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1.
Expert Opin Drug Metab Toxicol ; 15(11): 881-895, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31550939

RESUMO

Introduction: Therapeutic drug monitoring (TDM) has been shown to optimize the management of invasive fungal infections (IFIs), particularly for select antifungal agents with a well-defined exposure-response relationship and an unpredictable pharmacokinetic profile or a narrow therapeutic index. Select triazoles (itraconazole, voriconazole, and posaconazole) and flucytosine fulfill these criteria, while the echinocandins, fluconazole, isavuconazole, and amphotericin B generally do not do so. Given the morbidity and mortality associated with IFIs and the challenges surrounding the use of currently available antifungal agents, TDM plays an important role in therapy.Areas covered: This review seeks to describe the rationale for TDM of antifungal agents, summarize their pharmacokinetic and pharmacodynamic properties, identify treatment goals for efficacy and safety, and provide recommendations for optimal dosing and therapeutic monitoring strategies.Expert opinion: Several new antifungal agents are currently in development, including compounds from existing antifungal classes with enhanced pharmacokinetic or safety profiles as well as agents with novel targets for the treatment of IFIs. Given the predictable pharmacokinetics of these newly developed agents, use of routine TDM is not anticipated. However, expanded knowledge of exposure-response relationships of these compounds may yield a role for TDM to improve outcomes for adult and pediatric patients.


Assuntos
Antifúngicos/administração & dosagem , Monitoramento de Medicamentos/métodos , Infecções Fúngicas Invasivas/tratamento farmacológico , Adulto , Antifúngicos/farmacocinética , Antifúngicos/farmacologia , Criança , Desenvolvimento de Medicamentos , Humanos , Infecções Fúngicas Invasivas/microbiologia
2.
Clin Drug Investig ; 39(11): 1109-1116, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31432392

RESUMO

BACKGROUND AND OBJECTIVES: New intravenous and solid oral formulations of the antifungal agent posaconazole have been developed. This randomized, open-label, crossover study in 18 healthy adult Chinese male and female subjects evaluated the pharmacokinetics of single-dose posaconazole (oral 300-mg posaconazole tablet fasted, intravenous 300-mg posaconazole solution fasted, and oral 300-mg posaconazole tablet with standard high-fat breakfast). Primary objectives were to determine the single-dose pharmacokinetics of posaconazole in healthy Chinese subjects when administered as an intravenous solution and as an oral tablet under fasted conditions and the effect of food on the absorption of posaconazole. METHODS: The three treatments consisted of the following: a single oral dose of posaconazole 300 mg (fasted), a single oral dose of posaconazole 300 mg (high-fat breakfast), and a single intravenous dose of posaconazole 300 mg (fasted). Blood samples for pharmacokinetic analysis were collected before dosing and at regular intervals after dosing. Adverse events were monitored throughout. The pharmacokinetic population included the per-protocol population. The safety population included all subjects who received one or more doses of the study drug. RESULTS: Time to maximum plasma concentration of intravenous posaconazole coincided with the end of infusion; the half-life (t½) was 25.76 h. Geometric mean (% coefficient of variation) values of area under the plasma concentration-time curve from time 0 extrapolated to infinity (AUC0-∞) and maximum plasma concentration (Cmax) were 59,925 (36.2%) h·ng/mL and 3999 (28.5%) ng/mL, respectively. The posaconazole tablet had a time to maximum plasma concentration of 4 h and a t½ of 25.21 h after fasting. Geometric mean (coefficient of variation) values of AUC0-∞ and Cmax were 25,263 (39.9%) h·ng/mL and 674.5 (29.6%) ng/mL, respectively. Standard high-fat breakfast increased the exposure of posaconazole approximately twofold with geometric mean ratios (high-fat breakfast/fasted) for AUC0-∞ and Cmax of 2.06 (90% confidence interval 1.86-2.30) and 1.95 (90% confidence interval 1.65-2.31), respectively. The geometric mean absolute bioavailability of the tablet formulation was 42.2% in the fasted state and 87.1% under high-fat breakfast conditions. The most commonly reported adverse events were nausea, vomiting, dizziness, and first-degree atrioventricular block for intravenous posaconazole 300 mg and nausea for oral posaconazole 300 mg (high-fat breakfast). All adverse events were mild and resolved without sequelae. CONCLUSIONS: Posaconazole was generally well tolerated in healthy Chinese male and female subjects. The safety and the high-fat breakfast and fasted pharmacokinetics of posaconazole in healthy Chinese subjects are within exposures demonstrated to be generally well tolerated and efficacious and compare reasonably well with the overall posaconazole data across Western countries.


