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Expert Opinion on Drug Delivery May 2015Rapid clearance of drugs from the body results in short therapeutic half-life and is an integral property of many protein and peptide-based drugs. To maintain the... (Review)
Review
INTRODUCTION
Rapid clearance of drugs from the body results in short therapeutic half-life and is an integral property of many protein and peptide-based drugs. To maintain the desired therapeutic effect patients are required to administer higher doses more frequently, which is inconvenient and risks undesirable side effects. Drug delivery technologies aim to minimise the number of administrations and dose-related toxicity while maximising therapeutic efficacy.
AREAS COVERED
This review describes albumin's inherent biochemical and biophysical properties, which make it an attractive drug delivery platform and the developmental status of drugs that are associated, conjugated or genetically fused with albumin. Albumin interacts with a number of cell surface receptors including gp18, gp30, gp60, FcRn, cubilin and megalin. The importance of albumin's interaction with the FcRn receptor, the basis for albumin's long circulatory half-life, is described, as are engineered albumins with improved pharmacokinetics. Albumin naturally accumulates at tumours and sites of inflammation, a characteristic which can be augmented by the addition of targeting ligands. The development of albumin drug conjugates which reply upon this property is described.
EXPERT OPINION
Albumin's inherent biochemical and biophysical properties make it an ideal drug delivery platform. Recent advances in our understanding of albumin physiology and the improvement in albumin-based therapies strongly suggest that albumin-based therapies have a significant advantage over alternative technologies in terms of half-life, stability, versatility, safety and ease of manufacture. Given the importance of the albumin:FcRn interaction, the interpretation of the pharmacokinetic and pharmacodynamic profiles of albumin-based therapeutics with disturbed albumin:FcRn interaction may have to be reassessed. The FcRn receptor has additional functionality, especially in relation to immunology, antigen presentation and delivery of proteins across mucosal membranes, consequently albumin-based fusions and conjugates may have a future role in oral and pulmonary-based vaccines and drug delivery.
Topics: Albumins; Animals; Drug Delivery Systems; Half-Life; Histocompatibility Antigens Class I; Humans; Pharmacokinetics; Receptors, Cell Surface; Receptors, Fc
PubMed: 25518870
DOI: 10.1517/17425247.2015.993313 -
Kidney360 Jun 2023
Topics: Adult; Humans; Nephrosis, Lipoid; Chronic Disease; Recurrence; Albumins
PubMed: 37384885
DOI: 10.34067/KID.0000000000000169 -
Kidney360 Jun 2023Albumin kinetics not only reflected the pathophysiology of minimal change nephrotic syndrome but was also a predictor of relapse. The high estimated 24-hour albumin...
KEY POINTS
Albumin kinetics not only reflected the pathophysiology of minimal change nephrotic syndrome but was also a predictor of relapse. The high estimated 24-hour albumin clearance predicts the minimal change nephrotic syndrome relapse. The 24-hour albumin clearance can easily be calculated from only serum albumin and urinary protein excretion, which are routine laboratory measurements.
BACKGROUND
Although albuminuria leakage that occurs in minimal change nephrotic syndrome (MCNS) may be related to the disease state, albumin kinetics in MCNS has never been evaluated. In this study, we investigated albumin kinetics in adult Japanese patients with MCNS by the estimated 24-hour albumin clearance (eC) and examined the association between eC and relapse.
METHODS
We retrospectively identified 103 adult patients with a histological diagnosis of MCNS from four hospitals in Japan (2010–2020). The primary outcome is the first relapse in 2 years after complete remission after corticosteroid therapy. The eC [l/min] was defined as (2.71828 [g/24 hours])/(serum albumin [g/dl]×1440 [min/24 hours]) for women and (2.71828 [g/24 hours])/(serum albumin [g/dl]×1440 [min/24 hours]) for men.
