Safety and pharmacokinetics of polatuzumab vedotin in Japanese patients with relapsed/refractory B-cell non-Hodgkin lymphoma: a phase 1 dose-escalation study.

OBJECTIVE: A phase 1 dose-escalation study of polatuzumab vedotin (pola) was conducted to assess safety, pharmacokinetics and preliminary antitumor activity of pola in Japanese patients with relapsed/refractory B-cell non-Hodgkin lymphoma. METHODS: Patients received pola (1.0 or 1.8 mg/kg) intravenously every 21 days until disease progression or intolerance. Intra-patient dose escalation was prohibited. Tolerability was determined by the standard 3 + 3 rule. Blood sampling was performed to characterize pharmacokinetics. Antitumor activity was evaluated through computed tomography and bone marrow sampling. RESULTS: Four patients received pola 1.0 mg/kg; three received 1.8 mg/kg. Patients had follicular lymphoma (n = 4) or diffuse large B-cell lymphoma (n = 3), median age of 62 years, received a median of 3 prior therapies; six were female. Pola was well tolerated in both cohorts, with no dose-limiting toxicities observed. The most common adverse event was peripheral sensory neuropathy (n = 4). Grade 3 adverse events were cholecystitis and neutrophil count decreased (one each; both 1.0 mg/kg), and syncope and cataract (one each; both 1.8 mg/kg). The plasma half-life of antibody-conjugate monomethyl auristatin E was 4.43-7.98 days, and systemic exposure of unconjugated monomethyl auristatin E was limited in both cohorts. Four patients achieved objective responses (three complete, one partial) without disease progression during the study. CONCLUSIONS: This phase 1 dose-escalation study demonstrated that pola has an acceptable safety profile and offers encouraging antitumor activity to Japanese patients with relapsed/refractory B-cell non-Hodgkin lymphoma. Pola 1.8 mg/kg, the recommended phase 2 dose, was tolerable in Japanese patients.

Minoxidil-encapsulated poly(L-lactide-co-glycolide) nanoparticles with hair follicle delivery properties prepared using W/O/W solvent evaporation and sonication.

BACKGROUND: Nanoparticles with a diameter of 100-150 nm prepared using poly(lactide-co-glycolide) can be delivered to hair follicles. Moreover, it was shown that drug release from nanoparticles was prolonged by using poly(L-lactide-co-glycolide) (PLLGA). OBJECTIVE: The aim of this study was to prepared minoxidil-encapsulated PLLGA nanoparticles and accumulate minoxidil in hair follicles utilizing its drug delivery properties for effective treatment of male and female androgenetic alopecia. METHODS: Minoxidil-encapsulated PLLGA nanoparticles were prepared using W/O/W solvent evaporation and sonication, and the ability of PLLGA nanoparticles to deliver to hair follicles was evaluated by in vivo transdermal delivery study using C3H/He mice and tape stripping and cyanoacrylate skin surface biopsy. RESULTS: Eight hours after administration of samples, minoxidil-encapsulated PLLGA nanoparticles delivered 3.1 times more minoxidil in stratum corneum and 2.5 times more in hair follicles r compared to minoxidil aqueous solution. In addition, we found that 4.8% of the dose of minoxidil-encapsulated PLLGA nanoparticles were delivered to the hair follicles. CONCLUSIONS: In this study, it was shown that nanoparticulation using PLLGA7510 suppressed minoxidil release from nanoparticles and improved drug delivery amount to hair follicles.

Estradiol-loaded PLGA nanoparticles for improving low bone mineral density of cancellous bone caused by osteoporosis: Application of enhanced charged nanoparticles with iontophoresis.

Postmenopausal osteoporosis among older women, which occurs by an ovarian hormone deficiency, is one of the major public health problems. 17 ß-estradiol (E2) is used to prevent and treat this disease as a drug of hormone replacement therapy. In oral administration, E2 is significantly affected by first-pass hepatic metabolism, and high dose administration must be needed to obtain drug efficacy. Therefore, alternative administration route is needed, and we have focused on the transdermal drug delivery system. In this study, we have prepared E2-loaded poly(DL-lactide-co-glycolide) (PLGA) nanoparticles for osteoporosis by using a combination of an antisolvent diffusion method with preferential solvation. The average particle diameter of the nanoparticles was 110.0±41.0nm and the surface charge number density was 82 times higher than that of conventional E2-loaded PLGA nanoparticles. Therapeutic evaluation of E2-loaded PLGA nanoparticles was carried out using ovariectomized female rats. Therapeutic efficacy was evaluated to measure bone mineral density of cancellous bone using an X-ray CT system. When the E2-loaded PLGA nanoparticles were administrated once a week, bone mineral density was significantly higher than that of the non-treated group at 60days after the start of treatment. Also, in the group administered this nanoparticle twice a week, the bone mineral density increased significantly at 45days after the start of treatment. From these results, it was revealed that E2-loaded PLGA nanoparticles with iontophoresis were useful to recover bone mineral density of cancellous bone, and it was also suggested that they extend the dosing interval of E2.