Assuntos
Antifúngicos/efeitos adversos , Antifúngicos/farmacocinética , Jejum/fisiologia , Interações Alimento-Droga/fisiologia , Triazóis/efeitos adversos , Triazóis/farmacocinética , Administração Intravenosa , Administração Oral , Adulto , Antifúngicos/administração & dosagem , Estudos Cross-Over , Dieta Hiperlipídica , Feminino , Voluntários Saudáveis , Humanos , Masculino , Náusea/induzido quimicamente , Náusea/diagnóstico , Comprimidos , Triazóis/administração & dosagem , Adulto Jovem
3.
AAPS PharmSciTech ; 20(7): 297, 2019 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-31444661

RESUMO

Miconazole nitrate (MZ) is a BCS class II antifungal poorly water-soluble drug with limited dissolution properties and gastrointestinal side effects. Self-nanoemulsifying delivery system-based gel of MZ can improve both solubility and oral mucosal absorption with enhanced antifungal activity. The study aims to formulate MZ self-nanoemulsion (MZ-NE) and combine it within hyaluronic acid-based gel. MZ solubility in various oils, surfactants, and cosurfactant used in NE formulations were evaluated. Mixture design was implemented to optimize the levels of NE components as a formulation variable to study their effects on the mean globule size and antifungal inhibition zones. Further, the optimized MZ-NE was loaded into a hyaluronic acid gel base. Rheological behavior of the prepared gel was assessed. Ex vivo permeability of optimized formulation across buccal mucous of sheep and inhibition against Candida albicans were examined. Mixture design was used to optimize the composition of MZ-NE formulation as 22, 67, and 10% for clove oil, Labrasol, and propylene glycol, respectively. The optimized formulation indicated globule size of 113 nm with 29 mm inhibition zone. Pseudoplastic flow with thixotropic behavior was observed, which is desirable for oral gels. The optimized formulation exhibited higher ex vivo skin permeability and enhanced antifungal activity by 1.85 and 2.179, respectively, compared to MZ-SNEDDS, and by 1.52 and 1.72 folds, respectively, compared to marketed gel. Optimized MZ-NE hyaluronic acid-based oral gel demonstrated better antifungal activity, indicating its potential in oral thrush pharmacotherapy.


Assuntos
Antifúngicos/administração & dosagem , Candidíase Bucal/tratamento farmacológico , Química Farmacêutica/métodos , Ácido Hialurônico/administração & dosagem , Miconazol/administração & dosagem , Nanocápsulas/administração & dosagem , Administração Oral , Animais , Antifúngicos/síntese química , Antifúngicos/farmacocinética , Candidíase Bucal/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Avaliação Pré-Clínica de Medicamentos/métodos , Emulsões/administração & dosagem , Emulsões/síntese química , Emulsões/farmacocinética , Ácido Hialurônico/síntese química , Ácido Hialurônico/farmacocinética , Hidrogéis/administração & dosagem , Hidrogéis/síntese química , Hidrogéis/farmacocinética , Miconazol/síntese química , Miconazol/farmacocinética , Nanocápsulas/química , Ovinos
4.
Int J Infect Dis ; 86: 142-146, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31330325

RESUMO

OBJECTIVE: To describe the pharmacokinetic (PK) profile of anidulafungin and to evaluate its concentration in the peritoneal fluid (PF) of patients suspected of suffering from peritoneal infection undergoing abdominal surgery, in order to ensure that therapeutic levels are achieved within the peritoneal cavity. METHODS: A descriptive, open, prospective, observational, multicentre and non-interventional study was performed. Anidulafungin was used at conventional doses. Blood and PF samples were obtained on day 2 of treatment or on any of the following days. RESULTS: A total of 31 patients in a serious clinical condition, as demonstrated by high mean clinical severity scale scores (APACHE II and SOFA scores), were included in the study. The mean area under the curve (AUC) in PF was 30% (31±19%) of that determined in the plasma and the maximum concentration (Cmax) reached in PF (mg/l) was close to 1 (0.9±0.5). No adverse effects were observed in any of the 31 patients. CONCLUSIONS: Anidulafungin at conventional doses reaches PF concentrations that exceed the minimum inhibitory concentration of the usual Candida spp, which explains the proven efficacy of this echinocandin in the treatment of Candida peritonitis in critically ill patients.


Assuntos
Anidulafungina/farmacocinética , Antifúngicos/farmacocinética , Candidíase/tratamento farmacológico , Estado Terminal , Peritonite/tratamento farmacológico , APACHE , Idoso , Idoso de 80 Anos ou mais , Anidulafungina/uso terapêutico , Antifúngicos/uso terapêutico , Área Sob a Curva , Líquido Ascítico/metabolismo , Candida/efeitos dos fármacos , Equinocandinas/uso terapêutico , Feminino , Humanos , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Peritonite/microbiologia , Estudos Prospectivos
5.
Int J Antimicrob Agents ; 54(4): 463-470, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31279853

