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1.
J Pharmacokinet Pharmacodyn ; 50(5): 351-364, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37243877

RESUMO

Population pharmacokinetics (popPK) of bempedoic acid and the popPK/pharmacodynamic (popPK/PD) relationship between bempedoic acid concentrations and serum low-density lipoprotein cholesterol (LDL-C) from baseline were characterized. A two-compartment disposition model with a transit absorption compartment and linear elimination best described bempedoic acid oral pharmacokinetics (PK). Multiple covariates, including renal function, sex, and weight, had statistically significant effects on the predicted steady-state area under the curve. Mild (estimated glomerular filtration rate (eGFR) 60 to < 90 mL/min vs. ≥ 90 mL/min) and moderate (eGFR 30 to < 60 mL/min vs. ≥ 90 mL/min) renal impairment, female sex, low (< 70 kg vs. 70-100 kg) and high (> 100 kg vs. 70-100 kg) body weight were predicted to have a 1.36-fold (90% confidence interval (CI) 1.32, 1.41), 1.85-fold (90% CI 1.74, 2.00), 1.39-fold (90% CI 1.34, 1.47), 1.35-fold (90% CI 1.30, 1.41), and 0.75-fold (90% CI 0.72, 0.79) exposure difference relative to their reference populations, respectively. An indirect response model described changes in serum LDL-C with a model-predicted 35% maximal reduction and bempedoic acid IC50 of 3.17 µg/mL. A 28% reduction from LDL-C baseline was predicted for a steady-state average concentration of 12.5 µg/mL after bempedoic acid (180 mg/day) dosing, accounting for approximately 80% of the predicted maximal LDL-C reduction. Concurrent statin therapy, regardless of intensity, reduced the maximal effect of bempedoic acid but resulted in similar steady-state LDL-C levels. While multiple covariates had statistically significant effects on PK and LDL-C lowering, none were predicted to warrant bempedoic acid dose adjustment.


Assuntos
Dislipidemias , Hipercolesterolemia , Humanos , Feminino , LDL-Colesterol , Hipercolesterolemia/tratamento farmacológico , Voluntários Saudáveis , Dislipidemias/tratamento farmacológico
2.
J Antimicrob Chemother ; 77(9): 2516-2521, 2022 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-35678460

RESUMO

OBJECTIVES: Colistimethate sodium and tobramycin are important systemic antibiotics for treatment of cystic fibrosis (CF) pulmonary exacerbations but can induce acute kidney injury (AKI). We characterize the rate of AKI in CF patients treated with systemic colistimethate sodium compared with tobramycin. METHODS: This single-centre, retrospective cohort study included hospitalized CF patients treated with IV colistimethate sodium or tobramycin. The primary outcome was AKI defined using the RIFLE criteria. Multivariate logistic regression using a mixed model was performed to identify variables that were independently associated with AKI. RESULTS: Overall, 156 patients representing 507 care encounters were included. The OR of AKI was not increased with IV colistimethate sodium relative to IV tobramycin after adjusting for other potential predictor variables (aOR 1.00; 95% CI 0.16-6.03). The frequency of AKI was 9.5% across all encounters, 6.9% with IV colistimethate sodium and 9.9% with IV tobramycin, with RIFLE category R (risk) being the most common stage, accounting for 4.2% of encounters with IV colistimethate sodium and 9.2% with IV tobramycin. The concomitant use of another nephrotoxin (aOR 2.51; 95% CI 1.27-4.95) or the combination of vancomycin and piperacillin/tazobactam (aOR 5.95; 95% CI 2.05-17.3) were both associated with increased odds of AKI. CONCLUSIONS: Systemic treatment with colistimethate sodium or tobramycin in the CF patient population is associated with a similar rate of nephrotoxicity. However, clinicians should be mindful of the increased risk for AKI in patients treated with either IV colistimethate sodium or IV tobramycin when used concurrently with other nephrotoxic agents, particularly the combination of vancomycin and piperacillin/tazobactam.


