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1.
Br J Clin Pharmacol ; 85(12): 2824-2837, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31475367

RESUMO

AIMS: To characterize the population pharmacokinetics (PK) of sildenafil and its active metabolite, N-desmethyl sildenafil (DMS), in premature infants. METHODS: We performed a multicentre, open-label trial to characterize the PK of sildenafil in infants ≤28 weeks gestation and < 365 postnatal days (cohort 1) or < 32 weeks gestation and 3-42 postnatal days (cohort 2). In cohort 1, we obtained PK samples from infants receiving sildenafil as ordered per the local standard of care (intravenous [IV] or enteral). In cohort 2, we administered a single IV dose of sildenafil and performed PK sampling. We performed a population PK analysis and dose-exposure simulations using the software NONMEM®. RESULTS: We enrolled 34 infants (cohort 1 n = 25; cohort 2 n = 9) and collected 109 plasma PK samples. Sildenafil was given enterally (0.42-2.09 mg/kg) in 24 infants in cohort 1 and via IV (0.125 or 0.25 mg/kg) in all infants in cohort 2. A 2-compartment PK model for sildenafil and 1-compartment model for DMS, with presystemic conversion of sildenafil to DMS, characterized the data well. Coadministration of fluconazole (n = 4), a CYP3A inhibitor, resulted in an estimated 59% decrease in sildenafil clearance. IV doses of 0.125, 0.5 and 1 mg/kg every 8 hours (in the absence of fluconazole) resulted in steady-state maximum sildenafil concentrations that were generally within the range of those reported to inhibit phosphodiesterase type 5 activity in vitro. CONCLUSIONS: We successfully characterized the PK of sildenafil and DMS in premature infants and applied the model to inform dosing for a follow-up, phase II study.


Assuntos
Recém-Nascido Prematuro/sangue , Modelos Biológicos , Inibidores da Fosfodiesterase 5/farmacocinética , Citrato de Sildenafila/farmacocinética , Administração Oral , Estudos de Coortes , Citocromo P-450 CYP3A/sangue , Citocromo P-450 CYP3A/genética , Fluconazol/administração & dosagem , Fluconazol/farmacocinética , Idade Gestacional , Humanos , Hipertensão Pulmonar/sangue , Hipertensão Pulmonar/tratamento farmacológico , Lactente , Recém-Nascido , Doenças do Prematuro/sangue , Doenças do Prematuro/tratamento farmacológico , Injeções Intravenosas , Inibidores da Fosfodiesterase 5/administração & dosagem , Inibidores da Fosfodiesterase 5/sangue , Inibidores da Fosfodiesterase 5/uso terapêutico , Citrato de Sildenafila/administração & dosagem , Citrato de Sildenafila/sangue , Citrato de Sildenafila/uso terapêutico
2.
Vet Anaesth Analg ; 46(6): 745-752, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31401049

RESUMO

OBJECTIVE: To evaluate drug interactions between fluconazole and the intravenous (IV) anesthetic induction agents, ketamine and midazolam. STUDY DESIGN: Randomized parallel study. ANIMALS: A group of 12 adult healthy Beagle dogs. METHODS: Dogs were randomly allocated to two groups of six dogs. Dogs in group KM were administered IV ketamine (7 mg kg-1) and IV midazolam (0.25 mg kg-1), and dogs in group KMF were administered fluconazole (5 mg kg-1) orally 12 and 24 hours prior to ketamine-midazolam using the same doses as KM. Sedation scores (0-4) were assigned by investigators unaware of group assignment. Heart rate (HR) and times to sternal and standing were obtained and compared between groups for differences with p < 0.05 considered statistically significant. Blood was obtained and plasma drug concentrations were measured using liquid chromatography-mass spectrometry. RESULTS: The times to sternal, mean 32.3 and 24.6 minutes, for groups KMF and KM, respectively, were not different between the groups. The time to standing, 73 and 36 minutes in groups KMF and KM, respectively, was significantly different (p = 0.002). The duration of elevated HR compared with baseline was longer in KMF (110 minutes) than in KM (25 minutes) (p < 0.05). In group KMF, one dog developed hyperthermia (40.6 °C), which resolved spontaneously. The clearance of ketamine and midazolam was significantly slower (approximately 50%) and the area under the curves were significantly higher (two-fold) in group KMF (p = 0.02). CONCLUSIONS AND CLINICAL RELEVANCE: A significant interaction between oral fluconazole and IV ketamine-midazolam occurred, but the effects appear minor in healthy dogs. Based on these data, a single dose of ketamine-midazolam is not contraindicated in dogs treated with fluconazole, but the duration of effects and pharmacokinetics are altered.


