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1.
Pharm Res ; 37(2): 32, 2020 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-31919778

RESUMO

There was a mistake in the units of CL and Q, and in the parentheses of the formula for CL in the final model in Table 2. The corrected Table appears below.

2.
Med Mycol ; 2020 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-31965178

RESUMO

Triazole resistant A. fumigatus has been documented in many parts of the world. In the Netherlands, incidence is now above 10% and results in the need for long-term parenteral therapy with liposomal amphotericin B (LAmB). The long terminal half-life of LAmB suggests that intermittent dosing could be effective, making the application of outpatient antifungal therapy (OPAT) possible. Here, we report our experience with the use of OPAT for Invasive Fungal Infections (IFI). All adult patients treated with LAmB with a 2 or 3 times weekly administration via the outpatient departments in four academic tertiary care centers in the Netherlands and Belgium since January 2010 were included in our analysis. Patient characteristics were collected, as well as information about diagnostics, therapy dose and duration, toxicity, treatment history and outcome of the IFI. In total, 18 patients were included. The most frequently used regimen (67%) was 5 mg/kg 3 times weekly. A partial response to the daily treatment prior to discharge was confirmed by CT-scan in 17 (94%) of patients. A favorable outcome was achieved in 13 (72%) patients. Decrease in renal function occurred in 10 (56%) cases but was reversible in all and was treatment limiting in one patient only. The 100-day mortality and 1-year mortality after initiation of OPAT were 0% and 6%, respectively. In a selected population, and after confirmation of initial response to treatment, our data support the use of OPAT with LAmB for treatment of IFI in an intermittent dosing regimen.

3.
Artigo em Inglês | MEDLINE | ID: mdl-31971567

RESUMO

BACKGROUND: The prevalence of obesity has shown a dramatic increase over recent decades. Obesity is associated with underdosing of antimicrobial drugs for prophylaxis and treatment. Posaconazole is a broad-spectrum triazole antifungal drug licensed for prophylaxis and treatment of invasive fungal infections. It is unclear how posaconazole should be dosed in obese patients. METHODS: We performed a prospective study investigating the pharmacokinetics of posaconazole in morbidly obese (n = 16) and normal-weight (n = 8) subjects, with a weight ranging between 61.4 and 190 kg, after a 300 or 400 mg IV dose. Population pharmacokinetic modelling was used to assess the effect of body size on posaconazole pharmacokinetics. ClinicalTrials.gov Identifier: NCT03246386. RESULTS: Total body weight best predicted changes in CL and V. Model-based simulations demonstrated that, for treatment of fungal infections, a daily IV dose of 300 mg will result in a PTA of ≥90% in individuals up to 140 kg, after which both twice daily loading and the daily maintenance dose should be increased to 400 mg. For prophylaxis, a 300 mg IV dose is adequate in patients up to 190 kg. CONCLUSIONS: Body size has a significant impact on posaconazole CL and V, resulting in a lower exposure in obese subjects compared with normal-weight subjects. For therapeutic use of posaconazole, a dose increase is required in patients above 140 kg. For prophylaxis, a 300 mg IV dose is adequate. For oral treatment, these recommendations can act as a starting point followed by therapeutic drug monitoring.

4.
Mycoses ; 63(2): 122-130, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31660650

RESUMO

BACKGROUND: Oral follow-up therapy is problematic in moulds with reduced azole-susceptibility, such as azole-resistant Aspergillus fumigatus infection. Currently, only intravenous liposomal amphotericin B (L-AmB) is advocated by guidelines for the treatment of azole-resistant aspergillosis infections. Preclinical research indicates that high-dose posaconazole (HD-POS) might be a feasible option provided that high drug exposure (ie POS serum through levels >3 mg/L) can be achieved and is safe. OBJECTIVES: To describe our experience with the use of oral HD-POS as treatment strategies for patients infected with pathogens with a POS MIC close to the clinical breakpoint. PATIENTS/METHODS: We review evidence supporting the use of HD-POS and describe our experience on safety and efficacy in 16 patients. In addition, we describe the adverse events (AE) observed in 25 patients with POS concentrations at the higher end of the population distribution during treatment with the licensed dose. RESULTS: Sixteen patients were treated intentionally with HD-POS for voriconazole-resistant invasive aspergillosis (7/16), mucormycosis (4/16), salvage therapy for IA (4/16) and IA at a sanctuary site (spondylodiscitis) in 1. Grade 3-4 AEs were observed in 6, and all of them were considered at least possibly related. Grade 3-4 AEs were observed in 5 of the 25 patients with spontaneous high POS serum through levels considered at least possibly related using Naranjo scale. CONCLUSIONS: High-dose posaconazole is a treatment option if strict monitoring for both exposure and for AE is possible.

