Search

The pharmacokinetics of enarodustat were elucidated in healthy subjects and in patients with end‐stage renal disease (ESRD) on hemodialysis in phase 1 studies conducted in the United States and Japan. In healthy non‐Japanese and Japanese subjects, following single oral administration up to 400 mg, enarodustat was rapidly absorbed. Maximum plasma concentration and area under the plasma concentration‐time curve from the time of dosing to infinity were dose‐dependent, renal excretion of unchanged enarodustat was substantial (on average ≈45% of dose), and mean t1/2of <10 hours indicated negligible accumulation with once‐daily dosing. In general, with daily dosing (25, 50 mg), accumulation at steady‐state was ≈1.5‐fold (t1/2(eff)≈15 hours), presumably due to a decrease in renal drug excretion which is not clinically relevant in patients with ESRD. In the single‐ and multiple‐dose studies, plasma clearance (CL/F) was lower in healthy Japanese subjects. In non‐Japanese patients with ESRD on hemodialysis, following once‐daily dosing (2–15 mg), enarodustat was rapidly absorbed, steady‐state maximum plasma concentration and area under the plasma concentration‐time curve during the dosing interval were dose‐dependent, and interindividual variability in the exposure parameters was low‐to‐moderate (coefficient of variation, 27%–39%). Steady‐state CL/F was similar across doses, renal drug excretion was not significant (<10% of dose), mean t1/2and t1/2(eff)were similar (overall, 8.97–11.6 hours), and accumulation was minimal (≈20%), demonstrating predictable pharmacokinetics. Japanese patients with ESRD on hemodialysis (15 mg, single dose) exhibited similar pharmacokinetics with mean t1/2of 11.3 hours and low interindividual variability in the exposure parameters, albeit with lower CL/F versus non‐Japanese patients. Body weight‐adjusted clearance values were generally similar in non‐Japanese and Japanese healthy subjects and also in patients with ESRD on hemodialysis.

To investigate the efficacy of a single subconjunctival injection of dendrimer-dexamethasone conjugate in a rabbit model of induced autoimmune dacryoadenitis (AID).

Type 1 insulin-like growth factor receptor is deregulated in solid tumors. Cixutumumab, a monoclonal antibody that inhibits the activity of type 1 insulin-like growth factor receptor, was investigated in combination with pemetrexed/cisplatin in the frontline setting.

Retinal microglial/macrophage activation and optic nerve (ON) microglial/macrophage activation are glaucoma biomarkers and potential therapeutic targets for this blinding disease. We report targeting of activated microglia by PAMAM dendrimers in a rat glaucoma model and neuroprotection by N-acetylcysteine-conjugated dendrimer (D-NAC) conjugates in a post-injury rescue experiment. Intravitreally delivered fluorescently labeled dendrimer (D-Cy5) conjugates targeted and were retained in Iba-1-positive cells (90% at 7 days and 55% after 28 days) in the retina following intraocular pressure (IOP) elevation, while systemically delivered D-Cy5 targeted ON cells. A single intravitreal D-NAC dose given 1 week after IOP elevation significantly reduced transcription of pro-inflammatory (IL-6, MCP-1, IL-1β) and A1 astrocyte (Serping1, Fkbp5, Amigo2) markers and increased survival of retinal ganglion cells (39 ± 12%) versus BSS- (20 ± 15%, p= 0.02) and free NAC-treated (26 ± 14%, p= 0.15) eyes. These results highlight the potential of dendrimer-targeted microglia and macrophages for early glaucoma detection and as a neuroprotective therapeutic target.

Treatment of brain injury following circulatory arrest is a challenging health issue with no viable therapeutic options. Based on studies in a clinically relevant large animal (canine) model of hypothermic circulatory arrest (HCA)-induced brain injury, neuroinflammation and excitotoxicity have been identified as key players in mediating the brain injury after HCA. Therapy with large doses of valproic acid (VPA) showed some neuroprotection but was associated with adverse side effects. For the first time in a large animal model, we explored whether systemically administered polyamidoamine (PAMAM) dendrimers could be effective in reaching target cells in the brain and deliver therapeutics. We showed that, upon systemic administration, hydroxyl-terminated PAMAM dendrimers are taken up in the brain of injured animals and selectively localize in the injured neurons and microglia in the brain. The biodistribution in other major organs was similar to that seen in small animal models. We studied systemic dendrimer–drug combination therapy with two clinically approved drugs, N-acetyl cysteine (NAC) (attenuating neuroinflammation) and valproic acid (attenuating excitotoxicity), building on positive outcomes in a rabbit model of perinatal brain injury. We prepared and characterized dendrimer-NAC (D-NAC) and dendrimer-VPA (D-VPA) conjugates in multigram quantities. A glutathione-sensitive linker to enable for fast intracellular release. In preliminary efficacy studies, combination therapy with D-NAC and D-VPA showed promise in this large animal model, producing 24 h neurological deficit score improvements comparable to high dose combination therapy with VPA and NAC, or free VPA, but at one-tenth the dose, while significantly reducing the adverse side effects. Since adverse side effects of drugs are exaggerated in HCA, the reduced side effects with dendrimer conjugates and suggestions of neuroprotection offer promise for these nanoscale drug delivery systems.

AST‐120 is an orally administered adsorbent used to slow the progression of chronic kidney disease (CKD). This was a randomized, open‐label, 5‐way crossover study to assess the effect of AST‐120 on the pharmacokinetics of losartan and its active metabolite (E‐3174) in healthy subjects. Losartan (100 mg) was administered alone under fasting (A) and fed (B) conditions, and results were compared when AST‐120 (3 g thrice daily for 2 days) was administered 60 minutes after (C), 30 minutes prior to (D), and 30 minutes after (E) losartan. Plasma concentrations of losartan and E‐3174 were assayed by high‐performance liquid chromatography with mass spectrometry detection. Under fed conditions, treatment C had no significant effect on the AUC(0‐t)and Cmaxof losartan and E‐3174. Treatments D and E resulted in a marked decrease in Cmaxof losartan and E‐3174. Therefore, administration of AST‐120 60 minutes after losartan under fed conditions may be preferred over other dosing regimens for CKD patients.