Assuntos
Cães , Fluconazol/farmacocinética , Ketamina/farmacocinética , Midazolam/farmacocinética , Administração Intravenosa , Administração Oral , Animais , Área Sob a Curva , Interações Medicamentosas , Feminino , Fluconazol/administração & dosagem , Meia-Vida , Ketamina/administração & dosagem , Masculino , Midazolam/administração & dosagem
3.
Cancer Chemother Pharmacol ; 84(4): 749-757, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31324935

RESUMO

PURPOSE: Ruxolitinib is metabolized by cytochrome P450 (CYP)3A4 and CYP2C9. Dual inhibitors of these enzymes (like fluconazole) lead to increased ruxolitinib exposure relative to a single pathway inhibition of CYP3A4 or CYP2C9. The magnitude of this interaction, previously assessed via physiologically based pharmacokinetic (PBPK) models, was confirmed in an open-label, phase 1 study in healthy subjects. METHODS: The effect of multiple doses (200 mg) of fluconazole on single-dose (10 mg) PK of ruxolitinib was investigated including evaluation of the safety and tolerability. The PK parameters of ruxolitinib alone (reference) were compared to those of ruxolitinib combined with fluconazole (test). The point estimate and corresponding two-sided 90% confidence interval for the difference between means of test and reference parameters were determined. RESULTS: All enrolled subjects (N = 15) completed the study. When coadministered with fluconazole, geometric means of ruxolitinib PK parameters Cmax, AUClast, and AUCinf increased by 47%, 234%, and 232%, respectively, vs ruxolitinib alone. The median Tmax decreased slightly, apparent clearance decreased approximately threefold, and elimination half-life increased approximately 2.5-fold, upon ruxolitinib administration with fluconazole vs ruxolitinib alone. These results were consistent with the prospective predictions from a SimCYP PBPK model. Adverse events (AEs) were reported in six subjects (none were suspected to be related to ruxolitinib); no death or on-treatment serious AE was reported. CONCLUSIONS: Coadministration of ruxolitinib with fluconazole significantly increased ruxolitinib systemic exposure; however, no AEs were attributed to ruxolitinib. Concomitant use of ruxolitinib with fluconazole (dose ≤ 200 mg) may require dose reduction/modification of ruxolitinib.


Assuntos
Relação Dose-Resposta a Droga , Fluconazol/farmacocinética , Taxa de Depuração Metabólica/efeitos dos fármacos , Pirazóis/farmacocinética , Transdução de Sinais/efeitos dos fármacos , Adulto , Citocromo P-450 CYP2C9/metabolismo , Citocromo P-450 CYP3A/metabolismo , Esquema de Medicação , Interações Medicamentosas , Inibidores Enzimáticos/farmacocinética , Feminino , Meia-Vida , Voluntários Saudáveis , Humanos , Janus Quinases/metabolismo , Masculino , Pessoa de Meia-Idade
4.
J Antimicrob Chemother ; 74(10): 3056-3062, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31304536

RESUMO

OBJECTIVES: To evaluate the safety and efficacy of two dosing regimens of oral ibrexafungerp (formerly SCY-078), a novel orally bioavailable ß-glucan synthase inhibitor, in subjects with invasive candidiasis versus the standard of care (SOC) and to identify the dose to achieve target exposure (15.4 µM·h) in >80% of the intended population. METHODS: In a multinational, open-label study, patients with documented invasive candidiasis were randomized to receive step-down therapy to one of three treatment arms: two dosing regimens of novel oral ibrexafungerp or the SOC treatment following initial echinocandin therapy. Plasma samples were collected to evaluate exposure by population pharmacokinetic (PK) modelling. Safety was assessed throughout the study and global response at the end of treatment. RESULTS: Out of 27 subjects enrolled, 7 received ibrexafungerp 500 mg, 7 received ibrexafungerp 750 mg and 8 received the SOC. Five did not meet criteria for randomization. Population PK analysis indicated that an ibrexafungerp 750 mg regimen is predicted to achieve the target exposure in ∼85% of the population. The rate of adverse events was similar among patients receiving ibrexafungerp or fluconazole. Similar favourable response rates were reported among all groups: 86% (n = 6) in the ibrexafungerp 750 mg versus 71% (n = 5) in both the fluconazole and ibrexafungerp 500 mg treatment arms. The one subject treated with continued micafungin had a favourable global response. CONCLUSIONS: The oral ibrexafungerp dose estimated to achieve the target exposure in subjects with invasive candidiasis is 750 mg daily. This dose was well tolerated and achieved a favourable global response rate, similar to the SOC.