Assuntos
Injúria Renal Aguda , Fibrose Cística , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/epidemiologia , Antibacterianos/efeitos adversos , Colistina/análogos & derivados , Fibrose Cística/complicações , Fibrose Cística/tratamento farmacológico , Quimioterapia Combinada , Humanos , Combinação Piperacilina e Tazobactam/uso terapêutico , Estudos Retrospectivos , Tobramicina/efeitos adversos , Vancomicina/efeitos adversos
3.
Eur Heart J Cardiovasc Pharmacother ; 8(6): 578-586, 2022 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-34448822

RESUMO

AIMS: Many patients are unable to achieve guideline-recommended LDL cholesterol (LDL-C) targets, despite taking maximally tolerated lipid-lowering therapy. Bempedoic acid, a competitive inhibitor of ATP citrate lyase, significantly lowers LDL-C with or without background statin therapy in diverse populations. Because pharmacodynamic interaction between statins and bempedoic acid is complex, a dose-response model was developed to predict LDL-C pharmacodynamics following administration of statins combined with bempedoic acid. METHODS AND RESULTS: Bempedoic acid and statin dosing and LDL-C data were pooled from 14 phase 1-3 clinical studies. Dose-response models were developed for bempedoic acid monotherapy and bempedoic acid-statin combinations using previously published statin parameters. Simulations were performed using these models to predict change in LDL-C levels following treatment with bempedoic acid combined with clinically relevant doses of atorvastatin, rosuvastatin, simvastatin, and pravastatin. Dose-response models predicted that combining bempedoic acid with the lowest statin dose of commonly used statins would achieve a similar degree of LDL-C lowering as quadrupling that statin dose; for example, the predicted LDL-C lowering was 54% with atorvastatin 80 mg compared with 54% with atorvastatin 20 mg + bempedoic acid 180 mg, and 42% with simvastatin 40 mg compared with 46% with simvastatin 10 mg + bempedoic acid 180 mg. CONCLUSION: These findings suggest bempedoic acid combined with lower statin doses offers similar LDL-C lowering compared with statin monotherapy at higher doses, potentially sparing patients requiring additional lipid-lowering therapies from the adverse events associated with higher statin doses.


Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases , Atorvastatina , LDL-Colesterol , Ácidos Dicarboxílicos , Ácidos Graxos , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Sinvastatina/uso terapêutico
4.
Clin Pharmacokinet ; 61(2): 155-165, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34894345

RESUMO

Tocilizumab is one of few treatments that have been shown to improve mortality in patients with coronavirus disease 2019 (COVID-19), but increased demand has led to relative global shortages. Recently, it has been suggested that lower doses, or fixed doses, of tocilizumab could be a potential solution to conserve the limited global supply while conferring equivalent therapeutic benefit to the dosing regimens studied in major trials. The relationship between tocilizumab dose, exposure, and response in COVID-19 has not been adequately characterized. There are a number of pharmacokinetic (PK) parameters that likely differ between patients with severe COVID-19 and patients in whom tocilizumab was studied during the US FDA approval process. Likewise, it is unclear whether a threshold exposure is necessary for tocilizumab efficacy. The safety and efficacy of fixed versus weight-based dosing of tocilizumab has been evaluated outside of COVID-19, but it is uncertain if these observations are generalizable to severe or critical COVID-19. In the current review, we consider the potential advantages and limitations of alternative tocilizumab dosing strategies. Leveraging PK models and simulation analyses, we demonstrate that a fixed single dose of tocilizumab 400 mg is unlikely to produce PK exposures equivalent to those achieved in the REMAP-CAP trial, although weight-stratified dosing appears to produce more uniform exposure distribution. Data from current and future trials could provide PK/pharmacodynamic insight to better inform dosing strategies at the bedside. Ultimately, rational dosing strategies that balance available limited supply with patient needs are required.


Assuntos
Tratamento Farmacológico da COVID-19 , Anticorpos Monoclonais Humanizados , Humanos , SARS-CoV-2
5.
Antibiotics (Basel) ; 10(11)2021 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-34827306

RESUMO

Antibiotic efficacy determination in clinical trials often relies on non-inferiority designs because they afford smaller study sample sizes. These efficacy studies tend to exclude patients within specific populations or include too few patients to discern potential differences in their clinical outcomes. As a result, dosing guidance in patients with abnormal liver and kidney function, age across the lifespan, and other specific populations relies on drug exposure-matching. The underlying assumption for exposure-matching is that the disease course and the response to the antibiotic are similar in patients with and without the specific condition. While this may not be the case, clinical efficacy studies are underpowered to ensure this is true. The current paper provides an integrative review of the current approach to dose selection in specific populations. We review existing clinical trial endpoints that could be measured on a more continuous rather than a discrete scale to better inform exposure-response relationships. The inclusion of newer systemic biomarkers of efficacy can help overcome the current limitations. We use a modeling and simulation exercise to illustrate how an efficacy biomarker can inform dose selection better. Studies that inform response-matching rather than exposure-matching only are needed to improve dose selection in specific populations.