RESULTS
Relapse was observed in 44 patients (103 kidney biopsy samples; 42.7%). The mean patient age was 41.0 years. Patients had an eGFR of 71.0 ml/min per 1.73 m, urinary protein excretion of 6.8 g/d, serum albumin of 1.4 g/dl, and eC of 2.27 l/min. eC was strongly associated with hypoalbuminemia, severe proteinuria, lipid abnormalities, and coagulopathy. In the multivariable analysis, a high eC was significantly associated with relapse after adjusting for age, eGFR, time to complete remission, and urinary protein excretion (adjusted hazard ratio, 5.027; 95% confidence interval, 1.88 to 13.47; = 0.001).
CONCLUSIONS
This study revealed that eC, which could substitute albumin kinetics, reflected the severity of MCNS, and a high eC was associated with recurrence.
Topics: Humans; Nephrosis, Lipoid; Kidney Function Tests; Nephrotic Syndrome; Chronic Disease; Albumins; Recurrence
PubMed: 37166949
DOI: 10.34067/KID.0000000000000143 -
Pharmacology & Therapeutics Jan 2022The accuracy in predicting in vivo hepatic clearance of drugs from in vitro data (often termed as in vitro-to-in vivo extrapolation, IVIVE) has improved in part by... (Review)
Review
The accuracy in predicting in vivo hepatic clearance of drugs from in vitro data (often termed as in vitro-to-in vivo extrapolation, IVIVE) has improved in part by applying the extended-clearance concept that considers the interplay between hepatic metabolism and uptake/efflux processes. However, the IVIVE-based prediction performs poorly in predicting the hepatic uptake clearance of highly albumin-bound anionic drugs. Their hepatic uptake clearances tend to be much higher than expected based on the free-drug theory. Such observation can be attributable to a phenomenon called albumin-mediated hepatic uptake, for which various models have been thus far proposed. Our group has been applying a facilitated-dissociation model, which assumes the enhanced dissociation of the drug-albumin complex upon interaction with the cell surface. By considering the albumin-mediated hepatic uptake (using the facilitated-dissociation model or alternative kinetic models), a number of investigations demonstrated the improvement in the prediction accuracy for the hepatic clearance of highly protein-bound anionic drugs that are substrates for hepatic uptake transporters. This review summarizes the reported kinetic analyses of the albumin-mediated hepatic uptake of highly albumin-bound drugs concerning the IVIVE and the clinical and physiological relevance.
Topics: Albumins; Hepatocytes; Humans; Liver; Metabolic Clearance Rate; Models, Biological; Organic Anion Transporters; Pharmaceutical Preparations
PubMed: 34171335
DOI: 10.1016/j.pharmthera.2021.107938 -
Journal of Nuclear Medicine : Official... Jun 2022Fibroblast activation protein (FAP) has become an attractive target for diagnosis and therapy, and a series of FAP inhibitor (FAPI)-based radiotracers has been developed...
Fibroblast activation protein (FAP) has become an attractive target for diagnosis and therapy, and a series of FAP inhibitor (FAPI)-based radiotracers has been developed and had excellent performance for diagnosis outcomes in clinical applications. Yet, their fast clearance and insufficient tumor retention have hampered their further clinical application in cancer treatment. In this study, we developed 2 albumin binder-conjugated FAPI radiotracers, TEFAPI-06 and TEFAPI-07. They were derived from FAPI-04 and were optimized by conjugating 2 types of well-studied albumin binders, 4-(-iodophenyl) butyric acid moiety (TEFAPI-06) and truncated Evans blue moiety (TEFAPI-07), to try to overcome the above limitations at the expense of prolonging the blood circulation. TEFAPI-06 and TEFAPI-07 were synthesized and labeled with Ga, Y, and Lu successfully. A series of cell assays was performed to identify the binding affinity and FAP specificity in vitro. PET imaging, SPECT imaging, and biodistribution studies were performed to evaluate the pharmacokinetics in pancreatic cancer patient-derived xenograft (PDX) animal models. The cancer treatment efficacy of Lu-TEFAPI-06 and Lu-TEFAPI-07 were evaluated in pancreatic cancer PDX-bearing mice. The binding affinities (dissociation constants) to FAP of Ga-TEFAPI-06 and Ga-TEFAPI-07 were 10.16 ± 2.56 nM and 7.81 ± 2.28 nM, respectively, which were comparable with that of Ga-FAPI-04. Comparative PET imaging of HT-1080-FAP and HT-1080 tumor-bearing mice and a blocking study showed the FAP-targeting ability in vivo of these 2 tracers. Compared with Lu-FAPI-04, PET imaging, SPECT imaging, and biodistribution studies of TEFAPI-06 and TEFAPI-07 demonstrated their remarkably enhanced tumor accumulation and retention, respectively. Notable tumor growth inhibition by Lu-TEFAPI-06 and Lu-TEFAPI-07 were observed, whereas the control group and the group treated by Lu-FAPI-04 showed a slight therapeutic effect. Two albumin binder-conjugated FAPI radiopharmaceuticals have been developed and evaluated in vitro and in vivo. Significantly improved tumor uptake and retention were observed, compared with the original FAPI tracer. Both Lu-TEFAPI-06 and Lu-TEFAPI-07 showed remarkable growth inhibition of PDX tumors, whereas the side effects were almost negligible, demonstrating that these radiopharmaceuticals are promising for further clinical translational studies.