Assuntos
Antifúngicos/farmacocinética , Antifúngicos/uso terapêutico , Candidíase Invasiva/tratamento farmacológico , Equinocandinas/uso terapêutico , Glicosídeos/farmacocinética , Glicosídeos/uso terapêutico , Triterpenos/farmacocinética , Triterpenos/uso terapêutico , Administração Oral , Adulto , Idoso , Candida/efeitos dos fármacos , Equinocandinas/farmacocinética , Feminino , Fluconazol/farmacocinética , Fluconazol/uso terapêutico , Humanos , Masculino , Micafungina/farmacocinética , Micafungina/uso terapêutico , Testes de Sensibilidade Microbiana/métodos , Pessoa de Meia-Idade
5.
Br J Clin Pharmacol ; 85(9): 2108-2117, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31173645

RESUMO

AIMS: Quizartinib is an oral, highly potent and selective next-generation FMS-like tyrosine kinase 3 (FLT3) inhibitor under investigation in patients with FLT3-internal tandem duplication-mutated acute myeloid leukaemia. This drug-drug interaction study assessed the pharmacokinetics (PK) of quizartinib when coadministered with strong or moderate cytochrome P450 3A (CYP3A) inhibitors. METHODS: In this parallel-group study, subjects were randomised to receive: (i) quizartinib + ketoconazole; (ii) quizartinib + fluconazole; or (iii) quizartinib alone. On Days 1-28, subjects received ketoconazole 200 mg or fluconazole 200 mg twice daily, and on Day 8, all subjects received a single 30-mg quizartinib dose. Blood samples were collected for PK analyses, steady-state PK parameters were simulated by superpositioning, and safety was assessed. RESULTS: Ninety-three healthy subjects were randomised; 86 completed the study. When administered with ketoconazole, geometric mean ratios (90% confidence interval) for quizartinib maximum observed plasma concentration (Cmax ) and area under the plasma concentration-time curve (AUC) from time 0 extrapolated to infinity were 117% (105%, 130%) and 194% (169%, 223%), respectively, vs quizartinib alone. Steady-state PK simulation demonstrated ~2-fold increase of both steady-state Cmax and AUC from time 0 to the end of the dosing interval when quizartinib was administered with ketoconazole due to accumulation of quizartinib at steady state. When administered with fluconazole, geometric mean ratios (90% confidence interval) for quizartinib Cmax and AUC from time 0 extrapolated to infinity were 111% (100%, 124%) and 120% (104%, 138%), respectively, vs quizartinib alone. Overall, 5.4% of subjects experienced quizartinib-related adverse events; no serious adverse events or deaths occurred. CONCLUSIONS: These results suggest reducing the dose of quizartinib when coadministered with a strong CYP3A inhibitor, but not with a moderate or weak CYP3A inhibitor. This dose reduction was implemented in phase 3 evaluation of quizartinib.


Assuntos
Antifúngicos/farmacocinética , Benzotiazóis/farmacocinética , Inibidores do Citocromo P-450 CYP3A/farmacocinética , Compostos de Fenilureia/farmacocinética , Administração Oral , Adolescente , Adulto , Antifúngicos/administração & dosagem , Área Sob a Curva , Benzotiazóis/administração & dosagem , Citocromo P-450 CYP3A/metabolismo , Inibidores do Citocromo P-450 CYP3A/administração & dosagem , Relação Dose-Resposta a Droga , Interações Medicamentosas , Feminino , Fluconazol/administração & dosagem , Fluconazol/farmacocinética , Voluntários Saudáveis , Humanos , Infecções Fúngicas Invasivas/tratamento farmacológico , Infecções Fúngicas Invasivas/imunologia , Cetoconazol/administração & dosagem , Cetoconazol/farmacocinética , Leucemia Mieloide Aguda/complicações , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/imunologia , Masculino , Pessoa de Meia-Idade , Compostos de Fenilureia/administração & dosagem , Adulto Jovem , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Tirosina Quinase 3 Semelhante a fms/genética
6.
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
7.
CPT Pharmacometrics Syst Pharmacol ; 8(7): 500-510, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31087536

RESUMO

Fluconazole is used to treat hematogenous Candida meningoencephalitis in preterm and term infants. To characterize plasma and central nervous system exposure, an adult fluconazole physiologically-based pharmacokinetic (PBPK) model was scaled to infants, accounting for age dependencies in glomerular filtration and metabolism. The model was optimized using 760 plasma samples from 166 infants (median postmenstrual age (range) 28 weeks (24-50)) and 27 cerebrospinal fluid (CSF) samples from 22 infants (postmenstrual age 28 weeks (24-33)). Simulations evaluated achievement of the surrogate efficacy target of area under the unbound concentration-time curve ≥ 400 mg • hour/L over the dosing interval in plasma and CSF using dosing guidelines. Average fold error of predicted concentrations was 0.73 and 1.14 for plasma and CSF, respectively. Target attainment in plasma and CSF was reached faster after incorporating a loading dose of 25 mg/kg. PBPK modeling can be useful in exploring CNS kinetics of drugs in children.