RESUMO

Individualisation of the therapeutic strategy for the oral antifungal agent voriconazole (VCZ) is extremely important for treatment optimisation. To date, regulatory agencies include CYP2C19 as the only major pharmacogenetic (PGx) biomarker in their dosing guidelines; however, the effect of other genes might be important for VCZ dosing prediction. We developed an exploratory PGx study to identify new biomarkers related to VCZ pharmacokinetics. We first designed a 'clinical practice VCZ-AUC prediction model' based on CYP2C19 to be used as a reference model in this study. We then designed a multifactorial polygenic prediction model and found that genetic variability in FMO3, NR1I2, POR, CYP2C9 and CYP3A4 partially contributes to VCZ total area under the concentration-time curve (AUC0-∞) interindividual variability, and its inclusion in VCZ AUC0-∞ prediction algorithms improves model precision. To our knowledge, there are no PGx studies specifically relating POR, FMO3 and NR1I2 polymorphisms to VCZ pharmacokinetic variability. Further research is needed in order to test the model proposed here.


Assuntos
Antifúngicos/administração & dosagem , Antifúngicos/farmacocinética , Estudos de Associação Genética , Voriconazol/administração & dosagem , Voriconazol/farmacocinética , Administração Oral , Adulto , Feminino , Humanos , Masculino , Farmacogenética/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto , Espanha , Adulto Jovem
7.
Yakugaku Zasshi ; 139(6): 917-922, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31155536

RESUMO

The use of a drug administration plan and therapeutic drug monitoring (TDM) based on pharmacokinetic-pharmacodynamic (PK-PD) analysis is important for the effective use of antimicrobial agents to treat infections. We focused on the use of beta-lactam agents, anti-methicillin-resistant Staphylococcus aureus (MRSA) agents, and an antifungal agent as antimicrobial agents and examined their efficacy in patients under special clinical conditions from the viewpoint of safety and TDM. Our PK-PD analysis of the use of an administration plan to set an optimum serum level for beta-lactam agents or anti-MRSA drugs for the treatment of pneumonia, acute renal failure during continuous hemodialysis filtration, febrile neutropenia, or malignant tumors confirmed the necessity of managing the optimal serum level. PK-PD analysis was also useful for TDM of voriconazole and intubation administration in long-term use from the viewpoint of preventing the onset of side effects. PK-PD analysis appears to be a useful tool in antibiotic therapy and TDM for developing a pharmacokinetic "individual difference" for "individualization therapy" under special clinical conditions. PK-PD analysis utilizes the restrictive information that is obtained by a clinic to the maximum and allows coordination with the mission of hospital pharmacists to provide adequate antibiotic therapy.


Assuntos
Antibacterianos/administração & dosagem , Antibacterianos/farmacocinética , Antifúngicos/administração & dosagem , Antifúngicos/farmacocinética , Monitoramento de Medicamentos , Medicina de Precisão , Antibacterianos/efeitos adversos , Antifúngicos/efeitos adversos , Neutropenia Febril , Humanos , Neoplasias , Diálise Renal
8.
Crit Care ; 23(1): 205, 2019 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-31171022

RESUMO

BACKGROUND: The population pharmacokinetics of total and unbound posaconazole following intravenous administration has not yet been described for the critically ill patient population. The aim of this work was, therefore, to describe the total and unbound population pharmacokinetics of intravenous posaconazole in critically ill patients and identify optimal dosing regimens. METHODS: This was a prospective observational population pharmacokinetic study in critically ill adult patients with presumed/confirmed invasive fungal infection. A single dose of 300 mg posaconazole was administered intravenously as an add-on to standard antifungal therapy, and serial plasma samples were collected over 48 h. Total and unbound posaconazole concentrations, measured by chromatographic method, were used to develop a population pharmacokinetic model and perform dosing simulations in R using Pmetrics. RESULTS: From eight patients, 93 pairs of total and unbound concentrations were measured. A two-compartment linear model with capacity-limited plasma protein binding best described the concentration-time data. Albumin and body mass index (BMI) were included as covariates in the final model. Mean (SD) parameter estimates for the volume of the central compartment (V) and the elimination rate constant were 72 (43) L and 42.1 (23.7) h-1, respectively. Dosing simulations showed that high BMI was associated with a reduced probability of achieving target total and unbound posaconazole concentrations. Low serum albumin concentration was associated with a reduced probability of attaining target total but not unbound posaconazole concentrations. CONCLUSIONS: An important clinical message of this study is that critically ill patients with increased BMI may require larger than approved loading doses of intravenous posaconazole when considering currently recommended dosing targets. Variability in plasma albumin concentration appears unlikely to affect dosing requirements when the assessment is based on unbound concentrations. Where available, therapeutic drug monitoring of unbound concentrations may be useful.