6.
Antimicrob Agents Chemother ; 65(10): e0079221, 2021 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-34252297

RESUMO

The optimal polymyxin B dosage needed to achieve an efficacy target of 50 to 100 mg · h/liter when treating multidrug-resistant bacterial infections in adult cystic fibrosis (CF) patients is unclear. The pharmacokinetics of intravenous polymyxin B were evaluated to better inform dosing. This was a prospective, observational pharmacokinetic (PK) study of nine CF adults receiving intravenous polymyxin B as part of usual clinical care. Doses preceding PK sampling ranged from 50 to 100 mg every 12 h. Five PK samples were collected following the fourth or fifth dose and concentrations of polymyxin subcomponents B1 and B2 were quantified using liquid chromatography mass spectrometry (LC-MS). Population PK (NONMEM software) analysis was performed using pooled polymyxin B1+B2 concentrations. Participants were Caucasian, predominantly male, with mean age and weight of 31 years (range 21 to 57 years) and 58.0 kg (range 38.3 to 70.4 kg), respectively. A 1-compartment zero-order infusion and linear elimination model adequately described the data with estimated clearance and volume of distribution being 2.09 liters/h and 12.7 liters, respectively, corresponding to a 4.1 h mean half-life (t1/2). Although body weight was observed to influence the volume of distribution, a fixed dose of 75 mg every 12 h was predicted to achieve the target steady-state exposure. Neurotoxicities were reported in all patients, with acute kidney injury events in two patients. These events resolved within 2 to 4 days after discontinuing polymyxin B. Fixed maintenance dosing of polymyxin B without loading is predicted to achieve the targeted therapeutic exposure in CF adults. Treatment-limiting neurotoxicities are very common in this population.


Assuntos
Antibacterianos , Fibrose Cística , Polimixina B , Adulto , Antibacterianos/farmacocinética , Fibrose Cística/tratamento farmacológico , Farmacorresistência Bacteriana Múltipla , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polimixina B/farmacocinética , Estudos Prospectivos , Adulto Jovem
7.
Clin Transl Sci ; 14(4): 1464-1475, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33650272

RESUMO

Apomorphine is an on-demand treatment of "OFF" episodes in patients with Parkinson's disease (PD). A joint parent-metabolite population pharmacokinetic (PK) model characterized apomorphine and apomorphine-sulfate following administration of apomorphine sublingual film (APL) and two formulations of subcutaneous apomorphine. Overall, 2485 samples from 87 healthy subjects and 71 patients with PD and "OFF" episodes were analyzed using nonlinear mixed-effects modeling. Apomorphine PK was adequately described by a two-compartment model with first-order transit absorption via both routes of administration and first-order metabolism to apomorphine-sulfate with one-compartment disposition and first-order elimination. Bioavailability of apomorphine sublingual film was ~ 18% relative to subcutaneous apomorphine. Among covariates tested, only body weight had a large effect on apomorphine exposure (maximum plasma concentration and area under the concentration-time curve [AUC0-∞ ]), with greater weight resulting in lower exposure. Model-predicted apomorphine exposure was similar between apomorphine sublingual film 30 mg and subcutaneous apomorphine 5 mg (median AUC0-24 , 66.7 ng•h/mL, geometric mean ratio of 0.99; 90% confidence interval [CI], 0.96-1.03) and was comparable between apomorphine sublingual film 35 mg and subcutaneous apomorphine 6 mg (median AUC0-24 , 75.4 and 80.0 ng•h/mL, respectively; geometric mean ratio of 0.94; 90% CI, 0.90-0.97) administered every 2 h for a maximum of 5 doses per day. In a typical patient with PD, predicted apomorphine exposure increased with increasing doses of apomorphine sublingual film; however, the increase was less than dose proportional. Similar apomorphine exposure was predicted in patients with mild renal impairment versus normal renal function. PK properties of apomorphine sublingual film support its administration for a wide range of patients with PD and "OFF" episodes, regardless of demographic and clinical characteristics.


Assuntos
Antiparkinsonianos/farmacocinética , Apomorfina/farmacocinética , Modelos Biológicos , Doença de Parkinson/tratamento farmacológico , Administração Sublingual , Adulto , Idoso , Idoso de 80 Anos ou mais , Antiparkinsonianos/administração & dosagem , Apomorfina/administração & dosagem , Área Sob a Curva , Disponibilidade Biológica , Variação Biológica da População , Ensaios Clínicos como Assunto , Feminino , Voluntários Saudáveis , Humanos , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade , Absorção pela Mucosa Oral , Doença de Parkinson/sangue , Adulto Jovem
8.
Artigo em Inglês | MEDLINE | ID: mdl-33526494