6.
Clin Pharmacokinet ; 2019 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-31654367

RESUMO

BACKGROUND AND OBJECTIVE: Bodyweight-based dosing of tacrolimus is considered standard care. Currently, at first steady state, a third of pediatric kidney transplant recipients has a tacrolimus pre-dose concentration within the target range. We investigated whether adaptation of the starting dose according to a validated dosing algorithm could increase this proportion. METHODS: This was a multi-center, single-arm, prospective trial with a planned interim analysis after 16 patients, in which the tacrolimus starting dose was based on bodyweight, cytochrome P450 3A5 genotype, and donor status (living vs. deceased donor). RESULTS: At the interim analysis, 31% of children had a tacrolimus pre-dose concentration within the target range. As the original dosing algorithm was poorly predictive of tacrolimus exposure, the clinical trial was terminated prematurely. Next, the original model was improved by including the data of the children included in this trial, thereby doubling the number of children in the model building cohort. Data were best described with a two-compartment model with inter-individual variability, allometric scaling, and inter-occasion variability on clearance. Cytochrome P450 3A5 genotype, hematocrit, and creatinine influenced the tacrolimus clearance. A new starting dose model was developed in which the cytochrome P450 3A5 genotype was incorporated. Both models were successfully internally and externally validated. CONCLUSIONS: The weight-normalized starting dose of tacrolimus should be higher in patients with a lower bodyweight and in those who are cytochrome P450 3A5 expressers.

7.
Br J Clin Pharmacol ; 2019 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-31661553

RESUMO

AIMS: For vancomycin treatment in obese patients, there is no consensus on the optimal dose that will lead to the pharmacodynamic target (area under the curve 400-700 mg h L-1 ). This prospective study quantifies vancomycin pharmacokinetics in morbidly obese and nonobese individuals, in order to guide vancomycin dosing in the obese. METHODS: Morbidly obese individuals (n = 20) undergoing bariatric surgery and nonobese healthy volunteers (n = 8; total body weight [TBW] 60.0-234.6 kg) received a single vancomycin dose (obese: 12.5 mg kg-1 , maximum 2500 mg; nonobese: 1000 mg) with plasma concentrations measured over 48 h (11-13 samples per individual). Modelling, internal validation, external validation using previously published data and simulations (n = 10.000 individuals, TBW 60-230 kg) were performed using NONMEM. RESULTS: In a 3-compartment model, peripheral volume of distribution and clearance increased with TBW (both p < 0.001), which was confirmed in the external validation. A dose of 35 mg kg-1 day-1 (maximum 5500 mg/day) resulted in a > 90% target attainment (area under the curve > 400 mg h L-1 ) in individuals up to 200 kg, with corresponding trough concentrations of 5.7-14.6 mg L-1 (twice daily dosing). For continuous infusion, a loading dose of 1500 mg is required for steady state on day 1. CONCLUSION: In this prospective, rich sampling pharmacokinetic study, vancomycin clearance was well predicted using TBW. We recommend that in obese individuals without renal impairment, vancomycin should be dosed as 35 mg kg-1 day-1 (maximized at 5500 mg/day). When given over 2 daily doses, trough concentrations of 5.7-14.6 mg L-1 correspond to the target exposure in obese individuals.

8.
Clin Infect Dis ; 2019 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-31588493

RESUMO

In this prospective study, we examined the pharmacokinetics of 1 and 2 mg/kg liposomal amphotericin B in 16 morbidly obese individuals (104-177 kg). Body size had no effect on clearance. We recommend a fixed dose in patients ≥100 kg (ie, 300 or 500 mg rather than the current dose of 3 and 5 mg/kg, respectively). Clinical Trials Registration NCT02320604.

