ABSTRACT
Sulfurized polyacrylonitrile (SPAN) recently emerges as a promising cathode for high-energy lithium (Li) metal batteries owing to its high capacity, extended cycle life, and liberty from costly transition metals. As the high capacities of both Li metal and SPAN lead to relatively small electrode weights, the weight and specific energy density of Li/SPAN batteries are particularly sensitive to electrolyte weight, highlighting the importance of minimizing electrolyte density. Besides, the large volume changes of Li metal anode and SPAN cathode require inorganic-rich interphases that can guarantee intactness and protectivity throughout long cycles. This work addresses these crucial aspects with an electrolyte design where lightweight dibutyl ether (DBE) is used as a diluent for concentrated lithium bis(fluorosulfonyl)imide (LiFSI)-triethyl phosphate (TEP) solution. The designed electrolyte (d = 1.04 g mL-1) is 40%-50% lighter than conventional localized high-concentration electrolytes (LHCEs), leading to 12%-20% extra energy density at the cell level. Besides, the use of DBE introduces substantial solvent-diluent affinity, resulting in a unique solvation structure with strengthened capability to form favorable anion-derived inorganic-rich interphases, minimize electrolyte consumption, and improve cell cyclability. The electrolyte also exhibits low volatility and offers good protection to both Li metal anode and SPAN cathode under thermal abuse.
ABSTRACT
Sodium (Na)-metal batteries (SMBs) are considered one of the most promising candidates for the large-scale energy storage market owing to their high theoretical capacity (1,166 mAh g-1) and the abundance of Na raw material. However, the limited stability of electrolytes still hindered the application of SMBs. Herein, sulfolane (Sul) and vinylene carbonate (VC) are identified as effective dual additives that can largely stabilize propylene carbonate (PC)-based electrolytes, prevent dendrite growth, and extend the cycle life of SMBs. The cycling stability of the Na/NaNi0.68Mn0.22Co0.1O2 (NaNMC) cell with this dual-additive electrolyte is remarkably enhanced, with a capacity retention of 94% and a Coulombic efficiency (CE) of 99.9% over 600 cycles at a 5 C (750 mA g-1) rate. The superior cycling performance of the cells can be attributed to the homogenous, dense, and thin hybrid solid electrolyte interphase consisting of F- and S-containing species on the surface of both the Na metal anode and the NaNMC cathode by adding dual additives. Such unique interphases can effectively facilitate Na-ion transport kinetics and avoid electrolyte depletion during repeated cycling at a very high rate of 5 C. This electrolyte design is believed to result in further improvements in the performance of SMBs.
ABSTRACT
BACKGROUND: There are several types of benign renal diseases, such as urological stones, ureteropelvic junction obstruction, renal vascular disease, and inflammation, which are responsible for nonfunctioning kidneys. Laparoscopic nephrectomy (LN) is the gold standard for treating nonfunctioning kidneys with complications. This study presents the results of our initial experiences with 3D laparoscopic nephrectomy (3D-LN) for benign, nonfunctioning kidneys. METHODS: From July 2021 to July 2023, 40 consecutive patients who underwent 3D transperitoneal laparoscopic nephrectomy were retrospectively evaluated at the Department of Urology and Department of General Surgery, Hue Central Hospital, Hue, Vietnam. Patient demographics, intraoperative and early postoperative results, postoperative recovery, complications, and three-month follow-up results were recorded. RESULTS: The mean age was 58.35 ± 14.9 years. There were 13 (32.5%) male and 27 (67.5%) female patients. Flank pain was the main reason for hospitalization in 33 cases (82.5%); the common cause of a nonfunctioning kidney was urological stones (62.5%). Twenty-three out of 40 patients underwent a left nephrectomy. The average operative time was 92.57 ± 28.69 minutes. A statistically significant difference in surgery time was found between the group with no adhesion and the group with mild adhesion, as well as between the first 19 patients and the last 18 patients (p <0.05). The mean blood loss was 51.62 ± 24.35 ml. Three cases were converted to open surgery due to severe adhesions. The postoperative complications rate was 8.1%. The average length of the postoperative hospital stay was 7.89 ± 3.59 days. CONCLUSIONS: Three-dimensional laparoscopic nephrectomy is a safe and effective method that increases depth perception and spatial orientation for surgeons and can compensate for the remaining shortcomings of traditional 2D systems.
