and maximize the clinical benefits. Accordingly, front-loading of efforts for characterizing the candidate drugs at early stages of discovery is recommended.


Assuntos
Sistema Enzimático do Citocromo P-450/metabolismo , Desenho de Fármacos , Preparações Farmacêuticas/metabolismo , Adulto , Animais , Descoberta de Drogas/métodos , Indústria Farmacêutica/métodos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Humanos , Fígado/enzimologia , Fígado/metabolismo , Microssomos Hepáticos/metabolismo , Ligação Proteica
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