Topical Solution for Retinal Delivery: Bevacizumab and Ranibizumab Eye Drops in Anti-Aggregation Formula (AAF) in Rabbits.

PURPOSE: Wet age-related macular degeneration (AMD) is a blinding retinal disease. Monthly intravitreal anti-VEGF antibody injections of bevacizumab (off-label) and ranibizumab (FDA approved) are the standard of care. Antibody aggregation may interfere with ocular absorption/distribution. This study assessed topical delivery of dilute antibodies to the posterior segment of rabbit eyes using a novel anti-aggregation formula (AAF). METHODS: Bevacizumab, or biosimilar ranibizumab was diluted to 5 mg/ml in AAF. All rabbits were dosed twice daily. Substudy 1 rabbits (bevacizumab, 100 µl eye drops): Group 1 (bevacizumab/AAF, n = 6); Group 2 (bevacizumab/PBS, n = 7) and Vehicle control (AAF, n = 1). Substudy 2 rabbits (ranibizumab biosimilar/AAF, 50 µl eye drops): (ranibizumab biosimilar/AAF, n = 8). At 14.5 days, serum was drawn from rabbits. Aqueous, vitreous and retina samples were recovered from eyes and placed into AAF aliquots. Tissue analyzed using AAF as diluent. RESULTS: Bevacizumab in AAF permeated/accumulated in rabbit aqueous, vitreous and retina 10 times more, than when diluted in PBS. AAF/0.1% hyaluronic acid eye drops, dosed twice daily, provided mean tissue concentrations (ng/g) in retina (29.50), aqueous (12.34), vitreous (3.46), and serum (0.28 ng/ml). Additionally, the highest concentration (ng/g) of ranibizumab biosimilar was present in the retina (18.0), followed by aqueous (7.82) and vitreous (1.47). Serum concentration was negligible (< 0.04 ng/ml). No irritation was observed throughout the studies. CONCLUSIONS: Bevacizumab and ranibizumab, in an AAF diluent eye drop, can be delivered to the retina, by the twice daily dosing of a low concentration mAb formulation. This may prove to be an adjunct to intravitreal injections.

Therapeutic Drug Monitoring of Pazopanib in Renal Cell Carcinoma and Soft Tissue Sarcoma: A Systematic Review.

BACKGROUND: Pazopanib, an anti-angiogenic multitarget tyrosine kinase inhibitor, has been approved for the treatment of metastatic renal cell carcinoma and soft tissue sarcoma. However, its recommended dose does not always produce consistent outcomes, with some patients experiencing adverse effects or toxicity. This variability is due to differences in the systemic exposure to pazopanib. This review aimed to establish whether sufficient evidence exists for the routine or selective therapeutic drug monitoring of pazopanib in adult patients with approved indications. METHODS: A systematic search of the PubMed and Web of Science databases using search terms related to pazopanib and therapeutic drug monitoring yielded 186 and 275 articles, respectively. Ten articles associated with treatment outcomes or toxicity due to drug exposure were selected for review. RESULTS: The included studies were evaluated to determine the significance of the relationship between drug exposure/Ctrough and treatment outcomes and between drug exposure and toxicity. A relationship between exposure and treatment outcomes was observed in 5 studies, whereas the trend was nonsignificant in 4 studies. A relationship between exposure and toxicity was observed in 6 studies, whereas 2 studies did not find a significant relationship; significance was not reported in 3 studies. CONCLUSIONS: Sufficient evidence supports the therapeutic drug monitoring of pazopanib in adult patients to improve its efficacy and/or safety in the approved indications.

Efficacy and Safety of Biosimilar FYB201 Compared with Ranibizumab in Neovascular Age-Related Macular Degeneration.