ABSTRACT
Objective: Evaluation of the outcome of the miniaturized percutaneous nephrolithotomy in the treatment of nephrolithiasis with a lateral position based on the principle of a right triangle under the guidance of a C-Arm without contrast fluid. Materials and Methods: Sixty-nine cases of Mini-PCNL with the assistance of a vacuum-assisted sheath in the lateral position were performed at Central Hospital from March 2021 to August 2022. Percutaneous renal access was under the guidance of a non-rotational C-arm without contrast medium, and we determined the puncture location and depth of the needle based on the principle of right triangles. Results: The median age was 51.6 ± 12.5 years, and males accounted for 68.1% of the cases. 60.9% of all patients had normal weight. The median stone surface area was 361.1mm2, and 59.4% of all cases were graded as 2 regarding Guy's stone score. The successful renal access rate was 100%. The tunnel access from the middle and lower calyx accounted for 94.2%. The median access duration, fluoroscopy duration, and hospital length of stay were 271.7 seconds, 14.79 seconds, and 6.3 days, respectively. The complete stone clearance rate was 78.3%. Bleeding complications occurred in 2 patients without mortality. Three patients required an additional procedure. Conclusion: The puncture technique into the renal calyxes based on the principle of the right triangle under the guidance of a non-rotational C-Arm without contrast medium in PCNL is a fast, exact, and safe technique.
ABSTRACT
The pharmacokinetic (PK) characteristics of omalizumab and its pharmacodynamic (PD) effect in patients has yet to be fully characterized in chronic spontaneous urticaria, which could elucidate its pathogenesis and treatment response. This study has two objectives; (1) characterize the population PK of omalizumab and its PD effect on IgE, and (2) develop a drug effect model of omalizumab in urticaria (via change in weekly itch severity score). The target-mediated population of PK/PD model incorporating omalizumab-IgE binding and turnover adequately described PK and PD of omalizumab. The effect compartment model and linear drug effect and additive placebo response adequately described placebo and treatment effects of omalizumab. Several baseline covariates were identified for PK/PD and drug effect models. The developed model has the potential to aid in understanding variability in PK/PD as well as response to omalizumab treatment.
Subject(s)
Anti-Allergic Agents , Chronic Urticaria , Humans , Omalizumab/therapeutic use , Omalizumab/adverse effects , Anti-Allergic Agents/pharmacology , Anti-Allergic Agents/therapeutic use , Chronic Disease , Chronic Urticaria/drug therapy , Chronic Urticaria/chemically induced , Immunoglobulin E , Treatment OutcomeABSTRACT
Vorasidenib and ivosidenib inhibit mutant forms of isocitrate dehydrogenase (mIDH) and have shown preliminary clinical activity against mIDH glioma. We evaluated both agents in a perioperative phase 1 trial to explore the mechanism of action in recurrent low-grade glioma (IGG) and select a molecule for phase 3 testing. Primary end-point was concentration of D-2-hydroxyglutarate (2-HG), the metabolic product of mIDH enzymes, measured in tumor tissue from 49 patients with mIDH1-R132H nonenhancing gliomas following randomized treatment with vorasidenib (50 mg or 10 mg once daily, q.d.), ivosidenib (500 mg q.d. or 250 mg twice daily) or no treatment before surgery. Tumor 2-HG concentrations were reduced by 92.6% (95% credible interval (CrI), 76.1-97.6) and 91.1% (95% CrI, 72.0-97.0) in patients treated with vorasidenib 50 mg q.d. and ivosidenib 500 mg q.d., respectively. Both agents were well tolerated and follow-up is ongoing. In exploratory analyses, 2-HG reduction was associated with increased DNA 5-hydroxymethylcytosine, reversal of 'proneural' and 'stemness' gene expression signatures, decreased tumor cell proliferation and immune cell activation. Vorasidenib, which showed brain penetrance and more consistent 2-HG suppression than ivosidenib, was advanced to phase 3 testing in patients with mIDH LGGs. Funded by Agios Pharmaceuticals, Inc. and Servier Pharmaceuticals LLC; ClinicalTrials.gov number NCT03343197.