Assuntos
Antifúngicos/farmacocinética , Líquido Cefalorraquidiano/química , Fluconazol/farmacocinética , Plasma/química , Área Sob a Curva , Ensaios Clínicos como Assunto , Feminino , Humanos , Lactente , Recém-Nascido , Recém-Nascido Prematuro , Masculino , Modelos Teóricos , Software
8.
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 Medicamentosas , Feminino , Fluconazol/administração & dosagem , Fluconazol/farmacologia , Masculino , Metadona/administração & dosagem , Metadona/sangue , Metadona/farmacologia
9.
Artigo em Inglês | MEDLINE | ID: mdl-30910892

RESUMO

Fluconazole is an antifungal agent with reported evidence for its prophylactic effect against systemic fungal infection in preterm infants. The aim of this study was to build a population pharmacokinetic model to evaluate the pharmacokinetic characteristics of intravenous and oral fluconazole in preterm infants with the current prophylactic fluconazole dosing regimen. A pharmacokinetic model was developed using 301 fluconazole concentrations from 75 preterm infants with a baseline body weight (WT) ranging from 0.5 to 1.5 kg and an estimated glomerular filtration rate (eGFR) ranging from 12.9 to 58.5 ml/min/1.73 m2 Eligible infants received an intravenous or oral dose of 3 mg/kg of body weight of fluconazole, twice weekly with a ≥72-h dose interval, for 4 weeks. The model was qualified with basic goodness-of-fit diagnostics, visual predictive checks, and bootstrapping. The fluconazole pharmacokinetics was well described with a one-compartment linear model with a proportional residual error. The population clearance (CL) and volume of distribution (V) were derived as 0.0197 × (WT/1.00)0.746 × (eGFR/25.0)0.463 × exp(η) and 1.04 × WT × exp(η), respectively. Such covariate analyses augment the awareness of the need for personalized dosing in preterm infants. (This study has been registered at ClinicalTrials.gov under identifier NCT01683760).


Assuntos
Antifúngicos/farmacocinética , Antifúngicos/uso terapêutico , Candidíase Invasiva/tratamento farmacológico , Fluconazol/farmacocinética , Fluconazol/uso terapêutico , Recém-Nascido Prematuro/metabolismo , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Estudos Prospectivos
10.
AAPS PharmSciTech ; 20(1): 24, 2019 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-30604153

RESUMO

Tamoxifen is an antiestrogen drug that is widely used in the adjuvant chemotherapy of estrogen receptor-α (ERα)-positive breast cancer. Chemotherapy could suppress immune function in breast cancer patients, which may cause invasive fungal infections (IFIs). Triazoles (voriconazole, fluconazole, and itraconazole) were commonly used for IFI. The physiologically based pharmacokinetic (PBPK) models were developed to investigate the influence of different triazoles on tamoxifen pharmacokinetics in this paper. To investigate the influence of different triazoles (voriconazole, fluconazole, itraconazole) on tamoxifen pharmacokinetics. Adjusted physicochemical data and pharmacokinetic parameters of voriconazole, fluconazole, itraconazole, and tamoxifen were obtained from published literatures. PBPK models were built and verified in healthy subjects using GastroPlus™. Voriconazole, itraconazole, and tamoxifen were administered orally. Fluconazole was administered intravenously. Simulated plasma concentration-time curves of the voriconazole, fluconazole, itraconazole, and tamoxifen showed good agreement with the observed profiles, respectively. The DDI simulations showed that the pharmacokinetic parameters of tamoxifen were increased by various degrees when coadministered with different triazoles. In healthy subjects, the area under the plasma concentration-time curve from 0 to t h (AUC0-t) of tamoxifen was increased by 41%, 5%, and1% when coadministrated with voriconazole, fluconazole, and itraconazole, respectively. The PBPK models adequately characterized the pharmacokinetics of tamoxifen and triazoles. Among the three triazoles, voriconazole exhibited the greatest effect on tamoxifen pharmacokinetics. In clinical practice, an effective dosage adjustment of tamoxifen may need to be considered and TDM for tamoxifen is advisable to guide dosing and optimize therapy when coadministered with voriconazole.


Assuntos
Antifúngicos/farmacocinética , Conservadores da Densidade Óssea/farmacocinética , Modelos Biológicos , Tamoxifeno/farmacocinética , Triazóis/farmacocinética , Interações Medicamentosas/fisiologia , Feminino , Fluconazol/farmacocinética , Previsões , Humanos , Itraconazol/farmacologia , Pessoa de Meia-Idade , Voriconazol/farmacocinética
11.
Pharm Dev Technol ; 24(1): 48-62, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29210317

RESUMO

Fungal keratitis may cause vision loss if it is not treated. Methods other than ocular delivery exhibited several limitations. No previous studies investigated and compared ocular bioavailability of fluconazole (FLZ) from niosomal gels and microemulsions. Niosomal gels of FLZ (0.3% w/w) based on Span® 60 and cholesterol (CH) using 1% w/w carbopol® 934 (CP) were evaluated. FLZ microemulsions (0.3% w/v) containing isopropyl myristate (IPM, as oil phase) and a 3:1 mixture of Tween® 80 (as surfactant) and polyethylene glycol 400 (PEG 400, as cosurfactant) were characterized. Optimized formulations were compared for their ocular bioavailability in rabbit's. Nanoscopic niosomes (63.67-117.13 nm) and microemulsions (57.05-59.93 nm) showed respective negative zeta potential ranges of -45.37 to -61.40 and -20.50 to -31.90 mV and sustained release up to 12 h. Entrapment efficiency (EE%) of niosomes ranged from 56.48% to 70.67%. Niosomal gels were more sustainable than niosomes and microemulsions. The most stable niosomal gel based on Span® 60 and CH at a molar ratio of 5:5 and microemulsion containing 45% w/w IPM and 40% w/w of 3:1 Tween® 80-PEG 400 mixture significantly (p < 0.0001) enhanced FLZ ocular bioavailability compared with its solution. Niosomal gel showed higher bioavailability than microemulsion by ≈2-fold.