PURPOSE: This trial was conducted to investigate the clinical equivalence of the proposed biosimilar FYB201 and reference ranibizumab in patients with treatment-naive, subfoveal choroidal neovascularization caused by neovascular age-related macular degeneration (nAMD). DESIGN: This was a prospective, multicenter, evaluation-masked, parallel-group, 48-week, phase III randomized study. PARTICIPANTS: A total of 477 patients were randomly assigned to receive FYB201 (n = 238) or reference ranibizumab (n = 239). METHODS: Patients received FYB201 or reference ranibizumab 0.5 mg by intravitreal (IVT) injection in the study eye every 4 weeks. MAIN OUTCOME MEASURES: The primary end point was change from baseline in best-corrected visual acuity (BCVA) by Early Treatment Diabetic Retinopathy Study (ETDRS) letters at 8 weeks before the third monthly IVT injection. Biosimilarity of FYB201 to its originator was assessed via a 2-sided equivalence test, with an equivalence margin in BCVA of 3 ETDRS letters. RESULTS: The BCVA improved in both groups, with a mean improvement of +5.1 (FYB201) and +5.6 (reference ranibizumab) ETDRS letters at week 8. The analysis of covariance (ANCOVA) least squares mean difference for the change from baseline between FYB201 and reference ranibizumab was -0.4 ETDRS letters with a 90% confidence interval (CI) of -1.6 to 0.9. Primary end point was met as the 90% CI was within the predefined equivalence margin. Adverse events were comparable between treatment groups. CONCLUSIONS: FYB201 is biosimilar to reference ranibizumab in terms of clinical efficacy and ocular and systemic safety in the treatment of patients with nAMD.

Addition of an Fc-IgG induces receptor clustering and increases the in vitro efficacy and in vivo anti-tumor properties of the thrombospondin-1 type I repeats (3TSR) in a mouse model of advanced stage ovarian cancer.

OBJECTIVES: Tumor vasculature is structurally abnormal, with anatomical deformities, reduced pericyte coverage and low tissue perfusion. As a result of this vascular dysfunction, tumors are often hypoxic, which is associated with an aggressive tumor phenotype, and reduced delivery of therapeutic compounds to the tumor. We have previously shown that a peptide containing the thrombospondin-1 type I repeats (3TSR) specifically targets tumor vessels and induces vascular normalization in a mouse model of epithelial ovarian cancer (EOC). However, due to its small size, 3TSR is rapidly cleared from circulation. We now introduce a novel construct with the 3TSR peptide fused to the C-terminus of each of the two heavy chains of the Fc region of human IgG1 (Fc3TSR). We hypothesize that Fc3TSR will have greater anti-tumor activity in vitro and in vivo compared to the native compound. METHODS: Fc3TSR was evaluated in vitro using proliferation and apoptosis assays to investigate differences in efficacy compared to native 3TSR. In light of the multivalency of Fc3TSR, we also investigate whether it induces greater clustering of its functional receptor, CD36. We also compare the compounds in vivo using an orthotopic, syngeneic mouse model of advanced stage EOC. The impact of the two compounds on changes to tumor vasculature morphology was also investigated. RESULTS: Fc3TSR significantly decreased the viability and proliferative potential of EOC cells and endothelial cells in vitro compared to native 3TSR. High-resolution imaging followed by image correlation spectroscopy demonstrated enhanced clustering of the CD36 receptor in cells treated with Fc3TSR. This was associated with enhanced downstream signaling and greater in vitro and in vivo cellular responses. Fc3TSR induced greater vascular normalization and disease regression compared to native 3TSR in an orthotopic, syngeneic mouse model of advanced stage ovarian cancer. CONCLUSION: The development of Fc3TSR which is greater in size, stable in circulation and enhances receptor activation compared to 3TSR, facilitates its translational potential as a therapy in the treatment of metastatic advanced stage ovarian cancer.

Conjugation of VEGFR1/R2-targeting peptide with gold nanoparticles to enhance antiangiogenic and antitumoral activity.

