Population Pharmacokinetics of Polymyxin B

Manchandani, Pooja; Thamlikitkul, Visanu; Dubrovskaya, Yanina; Babic, Jessica T.; Lye, David C.; Lee, Lawrence S.; Tam, Vincent H.

doi:10.1002/cpt.981

Cited by 60 publications

(71 citation statements)

References 22 publications

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“…With a low correlation coefficient ( Supplementary Figure 1), this study found CrCL was a statistical covariate of polymyxin B clearance (Equ. 6), which was in agreement with other studies (Avedissian et al, 2018;Manchandani et al, 2018). However, Manchandani et al (2018) ; tvV2, typical value of volume of peripheral compartment distribution (V2); tvCl, typical value of central compartment clearance (Cl); tvQ, typical value of inter-compartmental clearance (Q, Cl2); dCldCrCL, fixed parameter coefficient of creatinine clearance (CrCL) to Cl; wV, variance of inter-individual variability for V; CorrV-Cl, correlation between V and Cl; stdev0, standard deviation; NA, not applicable.…”

Section: Discussionsupporting

confidence: 93%

“…While, as for patients with renal dysfunction, the regime of 50 mg maintenance dose twice daily would be a better option. These observations were in agreement with a previous study, although it did not provide a dosing recommendation for patients with renal dysfunction by using a one-compartment model (Manchandani et al, 2018).…”

Section: Discussionsupporting

confidence: 90%

“…To date, few studies have been conducted on population PK of polymyxin B (Kwa et al, 2008;Sandri et al, 2013;Kubin et al, 2018;Manchandani et al, 2018;Miglis et al, 2018). To our best knowledge, this study included the largest samples and most covariates from acutely-ill patients, aimed at evaluating the population PK of polymyxin B and identifying potential factors influencing the PK variability.…”

Section: Discussionmentioning

confidence: 99%

“…The result indicated a twocompartment model adequately described population PK of polymyxin B in Chinese patients. Although there were studies performed using the one-compartment model (Kwa et al, 2008;Kubin et al, 2018;Manchandani et al, 2018), which may be due to limited blood points collected at distribution and elimination phases. This study showed that the median polymyxin B CL was 1.786 L/h, which was less than those reported previously (range, 1.87-2.5 L/h).…”

Section: Discussionmentioning

confidence: 99%

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Population Pharmacokinetics and Limited Sampling Strategy for Therapeutic Drug Monitoring of Polymyxin B in Chinese Patients With Multidrug-Resistant Gram-Negative Bacterial Infections

et al. 2020

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Polymyxin B is used as a last therapeutic option for the treatment of multidrug-resistant Gram-negative bacterial infections. This study aimed to develop a population pharmacokinetic model and limited sampling strategy, a method to estimate the area under the concentration curve (AUC) by using a limited number of samples, to assist therapeutic drug monitoring of polymyxin B in Chinese patients. Population pharmacokinetic analysis was performed using Phoenix ® NLME with data obtained from 46 adult patients at steady state. Various demographic variables were investigated as potential covariates for population pharmacokinetic modeling. The limited sampling strategies based on the Bayesian approach and multiple linear regression were validated using the intraclass correlation coefficient and Bland-Altman analysis. As a result, the data was described by a two-compartment population pharmacokinetic model. Through the modeling, creatinine clearance was found to be a statistically significant covariate influencing polymyxin B clearance. The limited sampling strategies showed the twopoint model (C 0h and C 2h) could predict polymyxin B exposure with good linear relativity (r 2 > 0.98), and the four-point model (C 1h , C1 .5h , C 4h , and C 8h) performed best in predicting polymyxin B AUC (r 2 > 0.99). In conclusion, this study successfully developed a population pharmacokinetic model and limited sampling strategies that could be applied in clinical practice to assist in therapeutic drug monitoring of polymyxin B in Chinese patients.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Population Pharmacokinetics and Limited Sampling Strategy for Therapeutic Drug Monitoring of Polymyxin B in Chinese Patients With Multidrug-Resistant Gram-Negative Bacterial Infections

et al. 2020

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“…Polymyxin B is a cyclic polypeptide antibiotic that regained significant interest due to the inevitable appearance of MDR bacteria ( Rigatto et al., 2019 ). It is even being considered as last resort therapy against some intractable gram-negative bacteria ( Manchandani et al., 2018 ).…”

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confidence: 99%

Skin Hyperpigmentation in Coronavirus Disease 2019 Patients: Is Polymyxin B the Culprit?

Hou

2020

Front. Pharmacol.

