Pharmacokinetics of a Once-Daily extended-release formulation of pramipexole in healthy male volunteers: Three studies

• Published in: Clinical therapeutics 2009-11, Vol.31 (11), p.2698-2711
• Main Authors: Jenner, Peter, PhD, DSc, Könen-Bergmann, Michael, MD, Schepers, Cornelia, MSc, Haertter, Sebastian, PhD
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Antiparkinson Agents - administration & dosage; Antiparkinson Agents - adverse effects; Antiparkinson Agents - pharmacokinetics; Area Under Curve; Benzothiazoles - administration & dosage; Benzothiazoles - adverse effects; Benzothiazoles - pharmacokinetics; Bioavailability; Bioequivalence; Biological and medical sciences; Biological Availability; Body Mass Index; Chemistry, Pharmaceutical; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Delayed-Action Preparations; Dietary Fats; Dopamine; Drug dosages; Dyskinesia; extended release; Food-Drug Interactions; Health sciences; Humans; immediate release; Internal Medicine; Male; Medical Education; Medical sciences; Nervous system (semeiology, syndromes); Nervous system as a whole; Neurology; Parkinson's disease; Pharmacokinetics; Pharmacology. Drug treatments; pramipexole; Reproducibility of Results; steady state; Young Adult
• ISSN: 0149-2918; 1879-114X
• DOI: 10.1016/j.clinthera.2009.10.018

Abstract Background: Pramipexole is a dopamine agonist used in the treatment of Parkinson's disease. The currently available immediate-release (IR) formulation is taken orally 3 times daily. Objectives: These studies were conducted to evaluate the pharmacokinetic properties of a variety of prototypes for a once-daily extended-release (ER) formulation of pramipexole and to further characterize the prototype whose pharmacokinetics best matched those of the IR formulation. Methods: Three Phase I studies were conducted, all in healthy adult men aged ≤50 years with a body mass index of 18.5 to 29.9 kg/m2 . In the first study, 7 prototypes of a once-daily ER formulation with various release properties, including rate and pH dependence, were compared with the IR formulation taken 3 times daily to identify the optimal pharmacokinetic resemblance based on predefined criteria derived from plasma AUC0−24h , Cmax , and Cmin . In the second study, a level A in vitro/in vivo correlation (IVIVC) suitable for predicting an entire in vivo bioavailability time course based on in vitro dissolution was established and validated, and the single-dose pharmacokinetics of the optimal ER formulation identified in the first study were analyzed for food effect. In the third study, steady-state pharmacokinetics of the optimal ER formulation were assessed across a range of pramipexole doses (0.375–4.5 mg/d), including investigation of the food effect at steady state for the highest dose. Tolerability was assessed throughout all studies based on physical examinations, laboratory measurements, and adverse events (AEs). Results: The 3 studies included 18, 15, and 39 subjects, respectively. Among the ER prototypes tested at 0.75 mg once daily in study 1, a matrix tablet had the optimal pharmacokinetic resemblance to IR pramipexole 0.25 mg TID, with a geometric mean AUC0−24h,ss of 17.4 ng·h/mL (vs 16.0 ng·h/mL for the IR formulation), Cmax,ss of 0.967 ng/mL (vs 1.09 ng/mL), and Cmin,ss of 0.455 ng/mL (vs 0.383 ng/mL). For single-dose ER 0.375 mg administered in the fasted state in study 2, in vivo bioavailability was predictable from in vitro dissolution data, with internal mean absolute percent prediction errors of 3.18% for AUC0−30h and 4.87% for Cmax , and external mean absolute prediction errors of 6.61% and 3.34%, respectively, satisfying current guidelines for a level A IVIVC. For single-dose ER 0.375 mg administered in the fed state, the upper bound of the 90% CI for fed:fasted valu