Assuntos
Plasma/química , Triazóis/farmacocinética , Administração Intravenosa , Adulto , Albuminas/análise , Antifúngicos/efeitos adversos , Antifúngicos/farmacocinética , Índice de Massa Corporal , Estado Terminal/terapia , Feminino , Humanos , Unidades de Terapia Intensiva/organização & administração , Masculino , Espectrometria de Massas/métodos , Pessoa de Meia-Idade , Plasma/efeitos dos fármacos , Estudos Prospectivos , Ligação Proteica , Índice de Gravidade de Doença , Triazóis/efeitos adversos
9.
Int J Pharm ; 566: 565-572, 2019 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-31181305

RESUMO

The objective of the study was to evaluate the pharmacokinetic profile after different subcutaneous (s.c.) administrations of nano- and microparticle suspensions of griseofulvin to mice. The solubility of the compound was determined as approximately 40 µM, at 37 °C, independent of particle size, stabilizer mixtures investigated and solvent used for measurement. The present in vivo studies demonstrated non-linear absorption kinetics (in peak concentration, Cmax) for griseofulvin up to 50 mg/kg after s.c. administration of nanocrystals and microsuspensions but linear increase in area under the curve (AUC) at all occasions investigated. Cmax was higher for smaller particles administered. Both investigated suspensions, at 10 and 50 mg/kg, showed significantly sustained plasma profiles compared to i.v. and p.o. administration. Administering 10 and 50 mg/kg of griseofulvin nanocrystals as 10 mL/kg, instead of 2.5 mL/kg, improved Cmax but AUC was unchanged. The present study showed that the bioavailability of griseofulvin, administered as nano- and microparticles, increased significantly after s.c. administration (60-100%) compared with p.o. dosing (17%). The drug is currently orally administered and clearly exposed to a significant first pass metabolism, i.e. an ideal candidate for an alternative administration route, like s.c. injection.


Assuntos
Antifúngicos/administração & dosagem , Griseofulvina/administração & dosagem , Nanopartículas/administração & dosagem , Administração Oral , Animais , Antifúngicos/farmacocinética , Disponibilidade Biológica , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/farmacocinética , Feminino , Griseofulvina/farmacocinética , Injeções Subcutâneas , Camundongos Endogâmicos C57BL , Tamanho da Partícula
10.
Bioanalysis ; 11(12): 1217-1228, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31204857

RESUMO

The increase of fungal resistance to drugs, such as azole family, gave rise to the development of new antifungals. In this context, echinocandins emerged as a promising alternative for antifungal therapies. Following the commercialization of caspofungin in 2001, echinocandins became the first-line therapy for invasive candidiasis in different patient populations. The quantification of these drugs has gained importance since pharmacokinetic/pharmacodynamic and resistance studies are a paramount concern. This fact has led us to exhaustively examine the methodologies used for the analysis of echinocandins in biological fluids, which are mainly based on LC coupled to different detection techniques. In this review, we summarize the analytical methods for the quantification of echinocandins focusing on sample treatment, chromatographic separation and detection methods.


Assuntos
Antifúngicos/análise , Cromatografia/métodos , Testes de Química Clínica/métodos , Equinocandinas/análise , Métodos Analíticos de Preparação de Amostras , Animais , Antifúngicos/química , Antifúngicos/farmacocinética , Equinocandinas/farmacocinética , Equinocandinas/farmacologia , Humanos
11.
J Infect Chemother ; 25(10): 801-805, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31047782

RESUMO

Caspofungin (CPFG) is an echinocandin antifungal agent that inhibits the synthesis of ß-1, 3-D-glucan, a critical component of the cell wall of target fungi. Several clinical studies have confirmed the efficacy and safety of CPFG in patients with febrile neutropenia (FN); however, there are no reports available in Japanese patients with FN. Therefore, we investigated the therapeutic efficacy and pharmacokinetics of CPFG as an empirical therapy in a Japanese hospital. Twenty-four Japanese patients, who were diagnosed with FN at Gifu University Hospital from February 2014 to August 2017, were enrolled. Blood samples were collected at the end of CPFG dosing (0.5 h after the infusion) on day 1 and immediately prior to the next infusion on days 2, 3, and 4. The concentration of CPFG in plasma was measured by high-performance liquid chromatography. The efficacy was assessed by five of the component endpoints, and safety was monitored according to the Common Terminology Criteria for Adverse Events. CPFG showed an excellent effect against FN (75%, 18/24), without any serious hepatic or renal toxicity. Regarding the pharmacokinetics, the plasma concentration of CPFG was significantly correlated with body weight; although, no correlation was observed between the plasma concentration of CPFG and the other factors investigated, such as gender or laboratory results. These results suggest the high efficacy, safety, and tolerability of CPFG as an empirical antifungal therapy for Japanese patients with FN.