Assuntos
Antifúngicos/administração & dosagem , Química Farmacêutica/métodos , Sistemas de Liberação de Medicamentos , Fluconazol/administração & dosagem , Administração Oftálmica , Animais , Antifúngicos/farmacocinética , Disponibilidade Biológica , Preparações de Ação Retardada , Portadores de Fármacos/química , Emulsões , Olho/metabolismo , Fluconazol/farmacocinética , Géis , Lipossomos , Masculino , Tamanho da Partícula , Coelhos , Tensoativos/química
12.
J Clin Microbiol ; 56(12)2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30135234

RESUMO

The purpose of this review is to critically analyze published data evaluating the impact of azole pharmacokinetic and pharmacodynamic parameters, MICs, and Candida species on clinical outcomes in patients with candidemia. Clinical breakpoints (CBPs) for fluconazole and voriconazole, which are used to determine susceptibility, have been defined by the Clinical and Laboratory Standards Institute (CLSI) for Candida species. Studies evaluating the relationship between treatment efficacy and in vitro susceptibility, as well as the pharmacodynamic targets, have been conducted in patients treated with fluconazole for candidemia; however, for species other than Candida albicans and Candida glabrata, and for other forms of invasive candidiasis, data remain limited and randomized trials are not available. Limited data evaluating these relationships with voriconazole are available. While pharmacodynamic targets for posaconazole and isavuconazole have been proposed based upon studies conducted in murine models, CBPs have not been established by CLSI. Fluconazole remains an important antifungal agent for the treatment of candidemia, and data supporting its use based on in vitro susceptibility are growing, particularly for C. albicans and C. glabrata Further investigation is needed to establish the roles of voriconazole, posaconazole, and isavuconazole in the treatment of candidemia and for all agents in the treatment of other forms of invasive candidiasis.


Assuntos
Antifúngicos/farmacologia , Azóis/farmacologia , Candida/efeitos dos fármacos , Candidemia/microbiologia , Testes de Sensibilidade Microbiana/estatística & dados numéricos , Animais , Antifúngicos/farmacocinética , Antifúngicos/uso terapêutico , Azóis/farmacocinética , Azóis/uso terapêutico , Candida/classificação , Candidemia/tratamento farmacológico , Fluconazol/farmacocinética , Fluconazol/farmacologia , Fluconazol/uso terapêutico , Humanos , Testes de Sensibilidade Microbiana/normas , Especificidade da Espécie , Resultado do Tratamento
13.
CPT Pharmacometrics Syst Pharmacol ; 7(10): 629-637, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30033691

RESUMO

Extracorporeal life support (e.g., dialysis, extracorporeal membrane oxygenation (ECMO)) can affect drug disposition, placing patients at risk for therapeutic failure. In this population, dose selection to achieve safe and effective drug exposure is difficult. We developed a novel and flexible approach that uses physiologically based pharmacokinetic (PBPK) modeling to translate results from ECMO ex vivo experiments into bedside dosing recommendations. To determine fluconazole dosing in children on ECMO, we developed a PBPK model, which was validated using fluconazole pharmacokinetic (PK) data in adults and critically ill infants. Next, an ECMO compartment was added to the PBPK model and parameterized using data from a previously published ex vivo study. Simulations using the final ECMO PBPK model reasonably characterized observed PK data in infants on ECMO, and the model was used to derive dosing in children on ECMO across the pediatric age spectrum. This approach can be generalized to other forms of extracorporeal life support (ECLS), such as dialysis.