Subject(s)
Brain Neoplasms , Glioma , Humans , Pyridines/adverse effects , Isocitrate Dehydrogenase/genetics , Glioma/drug therapy , Glioma/genetics , Mutation/genetics , Pharmaceutical Preparations , Brain Neoplasms/drug therapy , Brain Neoplasms/geneticsABSTRACT
BACKGROUND: At the early stage of the pandemic, severe COVID-19 was thought to be rare among pregnant women. However, cumulating data showed that gestational state is a risk factor for severe pneumonia, particularly due to the hyperinflammatory state. Recent reports suggested the efficacy of pulse corticosteroids in stopping the cytokine storm in people infected with SARS-CoV-2, but limited data exists regarding its use in pregnant women. Moreover, pregnancy termination is a treatment option in this population, but it has been reported mainly in the third trimester and rarely in the second trimester. CASE PRESENTATION: A 37-year-old woman infected with SARS-CoV-2 at 23 weeks of gestation presented with fatigue and dyspnea but soon deteriorated to severely acute respiratory failure and cytokine storm requiring mechanical ventilation combined with hemodialysis just one day after hospitalization. Low-dose corticosteroids and antibiotics were initiated, followed by antiviral therapy, anticoagulant and high-dose corticosteroid therapy. On hospital day 3, a decision to terminate her pregnancy was made; termination led to significant improvement in her clinical condition and a gradual decrease in demand for oxygen supplementation as well as the corticosteroid dose. She was discharged two weeks after admission. CONCLUSIONS: Due to the specific immune response, pregnant women with COVID-19 may differ from others in their clinical presentation, especially the probability of classic acute respiratory distress syndrome (ARDS). This report provides evidence related to the efficacy of pulse corticosteroids on this group and the influence of the mid-trimester termination on recovery.
ABSTRACT
The development of sensitive and selective sensors using facile and low-cost methods for detecting neurotransmitter molecules is a critical factor in the health care system in regard to early diagnosis. In this research, an electrocatalyst derived from Mo,Zn dual-doped CuxO nanocrystals-based layer coating over one-dimensional copper nanowire arrays (Mo,Zn-CuxO/CuNWs) was successfully designed using a facile electrodeposition approach and used as an electrochemical sensor for non-enzymatic dopamine (DA) neurotransmitter detection. The synergistic effect caused by the dual-doping effect along with its excellent conductivity produced a large electroactive surface area and an improved hetero-charge transfer, thereby boosting DA sensing ability with a low limit detection of 0.32 µM, wide-range of detection (0.5 µM - 3.9 mM), long-term stability (5 weeks), and high selectivity in phosphate buffer solution (pH 7.4). Also, the sensor accurately determined DA in real blood serum-spiked solutions. The achieved results evidenced that the Mo,Zn-CuxO/CuNWs derived sensor is highly suitable for DA detection. Therefore, it also opens new windows for the development of low-cost, accurate, high-performance, and stable sensors for other neurotransmitter sensing for the purposes of better health care and early diagnosis.