RESUMO

The risk of vancomycin (VAN)-associated acute kidney injury (AKI) may be altered with combination regimens. The specific AKI risk when VAN is combined with imipenem-cilastatin/relebactam (IMP-C/REL) or piperacillin/tazobactam (TZP) has not been clearly defined. We sought to quantify the dose-AKI relationships of VAN alone and in combination with TZP or IMP-C/REL. Male C57BL/6J mice (Charles River Laboratory) aged 10 to 12 weeks were dosed with study drug regimens in three stages. Stage 1 consisted of a VAN dose-ranging design (0 to 600 mg/kg daily) over a 7-day period to identify the VAN monotherapy dose-AKI relationship in the murine model. Stage 2 evaluated the approximate VAN dose eliciting 50% AKI response in stage 1 in combination with the highest human equivalent doses (HEDs) used in preclinical murine models (2.5 and 320 mg/kg daily for TZP and IMP-C/REL, respectively). Stage 3 tested these combinations with fractionated doses of TZP or IMP-C/REL administered at 6- and 12-h intervals. In these studies, AKI was defined with biomarkers (serum creatinine [SCr], blood urea nitrogen [BUN]) and with histopathological assessment by a treatment-blinded pathologist. VAN doses of 300 to 500 mg/kg daily reproducibly led to development of AKI within 4 days of dosing. Mice treated with VAN alone had a near doubling of their baseline SCr and BUN levels compared with mice treated with control, IMP-C/REL alone, or TZP alone. Both VAN+IMP-C/REL and VAN+TZP had significantly (P < 0.05) lower SCr and BUN values than VAN alone when dosed once daily. This nephroprotective effect was retained with VAN+IMP-C/REL but not VAN+TZP when IMP-C/REL and TZP were administered every 6 h. Biomarker results were concordant with histopathological findings. The VAN dose-AKI relationship can be attenuated with single daily HEDs of TZP or IMP-C/REL in mice. IMP-C/REL, but not TZP, retained a nephroprotective effect compared with VAN monotherapy when administered as fractionated doses.


Assuntos
Injúria Renal Aguda , Vancomicina , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/tratamento farmacológico , Animais , Antibacterianos/uso terapêutico , Compostos Azabicíclicos , Combinação Imipenem e Cilastatina , Quimioterapia Combinada , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Combinação Piperacilina e Tazobactam , Estudos Retrospectivos
9.
Artigo em Inglês | MEDLINE | ID: mdl-32152085

RESUMO

In patients with renal impairment (n = 22 of 39), the median serum concentrations of linezolid, PNU-142300, and PNU-142586 were 1.6-, 3.3-, 2.8-fold higher, respectively, than in patients without renal impairment. Metabolite concentrations in paired samples were poorly correlated with linezolid concentrations (r2 = 0.26 for PNU-142300 and 0.06 for PNU-142586). Linezolid and its metabolites share potential toxicophores that deserve characterization to mitigate higher myelosuppression risk in patients with renal impairment.


Assuntos
Antibacterianos/efeitos adversos , Linezolida/análogos & derivados , Linezolida/efeitos adversos , Transtornos Mieloproliferativos/induzido quimicamente , Insuficiência Renal/sangue , Adulto , Antibacterianos/uso terapêutico , Medula Óssea/efeitos dos fármacos , Feminino , Humanos , Linezolida/antagonistas & inibidores , Linezolida/sangue , Linezolida/farmacocinética , Masculino , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/isolamento & purificação , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/isolamento & purificação , Streptococcus pneumoniae/efeitos dos fármacos , Streptococcus pneumoniae/isolamento & purificação , Enterococos Resistentes à Vancomicina/efeitos dos fármacos , Enterococos Resistentes à Vancomicina/isolamento & purificação
11.
Ann Pharmacother ; 54(5): 496-503, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31762287

