Ocular and Systemic Pharmacokinetics of Lotilaner Ophthalmic Solution, 0.25%, Following a Single Dose or Repeated Doses in Dutch-Belted Rabbits.

Purpose: To evaluate the ocular and systemic pharmacokinetics of lotilaner ophthalmic solution, 0.25%, following bilateral topical ocular administration of single and repeated doses in rabbits. Methods: Dutch-belted rabbits (n = 34) were administered lotilaner ophthalmic solution, 0.25%, eye drops, either in a single bilateral dose (Group 1) or twice a day bilaterally for 7 days and once on Day 8 (Group 2). The pharmacokinetics and tissue distribution levels of lotilaner were assessed following the single dose in Group 1 and the last dose in Group 2. The drug levels were examined in various ocular tissues and whole blood. The maximal concentration of the drug (Cmax), time to maximal concentration, the terminal phase elimination half-life, the area under the concentration-time curve (AUC), and total clearance of the drug were determined. Results: In the eyelid margins, lotilaner exhibited the highest observed concentrations at 0.25 hour (h), presenting a mean Cmax of 14,600 ng/mL in Group 1 and 20,100 ng/mL in Group 2. The highest AUC was in the eyelid margin at 242,000 h×ng/mL in Group 1 and 535,000 h×ng/mL in Group 2. In the eyelid margin, the observed clearance rate (0.634 mL/h in single dose, 0.288 mL/h in repeat dose) was the slowest among all ocular tissues in both groups, with the longest half-life of 152 h (∼6.3 days) observed in the repeat dose group. Conclusions: Lotilaner ophthalmic solution, 0.25%, demonstrated rapid ocular tissue absorption into the eyelid margin tissue with a long half-life of almost a week. No adverse effects were observed following topical ocular administration in Dutch-belted rabbits.

Lotilaner Ophthalmic Solution, 0.25%, for the Treatment of Demodex Blepharitis.

Demodex blepharitis, a chronic lid margin disease, is caused by an infestation of Demodex mites, the most common ectoparasites in human skin and eyelids. Lotilaner ophthalmic solution, 0.25% (Xdemvy, Tarsus Pharmaceuticals), is the first therapy approved to treat Demodex blepharitis. This narrative review characterizes lotilaner ophthalmic solution, 0.25%, and describes its efficacy, safety, and tolerability. The safety and efficacy of lotilaner ophthalmic solution, 0.25%, for treating Demodex blepharitis was evaluated in four phase 2 and two phase 3 trials. The data of 980 patients included in these phase 2 and 3 clinical trials revealed that the proportion of eyes with a clinically meaningful reduction to 10 or fewer collarettes (the cylindrical, waxy debris found at the base of the eyelashes) ranged from 81 to 93%. The mite eradication rate confirmed by a microscopy of epilated lashes ranged from 52 to 78%. No serious treatment-related adverse events were reported in any of these clinical studies. As high as 92% of the patients receiving lotilaner eyedrops in the phase 3 trials found it to be neutral to very comfortable. Given the positive safety and efficacy outcomes, the drug is likely to become the standard of care in the treatment of Demodex blepharitis.

Report of the AAPS Guidance Forum on the FDA Draft Guidance for Industry: "Drug Products, Including Biological Products, that Contain Nanomaterials".

To guide developers of innovative and generic drug products that contain nanomaterials, the U.S. Food and Drug Administration issued the draft guidance for industry titled: "Drug Products, Including Biological Products, that Contain Nanomaterials" in December 2017. During the AAPS Guidance Forum on September 11, 2018, participants from industry, academia, and regulatory bodies discussed this draft guidance in an open setting. Two questions raised by the AAPS membership were discussed in more detail: what is the appropriate regulatory pathway for approval of drug products containing nanomaterials, and how to determine critical quality attributes (CQAs) for nanomaterials? During the meeting, clarification was provided on how the new FDA center-led guidance relates to older, specific nanomaterial class, or specific product-related guidances. The lively discussions concluded with some clear observations and recommendations: (I) Important lessons can be learned from how CQAs were determined for, e.g., biologics. (II) Publication of ongoing scientific discussions on strategies and studies determining CQAs of drug products containing nanomaterials will significantly strengthen the science base on this topic. Furthermore, (III) alignment on a global level on how to address new questions regarding nanomedicine development protocols will add to efficient development and approval of these much needed candidate nanomedicines (innovative and generic). Public meetings such as the AAPS Guidance Forum may serve as the place to have these discussions.