9.
Clin Pharmacokinet ; 2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31432468

RESUMO

BACKGROUND: Pharmacokinetics (PK) are severely altered in critically ill patients due to changes in volume of distribution (Vd) and/or drug clearance (Cl). This affects the target attainment of antibiotics in critically ill children. We aimed to identify gaps in current knowledge and to compare published PK parameters and target attainment of antibiotics in critically ill children to healthy children and critically ill adults. METHODS: Systematic literature search in PubMed, EMBASE and Web of Science. Articles were labelled as relevant when they included information on PK of antibiotics in critically ill, non-neonatal, pediatric patients. Extracted PK-parameters included Vd, Cl, (trough) concentrations, AUC, probability of target attainment, and elimination half-life. RESULTS: 50 relevant articles were identified. Studies focusing on vancomycin were most prevalent (17/50). Other studies included data on penicillins, cephalosporins, carbapenems and aminoglycosides, but data on ceftriaxone, ceftazidime, penicillin and metronidazole could not be found. Critically ill children generally show a higher Cl and larger Vd than healthy children and critically ill adults. Reduced target-attainment was described in critically ill children for multiple antibiotics, including amoxicillin, piperacillin, cefotaxime, vancomycin, gentamicin, teicoplanin, amikacin and daptomycin. 38/50 articles included information on both Vd and Cl, but a dosing advice was given in only 22 articles. CONCLUSION: The majority of studies focus on agents where TDM is applied, while other antibiotics lack data altogether. The larger Vd and higher Cl in critically ill children might warrant a higher dose or extended infusions of antibiotics in this patient population to increase target-attainment. Studies frequently fail to provide a dosing advice for this patient population, even if the necessary information is available. Our study shows gaps in current knowledge and encourages future researchers to provide dosing advice for special populations whenever possible.

10.
Med Mycol ; 57(Supplement_3): S328-S343, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31292663

RESUMO

The high burden and growing prevalence of invasive fungal infections (IFIs), the toxicity and interactions associated with current antifungal drugs, as well as the increasing resistance, ask for the development of new antifungal drugs, preferably with a novel mode of action. Also, the availability of oral or once-weekly alternatives would enable ambulatory treatment resulting in an improved patient's comfort and therapy adherence. However, only one new azole and two new posaconazole-formulations were marketed over the last decade. This review focuses on the antifungal drugs in the pipeline undergoing clinical evaluation. First, the newest azole, isavuconazole, with its improved safety profile and reduction in DDIs, will be discussed. Moreover, there are two glucan synthase inhibitors (GSIs) in the antifungal pipeline: rezafungin (CD101), a long-acting echinocandin with an improved stability that enables once weekly administration, and SCY-078, an orally available GSI with efficacy against azole- and echinocandin resistant isolates. A new oral formulation of amphotericin B will also be presented. Moreover, the first representative of a new antifungal class, the orotomides, with a broad spectrum and no cross-resistance with current antifungal classes, will be discussed. Finally, an overview of other antifungals that are still in earlier clinical development phases, is provided.


Assuntos
Antifúngicos , Desenvolvimento de Medicamentos/tendências , Micoses/tratamento farmacológico , Antifúngicos/uso terapêutico , Humanos , Micoses/patologia
11.
Int J Antimicrob Agents ; 54(6): 790-797, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31284041

RESUMO

The increasing incidence of infections caused by extended-spectrum beta-lactamase (ESBL)/AmpC-producing bacteria leads to increasing use of carbapenems and risk of carbapenem resistance. Treatment success of carbapenem-sparing beta-lactams (CSBs) for ESBL infections is unclear. The aim of this study was to appraise the clinical cure rate and estimate the cost-effectiveness of meropenem vs. CSBs (piperacillin-tazobactam, temocillin, ceftazidime-avibactam, and ceftolozane-tazobactam) for urinary tract infections (UTIs) or intra-abdominal infections (IAIs) due to ESBL/AmpC-producing bacteria. A systematic literature search of the Cochrane library, EMBASE, PubMed, and Web of Science was conducted to identify studies assessing the clinical cure rate of the antibiotics. To assess the cost-effectiveness of CSBs vs. meropenem, a combined decision analytic and Markov model was probabilistically analysed over a 5-year period. The main outcome was presented as the incremental cost-effectiveness ratio and evaluated with a threshold of €20 000 per life year gained (LYG). From 656 identified articles, 17 and 14 studies were included in the qualitative synthesis and quantitative synthesis, respectively. A clinical cure of ceftazidime-avibactam and ceftolozane-tazobactam was comparable to meropenem in patients with complicated IAIs (cIAIs) due to ESBL (Risk ratio [RR]=1·04, 95% confidence interval [CI]=0·95-1·13). Both temocillin and ceftolozane-tazobactam were deemed cost-effective compared to meropenem with €157·58 and €13 398·34 per LYG, respectively, in patients with UTIs due to ESBL. However, only ceftazidime-avibactam (plus metronidazole) was cost-effective for the treatment of IAIs, with €16 916·77 per LYG. These results show that several CSBs can be considered as viable candidates for the treatment of UTIs and IAIs caused by ESBL.