BACKGROUND: Inhibition of tumor angiogenesis through simultaneous targeting of vascular endothelial growth factor receptor (VEGFR)-1 and -2 is highly efficacious. An antagonist peptide of VEGFA/VEGFB, referred to as VGB3, can recognize and neutralize both VEGFR1 and VEGFR2 on the endothelial and tumoral cells, thereby inhibits angiogenesis and tumor growth. However, improved efficacy and extending injection intervals is required for its clinical translation. Given that gold nanoparticles (GNPs) can enhance the efficacy of biotherapeutics, we conjugated VGB3 to GNPs to enhance its efficacy and extends the intervals between treatments without adverse effects. RESULTS: GNP-VGB3 bound to VEGFR1 and VEGFR2 in human umbilical vein endothelial (HUVE) and 4T1 mammary carcinoma cells. GNP-VGB3 induced cell cycle arrest, ROS overproduction and apoptosis and inhibited proliferation and migration of endothelial and tumor cells more effectively than unconjugated VGB3 or GNP. In a murine 4T1 mammary carcinoma tumor model, GNP-VGB3 more strongly than VGB3 and GNP inhibited tumor growth and metastasis, and increased animal survival without causing weight loss. The superior antitumor effects were associated with durable targeting of VEGFR1 and VEGFR2, thereby inhibiting signaling pathways of proliferation, migration, differentiation, epithelial-to-mesenchymal transition, and survival in tumor tissues. MicroCT imaging and inductively coupled plasma mass spectrometry showed that GNP-VGB3 specifically target tumors and exhibit greater accumulation within tumors than the free GNPs. CONCLUSION: Conjugation to GNPs not only improved the efficacy of VGB3 peptide but also extended the intervals between treatments without adverse effects. These results suggest that GNP-VGB3 is a promising candidate for clinical translation.

Ocular and systemic pharmacokinetics of BI-X, a nanobody targeting VEGF and Ang-2, after intravitreal dosing in cynomolgus monkeys - Evidence for half-life extension by albumin.

Half-life extension strategies to reduce the intravitreal dosing frequency of biomolecules for the treatment of retinal neovascular diseases are attracting increasing interest. This study investigated ocular and systemic pharmacokinetics of the trivalent nanobody BI-X (with affinity to VEGF, Ang-2 and human albumin) in cynomolgus monkeys after intravitreal injection. BI-X concentrations were measured in serial samples of plasma, vitreous humor, aqueous humor and retina. Ocular pharmacokinetics of BI-X exhibited two phases. Initially up to 2-4 weeks after dosing, BI-X concentrations in vitreal, aqueous humor and retina declined with half-lives of around 3 days, which is comparable to macromolecules with a similar molecular weight. Thereafter, only vitreal concentrations were measurable, with a terminal half-life of 13.2 days, which is considerably longer than expected based on the BI-X molecular weight or hydrodynamic radius. It is hypothesized that binding of BI-X to low levels of intraocular albumin resulted in this half-life extension. BI-X was detectable in plasma up to 10 weeks post-dosing. Plasma pharmacokinetics of BI-X exhibited a similar biphasic disposition profile to the vitreous body, with a terminal half-life of 11.8 days, thus reflecting input kinetics from the eye. In conclusion, an important half-life extension principle based on vitreal albumin binding could be confirmed in a primate model, and the data obtained can potentially be translated to humans taking into account the differing vitreal albumin concentrations.

Ocular Pharmacokinetics of Intravitreally Injected Protein Therapeutics: Comparison among Standard-of-Care Formats.

The current standard of care for antivascular endothelial growth factor (VEGF) treatment requires frequent intravitreal (IVT) injections of protein therapeutics, as a result of limited retention within the eye. A thorough understanding of the determinants of ocular pharmacokinetics (PK) and its translation across species is an essential prerequisite for developing more durable treatments. In this work, we studied the ocular PK in macaques of the protein formats that comprise today's anti-VEGF standard of care. Cynomolgus monkeys received a single IVT injection of a single-chain variable fragment (scFv, brolucizumab), antigen-binding fragment (Fab, ranibizumab), fragment crystallizable-fusion protein (Fc-fusion, aflibercept), or immunoglobulin G monoclonal antibody (IgG, VA2 CrossMAb). Drug concentrations were determined in aqueous humor samples collected up to 42 days postinjection using immunoassay methods. The ocular half-life (t1/2) was 2.28, 2.62, 3.13, and 3.26 days for scFv, Fab, Fc-fusion, and IgG, respectively. A correlation with human t1/2 values from the literature confirmed the translational significance of the cynomolgus monkey as an animal model for ocular research. The relation between ocular t1/2 and molecular size was also investigated. Size was inferred from the molecular weight (MW) or determined experimentally by dynamic light scattering. The MW and hydrodynamic radius were found to be good predictors for the ocular t1/2 of globular proteins. The analysis showed that molecular size is a determinant of ocular disposition and may be used in lieu of dedicated PK studies in animals.

