ABSTRACT
Rolofylline is a potent, selective adenosine A1 receptor antagonist that was under development for the treatment of patients with acute congestive heart failure and renal impairment. Rolofylline is metabolized primarily to the pharmacologically active M1-trans and M1-cis metabolites (metabolites) by cytochrome P450 (CYP) 3A4. The aim of this investigation was to provide a pharmacokinetic (PK) model for rolofylline and metabolites following intravenous administration to healthy volunteers. Data included for this investigation came from a randomized, double-blind, dose-escalation trial in four groups of healthy volunteers (N=36) where single doses of rolofylline, spanning 1 to 60 mg ,were infused over 1-2 h. The rolofylline and metabolite data were analyzed simultaneously using NONMEM. The simultaneous PK model comprised, in part, a two-compartment linear PK model for rolofylline, with estimates of clearance and volume of distribution at steady-state of 24.4 L/h and 239 L, respectively. In addition, the final PK model contained provisions for both conversion of rolofylline to metabolites and stereochemical conversion of M1-trans to M1-cis. Accordingly, the final model captured known aspects of rolofylline metabolism and was capable of simultaneously describing the PK of rolofylline and metabolites in healthy volunteers.
Subject(s)
Adenosine A1 Receptor Antagonists/pharmacokinetics , Models, Biological , Xanthines/pharmacokinetics , Adenosine A1 Receptor Antagonists/administration & dosage , Adenosine A1 Receptor Antagonists/blood , Adolescent , Adult , Biotransformation , Cytochrome P-450 CYP3A/metabolism , Double-Blind Method , Humans , Infusions, Intravenous , Linear Models , Male , Metabolic Clearance Rate , Xanthines/administration & dosage , Xanthines/blood , Young AdultABSTRACT
OBJECTIVE: The efficacy of antihistamines in perennial allergic rhinitis in children has been evaluated in studies using active comparators, whereas placebo-controlled studies are very few. A randomized, multicenter, double-blind, parallel-group clinical study was carried out to evaluate the dose-response relationship and superiority of olopatadine hydrochloride over placebo in children aged 7 to 16 years with perennial allergic rhinitis. METHODS: Subjects received twice daily treatment for two weeks with either olopatadine 2.5 mg, 5 mg or placebo after a one-week observation period. Efficacy was assessed based on the diary card score the subject (or guardian) recorded. RESULTS: Of the 302 subjects randomized, two were excluded from analysis: one did not receive treatment; the other was not monitored for efficacy parameters. The remaining 300 subjects (97 in the placebo group, 103 in the olopatadine 2.5-mg group and 100 in the olopatadine 5-mg group) constituted the full analysis set (FAS) for the efficacy analysis. As a primary endpoint, the total three nasal symptom score (for sneezing, rhinorrhea and nasal congestion) at final assessment was compared with baseline or the score obtained in the observation period. The change from baseline was then tested using analysis of covariance (ANCOVA) with the baseline score as covariate. Williams' test was applied to the least squares means estimated from this ANCOVA model for each treatment group, resulting in showing the monotonicity Williams' test assumed. The total three nasal symptom score significantly improved in the 5-mg group compared with the placebo group (p = 0.019). In contrast, the 2.5-mg group did not differ statistically from the placebo group. Adverse events occurred in 33.7% (33/98 subjects) in the placebo group, 35.9% (37/103 subjects) in the 2.5-mg group and 35.0% (35/100 subjects) in the 5-mg group. There were no serious or severe adverse events. CONCLUSIONS: Olopatadine hydrochloride 5 mg twice daily is an effective and safe treatment for perennial allergic rhinitis in children.