Assuntos
Antifúngicos/uso terapêutico , Caspofungina/uso terapêutico , Neutropenia Febril/tratamento farmacológico , Adulto , Idoso , Antifúngicos/farmacocinética , Peso Corporal , Caspofungina/farmacocinética , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Neutropenia Febril/sangue , Feminino , Humanos , Infusões Intravenosas , Japão , Rim/efeitos dos fármacos , Fígado/efeitos dos fármacos , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , Fatores Sexuais , Resultado do Tratamento , Adulto Jovem
12.
Pharm Dev Technol ; 24(7): 891-901, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31062987

RESUMO

This study was conducted to develop an in situ thermosensitive gel containing sertaconazole-loaded nanostructured lipid carriers (NLCs) for prolonged ocular drug delivery. To this end, sertaconazole-loaded NLCs (sertaconazole-NLCs) were prepared by emulsification solvent-diffusion method and the effects of different formulation variables were assessed using the fractional factorial design. Then, optimized sertaconazole-NLCs were incorporated into the pluronic F127 (PF127)/hydroxy propylmethylcellulose (HPMC) K4M hydrogel. The formulations were examined for pH, gelation temperature, rheological properties, in vitro permeation studies, and anti-fungal activity. The optimized sertaconazole-NLCs showed a mean particle size of 272.40 nm, encapsulation efficiency of 89.97%, zeta potential of 12.9 mV, and polydispersity index of 0.31. All the in situ formulations had acceptable pH, ranging from 5.89 to 6.28. The gelation temperature of the optimized formulation was 35.1 °C after dilution with simulated tear fluid (STF). Sertaconazole-NLCs showed a higher antifungal activity and permeation through the bovine cornea compared to the free drug and the in situ gel formulation. The cornea penetration of sertaconazole for the in situ gel of NLCs was also comparable to that for free drug. The obtained results indicated that the prepared nanocomposite system may have potential for treatment of fungal keratitis.


Assuntos
Antifúngicos/administração & dosagem , Portadores de Fármacos/química , Imidazóis/administração & dosagem , Lipídeos/química , Nanopartículas/química , Tiofenos/administração & dosagem , Animais , Antifúngicos/farmacocinética , Antifúngicos/farmacologia , Candida albicans/efeitos dos fármacos , Candidíase/tratamento farmacológico , Bovinos , Córnea/metabolismo , Liberação Controlada de Fármacos , Hidrogéis/química , Imidazóis/farmacocinética , Imidazóis/farmacologia , Ceratite/tratamento farmacológico , Nanopartículas/ultraestrutura , Poloxâmero/química , Temperatura Ambiente , Tiofenos/farmacocinética , Tiofenos/farmacologia
13.
Rev Peru Med Exp Salud Publica ; 36(1): 74-80, 2019.
Artigo em Espanhol | MEDLINE | ID: mdl-31116343

RESUMO

The objective of the study was to determine the therapeutic equivalence evaluated through in vitro studies of four brands of drugs containing amoxicillin, doxycycline, and fluconazole purchased at pharmaceutical facilities in Metropolitan Lima, and to establish their interchangeability with a reference product (RP). A validated method of visible ultraviolet spectrophotometry was used to determine the dissolution profile. The similarity factor (f2) was used to establish the therapeutic equivalence, being considered equivalent if the values of f2 were between 50 and 100. For doxycycline, the four drugs were equivalent in vitro to the RP; for amoxicillin, only two drugs were equivalent in vitro to the RP; and for fluconazole, none was equivalent in vitro to the RP. It is concluded that some amoxicillin and fluconazole drugs circulating in the national market do not meet the therapeutic equivalence assessed by in vitro studies; in other words, they are not interchangeable.


Assuntos
Amoxicilina/farmacocinética , Antibacterianos/farmacocinética , Antifúngicos/farmacocinética , Doxiciclina/farmacocinética , Fluconazol/farmacocinética , Estudos Transversais , Peru , Equivalência Terapêutica
14.
Vet Anaesth Analg ; 46(4): 501-509, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30982709

RESUMO

OBJECTIVE: To determine the effects of fluconazole on oral methadone pharmacokinetics and central effects mediated by opioid receptors in dogs. STUDY DESIGN: Prospective, incomplete block. ANIMALS: A total of 12 healthy Beagle dogs. METHODS: Dogs were randomly allocated into two groups of six dogs. In total, four treatments (two treatments/group) were administered including: oral methadone (1 mg kg-1); oral fluconazole (5 mg kg-1) every 12 hours starting 24 hours prior to oral methadone (1 mg kg-1); oral fluconazole (2.5 mg kg-1) every 12 hours starting 24 hours prior to oral methadone (1 mg kg-1); and oral fluconazole (5 mg kg-1) every 24 hours starting 12 hours prior to oral methadone (1 mg kg-1). At least 28 days were implemented as a washout period between fluconazole treatments. Rectal temperature (RT), heart rate (HR), respiratory rate (fR), sedation scores and blood samples were obtained for 24 hours after methadone administration. Plasma drug concentrations were measured with liquid chromatography/mass spectrometry. RESULTS: Significantly higher maximum plasma methadone concentration (mean, 25-46 ng mL-1) occurred in all fluconazole-administered treatments than in methadone alone (1.5 ng mL-1). The mean 12 hour methadone plasma concentration in fluconazole treatments was 11-20 ng mL-1. Significantly decreased RT and variable sedation occurred in all fluconazole treatments, but no changes occurred with methadone alone. There were no differences in HR or fR among treatments. CONCLUSIONS AND CLINICAL RELEVANCE: Fluconazole significantly increases the extent and duration of oral methadone exposure in dogs resulting in significant central opioid effects.