Phase 1 study of pomalidomide in children with recurrent, refractory, and progressive central nervous system tumors: A Pediatric Brain Tumor Consortium trial.

BACKGROUND: Central nervous system (CNS) malignancies are the most common solid tumors among children, and novel therapies are needed to help improve survival. Pomalidomide is an immunomodulatory agent that displays antiangiogenic and cytotoxic activity, making it an appropriate candidate to explore in pediatric CNS tumors. METHODS: A phase 1 first in pediatric trial of pomalidomide was conducted in children with recurrent, progressive, and refractory CNS tumors. The primary objective was to determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) when given orally once daily for 21 consecutive days of a 28-day cycle. Once the MTD was established, 12 additional patients were enrolled on expansion cohorts based on age and steroid use. RESULTS: Twenty-nine children were enrolled and 25 were evaluable for dose-limiting toxicity (DLT). The MTD was 2.6 mg/m2 (dose level 2). Four DLTs were observed in three patients at dose level 3 (3.4 mg/m2 ) includeding grade 3 diarrhea, grade 3 thrombocytopenia, grade 3 lung infection, and grade 4 neutropenia. The most common adverse events were grade 1 and 2 myelosuppression. One patient with an oligodendroglioma had stable disease for nine cycles, and a second patient with an anaplastic pleomorphic xanthoastrocytoma achieved a sustained partial response. Immunologic analyses suggested that pomalidomide triggers immunomodulation. CONCLUSIONS: The MTD of pomalidomide is 2.6 mg/m2 . It was well tolerated, and immune correlates showed a serum immune response. These data led to an industry-sponsored phase 2 trial of pomalidomide monotherapy in children with recurrent brain tumors (NCT03257631).

Structure Activity Relationship of Key Heterocyclic Anti-Angiogenic Leads of Promising Potential in the Fight against Cancer.

Pathological angiogenesis is a hallmark of cancer; accordingly, a number of anticancer FDA-approved drugs act by inhibiting angiogenesis via different mechanisms. However, the development process of the most potent anti-angiogenics has met various hurdles including redundancy, multiplicity, and development of compensatory mechanisms by which blood vessels are remodeled. Moreover, identification of broad-spectrum anti-angiogenesis targets is proved to be required to enhance the efficacy of the anti-angiogenesis drugs. In this perspective, a proper understanding of the structure activity relationship (SAR) of the recent anti-angiogenics is required. Various anti-angiogenic classes have been developed over the years; among them, the heterocyclic organic compounds come to the fore as the most promising, with several drugs approved by the FDA. In this review, we discuss the structure-activity relationship of some promising potent heterocyclic anti-angiogenic leads. For each lead, a molecular modelling was also carried out in order to correlate its SAR and specificity to the active site. Furthermore, an in silico pharmacokinetics study for some representative leads was presented. Summarizing, new insights for further improvement for each lead have been reviewed.

Phase I dose-escalation study of the safety, tolerability, and pharmacokinetics of aflibercept in combination with S-1 in Japanese patients with advanced solid malignancies.