Subject(s)
Electrochemical Techniques , Nanoparticles , Copper , Neurotransmitter Agents , ZincABSTRACT
PURPOSE: Lower grade gliomas (LGGs) are malignant brain tumors. Current therapy is associated with short- and long-term toxicity. Progression to higher tumor grade is associated with contrast enhancement on MRI. The majority of LGGs harbor mutations in the genes encoding isocitrate dehydrogenase 1 or 2 (IDH1/IDH2). Vorasidenib (AG-881) is a first-in-class, brain-penetrant, dual inhibitor of the mutant IDH1 and mutant IDH2 enzymes. PATIENTS AND METHODS: We conducted a multicenter, open-label, phase I, dose-escalation study of vorasidenib in 93 patients with mutant IDH1/2 (mIDH1/2) solid tumors, including 52 patients with glioma that had recurred or progressed following standard therapy. Vorasidenib was administered orally, once daily, in 28-day cycles until progression or unacceptable toxicity. Enrollment is complete; this trial is registered with ClinicalTrials.gov, NCT02481154. RESULTS: Vorasidenib showed a favorable safety profile in the glioma cohort. Dose-limiting toxicities of elevated transaminases occurred at doses ≥100 mg and were reversible. The protocol-defined objective response rate per Response Assessment in Neuro-Oncology criteria for LGG in patients with nonenhancing glioma was 18% (one partial response, three minor responses). The median progression-free survival was 36.8 months [95% confidence interval (CI), 11.2-40.8] for patients with nonenhancing glioma and 3.6 months (95% CI, 1.8-6.5) for patients with enhancing glioma. Exploratory evaluation of tumor volumes in patients with nonenhancing glioma showed sustained tumor shrinkage in multiple patients. CONCLUSIONS: Vorasidenib was well tolerated and showed preliminary antitumor activity in patients with recurrent or progressive nonenhancing mIDH LGG.
Subject(s)
Brain Neoplasms/drug therapy , Brain Neoplasms/genetics , Diamines/therapeutic use , Glioma/drug therapy , Glioma/genetics , Isocitrate Dehydrogenase/genetics , Mutation , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/genetics , Pyridines/therapeutic use , Adolescent , Adult , Aged , Brain Neoplasms/pathology , Disease Progression , Female , Glioma/pathology , Humans , Male , Middle Aged , Young AdultABSTRACT
Ivosidenib is a once daily (q.d.), orally available, potent mutant isocitrate dehydrogenase 1 (mIDH1) inhibitor approved for treatment of patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) and intensive chemotherapy ineligible AML with a susceptible IDH1 mutation. Population pharmacokinetics (PKs; N = 253), exposure-response (efficacy [n = 201] and safety [n = 253]), and concentration-corrected electrocardiogram QT interval (QTc; n = 171) analyses were performed using phase I data (100 mg twice daily and 300-1200 mg q.d.). Ivosidenib disposition was well-described by a two-compartment PK model with first-order absorption and elimination. Between-subject variability was moderate for PK parameters. Intrinsic factors did not affect ivosidenib PKs. Moderate/strong CYP3A4 inhibitors increased the area under the plasma ivosidenib concentration-time curve at steady state (AUCss ) by 60%. Efficacy responders and nonresponders had similar ivosidenib exposures. Based on AUCss , there was no apparent relationship between ivosidenib exposure and efficacy or adverse events. The plasma ivosidenib concentration-QT analysis showed a mean change in QTc using Fridericia's method (ΔQTcF) of 17.2 msec at the approved 500 mg q.d. dose. Because of the direct association between ivosidenib exposure and QTcF, patients should have their electrocardiograms and electrolytes monitored, and comedications that increase ivosidenib exposure or prolong the QT interval should be avoided. These model-based analyses quantitatively provide a framework to describe the relationship among ivosidenib dose, exposure, and clinical end points. With precautions for QTc prolongation, the exposure-response analyses support the 500 mg q.d. dose in patients with AML with a susceptible IDH1 mutation.