Evaluation of a series of naphthamides as potent, orally active vascular endothelial growth factor receptor-2 tyrosine kinase inhibitors.

We have previously shown N-arylnaphthamides can be potent inhibitors of vascular endothelial growth factor receptors (VEGFRs). N-Alkyl and N-unsubstituted naphthamides were prepared and found to yield nanomolar inhibitors of VEGFR-2 (KDR) with an improved selectivity profile against a panel of tyrosine and serine/threonine kinases. The inhibitory activity of this series was retained at the cellular level. Naphthamides 3, 20, and 22 exhibited good pharmacokinetics following oral dosing and showed potent inhibition of VEGF-induced angiogenesis in the rat corneal model. Once-daily oral administration of 22 for 14 days led to 85% inhibition of established HT29 colon cancer and Calu-6 lung cancer xenografts at doses of 10 and 20 mg/kg, respectively.

Naphthamides as novel and potent vascular endothelial growth factor receptor tyrosine kinase inhibitors: design, synthesis, and evaluation.

A series of naphthyl-based compounds were synthesized as potential inhibitors of vascular endothelial growth factor (VEGF) receptors. Investigations of structure-activity relationships led to the identification of a series of naphthamides that are potent inhibitors of the VEGF receptor tyrosine kinase family. Numerous analogues demonstrated low nanomolar inhibition of VEGF-dependent human umbilical vein endothelial cell (HUVEC) proliferation, and of these several compounds possessed favorable pharmacokinetic (PK) profiles. In particular, compound 48 demonstrated significant antitumor efficacy against established HT29 human colon adenocarcinoma xenografts implanted in athymic mice. A full account of the preparation, structure-activity relationships, pharmacokinetic properties, and pharmacology of analogues within this series is presented.

Equivalence of complex drug products: advances in and challenges for current regulatory frameworks.

Biotechnology and nanotechnology provide a growing number of innovator-driven complex drug products and their copy versions. Biologics exemplify one category of complex drugs, but there are also nonbiological complex drug products, including many nanomedicines, such as iron-carbohydrate complexes, drug-carrying liposomes or emulsions, and glatiramoids. In this white paper, which stems from a 1-day conference at the New York Academy of Sciences, we discuss regulatory frameworks in use worldwide (e.g., the U.S. Food and Drug Administration, the European Medicines Agency, the World Health Organization) to approve these complex drug products and their follow-on versions. One of the key questions remains how to assess equivalence of these complex products. We identify a number of points for which consensus was found among the stakeholders who were present: scientists from innovator and generic/follow-on companies, academia, and regulatory bodies from different parts of the world. A number of topics requiring follow-up were identified: (1) assessment of critical attributes to establish equivalence for follow-on versions, (2) the need to publish scientific findings in the public domain to further progress in the field, (3) the necessity to develop worldwide consensus regarding nomenclature and labeling of these complex products, and (4) regulatory actions when substandard complex drug products are identified.

Characterization of thermal behavior of deep eutectic solvents and their potential as drug solubilization vehicles.

Deep eutectic solvent (DES) is a new class of solvents typically formed by mixing choline chloride with hydrogen bond donors such as amines, acids, and alcohols. Most DES's are non-reactive with water, biodegradable, and have acceptable toxicity profiles. Urea-choline chloride and malonic acid-choline chloride eutectic systems were characterized using differential scanning calorimetry (DSC) and thermal microscopy. A potential new 2:1 urea-choline chloride cocrystal with a melting point of 25 degrees C was characterized at the eutectic composition. The formation of this cocrystal suggests that DES should not be universally explained by simple eutectic melting, and may be useful in guiding the search for new DES systems. The lack of nucleation of the malonic acid-choline chloride system prohibited the construction of a phase diagram for this system using DSC. We also investigated possible uses of DES in solubilizing poorly soluble compounds for enhanced bioavailability in early drug development such as toxicology studies. For five poorly soluble model compounds, solubility in DES is 5 to 22,000 folds more than that in water. Thus, DES can be a promising vehicle for increasing exposure of poorly soluble compounds in preclinical studies.