Background Aflibercept, a recombinant fusion protein binding VEGF-A, VEGF-B and placental growth factor, inhibits tumor growth by blocking angiogenesis. The aim of this phase I dose-escalation study was to determine the recommended phase II dose (RP2D) of aflibercept in combination with S-1 in Japanese patients with solid tumors. Patients and methods Sequential cohorts of 3-6 patients with metastatic or unresectable solid tumors, who had failed at least one prior line of standard treatment or who were not suitable for such treatment, were to receive escalating doses of aflibercept every 2 weeks, starting at 2 mg/kg, combined with S-1 at 40 mg/m2 twice daily (80 mg/m2/day; 4 weeks on/2 weeks off). Dose-escalation was to be based on the incidence of dose-limiting toxicity (DLT). Blood samples were collected for pharmacokinetic analysis. Results At the first dose level (aflibercept 2 mg/kg plus S-1) 1 of 6 patients experienced a DLT (grade 4 proteinuria). The aflibercept dose was consequently escalated to 4 mg/kg; 1 of 3 patients treated at this dose level had a DLT (grade 2 pleural effusion), and another patient experienced grade 3 reversible posterior leukoencephalopathy syndrome after the DLT assessment period. Additional patients were therefore enrolled into the first dose level to explore safety and tolerability. The study was subsequently terminated prematurely. The maximum tolerated dose was not reached and the RP2D was not determined in Japanese patients. Conclusions The tolerability and safety of aflibercept 2 mg/kg in combination with S-1 was confirmed in Japanese patients with advanced solid tumors.

Potential of subconjunctival aflibercept in treating choroidal neovascularization.

The study aimed to evaluate the intraocular pharmacokinetics and efficacy of aflibercept after subconjunctival injection in animal models for treating choroidal neovascularization (CNV) associated with Age-Related Macular Degeneration (AMD). New Zealand albino rabbits received aflibercept (2000 µg/50 µl) in one eye, and the other eye was used as control. At 7, 14, 21 and 28 days, the animals were sacrificed to dissect the ocular tissues, and serum was collected at 1hr, 3 h, 1, 7, 14, 21 and 28 days. The concentration of aflibercept in various ocular tissues and serum were measured using the immunoassay technique. The concentration maximum (Cmax) at the Retinal Pigment Epithelium (RPE)-choroid complex and retina in treated eyes was 261.55 and 33.83 ng/gm, respectively. The area under the curve (AUC0-last) for RPE-Choroid and retina were 2094.02 and 290.33 days. ng/gm respectively. The time maximum (Tmax) for the ocular tissues was reached on day 7. In the vitreous humour, a lower level of aflibercept was retrieved. The Cmax (1766.84 ng/mL) in the serum was reached on day 1, followed by a decline in the concentration till the end of the study period. In treated eyes, the levels of aflibercept in most of the ocular tissues were maintained for at least 21 days above the invitro IC50 concentration. The results of the efficacy study show that subconjunctival aflibercept could reach the therapeutic target to inhibit CNV. The subconjunctival aflibercept could be a less invasive route for treating CNV with AMD.

Involvement of Pazopanib and Sunitinib Aldehyde Reactive Metabolites in Toxicity and Drug-Drug Interactions in Vitro and in Patient Samples.

Tyrosine kinase inhibitors (TKI) are targeted anticancer drugs that have been successfully developed over the past 2 decades. To date, many of them (around 70%) require warnings for liver injury and five of them, including pazopanib and sunitinib, have Black Box Warning (BBW) labels. Although TKI-induced hepatotoxicity is the first cause of drug failures in clinical trials, BBW labels, and market withdrawals, the underlying mechanisms remain unclear. However, the recent discovery of new reactive metabolites (RM) with aldehyde structures during pazopanib and sunitinib metabolism offers new perspectives for investigating their involvement in the toxicity of these two TKI. These hard electrophiles have a high reactivity potential toward proteins and are thought to be responsible for cytochrome P450 inactivation, drug-drug interactions (DDI), and liver toxicity. We report here, for the first time, the presence of these aldehyde RM in human plasma samples obtained during drug monitoring. Docking experiments in the CYP3A4 active site were performed and showed that pazopanib and sunitinib fitting in the catalytic site are in accordance with their regioselective oxidation to aldehydes. They also suggested that aldehyde RM may react with lysine and arginine residues. Based on these results, we studied the reactivity of the aldehyde RM toward lysine and arginine residues as potential targets on the protein framework to better understand how these RM could be involved in liver toxicity and drug-drug interactions. Adduct formation with different hepatic and plasma proteins was investigated by LC-MS/MS, and adducts between pazopanib or sunitinib aldehyde derivatives and lysine residues on both CYP3A4 and plasma proteins were indeed shown for the first time.

