Background: The present study evaluated the safety, pharmacokinetics/pharmacodynamics (PK/PD), and absolute bioavailability (Fabs) of Dex nasal spray in healthy adult subjects, which serves as a bridge for the subsequent study in children.Methods: Part 1: a double-blind, placebo-controlled, single ascending dose study was performed on 48 subjects. For 20-/40-μg groups, every 6/2 subjects received either Dex/placebo nasal spray or Dex/placebo injection in two periods. In total, 12/4 subjects each received 100 μg Dex/placebo nasal spray. Part 2: a randomized, double-blind, placebo-controlled study; 12/4 subjects received 150 μg Dex/placebo nasal spray. Part 3: a randomized, open, self-crossover study; 12 subjects received 20 μg and 100 μg Dex nasal spray in two periods alternately. The method of administration was optimized in Part 2 and Part 3.Results: In part 1, Dex nasal spray was well tolerated up to the maximum dose of 100 μg, whereas the Fabs was tolerated to only 28.9%–32.3%. In Part 2 and Part 3, the optimized nasal spray method was adopted to promote the Fabs of Dex nasal spray to 74.1%–89.0%. A severe adverse event was found in Part 2. In Part 3 (100 μg), the Ramsay score increased the most and lasted the longest, whereas the BIS score decreased most significantly.Conclusion: Using the optimized nasal spray method, a single dose of 20/100 μg of the test drug was safe and tolerable, and 100 μg may have approached or reached the plateau of sedation. In addition, it is found that the optimized method can greatly improve the bioavailability of the test drug, leading to its higher reference value.

Abiraterone acetate tablets (I)(N-AbA) is a novel tablet co-formulated with the absorption enhancer sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (SNAC). This study aimed to compare the pharmacokinetics, bioequivalence, safety, and food effects of N-AbA with the reference ZYTIGA ® (R-AbA) in healthy Chinese male subjects. Patients and Methods: This study was conducted in three parts. Part I was an open, doseescalation trial conducted in 16 Chinese healthy males; Part II was a randomized, open-label, 2 × 4 crossover, single-dose bioequivalence trial conducted in 36 subjects; Part III was a randomized, 3 × 3 crossover trial conducted on 24 volunteers to investigate the effect of food on the pharmacokinetics of N-AbA. Results:The exposure (AUC 0-∞ ) and maximum concentration (C max ) of abiraterone and excipient SNAC were linear in the range of 75-450 mg dose. The bioavailability of N-AbA 300 mg was equivalent to that of R-AbA 1000 mg. The drug exposure of prednisone and prednisolone was not affected by SNAC co-administration. The C max of orally administered abiraterone as R-AbA in a modified fed state was 5.9 times and AUC 0-∞ was 4.3 times, respectively, higher than those in of orally administered abiraterone as N-AbA in a high-fat diet. The C max and AUC 0-∞ of orally administered abiraterone as N-AbA on a high-fat diet were 2.2 times and 2 times, respectively, higher than those on a fasting state. All adverse events reported in the three parts of the study were grade 1 or 2, and no serious adverse events were reported. Conclusion: These three Phase I trials showed that N-AbA and excipient SNAC had excellent linear pharmacokinetic characteristics. A single dose of N-AbA 300 mg was bioequivalent to R-AbA 1000 mg in healthy subjects under fasting conditions. Meanwhile, SNAC had no effect on the pharmacokinetics of prednisone and prednisolone. The effect of food on N-AbA was significantly lower than that on R-AbA.

Background: Skin prick test is usually the preferred test in the diagnostic workup for allergic diseases, while there are few types of standardized allergen extracts available. Besides, standardization and composition give no assurance that the allergen extracts are within the concentration range that give the best chance of a true diagnosis. We designed a first-in-human diagnostic skin test with fewer samples to identify the optimally diagnostic concentration for eight standardized extracts from frequent native allergens, and to assess the safety of the eight allergens extracts’ simultaneous administration for supporting clinical allergen screening.Methods: Patients aged 18-45 years who had a history of allergic diseases were enrolled in this two-part open-label, parallel study: Study 1, each patient was given three concentrations of one allergen extract in turn. Study 2, each patient was given two concentrations of eight allergens extracts. Negative and positive controls were given each time the allergen was given. Both safety and sensitivity were evaluated to determine the optimally diagnostic concentration. Related-Samples Friedman's Two-Way Analysis was used to evaluate the difference of wheal diameter between different concentrations of each allergen. SPSS Statistics 26 was used for statistical analysis, and the significance test level was 0.05.Results: The sensitivity of allergens increased with the increasing of concentration. The eight investigated allergens showed good safety and did not reach the dose limit toxicity whether used alone or in combination. The optimally diagnostic concentration for eight aeroallergens were respectively determined as 33333 DU/mL, 12000 DU/mL, 8667 DU/mL, 50000 DU/mL, 40000 DU/mL, 3333 DU/mL, 7000 DU/mL, and 5000 DU/mL.Conclusions: This study designed a solution to determine the optimally diagnostic concentration with fewer subjects for further clinical trials of the eight investigated allergens and the results of this phase I clinical trial support further clinical research of investigated allergens. Trial registration: The trial was registered on www.chictr.org.cn (ChiCTR1900023952, 06/19/2019, retrospectively registered).

Purpose Genetic mutations and phenotypic changes of CYP2C9, CYP2C19 and CYP2D6 are vital for individual variations in clinical drug responses. Elucidating the mutating frequencies and phenotypic distributions of these genes shall facilitate the implementation of preemptive pharmacogenetic testing. We analyzed the gene polymorphisms and phenotypic frequencies of CYP2C9, CYP2C19 and CYP2D6 in Han Chinese population. Methods Tests of CYP2C9, CYP2C19 and CYP2D6 were performed in over 3200 (3276-3293) samples in Han Chinese population; furthermore, systematic review was employed for analyzing the mutation frequency and phenotypic distribution of CYP2C9 and CYP2C19 in Han Chinese population. Results Among 9062 samples, the mutation frequency of CYP2C9 was 11.49% and the frequency of phenotypic changes 7.1%; in 8222 samples, the mutation frequency of CYP2C19 was 66.07% and the frequency of phenotypic changes 63.75%; among 3931 samples, the mutation frequency of CYP2D6 was 88.04% and the frequency of phenotypic changes 3.87%. Among 2690 samples, gene mutations and phenotypic distributions of CYP2C9, CYP2C19 and CYP2D6 were simultaneously examined and it was found that 96.36% samples became mutated and the frequency of phenotypic changes was 66.51%. Conclusions In Han Chinese population, the gene mutations and phenotypic changes of CYP2C9, CYP2C19 and CYP2D6 are all relatively frequent. Prior to dosing, preemptive pharmacogenetic testing of CYP2C9, CYP2C19 and CYP2D6 is recommended.