A Design-Conversed Strategy Establishes the Performance Safe Space for Doxorubicin Nanosimilars.

Nanomedicines exhibit multifaceted performances, yet their biopharmaceutics remain poorly understood and present several challenges in the translation from preclinical to clinical research. To address this issue and promote the production of high-quality nanomedicines, a systematic screening of the design space and in vivo performance is necessary. Establishing formulation performance specifications early on enables an informed selection of candidates and promotes the development of nanosimilars. The deconvolution of the pharmacokinetics enables the identification of key characteristics that influence their performances and disposition. Using an in vitro-in vivo rank-order relationship for doxorubicin nanoformulations, we defined in vitro release specifications for Doxil/Caelyx-like follow-on products. Additionally, our model predictions were used to establish the bioequivalence of Lipodox, a nanosimilar of Doxil/Caelyx. Furthermore, a virtual safe space was established, providing crucial insights into expected disposition kinetics and informing formulation development. By addressing bottlenecks in biopharmaceutics and formulation screening, our research advances the translation of nanomedicine from bench to bedside.

Two multicenter Phase I randomized trials to compare the bioequivalence and safety of a generic doxorubicin hydrochloride liposome injection with Doxil® or Caelyx® in advanced ovarian cancer.

PURPOSE: To compare the pharmacokinetic bioequivalence and safety of a generic pegylated liposomal doxorubicin formulation (SPIL DXR hydrochloride liposome injection) with that of the reference products, Caelyx or Doxil. METHODS: Two open-label, two-way reference crossover studies were conducted in patients with ovarian cancer. Cmax, AUC0 - t, and AUC0-∞, Vd, and Cl for total, free, and encapsulated DXR were evaluated in 18 blood samples taken pre-dose (t = 0), at increasing time intervals over the following 14 days. A washout period of 28 days was observed before crossing over. RESULTS: Studies 1 and 2 were completed by 24/29 and 41/60 patients, respectively. Pharmacokinetic data from 24 patients from each study established bioequivalence for free DXR in study 2, and for total and encapsulated DXR in both studies. Data from 29 and 54 patients, respectively, were included in the safety evaluation. Of these, 37 patients experienced 81 post-dose adverse events (40 related to the test product and 41 related to the reference product). In study 1, four patients were withdrawn owing to adverse events. Eleven patients experienced serious adverse events and one death occurred in study 2. CONCLUSIONS: Bioequivalence between the test and the reference products was established for total and encapsulated DXR in both studies, and for free DXR in the study with the larger sample size (study 2). There were no significant differences between the safety profiles of the generic formulation and the reference products. No correlation was found between drug level and adverse events. TRIAL REGISTRATION: Study 1 was registered retrospectively; registration number is NCT03055143, dated February 15, 2017. Study 2 registration number is NCT00862355, dated March 13, 2009.

Safety, tolerability, pharmacokinetics, and pharmacodynamics of compound SFDAC by intranasal administration of multiple escalating dose in healthy male subjects.

A novel corticosteroid compound (short form of IUPAC name: SFDAC) has been discovered by Sun Pharma Advanced Research Company (SPARC) Ltd. A randomized, observer-blind, active-controlled, parallel-groups, intranasal multiple escalating dose study was conducted in healthy male subjects to assess safety, tolerability, pharmacokinetics, and pharmacodynamics of compound SFDAC formulated as an aqueous suspension for intranasal administration. Intranasal sprays of SFDAC, active control fluticasone propionate (FP) and placebo were administered once in a day for 14 days as per randomization. Various clinical evaluations including 24-hour serum cortisol and urinary free cortisol (UFC) profiles were carried out. Blood samples were collected at pre-defined time-points and analyzed using a validated chromatographic method for estimation of SFDAC and its metabolite. The results of the study indicate that multiple dose of SFDAC intranasal spray upto 3,200 µg is safe and tolerated. Clinically significant suppression of hypothalamic pituitary adrenal (HPA) axis was not observed. The plasma concentration of SFDAC was found to be below the lower limit of quantification (LLQ) at most time-points for all subjects. SFDAC M1 metabolite was detected only at picogram level in plasma. The safety and pharmacokinetic characteristics of SFDAC observed in this study support further clinical development of the SFDAC nasal spray.