PMID- 17595888
OWN - NLM
STAT- MEDLINE
DCOM- 20070731
LR  - 20190608
IS  - 0946-1965 (Print)
IS  - 0946-1965 (Linking)
VI  - 45
IP  - 6
DP  - 2007 Jun
TI  - Assessment of the safety, tolerability, and PK/PD properties of two new 
      formulations of subcutaneously administered IFN-beta1a: a double-blind, 
      placebo-controlled comparison with the currently available formulation.
PG  - 307-18
AB  - OBJECTIVE: Application-site disorders are well-known adverse events (AEs) 
      associated with subcutaneous (s.c.) injection. With high-dose, high-frequency 
      interferon (IFN)-beta1a (Rebif) these AEs are generally mild but may lead to the 
      discontinuation of some patients. The objective of this study was to compare the 
      safety, tolerability, and the pharmacokinetic (PK) and pharmacodynamic (PD) 
      profiles of two new formulations of Rebif (Rebif New Formulation: RNF1 and RNF2) 
      with the current formulation (hereafter referred to as R) and placebo. METHODS: 
      In this double-blind, placebo-controlled, parallel-group, Phase I study, healthy 
      volunteers of both sexes were randomized 1:1:1:1 to receive a single 0.5 ml s.c. 
      dose of RNF1, RNF2, R or placebo (normal saline). The three active treatments 
      contained 44 microg IFN-beta1a. During the 24-hour post-dose period, safety and 
      tolerability assessments were conducted and blood samples were taken at regular 
      intervals for PK and PD analyses. Pain intensity on injection was measured using 
      the short-form McGill questionnaire and a 100 mm visual analogue scale (VAS). 
      Further safety assessments were performed and blood samples taken at 24-hour 
      intervals until Day 7 post-dose, with a final post-study visit 10- 14 days after 
      dosing. RESULTS: A total of 48 subjects (22 men, 26 women) were recruited and 
      allocated equally to each treatment (12 subjects per group). AEs were reported by 
      10 subjects in each active treatment group and by 3 subjects in the placebo 
      group. All AEs were consistent with the known safety profile of R. The number of 
      treatment-emergent AEs was lower in the RNF2 group than the RNF 1 or R groups 
      (21, 31 and 33 events, respectively). Redness at the injection site was mostly 
      mild and occurred in fewer subjects in the RNF2 group (n = 3) than the RNF 1 or R 
      groups (n = 7 and n = 4, respectively). Injection site pain was reported by 1 
      subject in the RNF2 group, compared with 4, 6 and 3 subjects, respectively, in 
      the RNF1, R and placebo groups. The worst pain intensity, as measured by VAS, was 
      lower in the RNF2 and RNFI groups than either the R or placebo groups. There was 
      considerable intersubject variability in the PK and PD profiles of the three 
      formulations of IFN-beta1a. Nevertheless, the PK and PD characteristics of RNF2 
      were similar to those of R. CONCLUSIONS: The results from this study suggest that 
      RNF2 may offer improved tolerability compared with the current formulation of R, 
      but retains comparable pharmacokinetic and pharmacodynamic characteristics.
FAU - Brearley, C
AU  - Brearley C
AD  - Merck Serono International S.A., Geneva, Switzerland.
FAU - Jaber, A
AU  - Jaber A
FAU - Bertolino, M
AU  - Bertolino M
FAU - Priestley, A
AU  - Priestley A
FAU - Seiberling, M
AU  - Seiberling M
LA  - eng
PT  - Comparative Study
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
PL  - Germany
TA  - Int J Clin Pharmacol Ther
JT  - International journal of clinical pharmacology and therapeutics
JID - 9423309
RN  - 0 (Recombinant Proteins)
RN  - 0 (beta 2-Microglobulin)
RN  - 670-65-5 (Neopterin)
RN  - 82115-62-6 (Interferon-gamma)
SB  - IM
MH  - Adolescent
MH  - Adult
MH  - Area Under Curve
MH  - Chemistry, Pharmaceutical
MH  - Double-Blind Method
MH  - Female
MH  - Half-Life
MH  - Humans
MH  - Hydrogen-Ion Concentration
MH  - Injections, Subcutaneous
MH  - Interferon-gamma/adverse effects/*pharmacokinetics/*pharmacology
MH  - Male
MH  - Middle Aged
MH  - Neopterin/blood
MH  - Pain/chemically induced/epidemiology
MH  - Pain Measurement/drug effects
MH  - Recombinant Proteins
MH  - Surveys and Questionnaires
MH  - Treatment Outcome
MH  - beta 2-Microglobulin/blood
EDAT- 2007/06/29 09:00
MHDA- 2007/08/01 09:00
CRDT- 2007/06/29 09:00
PHST- 2007/06/29 09:00 [pubmed]
PHST- 2007/08/01 09:00 [medline]
PHST- 2007/06/29 09:00 [entrez]
AID - 10.5414/cpp45307 [doi]
PST - ppublish
SO  - Int J Clin Pharmacol Ther. 2007 Jun;45(6):307-18. doi: 10.5414/cpp45307.