Musteata, Marcel Publications

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    Dosing Adjustments in Cases of Altered Plasma Protein Binding are Most Needed for Drugs with a Volume of Distribution Below 1.3 L/kg.
    (Clinical Pharmacokinetics, 2024-08) Musteata, Florin Marcel
    Background: The present literature offers conflicting views on the importance of changes in plasma protein binding in clinical therapeutics. Furthermore, there are no methods to calculate a new dosing regimen when such changes occur. Methods: Previous models developed by Balaz et al. and Greenblat et al. were used to calculate a plasma protein binding (PPB) score for individual drugs based on the volume of distribution for total concentration and the bound fraction of drug. The models were further used to calculate a new drug dosing interval for cases of altered plasma protein binding. The equations apply best for drugs with fast absorption and fast distribution; they can be used as approximations for drugs with slow distribution by using the volume of distribution at steady state and the rate constant of the elimination phase. Results: The newly developed equations show that changes in plasma protein binding are relevant only for drugs with a positive PPB score; such drugs must have a volume of distribution for total concentration below 1.3 L/kg and high protein binding. It is further shown that the drug dosing interval should be reduced when the remaining fraction of plasma protein binding is below the PPB score. Conclusion: A new method to rank drugs according to the impact of changes in plasma protein binding on their pharmacokinetic profile was developed. The new method was applied to show that drugs with high PPB scores need reductions in their dosing interval when the level of protein binding decreases
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    Measurement of free fraction, total concentration and protein binding for testosterone, triiodothyronine and thyroxine.
    (Bioanalysis, 10/17/2023) Klock, Emily*; Kane, Michael P; Musteata, Florin M
    Measuring the total and free concentrations of hormones is useful, but the technology to do this simultaneously is lacking. A new method offers the ability to measure these parameters concurrently for testosterone, thyroxine and triiodothyronine. The free concentrations showed significant correlations with patients' vital statistics. Overall, 67% of correlations for total concentration showed that the new and classical methods had equal accuracy, or that comprehensive ultrafiltration was more accurate. The protein binding term was found to correlate significantly with the patients' luteinizing hormone, prostate-specific antigen and height. Comprehensive ultrafiltration for measuring the total concentration, free concentration and protein binding term uses less sample and is much faster than measuring these parameters with three separate methods.
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    Patient-Specific Pharmacokinetics and Dasatinib Nephrotoxicity.
    (Clinical Journal of the American Society of Nephrology : CJASN, 2023-09) Adegbite, Benjamin O; Abramson, Matthew H; Gutgarts, Victoria; Musteata, Florin Marcel; Chauhan, Kinsuk; Muwonge, Alecia N; Meliambro, Kristin A; Salvatore, Steven P; El Ghaity-Beckley, Sebastian; Kremyanskaya, Marina; Marcellino, Bridget; Mascarenhas, John O; Campbell, Kirk N; Chan, Lili; Coca, Steven G; Berman, Ellin M; Jaimes, Edgar A; Azeloglu, Evren U
    Background: Dasatinib has been associated with nephrotoxicity. We sought to examine the incidence of proteinuria on dasatinib and determine potential risk factors that may increase dasatinib-associated glomerular injury. Methods: We examined glomerular injury through urine albumin-creatinine ratio (UACR) in 82 patients with chronic myelogenous leukemia who were on tyrosine-kinase inhibitor therapy for at least 90 days. t tests were used to compare mean differences in UACR, while regression analysis was used to assess the effects of drug parameters on proteinuria development while on dasatinib. We assayed plasma dasatinib pharmacokinetics using tandem mass spectroscopy and further described a case study of a patient who experienced nephrotic-range proteinuria while on dasatinib. Results: Participants treated with dasatinib ( n =32) had significantly higher UACR levels (median 28.0 mg/g; interquartile range, 11.5-119.5) than participants treated with other tyrosine-kinase inhibitors ( n =50; median 15.0 mg/g; interquartile range, 8.0-35.0; P < 0.001). In total, 10% of dasatinib users exhibited severely increased albuminuria (UACR >300 mg/g) versus zero in other tyrosine-kinase inhibitors. Average steady-state concentrations of dasatinib were positively correlated with UACR ( ρ =0.54, P = 0.03) and duration of treatment ( P = 0.003). There were no associations with elevated BP or other confounding factors. In the case study, kidney biopsy revealed global glomerular damage with diffuse foot process effacement that recovered on termination of dasatinib treatment. Conclusions: Exposure to dasatinib was associated with a significant chance of developing proteinuria compared with other similar tyrosine-kinase inhibitors. Dasatinib plasma concentration significantly correlated with higher risk of developing proteinuria while receiving dasatinib. Podcast: This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/CJASN/2023_09_08_CJN0000000000000219.mp3.
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    Comparison of liquid-liquid extraction, microextraction and ultrafiltration for measuring free concentrations of testosterone and phenytoin.
    (Bioanalysis, 1/17/2022) Cibotaru, Dorina*; Celestin, Marie N*; Kane, Michael P; Musteata, Florin M
    The purpose of the study was to find methods suitable for measuring the free concentrations of testosterone and phenytoin. Sample solutions of the compounds in buffer and human albumin were processed using liquid-liquid extraction, microextraction and ultrafiltration and analyzed by LC-MS/MS. Liquid-liquid extraction with dibutyl phthalate provided complete extraction from buffer solutions and partial extraction from albumin samples. Spintip C18 devices provided exhaustive extraction from buffer and albumin samples. Spintip C8 devices offered complete extraction from buffer and approximately 50% recovery from albumin samples. Centrifree ultrafiltration devices showed high recovery of free concentrations from all the samples, while Amicon and Nanosep devices provided partial recovery. Spintip C8 and Centrifree devices proved useful for measuring free concentrations.
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    Impact of Changes in Free Concentrations and Drug-Protein Binding on Drug Dosing Regimens in Special Populations and Disease States.
    (Journal of Pharmaceutical Sciences, 2021-10) Celestin, Marie N.*; Musteata, Florin Marcel
    Over the last few decades, scientists and clinicians have often focused their attention on the unbound fraction of drugs as an indicator of efficacy and the eventual outcome of drug treatments for specific illnesses. Typically, the total drug concentration (bound and unbound) in plasma is used in clinical trials to assess a compound's efficacy. However, the free concentration of a drug tends to be more closely related to its activity and interaction with the body. Thus far, measuring the unbound concentration has been a challenge. Several mechanistic models have attempted to solve this problem by estimating the free drug fraction from available data such as total drug and binding protein concentrations. The aims of this review are first, to give an overview of the methods that have been used to date to calculate the unbound drug fraction. Second, to assess the pharmacokinetic parameters affected by changes in drug protein binding in special populations such as pediatrics, the elderly, pregnancy, and obesity. Third, to review alterations in drug protein binding in some selected disease states and how these changes impact the clinical outcomes for the patients; the disease states include critical illnesses, transplantation, renal failure, chronic kidney disease, and epilepsy. And finally, to discuss how various disease states shift the ratio of unbound to total drug and the consequences of such shifts on dosing adjustments and reaching the therapeutic target.