Assuntos
Antifúngicos/farmacocinética , Oxigenação por Membrana Extracorpórea , Fluconazol/farmacocinética , Adulto , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Área Sob a Curva , Candidíase/tratamento farmacológico , Criança , Relação Dose-Resposta a Droga , Fluconazol/farmacologia , Fluconazol/uso terapêutico , Humanos , Masculino , Modelos Biológicos
14.
Eur J Clin Pharmacol ; 74(11): 1449-1459, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30032414

RESUMO

OBJECTIVES: The study aims to assess the population pharmacokinetics of fluconazole and the adequacy of current dosages and breakpoints against Candida albicans and non-albicans spp. in liver transplant (LT) patients. PATIENTS AND METHODS: Patients initiated i.v. fluconazole within 1 month from liver transplantation (LTx) for prevention or treatment of Candida spp. infections. Multiple assessments of trough and peak plasma concentrations of fluconazole were undertaken in each patient by means of therapeutic drug monitoring. Monte Carlo simulations were performed to define the probability of target attainment (PTA) with a loading dose (LD) of 400, 600, and 800 mg at day 1, 7, 14, and 28 from LTx, followed by a maintenance dose (MD) of 100, 200, and 300 mg daily of the pharmacokinetic/pharmacodynamic target of AUC24h/MIC ratio ≥ 55.2. RESULTS: Nineteen patients were recruited. A two-compartment model with first-order intravenous input and first-order elimination was developed. Patient's age and time elapsed from LTx were the covariates included in the final model. At an MIC of 2 mg/L, a LD of 600 mg was required for optimal PTAs between days 1 and 20 from LTx, while 400 mg was sufficient from days 21 on. A MD of 200 mg was required for patients aged 40-49 years old, while a dose of 100 mg was sufficient for patients aged ≥ 50 years. CONCLUSIONS: Fluconazole dosages of 100-200 mg daily may ensure optimal PTA against C. albicans, C. parapsilosis, and C. tropicalis. Higher dosages are required against C. glabrata. Estimated creatinine clearance is not a reliable predictor of fluconazole clearance in LT patients.


Assuntos
Antifúngicos/administração & dosagem , Candidíase/tratamento farmacológico , Fluconazol/administração & dosagem , Transplante de Fígado , Adulto , Fatores Etários , Antifúngicos/farmacocinética , Área Sob a Curva , Candida albicans/isolamento & purificação , Candidíase/etiologia , Candidíase/microbiologia , Relação Dose-Resposta a Droga , Feminino , Fluconazol/farmacocinética , Humanos , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Modelos Biológicos , Método de Monte Carlo , Estudos Retrospectivos , Fatores de Tempo
15.
Artigo em Inglês | MEDLINE | ID: mdl-29914943

RESUMO

Robust population pharmacokinetic (PK) data for fluconazole are scarce. The variability of fluconazole penetration into the central nervous system (CNS) is not known. A fluconazole PK study was conducted in 43 patients receiving oral fluconazole (usually 800 mg every 24 h [q24h]) in combination with amphotericin B deoxycholate (1 mg/kg q24h) for cryptococcal meningitis (CM). A four-compartment PK model was developed, and Monte Carlo simulations were performed for a range of fluconazole dosages. A meta-analysis of trials reporting outcomes of CM patients treated with fluconazole monotherapy was performed. Adjusted for bioavailability, the PK parameter means (standard deviation) were the following: clearance, 0.72 (0.24) liters/h; volume of the central compartment, 18.07 (6.31) liters; volume of the CNS compartment, 32.07 (17.60) liters; first-order rate constant from the central to peripheral compartment, 12.20 (11.17) h-1, from the peripheral to central compartment, 18.10 (8.25) h-1, from the central to CNS compartment, 35.43 (13.74) h-1, and from the CNS to central the compartment, 28.63 (10.03) h-1 Simulations of the area under concentration-time curve resulted in median (interquartile range) values of 1,143.2 (range, 988.4 to 1,378.0) mg · h/liter in plasma (AUCplasma) and 982.9 (range, 781.0 to 1,185.9) mg · h/liter in cerebrospinal fluid (AUCCSF) after a dosage of 1,200 mg q24h. The mean simulated ratio of AUCCSF/AUCplasma was 0.89 (standard deviation [SD], 0.44). The recommended dosage of fluconazole for CM induction therapy fails to attain the pharmacodynamic (PD) target in respect to the wild-type MIC distribution for C. neoformans The meta-analysis suggested modest improvements in both CSF sterility and mortality outcomes with escalating dosage. This study provides the pharmacodynamic rationale for the long-recognized fact that fluconazole monotherapy is an inadequate induction regimen for CM.


Assuntos
Antifúngicos/líquido cefalorraquidiano , Antifúngicos/farmacocinética , Sistema Nervoso Central/metabolismo , Fluconazol/líquido cefalorraquidiano , Fluconazol/farmacocinética , Meningite Criptocócica/tratamento farmacológico , Adulto , Idoso , Anfotericina B/uso terapêutico , Antifúngicos/uso terapêutico , Sistema Nervoso Central/microbiologia , Cryptococcus neoformans/efeitos dos fármacos , Ácido Desoxicólico/uso terapêutico , Combinação de Medicamentos , Quimioterapia Combinada , Feminino , Fluconazol/uso terapêutico , Humanos , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Uganda , Vietnã , Adulto Jovem
16.
Int J Pharm ; 546(1-2): 166-175, 2018 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-29778824