Subject(s)
Antineoplastic Agents/pharmacokinetics , Glycine/analogs & derivatives , Isocitrate Dehydrogenase/antagonists & inhibitors , Leukemia, Myeloid, Acute/drug therapy , Long QT Syndrome/diagnosis , Pyridines/pharmacokinetics , Administration, Oral , Adolescent , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Area Under Curve , Biological Variation, Population , Cytochrome P-450 CYP3A/metabolism , Cytochrome P-450 CYP3A Inhibitors/administration & dosage , Cytochrome P-450 CYP3A Inhibitors/pharmacokinetics , Drug Interactions , Electrocardiography , Female , Glycine/administration & dosage , Glycine/adverse effects , Glycine/pharmacokinetics , Humans , Isocitrate Dehydrogenase/genetics , Leukemia, Myeloid, Acute/blood , Leukemia, Myeloid, Acute/genetics , Long QT Syndrome/chemically induced , Male , Middle Aged , Models, Biological , Mutation , Pyridines/administration & dosage , Pyridines/adverse effects , Tissue Distribution , Treatment Outcome , Young AdultABSTRACT
PURPOSE: Develop a physiologically based pharmacokinetic (PBPK) model of ivosidenib using in vitro and clinical PK data from healthy participants (HPs), refine it with clinical data on ivosidenib co-administered with itraconazole, and develop a model for patients with acute myeloid leukemia (AML) and apply it to predict ivosidenib drug-drug interactions (DDI). METHODS: An HP PBPK model was developed in Simcyp Population-Based Simulator (version 15.1), with the CYP3A4 component refined based on a clinical DDI study. A separate model accounting for the reduced apparent oral clearance in patients with AML was used to assess the DDI potential of ivosidenib as the victim of CYP3A perpetrators. RESULTS: For a single 250 mg ivosidenib dose, the HP model predicted geometric mean ratios of 2.14 (plasma area under concentration-time curve, to infinity [AUC0-∞]) and 1.04 (maximum plasma concentration [Cmax]) with the strong CYP3A4 inhibitor, itraconazole, within 1.26-fold of the observed values (2.69 and 1.0, respectively). The AML model reasonably predicted the observed ivosidenib concentration-time profiles across all dose levels in patients. Predicted ivosidenib geometric mean steady-state AUC0-∞ and Cmax ratios were 3.23 and 2.26 with ketoconazole, and 1.90 and 1.52 with fluconazole, respectively. Co-administration of the strong CYP3A4 inducer, rifampin, predicted a greater DDI effect on a single dose of ivosidenib than on multiple doses (AUC ratios 0.35 and 0.67, Cmax ratios 0.91 and 0.81, respectively). CONCLUSION: Potentially clinically relevant DDI effects with CYP3A4 inducers and moderate and strong inhibitors co-administered with ivosidenib were predicted. Considering the challenges of conducting clinical DDI studies in patients, this PBPK approach is valuable in ivosidenib DDI risk assessment and management.
Subject(s)
Antineoplastic Agents/pharmacokinetics , Cytochrome P-450 CYP3A Inducers/pharmacokinetics , Cytochrome P-450 CYP3A Inhibitors/pharmacokinetics , Itraconazole/pharmacokinetics , Leukemia, Myeloid, Acute/drug therapy , Administration, Oral , Antineoplastic Agents/administration & dosage , Area Under Curve , Computer Simulation , Cytochrome P-450 CYP3A/metabolism , Cytochrome P-450 CYP3A Inducers/administration & dosage , Cytochrome P-450 CYP3A Inhibitors/administration & dosage , Drug Interactions , Female , Fluconazole/administration & dosage , Fluconazole/pharmacokinetics , Glycine/administration & dosage , Glycine/analogs & derivatives , Glycine/pharmacokinetics , Healthy Volunteers , Humans , Itraconazole/administration & dosage , Ketoconazole/administration & dosage , Ketoconazole/pharmacokinetics , Male , Microsomes, Liver , Models, Biological , Pyridines/administration & dosage , Pyridines/pharmacokinetics , Rifampin/administration & dosage , Rifampin/pharmacokineticsABSTRACT
Quantitative systems pharmacology (QSP) approaches have been increasingly applied in the pharmaceutical since the landmark white paper published in 2011 by a National Institutes of Health working group brought attention to the discipline. In this perspective, we discuss QSP in the context of other modeling approaches and highlight the impact of QSP across various stages of drug development and therapeutic areas. We discuss challenges to the field as well as future opportunities.
