A need to revisit clinical breakpoints of tigecycline: effect of atypical non-linear plasma protein binding

Singh, Ravi Shankar Prasad; Mukker, Jatinder Kaur; Drescher, Stefanie K.; Deitchman, Amelia N.; Derendorf, Hartmut

doi:10.1016/j.ijantimicag.2016.12.008

Cited by 18 publications

(12 citation statements)

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“…Increased capillary permeability in sepsis causes the shift of the fluids from blood vessels to interstitial space, which can increase the volume of distribution of the central compartment ( 9 ). The hypoalbuminemia present in critically ill patients can also affect the volume of distribution, especially since tigecycline is highly bound to proteins and shows nonlinear plasma protein binding ( 4 ). This is not supported by the study of critically ill patients by Xie et al ( 21 ), where the estimated value of V 1 was approximately half of the value estimated in our study (72.5 liters and 162 liters, respectively).…”

Section: Discussionmentioning

confidence: 99%

“…The drug is eliminated mainly by fecal excretion of unchanged tigecycline with a minor renal elimination of unchanged drug, glucuronide conjugates, and N -acetyl-9-aminominocycline metabolite ( 3 ). It is highly bound to plasma proteins and exhibits atypical nonlinear protein binding ( 4 ).…”

Section: Introductionmentioning

confidence: 99%

“…The recommended dosage regimen for tigecycline is a 100-mg initial dose, followed by 50 mg every 12 h ( 1 ). However, dosing recommended in package inserts might be insufficient in critically ill patients ( 14 ) and result in underdosing of tigecycline ( 4 , 15 ). Adequate dosing of antibiotics in patients with sepsis or septic shock is of special importance, as underdosing can lead to insufficient antimicrobial activity and negatively affect the patient's outcomes ( 10 , 14 ).…”

Section: Introductionmentioning

confidence: 99%

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Population Pharmacokinetics of High-Dose Tigecycline in Patients with Sepsis or Septic Shock

Moor

Rypulak

Potręć

et al. 2018

Antimicrob Agents Chemother

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Tigecycline is a glycylcycline often used in critically ill patients as the antibiotic of last resort. The pharmacokinetics (PK) of tigecycline in intensive care unit (ICU) patients can be affected by severe pathophysiological changes so that standard dosing might not be adequate. The aim of this study was to describe population PK of high-dose tigecycline in patients with sepsis or septic shock and evaluate the relationship between individual PK parameters and patient covariates. The study population consisted of 37 adult ICU patients receiving a 200-mg loading dose of tigecycline followed by multiple doses of 100 mg every 12 h. Blood samples were collected at 0.5, 2, 4, 8, and 12 h after dose administration. A two-compartment model with interindividual (IIV) and interoccasion (IOV) variability in PK parameters was used to describe the concentration-time course of tigecycline. The estimated values of mean population PK parameters were 22.1 liters/h and 69.4 liters/h for elimination and intercompartmental clearance, respectively, and 162 liters and 87.9 liters for volume of the central and peripheral compartment, respectively. The IIV and IOV in clearance were less than 20%. The estimated values of distribution volumes were different from previously published values, which might be due to pathophysiological changes in ICU patients. No systematic relationship between individual PK parameters and patient covariates was found. The developed model does not show evidence that individual tigecycline dosing adjustment based on patient covariates is necessary to obtain the same target concentration in patients with sepsis or septic shock. Dosing adjustments should be based on the pathogens, their susceptibility, and PK targets.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Population Pharmacokinetics of High-Dose Tigecycline in Patients with Sepsis or Septic Shock

Moor

Rypulak

Potręć

et al. 2018

Antimicrob Agents Chemother

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“…Clinical PK effects of these atypical phenomena have not been studied in clinical trials or modeled with the changing f u in mind. One study has investigated the use of the f u in clinical breakpoint determination for tigecycline 27 , which has also been adopted by others for eravacycline 28 . There is a clear gap in work examining the expected PK alterations due to increase binding with total concentration.…”

Section: 0 Theoretical Implications and Examplesmentioning

confidence: 99%

“…Use of these models in predictions may lead to error in PK profiles and expected exposures. Our group modified a population PK model of tigecycline in healthy volunteers 29 to incorporate nonlinear protein binding based on a previously developed model 27 . Fourteen-day dosage regimens were simulated in NONMEM (Version 7.3) for linear and nonlinear scenarios for doses ranging from 25 to 200 mg every 12 hours.…”

Section: 0 Theoretical Implications and Examplesmentioning

confidence: 99%

Nonlinear Protein Binding: Not What You Think

Deitchman

Singh

Derendorf

2018

Journal of Pharmaceutical Sciences

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Nonlinear protein binding is traditionally thought of as an increasing fraction unbound with increasing total drug concentration. In the past several years, research into the protein binding of several tetracyclines has shown that an unexpected and counterintuitive phenomenon has been observed, specifically that of decreasing unbound drug fraction with increasing total concentrations of drug over certain concentration ranges. Although several studies of tigecycline have shown the importance calcium and its chelation may play in the protein-drug interaction, the potential clinical implications and relevance have not been explored. Here, we define typical and atypical nonlinear protein binding, overview protein binding theory, and discuss theoretical implications on pharmacokinetics. Using tigecycline as an example, in silico simulations and calculations show how when atypical nonlinear protein binding is not accounted for free drug exposure, and drug tissue penetration may be overestimated. It is important to revisit the impacts of nonlinearity in protein binding on clinical pharmacokinetics and pharmacodynamics, and ultimately, clinical efficacy. Although this phenomenon could potentially warrant clinical dose adjustment for certain compounds, it also presents a potential opportunity to exploit underlying mechanisms to develop new therapies and better understand molecular interactions of xenobiotics within the physiological system.

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