RESUMO

Carbopol is a good bio-adhesive polymer that increases the residence time in the eye. However, the effect of blinking and lacrimation still reduce the amount of polymer and the incorporated drug available for bioadhesion. Gel-core liposomes are advanced systems offering benefits making it a good tool for improved ocular drug delivery and residence time. Incorporation of carbopol in gel-core liposomes and their potential in ocular delivery have not so far been investigated. Fluconazole (FLZ) was selected as a challenging important ocular antifungal suffering from poor corneal permeation and short residence time. In this study, gel-core carbosomes have been elaborated as novel carbopol-based ophthalmic vehicles to solve ocular delivery obstacles of FLZ and to sustain its effect. Full in vitro appraisal was performed considering gel-core structure, entrapment efficiency, particle size and stability of the vesicles as quality attributes. Structure elucidation of the nanocarrier was performed using optical, polarizing and transmission electron microscopy before and after Triton-X100 addition. Ex-vivo ocular permeation and in vivo performance were investigated on male albino rabbits. Optimized formulation (CBS5) showed gel-core structure, nanosize (339.00 ±â€¯5.50 nm) and not defined before (62.00% ±â€¯1.73) entrapment efficiency. Cumulative amount of CBS5 permeated ex-vivo after 6 h, was 2.43 and 3.43 folds higher than that of conventional liposomes and FLZ suspension, respectively. In-vivo corneal permeation of CBS5 showed significantly higher AUC0-24 h (487.12 ±â€¯74.80) compared to that of FLZ suspension (204.34 ±â€¯7.46) with longer residence time in the eye lasts for more than 18 h. In conclusion, novel gel-core carbosomes could successfully be used as a promising delivery system for chronic ocular diseases.


Assuntos
Resinas Acrílicas , Antifúngicos , Portadores de Fármacos , Olho/metabolismo , Fluconazol , Resinas Acrílicas/administração & dosagem , Resinas Acrílicas/química , Resinas Acrílicas/farmacocinética , Resinas Acrílicas/toxicidade , Administração Oftálmica , Animais , Antifúngicos/administração & dosagem , Antifúngicos/química , Antifúngicos/farmacocinética , Antifúngicos/toxicidade , Preparações de Ação Retardada/química , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/toxicidade , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Olho/anatomia & histologia , Olho/efeitos dos fármacos , Fluconazol/administração & dosagem , Fluconazol/química , Fluconazol/farmacocinética , Fluconazol/toxicidade , Géis , Lipossomos , Masculino , Tamanho da Partícula , Permeabilidade , Coelhos , Testes de Toxicidade
17.
Br J Clin Pharmacol ; 84(9): 1989-1999, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29744900

RESUMO

AIMS: The pharmacokinetics (PK) of fluconazole and micafungin differ in neonates compared with children and adults. Dosing instructions in product labels appear to be inconsistent with the emerging scientific evidence. Limited information is available on the safety profile of these agents in neonates. Our objective was to study the population PK and safety of both drugs, randomly administered in neonates with suspected or confirmed systemic candidiasis. METHODS: Neonates were randomized 1:1 to fluconazole (loading dose 25 mg kg-1 ; maintenance dose 12 mg kg-1 day-1 or 20 mg kg-1 day-1 , respectively, for infants <30 weeks or ≥30 weeks' corrected gestational age) or micafungin (loading dose 15 mg kg-1 day-1 ; maintenance dose 10 mg kg-1 day-1 ). PK samples were taken on treatment days 1 and 5. Population parameters were determined using NONMEM and Monte Carlo simulations performed to reach predefined targets. Clinical and laboratory data, and adverse events were collected up to 36 weeks' corrected gestational age or hospital discharge. RESULTS: Thirty-six neonates were enrolled. The median (range) gestational age was 28.2 (24.1-40.1) and 26.8 (23.5-40.0) weeks for fluconazole and micafungin, respectively. Based on 163 PK samples, the median population clearance (l h-1 kg-1 ) and volume of distribution (l kg-1 ) for fluconazole were: 0.015 [95% confidence interval (CI) 0.008, 0.039] and 0.913, and for micafungin were: 0.020 (95% CI 0.010, 0.023) and 0.354 (95% CI 0.225, 0.482), respectively. The loading dose was well tolerated. No adverse events associated with micafungin or fluconazole were reported. CONCLUSION: Based on Monte Carlo simulations, a loading dose for fluconazole and dosing higher than recommended for both drugs are required to increase the area under the plasma drug concentration-time curve target attainment rate in neonates.