Assuntos
Analgésicos Opioides/farmacocinética , Antifúngicos/farmacocinética , Fluconazol/farmacocinética , Metadona/farmacocinética , Administração Oral , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/farmacologia , Animais , Antifúngicos/administração & dosagem , Estudos Cross-Over , Cães , Relação Dose-Resposta a Droga , Interações de Medicamentos , Feminino , Fluconazol/administração & dosagem , Fluconazol/farmacologia , Masculino , Metadona/administração & dosagem , Metadona/sangue , Metadona/farmacologia
15.
Expert Rev Clin Pharmacol ; 12(5): 443-452, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30952196

RESUMO

INTRODUCTION: Recalcitrant dermatophytoses is on the rise. Though myriad factors contribute to recalcitrance including terbinafine resistance, itraconazole largely remains sensitive. However, there are increasing instances of patients not responding adequately to itraconazole despite low MICs, probably due to issues plaguing the pelletization process, resulting in suboptimal quality. Data on this topic was searched on pubmed using the search items: itraconazole, MIC, MFC, quality, assay, pharmacokinetics, pharmacodynamics, dermatophytoses, and recalcitrance. Areas covered: A detailed analysis of the manufacturing process of itraconazole with emphasis on pelletization and parameters affecting the dissolution and bioavailability is presented. Important formulation factors including drug-polymer ratio, polymer type, coating thickness, bead size, and number are discussed. Also covered is the rationale of dosimetry of itraconazole in dermatophytoses based on the skin pharmacokinetics and MIC of the organism. Expert opinion: The process of pelletization has multiple components aiming to achieve maximum dissolution of the drug. Variations in the process, pellet quality, number, and polymer determine absorption. Morphometric analysis of pellets is a simple method to quantify quality of the drug. Once the process has been standardized, dosimetry depends on the route of secretion and site of infection, accounting for the variation of doses from 100 mg to 400 mg/day.


Assuntos
Antifúngicos/administração & dosagem , Itraconazol/administração & dosagem , Tinha/tratamento farmacológico , Antifúngicos/química , Antifúngicos/farmacocinética , Química Farmacêutica/métodos , Composição de Medicamentos/métodos , Humanos , Itraconazol/química , Itraconazol/farmacocinética , Testes de Sensibilidade Microbiana , Polímeros/química , Solubilidade , Resultado do Tratamento
16.
Rev. esp. quimioter ; 32(2): 183-188, abr. 2019. tab, graf
Artigo em Inglês | IBECS | ID: ibc-182820

RESUMO

Objetivos. Candida albicans continúa siendo la causa más frecuente de candidiasis invasiva; sin embargo, la incidencia de candidiasis causadas por especies diferentes a C. albicans, como Candida parapsilosis, está aumentando. El efecto postantifúngico (PAFE) es relevante para establecer pautas de dosificación en la terapia antifúngica, ya que la frecuencia de administración de los fármacos antifúngicos podría cambiar dependiendo del PAFE. El objetivo de este estudio fue evaluar el PAFE de anidulafungina contra C. albicans, Candida dubliniensis, Candida africana, C. parapsilosis, Candida metapsilosis y Candida orthopsilosis. Material y métodos: Se evaluaron 21 cepas de Candida. Para llevar a cabo los estudios PAFE, las células se expusieron durante 1 h a concentraciones entre 0,12 y 8 mg/L de anidulafungina. Las curvas de letalidad (TK) se obtuvieron empleando las mismas concentraciones. Los experimentos se realizaron utilizando un inóculo de 1-5 x 105 células/mL, durante 48 h de incubación. Las lecturas de PAFE y TK se realizaron a las 0, 2, 4, 6, 24 y 48 h. Resultados: Anidulafungina, en los experimentos PAFE, fue fungicida contra 2 de 14 (14%) cepas de las especies relacionadas con C. albicans y ejerció un PAFE prolongado (≥ 33,6 h) contra 13 de 14 (93%) cepas (2 mg/L). El límite fungicida de anidulafungina se alcanzó contra 1 de 7 (14%) cepas del complejo C. parapsilosis, con un PAFE prolongado (≥ 42 h) contra 6 de 7 (86%) cepas. Conclusiones: Anidulafungina produce un PAFE significativo y prolongado contra C. albicans y C. parapsilosis y las especies relacionadas con estas