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From mid-December 2019, the outbreak of the coronavirus disease 2019 (COVID-19) in Wuhan has spread worldwide and become an emergency of major international concerns (Pascarella et al., 2020). Recently, a television report has drawn extensive attention of the public in China. Two frontline doctors of the central hospital of Wuhan, Fan Yi and Weifeng Hu, were unfortunately infected by COVID-19. Cutaneous hyperpigmentation of the two doctors was noticed in the TV interview. Many people expressed grave concerns about the pathogenesis and prognosis of their skin pigmentary disorder. Fan Yi and Weifeng Hu were diagnosed with COVID-19 infection on January 18 and January 28, respectively. The illness progress of the two doctors was very rapid and they were transferred to the intensive care unit for further treatment. Extracorporeal membrane oxygenation (ECMO) was provided as rescue therapy for respiratory failure. Because of prolonged hospital stay, mechanical ventilation, and presence of invasive devices, some critically ill patients suffered from infections caused by multidrug-resistant (MDR) bacteria (Bassetti et al., 2018). Polymyxin B was used in these two doctors for the treatment of MDR infections. Polymyxin B is a cyclic polypeptide antibiotic that regained significant interest due to the inevitable appearance of MDR bacteria (Rigatto et al., 2019). It is even being considered as last resort therapy against some intractable gram-negative bacteria (Manchandani et al., 2018). Acquired skin hyperpigmentation is a common dermatologic complaint, which is attributable to drugs up to 20% of all cases (Nahhas et al., 2019). Many drugs are associated with skin hyperpigmentation such as nonsteroidal anti-inflammatory agents, antihypertensive agents, antibiotics, and psychoactive agents (Gimeńez Garcıá and Carrasco Molina, 2018). Nephrotoxicity and neurotoxicity are common adverse reactions of polymyxin B, while skin hyperpigmentation was also reported as a side effect recently (Li et al., 2020). Reports of polymyxin B associated skin hyperpigmentation in adults were rare, unlike in neonates (Zavascki et al., 2015; Gothwal et al., 2016). Polymyxin B is mainly excreted through the kidney, dosage adjustment is required in patients with lower creatinine clearance (Zheng et al., 2018). The cumulation of polymyxin B might be a possible reason for skin hyperpigmentation in neonates due to their immature kidney function (Gothwal et al., 2016; Li et al., 2020). Kidney involvement is prevalent in patients with COVID-19. Acute kidney injury (AKI) has been reported in approximately 20%-40% of critically ill or deceased COVID-19 patients (Ronco et al., 2020). Several mechanisms are possibly involved in COVID-19 associated AKI, including direct damage action of the virus, hemodynamic alterations, inflammatory cytokines, administration of nephrotoxic drugs, and mechanical ventilation (Gabarre et al., 2020; Martinez-Rojas et al., 2020). According to these findings, we speculate that AKI may be an important factor

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Assessing the predictive performance of population pharmacokinetic models for intravenous polymyxin B in critically ill patients

Hanafin

Nation

Scheetz

et al. 2021

CPT Pharmacom & Syst Pharma

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Polymyxin B (PMB) has reemerged as a last-line therapy for infections caused by multidrug-resistant gram-negative pathogens, but dosing is challenging because of its narrow therapeutic window and pharmacokinetic (PK) variability.Population PK (POPPK) models based on suitably powered clinical studies with appropriate sampling strategies that take variability into consideration can inform PMB dosing to maximize efficacy and minimize toxicity and resistance.Here we reviewed published PMB POPPK models and evaluated them using an external validation data set (EVD) of patients who are critically ill and enrolled in an ongoing clinical study to assess their utility. Seven published POPPK models were employed using the reported model equations, parameter values, covariate relationships, interpatient variability, parameter covariance, and unexplained residual variability in NONMEM (Version 7.4.3). The predictive ability of the models was assessed using prediction-based and simulation-based diagnostics. Patient characteristics and treatment information were comparable across studies and with the EVD (n = 40), but the sampling strategy was a main source of PK variability across studies. All models visually and statistically underpredicted EVD plasma concentrations, but the two-compartment models more accurately described the external data set. As current POPPK models were inadequately predictive of the EVD, creation of a new POPPK model based on an appropriately powered clinical study with an informed PK sampling strategy would be expected to improve characterization of PMB PK and identify covariates to explain interpatient variability. Such a model would support modelinformed precision dosing frameworks, which are urgently needed to improve PMB treatment efficacy, limit resistance, and reduce toxicity in patients who are critically ill.

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Population Pharmacokinetics of Polymyxin B

Cited by 60 publications

References 22 publications

Population Pharmacokinetics and Limited Sampling Strategy for Therapeutic Drug Monitoring of Polymyxin B in Chinese Patients With Multidrug-Resistant Gram-Negative Bacterial Infections

Population Pharmacokinetics and Limited Sampling Strategy for Therapeutic Drug Monitoring of Polymyxin B in Chinese Patients With Multidrug-Resistant Gram-Negative Bacterial Infections

Skin Hyperpigmentation in Coronavirus Disease 2019 Patients: Is Polymyxin B the Culprit?

Assessing the predictive performance of population pharmacokinetic models for intravenous polymyxin B in critically ill patients

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