Intravitreal Pharmacokinetic Study of the Antiangiogenic Glycoprotein Opticin.

Opticin is an endogenous vitreous glycoprotein that may have therapeutic potential as it has been shown that supranormal concentrations suppress preretinal neovascularization. Herein we investigated the pharmacokinetics of opticin following intravitreal injection in rabbits. To measure simultaneously concentrations of human and rabbit opticin, a selected reaction monitoring mass spectrometry assay was developed. The mean concentration of endogenous rabbit opticin in 7 uninjected eyes was measured and found to be 19.2 nM or 0.62 µg/mL. When the vitreous was separated by centrifugation into a supernatant and collagen-containing pellet, 94% of the rabbit opticin was in the supernatant. Intravitreal injection of human opticin (40 µg) into both eyes of rabbits was followed by enucleation at 5, 24, and 72 h and 7, 14, and 28 days postinjection (n = 6 at each time point) and measurement of vitreous human and rabbit opticin concentrations in the supernatant and collagen-containing pellet following centrifugation. The volume of distribution of human opticin was calculated to be 3.31 mL, and the vitreous half-life was 4.2 days. Assuming that rabbit and human opticin are cleared from rabbit vitreous at the same rate, opticin is secreted into the vitreous at a rate of 0.14 µg/day. We conclude that intravitreally injected opticin has a vitreous half-life that is similar to currently available antiangiogenic therapeutics. While opticin was first identified bound to vitreous collagen fibrils, here we demonstrate that >90% of endogenous opticin is not bound to collagen. Endogenous opticin is secreted by the nonpigmented ciliary epithelium into the rabbit vitreous at a remarkably high rate, and the turnover in vitreous is approximately 15% per day.

A phase I trial of lenalidomide and radiotherapy in children with diffuse intrinsic pontine gliomas or high-grade gliomas.

PURPOSE: This study was performed to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of the immunomodulatory agent, lenalidomide, when administered daily during 6 weeks of radiation therapy to children with newly diagnosed diffuse intrinsic pontine glioma (DIPG) or high-grade glioma (HGG) PATIENTS & METHODS: Children and young adults < 22 years of age with newly diagnosed disease and no prior chemotherapy or radiation therapy were eligible. Children with HGG were required to have an inoperable or incompletely resected tumor. Eligible patients received standard radiation therapy to a prescription dose of 54-59.4 Gy, with concurrent administration of lenalidomide daily during radiation therapy in a standard 3 + 3 Phase I dose escalation design. Following completion of radiation therapy, patients had a 2-week break followed by maintenance lenalidomide at 116 mg/m2/day × 21 days of a 28-day cycle. RESULTS: Twenty-nine patients (age range 4-19 years) were enrolled; 24 were evaluable for dose finding (DIPG, n = 13; HGG, n = 11). The MTD was not reached at doses of lenalidomide up to 116 mg/m2/day. Exceptional responses were noted in DIPG and malignant glioma (gliomatosis cerebri) notably at higher dose levels and at higher steady state plasma concentrations. The primary toxicity was myelosuppression. CONCLUSION: The RP2D of lenalidomide administered daily during radiation therapy is 116 mg/m2/day. Children with malignant gliomas tolerate much higher doses of lenalidomide during radiation therapy compared to adults. This finding is critical as activity was observed primarily at higher dose levels suggesting a dose response.

Possibility for Dose Optimization of Pazopanib from Its Plasma Concentration in Japanese Patients with Cancer.

The currently approved dose of pazopanib (800 mg) is being re-examined owing to its adverse effects. The aim of this study was to evaluate the relationships among starting or maintenance doses of pazopanib, estimated pazopanib Cmin, and other clinical factors, including albumin and α-1 acid glycoprotein levels, in soft-tissue sarcoma and renal cell carcinoma. We also determined whether therapeutic drug monitoring of pazopanib concentrations may be used to improve its therapeutic efficacy and prevent adverse effects. Forty patients who received pazopanib for renal cancer or soft-tissue sarcoma at the Hokkaido Cancer Center were evaluated prospectively. Cmin for pazopanib was calculated based on the measured values from the plasma samples. The efficacy and time to treatment failure were then assessed. The pazopanib maintenance doses were 200 (n = 4), 400 (n = 34), 600 (n = 4), and 800 mg (n = 1). Most patients (65%) who received a 400 mg dose had an effective pazopanib concentration (≧20 µg/mL), whereas 35% of patients who received the 400 mg dose had ineffective concentrations (<20 µg/mL). Logistic regression analysis revealed that only the albumin level was significantly associated with effective pazopanib concentrations (odds ratio: 1.37, p = 0.0234). In conclusion, a dose of 400 mg had been effective and well tolerated in more than half of patients in this study. However, therapeutic drug monitoring is necessary during pazopanib therapy.