12.
J Pharm Biomed Anal ; 174: 161-167, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31170629

RESUMO

Nitrofurantoin is an antimicrobial drug that has been used in the treatment of lower urinary tract infections for more than 50 years. Despite its long use, surprisingly little is known of the pharmacokinetics of nitrofurantoin, whereas this is essential to optimize patient treatment. We developed a novel analytical method for the quantification of nitrofurantoin in plasma and urine using ultra-high performance liquid chromatography and diode array detection to allow pharmacokinetic studies in these two matrices. The sample preparation method consisted of protein precipitation for plasma and liquid-liquid extraction for urine. 100 µL was needed for the sample preparation. Furazolidone was used as internal standard. Gradient chromatographic separation was performed on a HSS-T3 column. UV detection was performed at a wavelength of 369 nm. The analysis time was 5 min. The method was successfully validated according to the FDA-guidelines (2018). Linearity was confirmed over a concentration range from 50 to 1250 µg/L in plasma and from 4 to 200 mg/L in urine (r2 > 0.95). Validation results of five QC concentrations for plasma and urine, respectively, are for within-day accuracy <± 13% in both matrices, for between-day accuracy <± 7% and <± 9%, for within-day precision <10% and <4% and for between-day precision <10% and <5%. Plasma samples are stable for seven days at 4 °C, and for 2 years at -20 °C and-80 °C. Urine samples are stable for at least seven days at 4 °C and at room temperature and for 2 years at -20 °C andat -80 °C, except from the lower concentrated samples, which are only stable at -80 °C. All samples were kept from daylight using amber colored glassware. The presented method meets all validation requirements and was successfully used in a clinical study where the pharmacokinetics of nitrofurantoin were investigated in healthy volunteers. The easy sample preparation method and the short analysis time make this method suitable for use during routine clinical practice to study the pharmacokinetics of nitrofurantoin.

13.
Pharm Res ; 36(8): 112, 2019 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-31147853

RESUMO

PURPOSE: Tobramycin is an aminoglycoside antibiotic of which the 24 h exposure correlates with efficacy. Recently, we found that clearance of the aminoglycoside gentamicin correlates with total body weight (TBW). In this study, we investigate the full pharmacokinetic profile of tobramycin in obese and non-obese individuals with normal renal function. METHODS: Morbidly obese individuals (n = 20) undergoing bariatric surgery and non-obese healthy volunteers (n = 8), with TBW ranging 57-194 kg, received an IV dose of tobramycin with plasma concentrations measured over 24 h (n = 10 per individual). Statistical analysis, modelling and simulations were performed using NONMEM. RESULTS: In a two-compartment model, TBW was the best predictor for central volume of distribution (p < 0.001). For clearance, MDRD (de-indexed for body surface area) was identified as best covariate (p < 0.001), and was superior over TBW ((p < 0.05). Other renal function estimates (24 h urine GFR and de-indexed CKD-EPI) led to similar results as MDRD (all p < 0.001)). CONCLUSIONS: In obese and non-obese individuals with normal renal function, renal function estimates such as MDRD were identified as best predictors for tobramycin clearance, which may imply that other processes are involved in clearance of tobramycin versus gentamicin. To ensure similar exposure across body weights, we propose a MDRD-based dosing nomogram for obese patients.


