Population pharmacokinetic analysis of pramipexole extended-release formulation in Parkinson’s Disease (PD) patients
C Dansirikul1, A Staab1, L Salin2, S Haertter1, and T Lehr1
1Boehringer Ingelheim Pharma GmbH & Co. KG, Department of Drug Metabolism and Pharmacokinetics, 88397 Biberach an der Riss, Germany; 2 Boehringer Ingelheim France, Medical and Drug Regulatory Affairs, 12 rue André Huet, 51060 Reims cedex, France
Background and Objectives: A pramipexole extended release (ER) formulation administered once daily was developed to facilitate improved compliance compared to the immediate release (IR) formulation administered three times daily. A recently performed phase III study investigating the efficacy and safety of pramipexole ER in early PD patients included sparse pharmacokinetic (PK) sampling. Objectives of this analysis were to describe the PK and to investigate possible covariates for their influence on the PK of pramipexole in early PD patients, as well as to provide dosing recommendation for the use of pramipexole ER in renally impaired PD patients.
Methods: Concentration-time data from 146 early PD patients (699 plasma concentrations) who received pramipexole IR or ER formulation were available. Model development was based on Phase I data (1058 plasma concentrations, from 39 healthy volunteers). The developed base model was fitted to the phase III data and refined. Stepwise covariate analysis was performed. A dosage regimen for early PD patients with mild (creatinine clearance (CRCL) 50 to 80 mL/min) and moderate (CRCL 30 to 50 mL/min) renal impairment was defined using a simulation approach.
Results: Pramipexole plasma concentrations were best described by a two-compartment model with first order elimination. For the IR formulation, absorption was described by a first-order rate constant and a lag time. For the ER formulation, a sequential zero and first order absorption process was applied. The effect of CRCL on pramipexole apparent clearance (CL/F) and of body weight on apparent volume distribution of peripheral compartment (V3/F) for pramipexole ER were identified. The typical CL/F was 29.2 L/h when CRCL is greater than or equal to 121 mL/min. It was reduced by 0.74% for one unit smaller in CRCL. The typical V3/F for a 75 kg patient was 313 L, which changed by 2.26% for 1 kg change in body weight. Patients with mild renal impairment do not need any dose adaptation. Patients with moderate renal impairment should receive an initial dose of 0.375 mg (lowest dose) every second day for the first 7 days. In patients with moderate renal impairment, administration every second day provided a similar exposure to patients with mild to no renal impairment who received a once daily dose.
Conclusions: The PK model was successfully developed to describe the sparse data in early PD patients. CRCL was the clinically relevant covariate that leads to a dosing schedule adjustment for patients with moderate renal impairment.