Topics: Albumins; Animals; Cell Line, Tumor; Endopeptidases; Fibroblasts; Gallium Radioisotopes; Humans; Membrane Proteins; Mice; Pancreatic Neoplasms; Radiopharmaceuticals; Tissue Distribution
PubMed: 34593598
DOI: 10.2967/jnumed.121.262533 -
Journal of Hepatology Sep 2022The choice of resuscitation fluid in patients with cirrhosis and sepsis-induced hypotension is unclear. 5% albumin was superior to normal saline in the FRISC study. We... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND & AIMS
The choice of resuscitation fluid in patients with cirrhosis and sepsis-induced hypotension is unclear. 5% albumin was superior to normal saline in the FRISC study. We compared the efficacy and safety of 20% albumin, which has greater oncotic properties, to plasmalyte in reversing sepsis-induced hypotension.
METHODS
Critically ill patients with cirrhosis underwent open-label randomization to receive either 20% albumin (0.5-1.0 g/kg over 3 hours; n = 50) or plasmalyte (30 ml/kg over 3 hours, n = 50). The primary endpoint of the study was the attainment of mean arterial pressure (MAP) above 65 mmHg at 3 hours.
RESULTS
Baseline characteristics were comparable in albumin and plasmalyte groups; arterial lactate (6.16±3.18 mmol/L vs. 6.38±4.77 mmol/L; p = 0.78), MAP (51.4±6.52 mmHg vs. 49.9±4.45 mmHg; p = 0.17) and SOFA score (10.8±2.96 vs. 11.1±4.2; p = 0.68), respectively. Most patients were alcoholics (39%) and had pneumonia (40%). In the intention-to-treat analysis, albumin was superior to plasmalyte in achieving the primary endpoint (62% vs. 22%; p <0.001). A faster decline in arterial lactate (p = 0.03), a reduced need for dialysis (48% vs. 62%; p = 0.16), and a longer time to initiation of dialysis (in hours) (68.13±47.79 vs. 99.7± 63.4; p = 0.06) were seen with albumin. However, the 28-day mortality rate was not different (58% vs. 62%, p = 0.57) and treatment had to be discontinued in 11 (22%) patients in the albumin group due to adverse effects compared to no discontinuations in the plasmalyte group.
CONCLUSION
In patients with cirrhosis and sepsis-induced hypotension, 20% albumin leads to a faster improvement in hemodynamics and lactate clearance than plasmalyte, while 28-day survival was similar. However, patients on 20% albumin need to be closely monitored as it was more often associated with pulmonary complications.
CLINICAL TRIAL REGISTRATION
NCT02721238.
LAY SUMMARY
The current randomized-controlled trial performed in critically ill patients with cirrhosis and sepsis-induced hypotension highlights that 20% albumin restores arterial pressure more quickly but causes more pulmonary complications than plasmalyte. The impact on renal functions was also modest. These effects did not result in improvement in survival at 28 days. Plasmalyte is safer and well-tolerated and can be considered for volume resuscitation in patients with cirrhosis and sepsis-induced hypotension.