Subject(s)
Drug Discovery/methods , Systems Biology/methods , Humans , Models, Biological , Research DesignABSTRACT
: This paper analyzes the nonlinear buckling and post-buckling characteristics of the porous eccentrically stiffened functionally graded sandwich truncated conical shells resting on the Pasternak elastic foundation subjected to axial compressive loads. The core layer is made of a porous material (metal foam) characterized by a porosity coefficient which influences the physical properties of the shells in the form of a harmonic function in the shell's thickness direction. The physical properties of the functionally graded (FG) coatings and stiffeners depend on the volume fractions of the constituents which play the role of the exponent in the exponential function of the thickness direction coordinate axis. The classical shell theory and the smeared stiffeners technique are applied to derive the governing equations taking the von Kármán geometrical nonlinearity into account. Based on the displacement approach, the explicit expressions of the critical buckling load and the post-buckling load-deflection curves for the sandwich truncated conical shells with simply supported edge conditions are obtained by applying the Galerkin method. The effects of material properties, core layer thickness, number of stiffeners, dimensional parameters, semi vertex angle and elastic foundation on buckling and post-buckling behaviors of the shell are investigated. The obtained results are validated by comparing with those in the literature.
ABSTRACT
A cross-industry survey was conducted to assess the landscape of preclinical quantitative systems pharmacology (QSP) modeling within pharmaceutical companies. This article presents the survey results, which provide insights on the current state of preclinical QSP modeling in addition to future opportunities. Our results call attention to the need for an aligned definition and consistent terminology around QSP, yet highlight the broad applicability and benefits preclinical QSP modeling is currently delivering.
Subject(s)
Drug Discovery/methods , Drug Evaluation, Preclinical/standards , Pharmacology, Clinical/methods , Drug Design , Drug Discovery/standards , Drug Industry , Humans , Models, Biological , Pharmacology, Clinical/standards , Surveys and QuestionnairesABSTRACT
Geographic atrophy is an advanced form of age-related macular degeneration (AMD) and a leading cause of vision loss for which there are no approved treatments. Genetic studies in AMD patients have implicated dysregulation of the alternative complement pathway in the pathogenesis of geographic atrophy. Lampalizumab is a potential therapeutic that targets complement factor D, a pivotal activator of the alternative complement pathway. The MAHALO phase 2 clinical trial was a multicenter, randomized, controlled study that evaluated lampalizumab administered by intravitreal injection monthly (n = 42) and every other month (n = 41) versus sham control (n = 40) in patients with geographic atrophy secondary to AMD. The primary endpoint was the mean change in lesion area from baseline to month 18 as measured by fundus autofluorescence. Specific AMD-associated genetic polymorphisms were also analyzed. The MAHALO study met its primary efficacy endpoint with an acceptable safety profile; monthly lampalizumab treatment demonstrated a 20% reduction in lesion area progression versus sham control [80% confidence interval (CI), 4 to 37%]. A more substantial monthly treatment benefit of 44% reduction in geographic atrophy area progression versus sham control (95% CI, 15 to 73%) was observed in a subgroup of complement factor I (CFI) risk-allele carriers (57% of the patients analyzed were CFI risk-allele carriers). The MAHALO study shows a potential treatment effect in patients with geographic atrophy and supports therapeutic targeting of the alternative complement pathway for treating AMD pathogenesis.