Assuntos
Antifúngicos/farmacocinética , Candidíase/tratamento farmacológico , Fluconazol/farmacocinética , Micafungina/farmacocinética , Fatores Etários , Animais , Antifúngicos/administração & dosagem , Antifúngicos/efeitos adversos , Área Sob a Curva , Feminino , Fluconazol/administração & dosagem , Fluconazol/efeitos adversos , Humanos , Lactente , Recém-Nascido , Recém-Nascido Prematuro , Masculino , Micafungina/administração & dosagem , Micafungina/efeitos adversos , Camundongos , Estudos Prospectivos
18.
Biomed Pharmacother ; 99: 438-444, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29665644

RESUMO

BACKGROUND: Candida spp is an etiologic agent of fungal infections in hospitals and resistance to treatment with antifungals has been extensively reported. Thus, it is very important to develop formulations that increase effectiveness with low toxicity. In this sense, nanocarriers have been investigated, once they modify drug biodistribution profile. Thus, this study aimed to evaluate the biodistribution of free and encapsulated 99mTc-fluconazole into nanocapsules (NCs) in an experimental immunosuppressed murine model of Candida albicans infection. METHODS: Fluconazole was radiolabeled with technetium-99 metastable (99mTc) and encapsulated into conventional (99mTc-Fluconazole-PLA-POLOX) and surface-modified (99mTc-Fluconazole-PLA-PEG) NCs by the interfacial deposition of the preformed biodegradable polymer [poly (D,L-lactic acid) (PLA) and PLA-PEG (polyethyleneglycol)] followed by solvent evaporation. The size distribution and zeta potential of the NCs preparations were determined in a Zetasizer by photon correlation spectroscopy and laser Doppler anemometry, respectively. Free and encapsulated 99mTc-fluconazole were administered intravenously in immunosuppressed mice bearing a local infection induced by Candida Albicans inoculation in the right thigh muscle. At pre-established time intervals, tissues and organs of interest were removed and radioactivity was measured in an automatic gamma radiation counter. RESULTS: The NCs diameter was between 200 and 400 nm with negative zeta potential values. Free 99mTc-fluconazole was more rapidly eliminated by the renal system compared to the encapsulated drug in NCs, which remained longer in blood circulation. The uptake of conventional NCs by mononuclear phagocyte system organs was higher than the one demonstrated by the surface-modified NCs. Both NCs remained longer in the infectious focus when compared to free 99mTc-fluconazole, but the results did not show a significant difference between NC formulations. CONCLUSION: These data indicate that these NCs might represent a therapeutic alternative for the treatment of candidiasis, once they remain more time in the infectious focus, allowing high retention of 99mTc-fluconazole at this site.


Assuntos
Candida albicans/fisiologia , Candidíase/metabolismo , Fluconazol/farmacocinética , Tecnécio/farmacocinética , Administração Intravenosa , Animais , Candida albicans/efeitos dos fármacos , Candidíase/sangue , Candidíase/patologia , Modelos Animais de Doenças , Fluconazol/administração & dosagem , Fluconazol/sangue , Fluconazol/farmacologia , Masculino , Camundongos , Músculos/patologia , Nanocápsulas/química , Compostos Radiofarmacêuticos/administração & dosagem , Compostos Radiofarmacêuticos/sangue , Compostos Radiofarmacêuticos/farmacocinética , Compostos Radiofarmacêuticos/farmacologia , Tecnécio/administração & dosagem , Tecnécio/sangue , Tecnécio/farmacologia , Distribuição Tecidual/efeitos dos fármacos
19.
Artigo em Inglês | MEDLINE | ID: mdl-29581112

RESUMO

Robust pharmacodynamic indices that align fluconazole dose or exposure with outcomes in invasive candidiasis due to Candida glabrata remain elusive. The purpose of this retrospective multicenter study was to evaluate a cohort of 127 patients with C. glabrata fungemia treated with fluconazole, using adjusted analyses to identify risk factors for 28-day death. No significant correlations were found between fluconazole area under the curve (AUC), AUC/MIC ratio, or MIC and survival. In multivariate logistic regression analyses, however, higher average fluconazole dose (odds ratio [OR], 1.006 [95% confidence interval [CI], 1.001 to 1.010]; P = 0.008), average fluconazole dose of ≥400 mg (OR, 3.965 [95% CI, 1.509 to 10.418]; P = 0.005), and higher fluconazole dose on day 1 of therapy (OR, 1.007 [95% CI, 1.002 to 1.011]; P = 0.002) were found to be independent predictors of 28-day survival. Additionally, the presence of a central venous catheter at the time of infection was found to be a significant risk factor for death. In conclusion, we found fluconazole dose to be an independent predictor of 28-day survival for patients with C. glabrata fungemia, with doses of ≥400 mg/day being associated with 28-day survival rates approaching 90%. These data indicate the use and efficacy of fluconazole in the treatment of this serious infection. Aggressive dosing appears to be necessary when fluconazole is used for the treatment of C. glabrata fungemia, irrespective of MIC.


Assuntos
Antifúngicos/farmacocinética , Candida glabrata/efeitos dos fármacos , Candida glabrata/patogenicidade , Candidíase/tratamento farmacológico , Candidíase/microbiologia , Fluconazol/uso terapêutico , Adulto , Idoso , Feminino , Fluconazol/farmacocinética , Fungemia/tratamento farmacológico , Fungemia/microbiologia , Humanos , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Estudos Retrospectivos
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