Topics: Albumins; Critical Illness; Electrolytes; Fluid Therapy; Humans; Hypotension, Controlled; Lactic Acid; Liver Cirrhosis; Sepsis; Shock, Septic
PubMed: 35460725
DOI: 10.1016/j.jhep.2022.03.043 -
Expert Opinion on Drug Metabolism &... Aug 2019: In quantitative modeling, the resolving of underpredictions and overpredictions of hepatic clearance (CLh) makes a top priority for pharmacokinetic modelers. Clearly,... (Review)
Review
The potential protein-mediated hepatic uptake: discussion on the molecular interactions between albumin and the hepatocyte cell surface and their implications for the in vitro-to-in vivo extrapolations of hepatic clearance of drugs.
: In quantitative modeling, the resolving of underpredictions and overpredictions of hepatic clearance (CLh) makes a top priority for pharmacokinetic modelers. Clearly, the 'protein-mediated hepatic uptake' is a violation of 'the free drug hypothesis', but the lack of its consideration in CLh-predictive approaches may be one of the reasons to explain the discrepancies between predicted and observed values. : We first review the two 'albumin-facilitated hepatic uptake' models that were recently challenged to improve the extrapolation (IVIVE) of CLh by reducing the underprediction bias, particularly in the absence of albumin (ALB) compared to the presence of ALB . Second, we identify three types of interactions related to the ALB-bound drug moiety (i.e., ALB-lipids, ALB-proteins, and ALB-ligand allosteric interactions) that may be behind the 'ALB-mediated hepatic uptake' mechanism(s) for highly bound drugs. Main keywords used in our search are IVIVE; albumin; allostery; protein-mediated uptake; hepatic clearance; polarized hepatocytes. : Understanding the implication of these interactions and the enzyme/transporter interplay for each drug would help selecting the appropriate IVIVE model. Therefore, we have proposed a tree of decision for guidance. The next step is to improve the 'ALB-facilitated hepatic uptake' models to cover the remaining uncertainties.
Topics: Albumins; Biological Transport; Hepatocytes; Humans; Lipids; Liver; Models, Biological; Pharmaceutical Preparations; Pharmacokinetics; Protein Binding; Proteins
PubMed: 31274340
DOI: 10.1080/17425255.2019.1640679 -
Antimicrobial Agents and Chemotherapy Jun 2022The objective of this study was to describe the total and unbound population pharmacokinetics of ceftriaxone in critically ill adult patients and to define optimized...
The objective of this study was to describe the total and unbound population pharmacokinetics of ceftriaxone in critically ill adult patients and to define optimized dosing regimens. Total and unbound ceftriaxone concentrations were obtained from two pharmacokinetic studies and from a therapeutic drug monitoring (TDM) program at a tertiary hospital intensive care unit. Population pharmacokinetic analysis and Monte Carlo simulations were used to assess the probability of achieving a free trough concentration/MIC ratio of ≥1 using Pmetrics for R. A total of 474 samples (267 total and 207 unbound) were available from 36 patients. A two-compartment model describing ceftriaxone-albumin binding with both nonrenal and renal elimination incorporating creatinine clearance to explain the between-patient variability best described the data. An albumin concentration of ≤20 g/L decreased the probability of target attainment (PTA) by up to 20% across different dosing regimens and simulated creatinine clearances. A ceftriaxone dose of 1 g twice daily is likely therapeutic in patients with creatinine clearance of <100 mL/min infected with susceptible isolates (PTA, ~90%). Higher doses administered as a continuous infusion (4 g/day) are needed in patients with augmented renal clearance (creatinine clearance, >130 mL/min) who are infected by pathogens with a MIC of ≥0.5 mg/L. The ceftriaxone dose should be based on the patient's renal function and albumin concentration, as well as the isolate MIC. Hypoalbuminemia decreases the PTA in patients receiving intermittent dosing by up to 20%.
Topics: Adult; Albumins; Anti-Bacterial Agents; Ceftriaxone; Creatinine; Critical Illness; Humans; Microbial Sensitivity Tests; Monte Carlo Method
PubMed: 35575578
DOI: 10.1128/aac.02189-21 -
Brain Research Sep 2011Ultrasound-mediated opening of the blood-brain barrier (BBB) in the presence of gas-filled microbubbles is a potential strategy for drug delivery across the blood-brain...