Assuntos
Antibacterianos/farmacocinética , Rim/fisiopatologia , Obesidade Mórbida/metabolismo , Tobramicina/farmacocinética , Adulto , Cirurgia Bariátrica , Peso Corporal , Simulação por Computador , Feminino , Taxa de Filtração Glomerular , Humanos , Rim/metabolismo , Masculino , Pessoa de Meia-Idade , Obesidade Mórbida/fisiopatologia , Obesidade Mórbida/cirurgia , Estudos Prospectivos
14.
Clin Infect Dis ; 68(Supplement_4): S260-S274, 2019 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-31222253

RESUMO

Since its introduction in the 1990s, liposomal amphotericin B (LAmB) continues to be an important agent for the treatment of invasive fungal diseases caused by a wide variety of yeasts and molds. This liposomal formulation was developed to improve the tolerability of intravenous amphotericin B, while optimizing its clinical efficacy. Since then, numerous clinical studies have been conducted, collecting a comprehensive body of evidence on its efficacy, safety, and tolerability in the preclinical and clinical setting. Nevertheless, insights into the pharmacokinetics and pharmacodynamics of LAmB continue to evolve and can be utilized to develop strategies that optimize efficacy while maintaining the compound's safety. In this article, we review the clinical pharmacokinetics, pharmacodynamics, safety, and efficacy of LAmB in a wide variety of patient populations and in different indications, and provide an assessment of areas with a need for further clinical research.

15.
Clin Infect Dis ; 68(Supplement_4): S244-S259, 2019 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-31222254

RESUMO

The improved safety profile and antifungal efficacy of liposomal amphotericin B (LAmB) compared to conventional amphotericin B deoxycholate (DAmB) is due to several factors including, its chemical composition, rigorous manufacturing standards, and ability to target and transit through the fungal cell wall. Numerous preclinical studies have shown that LAmB administered intravenously distributes to tissues frequently infected by fungi at levels above the minimum inhibitory concentration (MIC) for many fungi. These concentrations can be maintained from one day to a few weeks, depending upon the tissue. Tissue accumulation is dose-dependent with drug clearance occurring most rapidly from the brain and slowest from the liver and spleen. LAmB localizes in lung epithelial lining fluid, within liver and splenic macrophages and in kidney distal tubules. LAmB has been used successfully in therapeutic and prophylactic animal models to treat many different fungal pathogens, significantly increasing survival and reducing tissue fungal burden.

16.
Lancet ; 393(10184): 1936, 2019 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-31084967
17.
Clin Pharmacokinet ; 58(10): 1333-1343, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31016671

RESUMO

BACKGROUND AND OBJECTIVE: Gentamicin is an aminoglycoside antibiotic predominantly used in bloodstream infections. Although the prevalence of obesity is increasing dramatically, there is no consensus on how to adjust the dose in obese individuals. In this prospective clinical study, we study the pharmacokinetics of gentamicin in morbidly obese and non-obese individuals to develop a dosing algorithm that results in adequate drug exposure across body weights. METHODS: Morbidly obese subjects undergoing bariatric surgery and non-obese healthy volunteers received one intravenous dose of gentamicin (obese: 5 mg/kg based on lean body weight, non-obese: 5 mg/kg based on total body weight [TBW]) with subsequent 24-h sampling. All individuals had a normal renal function. Statistical analysis, modelling and Monte Carlo simulations were performed using R version 3.4.4 and NONMEM® version 7.3. RESULTS: A two-compartment model best described the data. TBW was the best predictor for both clearance [CL = 0.089 × (TBW/70)0.73] and central volume of distribution [Vc = 11.9 × (TBW/70)1.25] (both p < 0.001). Simulations showed how gentamicin exposure changes across the weight range with currently used dosing algorithms and illustrated that using a nomogram based on a 'dose weight' [70 × (TBW/70)0.73] will lead to similar exposure across the entire population. CONCLUSIONS: In this study in morbidly obese and non-obese individuals ranging from 53 to 221 kg we identified body weight as an important determinant for both gentamicin CL and Vc. Using a body weight-based dosing algorithm, optimized exposure across the entire population can be achieved, thereby potentially improving efficacy and safety of gentamicin in the obese and morbidly obese population. TRIAL REGISTRATION: Registered in the Dutch Trial Registry (NTR6058).