Subject(s)
Geographic Atrophy/drug therapy , Geographic Atrophy/metabolism , Immunoglobulin Fab Fragments/therapeutic use , Macular Degeneration/drug therapy , Macular Degeneration/metabolism , Aged , Complement Factor D/antagonists & inhibitors , Complement Factor D/metabolism , Complement Pathway, Alternative , Disease Progression , Female , Geographic Atrophy/pathology , Humans , Macular Degeneration/pathology , Male , Middle AgedABSTRACT
PURPOSE: To evaluate the systemic pharmacokinetics (PKs) of aflibercept, bevacizumab, and ranibizumab in patients with neovascular age-related macular degeneration (AMD), diabetic macular edema (DME), or retinal vein occlusion (RVO). METHODS: Prospective, open-label, nonrandomized clinical trial of patients with AMD, DME, or RVO who were antivascular endothelial growth factor (VEGF) naïve or had not received anti-VEGF for ≥4 months. Patients received 3 monthly intravitreal injections of aflibercept 2.0 mg, bevacizumab 1.25 mg, or ranibizumab (0.5 mg for AMD/RVO, 0.3 mg for DME). The main outcome measures were serum PKs and plasma free-VEGF concentrations after the first and third injections. RESULTS: A total of 151 patients were included. In AMD/DME/RVO, systemic exposure to each drug was highest with bevacizumab, then aflibercept, and lowest with ranibizumab. Ranibizumab cleared from the bloodstream more quickly than bevacizumab or aflibercept. Aflibercept treatment resulted in the greatest reductions in plasma free-VEGF relative to baseline levels, whereas ranibizumab treatment resulted in the smallest decreases in plasma free-VEGF. CONCLUSION: The three anti-VEGF treatments examined in this analysis demonstrated notable differences in systemic PKs. Generally, the reduction in plasma free-VEGF levels correlated with elevated levels of circulating anti-VEGF agents, with the reduction in free-VEGF levels greatest with aflibercept and least with ranibizumab.
Subject(s)
Bevacizumab/pharmacokinetics , Diabetic Retinopathy/drug therapy , Macular Edema/drug therapy , Ranibizumab/pharmacokinetics , Recombinant Fusion Proteins/pharmacokinetics , Wet Macular Degeneration/drug therapy , Aged , Angiogenesis Inhibitors/administration & dosage , Angiogenesis Inhibitors/pharmacokinetics , Bevacizumab/administration & dosage , Diabetic Retinopathy/blood , Diabetic Retinopathy/complications , Enzyme-Linked Immunosorbent Assay , Female , Follow-Up Studies , Humans , Intravitreal Injections , Macular Edema/blood , Macular Edema/etiology , Male , Middle Aged , Prospective Studies , Ranibizumab/administration & dosage , Receptors, Vascular Endothelial Growth Factor/administration & dosage , Recombinant Fusion Proteins/administration & dosage , Vascular Endothelial Growth Factor A/antagonists & inhibitors , Vascular Endothelial Growth Factor A/blood , Wet Macular Degeneration/blood , Wet Macular Degeneration/diagnosisABSTRACT
Lampalizumab is an antigen-binding fragment of a humanized monoclonal antibody against complement factor D (CFD), a rate-limiting enzyme in the activation and amplification of the alternative complement pathway (ACP), which is in phase III clinical trials for the treatment of geographic atrophy. Understanding of the pharmacokinetics, pharmacodynamics, and biodistribution of lampalizumab following intravitreal administration in the ocular compartments and systemic circulation is limited but crucial for selecting doses that provide optimal efficacy and safety. Here, we sought to construct a semimechanistic and integrated ocular-systemic pharmacokinetic-pharmacodynamic model of lampalizumab in the cynomolgus monkey to provide a quantitative understanding of the ocular and systemic disposition of lampalizumab and CFD inhibition. The model takes into account target-mediated drug disposition, target turnover, and drug distribution across ocular tissues and systemic circulation. Following intravitreal administration, lampalizumab achieves rapid equilibration across ocular tissues. Lampalizumab ocular elimination is relatively slow, with a τ1/2 of approximately 3 days, whereas systemic elimination is rapid, with a τ1/2 of 0.8 hours. Target-independent linear clearance is predominant in the eye, whereas target-mediated clearance is predominant in the systemic circulation. Systemic CFD synthesis was estimated to be high (7.8 mg/day); however, the amount of CFD entering the eye due to influx from the systemic circulation was small (<10%) compared with the lampalizumab dose and is thus expected to have an insignificant impact on the clinical dose-regimen decision. Our findings support the clinical use of intravitreal lampalizumab to achieve significant ocular ACP inhibition while maintaining low systemic exposure and minimal systemic ACP inhibition.