RESUMO

Objective: To address the background and rationale for the recent introduction of the Modification of Diet in Renal Disease (MDRD) equation for renal dose adjustment of antimicrobials and to provide recommendations for pharmacists dosing new antimicrobial agents. Data Sources: Comprehensive MEDLINE and EMBASE literature searches (from August 2018 to October 2019) were performed. Search terms included creatinine clearance, Cockcroft-Gault, MDRD, and glomerular filtration rate and a subsequent search included the preceding terms AND antimicrobials OR antibiotics. Study Selection and Data Extraction: Available English-language studies on the derivation and/or use of the Cockcroft-Gault (CG) and MDRD study equation were evaluated as well as those that specifically discussed their use for dosing antimicrobial agents. Data Synthesis: The US Food and Drug Administration (FDA) approval of delafloxacin and meropenem-vaborbactam in 2017 ushered in a new era in renal dosing of antibiotics, in that both agents are recommended to be dosed by the MDRD equation. Studies demonstrate that the CG and MDRD equations can result in discrepant dosing recommendations. Relevance to Patient Care and Clinical Practice: The renal estimation equation recommended in a new antibiotic label should dictate the dosing of that medication. It is noteworthy that these equations are not interchangeable. Conclusion: Recently approved antimicrobials utilizing the MDRD equation for renal dose adjustment will be interspersed with old and new antimicrobials utilizing the CG equation because of lack of singular guidance by the FDA. This requires pharmacists to be vigilant in evaluating drug labels to determine which equation is recommended and to understand the differences, strengths, and limitations of each equation.


Assuntos
Anti-Infecciosos/administração & dosagem , Nefropatias/metabolismo , Nefropatias/fisiopatologia , Rim/efeitos dos fármacos , Adulto , Idoso , Anti-Infecciosos/farmacocinética , Anti-Infecciosos/uso terapêutico , Creatinina/sangue , Desenvolvimento de Medicamentos , Feminino , Taxa de Filtração Glomerular , Humanos , Rim/fisiopatologia , Masculino , Pessoa de Meia-Idade , Farmacêuticos , Estados Unidos , United States Food and Drug Administration
12.
J Pharm Biomed Anal ; 178: 112968, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-31727360

RESUMO

Linezolid (LZD) is a widely used antimicrobial that is active against a broad range of disease-causing bacteria. Myelosuppression is major treatment-limiting toxicity of LZD that occurs more frequently in patients with renal insufficiency. Quantification of LZD and its two primary metabolites (PNU-142300 and PNU-142586), which undergo significant renal elimination, may support design of improved dosing strategies to mitigate the risk of myelosuppression. In this study, we established the first liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the simultaneous quantification of LZD and its main metabolites in human serum. Proteins in serum samples were precipitated with acetonitrile containing a deuterated internal standard. Chromatographic separation of analytes was performed with Waters X-bridge column (C18, 150 × 4.6 mm, 3.5 µm) at 25 °C and subjected to mass analysis using positive electro-spray ionization. The mobile phase A was water with 0.1% formic acid, and mobile phase B was acetonitrile with 0.1% formic acid at a flow rate of 0.6 mL/min, within a 15 min run time. Standard curves were linear and correlation coefficients (r2) were ≥0.99 for concentration ranges of 0.1-50 µg/mL for LZD and PNU-142300, and 0.1-25 µg/mL for PNU-142586. The inter- and intra-assay precisions were <15% for all analytes in quality control samples, and the accuracies ranged from 97 to 112%. Extraction recoveries ranged from 78 to 103% for all analytes, and there was no significant matrix effect. Samples from 10 patients (5 with renal impairment) were assayed. Mean (SD) LZD, PNU-142300 and PNU-142586 trough concentrations were 19.4(6.8), 11.6(6.8), 25.7(16.4) µg/mL, respectively, in patients with renal impairment. These values were 2.5-, 5.8-, and 6.8-fold higher for LZD, PNU-142300 and PNU-142586, respectively compared to patients without renal impairment. The method was effectively applied in the determination of LZD and its main metabolites in human serum.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Linezolida/análogos & derivados , Linezolida/sangue , Espectrometria de Massas em Tandem/métodos , Acetonitrilas/sangue , Adulto , Idoso , Feminino , Humanos , Limite de Detecção , Linezolida/metabolismo , Masculino , Pessoa de Meia-Idade , Adulto Jovem
13.
Am J Health Syst Pharm ; 76(24): 2013-2018, 2019 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-31630155