18.
PLoS One ; 14(3): e0213913, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30897127

RESUMO

Low plasma CsA concentrations (<300-350 ng/mL) early following allogeneic hematopoietic stem cell transplantation (HSCT) is associated with an increased risk of developing acute graft-versus-host disease (aGvHD). Nevertheless, the current optimal target trough concentration for CsA following HSCT is considered to be 200-400 ng/mL. Here, we performed a retrospective analysis of a homogeneous group of 129 patients who received HSCT after non-myeloablative conditioning, and we analyzed the impact of CsA trough concentration measured during the first four weeks (CsA W1-4) on the incidence aGvHD, relapse-free survival (RFS), non-relapse mortality (NRM), overall survival (OS), and toxicity. The 180-day incidence of grade II-IV aGvHD was 25% (32/129 patients). In multivariate analysis the incidence of grade II-IV aGvHD was significantly lower among patients with a CsA W1-4 concentration ≥350 ng/mL compared to patients with a concentration <350 ng/mL (18% versus 38%, respectively; P = 0.007), with a hazard ration (HR) of 0.38 (95% CI: 0.19-0.77). In contrast, we found no correlation between CsA trough concentration and RFS, NRM, or OS. Moreover, we found an increased incidence of hypomagnesemia at higher CsA concentrations, but no difference in the incidence of acute renal toxicity, hepatic toxicity, or electrolyte imbalance. Interestingly, 30% of patients experienced hyponatremia with no apparent cause other than the use of CsA, with urinalysis suggesting SIADH as the underlying cause. Our findings suggest that a CsA trough concentration of 350-500 ng/mL might be more appropriate in the first month following non-myeloablative HSCT.


Assuntos
Inibidores de Calcineurina/sangue , Ciclosporina/sangue , Doença Enxerto-Hospedeiro/sangue , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Doença Aguda , Adulto , Idoso , Inibidores de Calcineurina/administração & dosagem , Inibidores de Calcineurina/efeitos adversos , Estudos de Coortes , Ciclosporina/administração & dosagem , Ciclosporina/efeitos adversos , Feminino , Neoplasias Hematológicas/terapia , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/efeitos adversos , Imunossupressores/sangue , Rim/efeitos dos fármacos , Fígado/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Países Baixos , Estudos Retrospectivos , Transplante Homólogo/efeitos adversos , Resultado do Tratamento , Desequilíbrio Hidroeletrolítico/etiologia , Adulto Jovem
19.
J Antimicrob Chemother ; 74(6): 1656-1661, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30859184

RESUMO

BACKGROUND: Use of nitrofurantoin has increased significantly since its recent repositioning as a first-line agent for uncomplicated cystitis by multiple guidelines. However, current dosing regimens were developed in an era before robust pharmacokinetic testing and may not be optimal. Furthermore, formulations have been modified over the years. OBJECTIVES: To reassess the plasma and urinary pharmacokinetic profile of macrocrystalline nitrofurantoin in two commonly used dosing regimens. METHODS: In this open-label, randomized crossover pharmacokinetic trial, 12 healthy adult female volunteers were randomized to receive oral nitrofurantoin 100 mg q8h on days 1 and 2 and, after a washout period, 50 mg q6h on days 30 and 31, or the same dosing schemes in reversed order. Urine and blood were collected at steady state and analysed by UPLC. Pharmacokinetic analysis was performed by WinNonlin. RESULTS: Plasma peak concentrations were low (mean 0.33 mg/L, SD 0.08, and 0.69 mg/L, SD 0.35, after 50 and 100 mg, respectively) and dose dependent. The AUC0-24 was higher (6.49 versus 4.43 mg·h/L, P = 0.021) for the 100 mg q8h dosing regimen, but the dose-normalized AUC was similar for the two regimens. In contrast, urinary concentrations were dose independent: increasing the nitrofurantoin dose delayed the time to peak urinary concentration, while steady-state AUC0-24 values remained unchanged (943.49 and 855.95 mg·h/L at 50 mg q6h and 100 mg q8h, respectively). CONCLUSIONS: Plasma concentrations were relatively low and dose dependent. The dose-independent urinary concentrations suggest that excretion of nitrofurantoin into the urine is saturable. Pharmacodynamic studies are urgently required to determine the impact of these findings.

20.
Clin Pharmacokinet ; 58(7): 859-874, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30758736

RESUMO

Eculizumab is the first drug approved for the treatment of complement-mediated diseases, and current dosage schedules result in large interindividual drug concentrations. This review provides insight into the pharmacokinetic and pharmacodynamic properties of eculizumab, both for reported on-label (paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, generalized myasthenia gravis) and off-label (hematopoietic stem cell transplantation-associated thrombotic microangiopathy) indications. Furthermore, we discuss the potential of therapeutic drug monitoring to individualize treatment and reduce costs.

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