Subject(s)
Antibodies, Monoclonal, Humanized/pharmacology , Complement Factor D/antagonists & inhibitors , Geographic Atrophy/metabolism , Immunoglobulin Fab Fragments/pharmacology , Administration, Intravenous , Animals , Antibodies, Monoclonal, Humanized/pharmacokinetics , Antibodies, Monoclonal, Humanized/therapeutic use , Aqueous Humor/metabolism , Female , Geographic Atrophy/drug therapy , Immunoglobulin Fab Fragments/therapeutic use , Intravitreal Injections , Macaca fascicularis , Male , Models, Biological , Retina/metabolism , Vitreous Body/metabolismABSTRACT
Anti-factor D (AFD; FCFD4514S, lampalizumab) is a humanized IgG Fab fragment directed against factor D (fD), a rate-limiting serine protease in the alternative complement pathway (AP). Evaluation of AFD as a potential intravitreal (IVT) therapeutic for dry age-related macular degeneration patients with geographic atrophy (GA) is ongoing. However, it is unclear whether IVT administration of AFD can affect systemic AP activation and potentially compromise host-immune responses. We characterized the pharmacologic properties of AFD and assessed the effects of AFD administered IVT (2 or 20 mg) or intravenous (0.2, 2, or 20 mg) on systemic complement activity in cynomolgus monkeys. For the IVT groups, serum AP activity was reduced for the 20 mg dose group between 2 and 6 hours postinjection. For the intravenous groups, AFD inhibited systemic AP activity for periods of time ranging from 5 minutes (0.2 mg group) to 3 hours (20 mg group). Interestingly, the concentrations of total serum fD increased up to 10-fold relative to predose levels following administration of AFD. Furthermore, AFD was found to inhibit systemic AP activity only when the molar concentration of AFD exceeded that of fD. This occurred in cynomolgus monkeys at serum AFD levels ≥2 µg/ml, a concentration 8-fold greater than the maximum serum concentration observed following a single 10 mg IVT dose in a clinical investigation in patients with GA. Based on these findings, the low levels of serum AFD resulting from IVT administration of a clinically relevant dose are not expected to appreciably affect systemic AP activity.
Subject(s)
Complement C3a/antagonists & inhibitors , Complement Factor D/antagonists & inhibitors , Immunoglobulin Fab Fragments/administration & dosage , Macular Degeneration/drug therapy , Animals , Cattle , Complement C3a/immunology , Complement Factor D/immunology , Dose-Response Relationship, Drug , Female , Humans , Immunoglobulin Fab Fragments/immunology , Intravitreal Injections , Macaca fascicularis , Macular Degeneration/blood , Macular Degeneration/immunology , Male , Mice , Treatment OutcomeABSTRACT
BACKGROUND: Data comparing systemic exposure and systemic vascular endothelial growth factor (VEGF) suppression of ranibizumab, bevacizumab and aflibercept following intravitreal injection are lacking. METHODS: Fifty-six patients with wet age-related macular degeneration received intravitreal ranibizumab (0.5â mg), bevacizumab (1.25â mg), or aflibercept (2.0â mg). Serum pharmacokinetics and plasma free VEGF were evaluated after the first and third injections. RESULTS: Following the first dose, systemic exposure to aflibercept was 5-, 37-, and 9-fold higher than ranibizumab, whereas, bevacizumab was 9-, 310-, and 35-fold higher than ranibizumab, based on geometric mean ratio of peak and trough concentrations and area under the curve, respectively. The third dose showed accumulation of bevacizumab and aflibercept but not ranibizumab. Aflibercept substantially suppressed plasma free VEGF, with mean levels below lower limit of quantitation (10â pg/mL) as early as 3â h postdose until ≥7â days postdose. Mean free (unbound) VEGF levels with ranibizumab were largely unchanged, with mean trough level of 14.4â pg/mL compared with baseline of 17â pg/mL. CONCLUSIONS: There are notable differences in systemic pharmacokinetics and pharmacodynamics among anti-VEGF treatments after intravitreal administration. All three agents rapidly moved into the bloodstream, but ranibizumab very quickly cleared, whereas bevacizumab and aflibercept demonstrated greater systemic exposure and produced a marked reduction in plasma free VEGF. TRIAL REGISTRATION NUMBER: NCT02118831.