Objectives: Candida albicans remains the most common aetiology of invasive candidiasis, leading to high morbidity and mortality. Nevertheless, the incidence of candidiasis due to non-C. albicans species, such as Candida parapsilosis, is increasing. Postantifungal effect (PAFE) is relevant for establishing dosage schedules in antifungal therapy, as the frequency of antifungal administration could change depending on PAFE. The aim of this study was to evaluate the PAFE of anidulafungin against C. albicans, Candida dubliniensis, Candida africana, C. parapsilosis, Candida metapsilosis and Candida orthopsilosis. Material and methods: Twenty-one Candida strains were evaluated. Cells were exposed to anidulafungin for 1 h at concentrations ranging from 0.12 to 8 mg/L for PAFE studies. Time-kill experiments (TK) were conducted at the same concentrations. The experiments were performed using an inoculum of 1-5 x 105 cells/mL and 48 h incubation. Readings of PAFE and TK were done at 0, 2, 4, 6, 24 and 48 h. Results: Anidulafungin was fungicidal against 2 out of 14 (14%) strains of C. albicans related species in PAFE experiments. Moreover, 2 mg/L of anidulafungin exerted a prolonged PAFE (≥ 33.6 h) against 13 out of 14 (93%) strains. Similarly, fungicidal endpoint was achieved against 1 out of 7 (14%) strains of C. parapsilosis complex, being PAFE prolonged (≥ 42 h) against 6 out of 7 (86%) strains. Conclusions: Anidulafungin induced a significant and prolonged PAFE against C. albicans and C. parapsilosis and their related species


Assuntos
Humanos , Anidulafungina/farmacocinética , Candida albicans/efeitos dos fármacos , Candida parapsilosis/efeitos dos fármacos , Candida/efeitos dos fármacos , Candidíase/tratamento farmacológico , Antifúngicos/farmacocinética , Técnicas In Vitro/métodos , Candida/patogenicidade
17.
PLoS One ; 14(3): e0212837, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30913226

RESUMO

BACKGROUND: Posaconazole (POS) is a potent triazole antifungal agent approved in adults for treatment and prophylaxis of invasive fungal infections (IFIs). The objectives of this study were to evaluate the pharmacokinetics (PK), safety, and tolerability of POS oral suspension in pediatric subjects with neutropenia. METHODS: This was a prospective, multicenter, sequential dose-escalation study. Enrolled subjects were divided into 3 age groups: AG1, 7 to <18 years; AG2, 2 to <7 years; and AG3, 3 months to <2 years. AG1 and AG2 were divided into 3 dosage cohorts: DC1, 12 mg/kg/day divided twice daily (BID); DC2, 18 mg/kg/day BID; and DC3, 18 mg/kg/day divided thrice daily (TID). AG3 was also divided into DC1 and DC2; however, no subjects were enrolled in DC2. Subjects received 7-28 days of POS oral suspension. PK samples were collected at predefined time points. The POS PK target was predefined as ~90% of subjects with Cavg (AUC /dosing interval) between 500 and 2500 ng/mL, with an anticipated mean steady state Cavg exposure of ~1200 ng/mL. RESULTS: The percentage of subjects meeting the PK target was <90% across all age groups and dosage cohorts (range: 31% to 80%). The percentage of subjects that achieved the Cavg target of 500 to 2500 ng/mL on Day 7 ranged from 31% to 80%, with the lowest proportion in subjects 2 to <7 years receiving 12 mg/kg/day BID (AG2/DC1) and the highest proportion in subjects 7 to <18 years receiving 18 mg/kg/day TID (AG1/DC3). At all three dose levels (12 mg/kg/day BID, 18 mg/kg/day BID and 18 mg/kg/day TID), subjects in AG1 (7 to <18 years old) had higher mean PK exposures at steady state than those in AG2. High variability in exposures was observed in all groups. POS oral suspension was generally well tolerated and most of the reported adverse events were related to the subjects' underlying diseases. CONCLUSION: The POS PK target of 90% of subjects with Cavg between 500 and 2500 ng/mL was not achieved in any of the age groups across the different dosage cohorts. New formulations of the molecule with a greater potential to achieve the established PK target are currently under investigation. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01716234.


Assuntos
Antifúngicos/farmacocinética , Área Sob a Curva , Hospedeiro Imunocomprometido , Triazóis/farmacocinética , Administração Oral , Adolescente , Fatores Etários , Antifúngicos/administração & dosagem , Antifúngicos/efeitos adversos , Antineoplásicos , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Lactente , Infecções Fúngicas Invasivas/tratamento farmacológico , Infecções Fúngicas Invasivas/imunologia , Infecções Fúngicas Invasivas/prevenção & controle , Masculino , Neoplasias/tratamento farmacológico , Neutropenia/induzido quimicamente , Neutropenia/complicações , Neutropenia/imunologia , Estudos Prospectivos , Triazóis/administração & dosagem , Triazóis/efeitos adversos
18.
Rev Iberoam Micol ; 36(1): 24-29, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30837186