RESUMO

PURPOSE: To compare methods of estimating vancomycin volume of distribution (V) in adults with class III obesity. METHODS: A retrospective, multicenter pharmacokinetic analysis of adults treated with vancomycin and monitored through measurement of peak and trough concentrations was performed. Individual pharmacokinetic parameter estimates were obtained via maximum a posteriori Bayesian analysis. The relationship between V and body weight was assessed using linear regression. Mean bias and root-mean-square error (RMSE) were calculated to assess the precision of multiple methods of estimating V. RESULTS: Of 241 patients included in the study sample, 159 (66.0%) had a body mass index (BMI) of 40.0-49.9 kg/m2, and 82 (34.0%) had a BMI of ≥50.0 kg/m2. The median (5th, 95th percentile) weight of patients was 136 (103, 204) kg, and baseline characteristics were similar between BMI groups. The mean ± S.D. V was lower in patients with a BMI of 40.0-49.9 kg/m2 than in those with a BMI of ≥50.0 kg/m2 (72.4 ± 19.6 L versus 79.3 ± 20.6 L, p = 0.009); however, body size poorly predicted V in regression analyses (R2 < 0.20). A fixed estimate of V (75 L) and use of a weight-based value (0.52 L/kg by total body weight [TBW]) yielded similar bias and error in this population. CONCLUSION: Results of the largest analysis of vancomycin V in class III obesity to date indicated that use of a fixed V value (75 L) and use of a TBW-based estimate (0.52 L/kg) for estimation of vancomycin V in patients with a BMI of ≥40.0 kg/m2 have similar bias. Two postdistribution vancomycin concentrations are needed to accurately determine patient-specific pharmacokinetic parameters, estimate area under the curve, and improve the precision of vancomycin dosing in this patient population.


Assuntos
Antibacterianos/metabolismo , Índice de Massa Corporal , Obesidade/metabolismo , Distribuição Tecidual/efeitos dos fármacos , Distribuição Tecidual/fisiologia , Vancomicina/metabolismo , Adulto , Idoso , Antibacterianos/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Vancomicina/farmacologia
14.
Artigo em Inglês | MEDLINE | ID: mdl-31109977

RESUMO

Linezolid is administered as a fixed dose to all patients despite evidence of increased exposure and myelosuppression in renal impairment. The objectives of these studies were to assess the risk of thrombocytopenia with standard-dose linezolid in renal impairment and to identify an alternate dosing strategy. In study 1, data from adult patients receiving linezolid for ≥10 days were retrospectively reviewed to determine the frequency of thrombocytopenia in patients with and without renal impairment. Time-to-event analyses were performed using Cox proportional-hazards models. In study 2, population pharmacokinetic modeling was employed to build covariate-structured models using an independent data set of linezolid concentrations obtained during routine therapeutic drug monitoring (TDM). Monte Carlo simulations were performed to identify linezolid dosing regimens that maximized attainment of therapeutic trough concentrations (2 to 8 mg/liter) across various renal-function groups. Toxicity analysis (study 1) included 341 patients, 133 (39.0%) with renal impairment. Thrombocytopenia occurred more frequently among patients with renal impairment (42.9% versus 16.8%; P < 0.001), and renal impairment was independently associated with this toxicity in multivariable analysis (adjusted hazard ratio [aHR], 2.37; 95% confidence interval [CI], 1.52 to 3.68). Pharmacokinetic analyses (study 2) included 1,309 linezolid concentrations from 603 adult patients. Age, body surface area, and estimated glomerular filtration rate (eGFR) were identified as covariates of linezolid clearance. Linezolid dose reductions improved the probability of achieving optimal exposures in simulated patients with eGFR values of <60 ml/min. Thrombocytopenia occurs more frequently in patients with renal impairment receiving standard linezolid doses. Linezolid dose reduction and trough-based TDM are predicted to mitigate this treatment-limiting toxicity.


Assuntos
Antibacterianos/administração & dosagem , Antibacterianos/efeitos adversos , Linezolida/administração & dosagem , Linezolida/efeitos adversos , Insuficiência Renal/induzido quimicamente , Área Sob a Curva , Monitoramento de Medicamentos/métodos , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Método de Monte Carlo , Estudos Retrospectivos , Trombocitopenia
15.
Clin Pharmacokinet ; 58(10): 1323-1332, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-30972695

RESUMO

BACKGROUND: The estimated glomerular filtration rate (eGFR) is often used to model drug clearance (CL) and scale doses across age and body size. Over their lifetime, patients with cystic fibrosis (CF) receive repeated courses of tobramycin, an antibiotic with eGFR-dependent CL, for the treatment of pulmonary exacerbations. Tobramycin population pharmacokinetic (PK) modeling can be used to decipher the best approach to define eGFR for pediatric bridging studies. METHODS: Inpatients with CF who received intravenous tobramycin between 1 January 2006 and 30 May 2018 were eligible for inclusion. Encounters without tobramycin concentration measurement or missing covariate data were excluded. Population PK analysis was performed using NONMEM.Covariate models were built  following identification of the base model, with specific emphasis on the effect of different methods of estimating renal function as a covariate of tobramycin CL. RESULTS: A total of 296 CF patients contributed 1029 care encounters (420 pediatric, 609 adult) and 4352 tobramycin concentrations to this analysis. The median (minimum, maximum) age at encounter was 19 years (0.2, 60), with serum creatinine of 0.60 mg/dL (0.10, 3.41). A two-compartment model best described the observed data, with height and eGFR as significant covariates of tobramycin CL. eGFR was best modeled using a combination of the modified Schwartz and Chronic Kidney Disease Epidemiology Collaboration (CKDEPI) equations expressed in absolute units. CONCLUSIONS: The CKDEPI equation bridges PK data generated in adults to adolescents with CF better than the current regulatory standard. The eGFR should be expressed in absolute units (mL/min) for PK analyses.


