title: Pharmacokinetics and safety of subcutaneous pasireotide and intramuscular pasireotide long-acting release in Chinese male healthy volunteers: a phase I, single-center, open-label, randomized study.
abstract: OBJECTIVE
  The purpose of this study was to assess the pharmacokinetic (PK) properties and safety of single and multiple doses of subcutaneous (SC) pasireotide and a single-dose intramuscular (IM) long-acting release (LAR) formulation of pasireotide in Chinese healthy volunteers (HVs) versus the PK properties in Western HVs (pooled from previous PK studies).
  
  
  METHODS
  In this phase I, single-center, open-label study, 45 Chinese male HVs were evenly randomized to 1 to 9 treatment sequences: each volunteer received a single dose of 300, 600, or 900 μg of pasireotide SC on day 1, followed by administration of the same dose BID from day 15 to the morning of day 19, and then a single IM dose of 20, 40, or 60 mg of pasireotide LAR on day 33. The PK parameters were assessed with noncompartmental analysis. Statistical comparison of PK parameters, including AUC, Cmax, and CL/F from both formulations, was made for Chinese versus Western male HVs. The safety profile was also assessed. Metabolic parameters, including blood glucose, insulin, and glucagon, and measures that reflect the effects of pasireotide LAR on relatively long-term glucose control, lipid metabolism, and systemic concentrations of pancreatic enzymes and thyrotropin were evaluated.
  
  
  RESULTS
  Of the 45 randomized HVs, 42 completed the study per protocol, 1 withdrew his informed consent for personal reasons, and 2 prematurely discontinued the study because of adverse events (AEs). Concentration-time and safety profiles of both formulations were similar to those reported in Western HVs. Mean geometric mean ratios (GMRs) of Chinese versus Western HVs ranged from 0.79 to 1.42. For most primary PK parameters, 90% CIs for GMRs were within a predefined ethnic insensitivity interval (90% CI, 0.70-1.43). After considering age and weight as covariates in the statistical model, the GMRs and 90% CIs for other PK parameters were within the predefined interval (Cmax in single-dose SC administration) or significantly decreased (Cmin,ss in multiple BID SC doses and first peak Cmax in the single-dose LAR formulation). No serious AEs were reported. Both formulations were well tolerated; pasireotide SC caused transient changes in glucose metabolism. Owing to the differential binding affinity to the somatostatin receptor subtypes, pasireotide LAR elicited a concentration-dependent increase of fasting blood glucose, substantial reduction in triglyceride, and a mild decrease in cholesterol. The most frequently reported AEs after single-dose and multiple-dose pasireotide SC were injection site reaction, nausea, dizziness, and diarrhea; most HVs developed diarrhea with single-dose pasireotide LAR.
  
  
  CONCLUSIONS
  The pasireotide formulations had similar PK and safety profiles between Chinese and Western male HVs. Thus, no ethnic sensitivity was found for pasireotide SC or LAR.
authors.affiliation: Clinical Pharmacology Research Centre, Peking Union Medical College Hospital, Beijing, China.
authors.forename: Xia
authors.initials: X
authors.lastname: Chen
authors.affiliation: Novartis Pharmaceutical Corporation, Oncology Business Unit, East Hanover, New Jersey.
authors.forename: Guoxiang
authors.initials: G
authors.lastname: Shen
authors.affiliation: Clinical Pharmacology Research Centre, Peking Union Medical College Hospital, Beijing, China.
authors.forename: Ji
authors.initials: J
authors.lastname: Jiang
authors.affiliation: Clinical Pharmacology Research Centre, Peking Union Medical College Hospital, Beijing, China.
authors.forename: Hongzhong
authors.initials: H
authors.lastname: Liu
authors.affiliation: Novartis Pharmaceutical Corporation, Oncology Business Unit, East Hanover, New Jersey.
authors.forename: Ke
authors.initials: K
authors.lastname: Hu
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: Christelle
authors.initials: C
authors.lastname: Darstein
authors.affiliation: Novartis Pharmaceutical Corporation, Oncology Business Unit, East Hanover, New Jersey.
authors.forename: Janet
authors.initials: J
authors.lastname: Lasher
authors.affiliation: Clinical Pharmacology Research Centre, Peking Union Medical College Hospital, Beijing, China. Electronic address: pei.hu.pumc@gmail.com.
authors.forename: Pei
authors.initials: P
authors.lastname: Hu
mesh_terms: D000328:Adult; D044466:Asian People; D001786:Blood Glucose / Q000187:drug effects; D002681:China; D002784:Cholesterol / Q000097:blood; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D003967:Diarrhea / Q000139:chemically induced; D004244:Dizziness / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D004333:Drug Administration Routes; D005934:Glucagon / Q000187:drug effects; D064368:Healthy Volunteers; D006801:Humans; D007273:Injections, Intramuscular; D007279:Injections, Subcutaneous; D007328:Insulin / Q000097:blood; D008297:Male; D009325:Nausea / Q000139:chemically induced; D013004:Somatostatin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D014280:Triglycerides / Q000097:blood; D055815:Young Adult
chemical_list: D001786:Blood Glucose; D003692:Delayed-Action Preparations; D007328:Insulin; D014280:Triglycerides; D013004:Somatostatin; D005934:Glucagon; D002784:Cholesterol; C517782:pasireotide
keywords: Chinese; healthy volunteers; long-acting release; pasireotide; pharmacokinetics; subcutaneous