RESUMO

BACKGROUND: Candida parapsilosis, Candida metapsilosis and Candida orthopsilosis are emerging as relevant causes of candidemia. Moreover, they show differences in their antifungal susceptibility and virulence. The echinocandins are different in terms of in vitro antifungal activity against Candida. Time-kill (TK) curves represent an excellent approach to evaluate the fungicidal activity of antifungal drugs. AIMS: To compare the fungicidal activities of anidulafungin, caspofungin and micafungin against C. parapsilosis species complex by TK curves. METHODS: Antifungal activities of three echinocandins against C. parapsilosis, C. metapsilosis and C. orthopsilosis were studied by TK curves. Drug concentrations assayed were 0.25, 2 and 8µg/ml. CFU/ml were determined at 0, 2, 4, 6, 24 and 48h. RESULTS: Killing activities of echinocandins were species-, isolates- and concentration-dependent. Anidulafungin reached the fungicidad endpoint for 6 out of 7 isolates (86%); it required between 13.34 and 29.67h to reach this endpoint for the three species studied, but more than 48h were needed against one isolate of C. orthopsilosis (8µg/ml). Caspofungin fungicidal endpoint was only achieved with 8µg/ml against one isolate of C. metapsilosis after 30.12h (1 out of 7 isolates; 14%). Micafungin fungicidal endpoint was reached in 12.74-28.38h (8µg/ml) against one isolate each of C. parapsilosis and C. orthopsilosis, and against both C. metapsilosis isolates (4 out of 7 isolates; 57%). CONCLUSIONS: C. metapsilosis was the most susceptible species to echinocandins, followed by C. orthopsilosis and C. parapsilosis. Anidulafungin was the most active echinocandin against C. parapsilosis complex.


Assuntos
Anidulafungina/farmacocinética , Antifúngicos/farmacocinética , Candida parapsilosis/efeitos dos fármacos , Caspofungina/farmacocinética , Micafungina/farmacocinética , Testes de Sensibilidade Microbiana , Fatores de Tempo
19.
J Clin Pharm Ther ; 44(4): 572-578, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30851209

RESUMO

WHAT IS KNOWN AND OBJECTIVE: Several authors have demonstrated the relationship between voriconazole concentrations and the risk of therapeutic failure and adverse events However, the information about voriconazole concentrations in the critically ill patient is scarce. The aim of this study was to analyse the plasma concentrations and pharmacokinetic behaviour of voriconazole in critically ill patients and their association with the treatment response and development of toxicity. METHODS: A prospective, observational study was conducted. Patients admitted to an intensive care unit and on treatment with intravenous voriconazole were included. Plasma concentrations were measured between days 4 and 7 from the start of the treatment. The pharmacokinetic analysis was performed using the NONMEM® software. A regression model was used to evaluate the variables associated with the values outside the therapeutic range, as well as the relationship between the plasma concentrations and the treatment response and the development of hepatotoxicity. RESULTS AND DISCUSSION: A total of 33 patients were included. Plasma concentrations outside the therapeutic range (1-5.5 mg/L) were observed in 15 patients, being above the established range in 9 (27.3%) cases, and below it in 6 (18.2%) cases. The presence of a bilirubin value of >1.5 mg/dL and a C-reactive protein >100 mg/dL was associated with supra-therapeutic concentrations. Voriconazole concentrations greater than 5.5 mg/dL were associated with the development of hepatotoxicity. WHAT IS NEW AND CONCLUSIONS: There is a wide variation in voriconazole concentrations in critically ill patients, being associated with a high frequency of adverse events. Close monitoring of these values is required in order to decrease the risk of therapeutic failure and toxicity.


Assuntos
Antifúngicos/sangue , Antifúngicos/farmacocinética , Voriconazol/sangue , Voriconazol/farmacocinética , Bilirrubina/metabolismo , Estado Terminal , Feminino , Humanos , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade , Plasma/metabolismo , Estudos Prospectivos
20.
Med Mycol ; 57(Supplement_2): S161-S167, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30816968

RESUMO

Despite advances in antifungal therapy, invasive fungal infections remain a significant cause of morbidity and mortality worldwide. One important factor contributing to the relative ineffectiveness of existing antifungal drugs is insufficient drug exposure at the site of infection. Despite the importance of this aspect of antifungal therapy, we generally lack a full appreciation of how antifungal drugs distribute, penetrate, and interact with their target organisms in different tissue subcompartments. A better understanding of drug distribution will be critical to guide appropriate use of currently available antifungal drugs, as well as to aid development of new agents. Herein we briefly review current perspectives of antifungal drug exposure at the site of infection and describe a new technique, matrix-assisted laser desorption ionization (MALDI) mass spectrometry imaging, which has the potential to greatly expand our understanding of drug penetration.


Assuntos
Antifúngicos/administração & dosagem , Antifúngicos/farmacocinética , Infecções Fúngicas Invasivas/tratamento farmacológico , Humanos , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz
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