Assuntos
Antibacterianos/farmacocinética , Fibrose Cística/metabolismo , Fibrose Cística/fisiopatologia , Taxa de Filtração Glomerular , Modelos Biológicos , Tobramicina/farmacocinética , Adolescente , Adulto , Envelhecimento/fisiologia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Adulto Jovem
16.
Diagn Microbiol Infect Dis ; 93(2): 131-135, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30279024

RESUMO

The management of Staphylococcus aureus bacteremia is limited by high rates of methicillin resistance and the paucity of antibiotic agents with proven efficacy in complicated infectious syndromes, such as endocarditis. Vancomycin is the mainstay of therapy; however, salvage therapy is frequently required due to persistence of infection or drug toxicity. Daptomycin is FDA-approved for S. aureus bacteremia and right-sided endocarditis, but controversy exists regarding the role of this agent in the setting of septic pulmonary emboli. Sequestration by pulmonary surfactant renders daptomycin ineffective in bronchoalveolar pneumonia; however, the impact of this drug property on efficacy in hematogenous pulmonary infections is unclear. Herein we review the available evidence in order to inform the rationale use of daptomycin in S. aureus infections complicated by septic pulmonary emboli.


Assuntos
Antibacterianos , Daptomicina , Endocardite Bacteriana , Embolia Pulmonar , Infecções Estafilocócicas , Adulto , Idoso , Idoso de 80 Anos ou mais , Antibacterianos/administração & dosagem , Antibacterianos/uso terapêutico , Daptomicina/administração & dosagem , Daptomicina/uso terapêutico , Endocardite Bacteriana/complicações , Endocardite Bacteriana/tratamento farmacológico , Feminino , Humanos , Masculino , Embolia Pulmonar/tratamento farmacológico , Embolia Pulmonar/etiologia , Terapia de Salvação , Infecções Estafilocócicas/complicações , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus aureus , Adulto Jovem
17.
J Antimicrob Chemother ; 74(1): 126-129, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30252050

RESUMO

Background: Empirical models to predict ß-lactam pharmacokinetics (PK) using information from routine aminoglycoside therapeutic drug monitoring (TDM) have been proposed for critically ill patients; however, no such models exist for patients with cystic fibrosis (CF). Objectives: To investigate whether PK parameters of tobramycin could be used to predict those of piperacillin. Methods: A non-interventional, open-label PK study was conducted in hospitalized adults treated with piperacillin/tazobactam and tobramycin for acute pulmonary exacerbations of CF. Six serum samples per patient were collected and analysed. One- and two-compartment population PK models with linear, Michaelis-Menten or mixed elimination were evaluated for both drugs within the PmetricsTM package for R. Models were developed and compared iteratively using the log-likelihood and Akaike information criterion (AIC) objective functions. Results: Nine primarily female (n = 8) and Caucasian (100%) adult CF patients were enrolled. The median (IQR) age, height, weight and serum creatinine of included patients was 31 (27-32) years, 51.4 (49.9-55.8) kg, 162.6 (160.0-165.1) cm and 0.6 (0.5-0.6) mg/dL, respectively. The final model with the lowest objective function values consisted of one compartment with first-order elimination for tobramycin and two compartments with mixed-order elimination for piperacillin with the elimination rate constant of piperacillin modelled as a linear function of the elimination rate constant of tobramycin. Conclusions: A relationship was identified between the elimination rate constants of tobramycin and piperacillin. Validation of this relationship in larger studies of adult patients with CF is needed before application to the precision dosing of piperacillin/tazobactam in this patient population.