The co-crystal approach to improve the exposure of a water-insoluble compound: AMG 517 sorbic acid co-crystal characterization and pharmacokinetics.

Co-crystals are relatively novel in the pharmaceutical field and are not reported extensively. AMG 517 is an insoluble small molecule VR1 (vanilloid receptor 1) antagonist. In animal studies, good exposure of AMG 517 is seen from a 10% (w/v) Pluronic F108 in OraPlus suspension. Investigation of the suspension formulation revealed that AMG 517 forms a co-crystal with sorbic acid, a preservative in OraPlus. This co-crystal of AMG 517 was isolated by coslurrying AMG 517 and sorbic acid; studied by DSC and XRD; and identified by solution NMR, TGA, and HPLC to be a 1:1 association of AMG 517 and sorbic acid. Single crystal structure analysis revealed a 1:1 co-crystal of AMG 517 and sorbic acid, held together by two hydrogen bonds and other noncovalent, nonionic forces. The co-crystal has better aqueous solubility initially as compared to AMG 517 free base but does revert back to a form of the free base hydrate during prolonged slurry in FaSIF (fasted simulated intestinal fluid). Pharmacokinetic evaluation of the co-crystal in rats using 10% (w/v) Pluronic F108 in OraPlus suspensions revealed that a 30 mg/kg dose in suspension had comparable exposure to a 500 mg/kg dose of the free base.

Discovery of N-phenyl nicotinamides as potent inhibitors of Kdr.

Inhibition of tumor-induced angiogenesis is a promising strategy in anticancer research. Neovascularization is a process required for both tumor growth and metastasis. Enhanced understanding of the underlying molecular mechanisms has led to the discovery of a variety of pharmaceutically attractive targets. Decades of investigation suggest that vascular endothelial growth factor (VEGF) and its receptors, in particular VEGFR2 or kinase insert-domain-containing receptor (Kdr), play a critical role in the growth and survival of endothelial cells in newly forming vasculature. The clinical utility of inhibitors of this receptor tyrosine kinase is currently under intense investigation. Herein we report our efforts in this arena.

AMG 706, an oral, multikinase inhibitor that selectively targets vascular endothelial growth factor, platelet-derived growth factor, and kit receptors, potently inhibits angiogenesis and induces regression in tumor xenografts.

The growth of solid tumors is dependent on the continued stimulation of endothelial cell proliferation and migration resulting in angiogenesis. The angiogenic process is controlled by a variety of factors of which the vascular endothelial growth factor (VEGF) pathway and its receptors play a pivotal role. Small-molecule inhibitors of VEGF receptors (VEGFR) have been shown to inhibit angiogenesis and tumor growth in preclinical models and in clinical trials. A novel nicotinamide, AMG 706, was identified as a potent, orally bioavailable inhibitor of the VEGFR1/Flt1, VEGFR2/kinase domain receptor/Flk-1, VEGFR3/Flt4, platelet-derived growth factor receptor, and Kit receptors in preclinical models. AMG 706 inhibited human endothelial cell proliferation induced by VEGF, but not by basic fibroblast growth factor in vitro, as well as vascular permeability induced by VEGF in mice. Oral administration of AMG 706 potently inhibited VEGF-induced angiogenesis in the rat corneal model and induced regression of established A431 xenografts. AMG 706 was well tolerated and had no significant effects on body weight or on the general health of the animals. Histologic analysis of tumor xenografts from AMG 706-treated animals revealed an increase in endothelial apoptosis and a reduction in blood vessel area that preceded an increase in tumor cell apoptosis. In summary, AMG 706 is an orally bioavailable, well-tolerated multikinase inhibitor that is presently under clinical investigation for the treatment of human malignancies.