REVIEW OF OPHTHALMIC AND BREASTFEEDING MEDICINE EVIDENCE: Real and Theoretical Risks of Intravitreal Anti-Vascular Endothelial Growth Factor Administration in Lactating Women.

BACKGROUND/PURPOSE: There is limited research regarding the consequences of treating lactating mothers with intravitreal anti-vascular endothelial growth factor (VEGF) agents. Balancing the need for vision-saving treatment, the benefits of breastfeeding, and the concern for affecting the newborn can present a conflict for both mothers and ophthalmologists. This review summarizes the state of the literature regarding the use of intravitreal anti-VEGF agents during breastfeeding along with details about their pharmacology. RESULTS: Bevacizumab and aflibercept have Fc domains subjecting them to FcRn recycling and extending their half-life compared with ranibizumab which is an antibody fragment and lacks the Fc domain. Case reports and small studies have shown that ranibizumab has the lowest serum concentration after intravitreal injection and the least effect on plasma-free VEGF concentrations and breastmilk VEGF levels. CONCLUSION: Clinical and pharmacologic data suggest that ranibizumab has less systemic circulation and effect on maternal serum and breastmilk VEGF levels when compared to bevacizumab and aflibercept. However, there is significant need for further research on the degree and duration to which intravitreal agents circulate systemically, what fraction is transferred into breastmilk and is absorbed, and whether this results in any functional adverse effects to the infant. Other factors to consider in the medical decision-making of lactating mothers necessitating intravitreal anti-VEGF treatment include the gestational and post-natal age of the child and whether it is feasible to avoid breastfeeding for the half-life duration of the intravitreal agent rather than ceasing breastfeeding altogether.

PHARMACOKINETIC STUDY OF INTRAVITREAL AFLIBERCEPT IN HUMANS WITH NEOVASCULAR AGE-RELATED MACULAR DEGENERATION.

PURPOSE: To investigate the half-life of aflibercept in aqueous humor after a single intravitreal injection in patients with neovascular age-related macular degeneration. METHODS: Prospective, noncomparative, interventional case series of five eyes with neovascular age-related macular degeneration naive to anti-vascular endothelial growth factor therapy were enrolled and treated with intravitreal aflibercept. At baseline, best-corrected visual acuity, optical coherence tomography imaging, and aqueous humor (treatment eye) and blood/plasma samples were taken. Patients underwent best-corrected visual acuity, optical coherence tomography imaging, and sampling of aqueous humor from the eye and blood/plasma at six additional post-treatment time points of 4 hours and Days 1, 3, 7, 14, and 28. Concentrations of aflibercept were quantified using an enzyme-linked immunosorbent assay. RESULTS: Median peak concentration (Cmax) of free aflibercept in the aqueous was 122 mg/L. The median half-life of free aflibercept was 11 days in the eye. In plasma, the concentrations of free aflibercept were low and transient, reaching undetectable levels during the first week after injection, and undetectable in all patients at time points beyond 7 days. CONCLUSION: The pharmacokinetic profile in the aqueous humor described here together with the previously reported affinity of aflibercept for vascular endothelial growth factor is consistent with and adds to our understanding for the duration of its clinical efficacy.

A Prediction Model for the Intraocular Pharmacokinetics of Intravitreally Injected Drugs Based on Molecular Physicochemical Properties.