Assuntos
Antibacterianos/administração & dosagem , Antibacterianos/farmacocinética , Fibrose Cística/complicações , Combinação Piperacilina e Tazobactam/administração & dosagem , Combinação Piperacilina e Tazobactam/farmacocinética , Tobramicina/administração & dosagem , Tobramicina/farmacocinética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Infecções Bacterianas/tratamento farmacológico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto Jovem , Inibidores de beta-Lactamases/administração & dosagem , Inibidores de beta-Lactamases/farmacocinética
18.
Clin Infect Dis ; 68(9): 1596-1602, 2019 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-30219824

RESUMO

Antibiotic renal dose adjustments are determined in patients with stable chronic kidney disease and may not translate to patients in late-phase trials and practice. Ceftolozane/tazobactam, ceftazidime/avibactam, and telavancin all carry precautionary statements for reduced clinical response in patients with baseline creatinine clearance of 30-50 mL/min, potentially due to unnecessary dose reduction in the setting of acute kidney injury (AKI). In this review, we discuss the regulatory landscape for antibiotics eliminated by the kidney and highlight the importance of the first 48 hours of therapy. Using a clinical database, we identified AKI on admission in a substantial proportion of patients with pneumonia (27.1%), intraabdominal (19.5%), urinary tract (20.0%), or skin and skin structure infections (9.7%) that resolved by 48 hours in 57.2% of cases. We suggest that deferred renal dose reduction of wide therapeutic index antibiotics could improve outcomes in patients with infectious diseases.


Assuntos
Injúria Renal Aguda/etiologia , Antibacterianos/administração & dosagem , Doenças Transmissíveis/complicações , Doenças Transmissíveis/tratamento farmacológico , Rim/efeitos dos fármacos , Adulto , Idoso , Antibacterianos/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
19.
J Clin Pharmacol ; 59(2): 159-167, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30184267

RESUMO

Renal function is the most commonly applied patient-specific quantitative variable used to determine drug doses. Measurement of renal function is not practical in most clinical settings; therefore, clinicians often rely on estimates when making dosing decisions. Similarly, renal function estimates are used to assign subjects in phase 1 pharmacokinetic studies, which inform dosing in late-phase clinical trials and ultimately the product label. The Cockcroft-Gault estimate of creatinine clearance has been the standard renal function metric; however, this paradigm is shifting toward the Modification of Diet in Renal Diseases (MDRD) estimate of the glomerular filtration rate (GFR). The proportion of approved new drug labels with dosing recommendations based on the MDRD equation was 16.7% in 2015, 70.0% in 2016, and 46.7% in 2017. Disharmonious recommendations from the United States Food and Drug Administration and the European Medicines Agency will continue to increase this heterogeneity in the assessment of renal function in drug development and negatively impact industry, health systems, and clinicians. In this review, we discuss the current regulatory guidance for the conduct of renal impairment pharmacokinetic studies and review the implications of this guidance across the medication use system with 3 recently approved antibiotics: ceftazidime/avibactam, delafloxacin, and meropenem/vaborbactam. Finally, we suggest measuring GFR in phase 1 studies and employing the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation to integrate data across clinical trials. This will help to harmonize CKD staging, population pharmacokinetic analyses, and dosing by estimated renal function.


Assuntos
Desenvolvimento de Medicamentos/legislação & jurisprudência , Desenvolvimento de Medicamentos/normas , Insuficiência Renal Crônica/tratamento farmacológico , Creatinina/análise , Cálculos da Dosagem de Medicamento , Taxa de Filtração Glomerular/efeitos dos fármacos , Humanos , Estados Unidos
20.
Pharmacotherapy ; 39(2): 182-195, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30589457

RESUMO

Novel ß-lactamase inhibitors have extended the reach of new and existing ß-lactams against multidrug-resistant bacteria expressing ß-lactamases. The efficacy of these combination therapeutics relies on a complex two-component pharmacodynamic (PD) system where the ß-lactamase inhibitor inactivates the bacterial ß-lactamase enzyme and frees the companion ß-lactam to act against its penicillin-binding protein target. Despite considerable investigation into the pharmacokinetics (PK) and pharmacodynamics of ß-lactams, the pharmacology of their companion ß-lactamase inhibitors has only recently been rigorously explored. This review describes the diversity of ß-lactamase enzymes, mechanisms of enzyme inhibition, and factors impacting the efficacy of clinically available ß-lactamase inhibitors. Relevant PK differences among available inhibitors and the PK/PD properties of these agents are described independently of their companion ß-lactams. In the modern era of antibiotic resistance, a comprehensive understanding of the pharmacology, PK, and PD of ß-lactamase inhibitors is paramount to maximizing the therapeutic efficacy of existing ß-lactam/ß-lactamase inhibitor combinations and protecting novel agents in the drug development pipeline.


Assuntos
Antibacterianos/farmacologia , Antibacterianos/farmacocinética , Inibidores de beta-Lactamases/farmacologia , Inibidores de beta-Lactamases/farmacocinética , Farmacorresistência Bacteriana Múltipla , Humanos , Testes de Sensibilidade Microbiana
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