Ultrasound-mediated opening of the blood-brain barrier (BBB) in the presence of gas-filled microbubbles is a potential strategy for drug delivery across the blood-brain barrier to promote regeneration after ischemic stroke. However, related bioeffects and potential side-effects that could limit a translation into clinical application are poorly understood so far. We therefore examined the clearance of extravasated albumin following ultrasound-mediated BBB opening. Autofluorescence of albumin-bound Evans Blue dye indicated cellular albumin uptake as soon as 30min after insonation (2±0.72 cells/optical field). Cellular albumin uptake increased constantly over 24h (22±3.33 cells/optical field, p<0.05). Initially, the majority of albumin-positive cells were located in the periphery of brain capillaries. Most albumin phagocyting cells stained positive for CD163 and Iba-1, identifying them as activated microglia. Further, a small fraction of albumin-positive cells stained positive for the astroglial markers GFAP/S100B. Some perivascular cells with intracellular albumin were shown to express the endothelial marker protein EN4. Albumin uptaking cells stained negative for the neuronal TubulinIII. Thus, ultrasound-induced BBB opening leads to albumin extravasation which is phagocytized predominantly by activated microglia, astrocytes and endothelial cells. As albumin uptake into neurons has been shown to be neurotoxic, rapid albumin clearance by microglia might prevent neuronal cell death.
Topics: Albumins; Animals; Blood-Brain Barrier; Coloring Agents; Contrast Media; Evans Blue; Fluorescent Antibody Technique; Functional Laterality; Male; Microscopy, Confocal; Nerve Tissue Proteins; Neuroglia; Neurons; Phagocytosis; Rats; Rats, Wistar; Ultrasonics
PubMed: 21820103
DOI: 10.1016/j.brainres.2011.07.006 -
European Journal of Gastroenterology &... Sep 2023Serum biomarkers for predicting HBeAg clearance in patients with chronic hepatitis B (CHB) virus infection during antiviral therapy remain lacking. This study aimed to...
BACKGROUND
Serum biomarkers for predicting HBeAg clearance in patients with chronic hepatitis B (CHB) virus infection during antiviral therapy remain lacking. This study aimed to investigate baseline albumin-bilirubin (ALBI) score for assessing HBeAg clearance in HBeAg-positive CHB patients treated with nucleos(t)ide analogues (NAs).
METHODS
Six hundred and ninety-nine HBeAg-positive CHB patients treated with first-line NAs were retrospectively included. Kaplan-Meier curves were used to compare the possibility of HBeAg clearance and HBeAg seroconversion in different ALBI groups. Cox regression models were used to identify factors associated with HBeAg clearance and HBeAg seroconversion.
RESULTS
Of the patients, 69.8% were male, with a median age of 36.0 years. 174 (24.9%) patients achieved HBeAg clearance after a median of 92.0 (interquartile range 48.0-134.0) weeks of antiviral treatment and 108 (15.5%) patients achieved HBeAg seroconversion. 74.0% and 26.0% of patients were classified as ALBI grade 1 and ALBI grade 2-3, respectively. ALBI grade 2-3 was identified as an independent predictor of HBeAg clearance (hazard ratio 1.570, 95% confidence interval 1.071-2.301, P = 0.021). The cumulative incidence of HBeAg clearance and HBeAg seroconversion was significantly higher in ALBI grade 2-3 group than group of ALBI grade 1 ( P < 0.001). Similar results were observed in different subgroups with different antiviral drugs, cirrhosis status, and ALT levels.
CONCLUSION
Baseline ALBI score may be a valuable indicator for predicting antiviral response in HBeAg-positive CHB patients treated with NAs.
Topics: Humans; Male; Adult; Female; Hepatitis B e Antigens; Hepatitis B, Chronic; Bilirubin; Retrospective Studies; Treatment Outcome; Antiviral Agents; Albumins; Hepatitis B virus; DNA, Viral
PubMed: 37395182
DOI: 10.1097/MEG.0000000000002598