PURPOSE: This study was aimed at determining the intraocular pharmacokinetics based on molecular physicochemical properties in a rabbit model. METHODS: The entire dataset was obtained from previous literature, and research articles regarding 70 molecular compounds were investigated. The intravitreal half-lives in rabbit eyeballs of 22 macromolecules and 48 micromolecules were analyzed. Multiple linear regression analysis was carried out with non-collinear independent variables (molecular weight [MW] and lipophilicity) influencing intravitreal half-lives. The best-fit equations were selected based on the correlation coefficients and goodness-of-fit statistics. RESULTS: The best-fit models obtained from the entire dataset, macromolecules, and micromolecules suggest the correlation between molecular physicochemical properties (MW and lipophilicity) and intravitreal half-life. Exclusion of outlier molecules (amphotericin B and foscarnet) leads to a better-fit correlation. MW is the definite single factor affecting intravitreal half-lives of macromolecules (Log t1/2 = 0.148 + 0.370 Log MW, R2 = 0.769), while both MW and lipophilicity influence the intraocular pharmacokinetics of micromolecules (Log t1/2 = -1.213 + 0.762 Log MW - 0.115 Log p, R2 = 0.554). CONCLUSION: The present study indicates that intravitreal half-life could be predicted based on molecular physicochemical properties (MW and lipophilicity). Also, increasing MW while reducing lipophilicity would be a reliable method for prolonging the intravitreal half-life of small chemical drugs, while MW is the single major determinant for large biologic drugs.

Pharmacogenetics in Model-Based Optimization of Bevacizumab Therapy for Metastatic Colorectal Cancer.

Vascular endothelial growth factor A (VEGF-A) and intercellular adhesion molecule 1 (ICAM-1) are significant regulators of angiogenesis, an important biological process involved in carcinogenesis. Bevacizumab, an anti-VEGF monoclonal antibody (MAB), is approved for the treatment of metastatic Colorectal cancer (mCRC), however clinical outcomes are highly variable. In the present study, we developed a pharmacokinetic (PK), a simplified quasi-steady state (QSS) and a pharmacokinetic/pharmacodynamic (PK/PD) model to identify potential sources of variability. A total of 46 mCRC patients, who received bevacizumab in combination with chemotherapy were studied. VEGF-A (rs2010963, rs1570360, rs699947) and ICAM-1 (rs5498, rs1799969) genes' polymorphisms, age, gender, weight, and dosing scheme were investigated as possible co-variates of the model's parameters. Polymorphisms, trough, and peak levels of bevacizumab, and free VEGF-A were determined in whole blood and serum. Data were analyzed using nonlinear mixed-effects modeling. The two-compartment PK model showed that clearance (CL) was significantly lower in patients with mutant ICAM-1 rs1799969 (p < 0.0001), inter-compartmental clearance (Q) was significantly higher with mutant VEGF-A rs1570360 (p < 0.0001), and lower in patients with mutant VEGF-A rs699947 (p < 0.0001). The binding QSS model also showed that mutant ICAM-1 rs1799969 was associated with a lower CL (p = 0.0177). Mutant VEGF-A rs699947 was associated with a lower free VEGF-A levels, prior to the next dose (p = 0.000445). The above results were confirmed by the PK/PD model. Findings of the present study indicated that variants of the genes regulating angiogenesis might affect PK and PD characteristics of bevacizumab, possibly influencing the clinical outcomes.

Resveratrol and Its Nanoformulation Attenuate Growth and the Angiogenesis of Xenograft and Orthotopic Colon Cancer Models.

Cancer is a multifactorial disorder that induces mortality worldwide, and the colorectal type is the third most common cancer globally. Resveratrol (RSV) is a natural compound with an effective anticancer effect, especially against colorectal cancer, and therefore numerous studies recommended its use in colorectal cancer prevention and treatment. The current study investigated the effect of either RSV or its nanoformulation (NP-RSV) on the growth and vascularity of xenograft and orthotopic mice models in colon cancer (COLO205-luc). Both RSV and NP-RSV induced significant reductions in tumor growth and the hemoglobin percentages of the tumor mass, but NP-RSV showed greater bioavailability and efficacy than RSV. Generally, we recommend using NP-RSV as a therapeutic to control colon cancer.