RESUMO
Pramipexole is the first-line medication recommended by the British National Institute for Health and Care Excellence. Pramipexole is predominantly eliminated by renal excretion. The aim was to develop a physiologically based pharmacokinetic (PBPK) model of pramipexole, providing a basis for its individualized administration. The role of glomerular filtration and organic cation transporter 2 (OCT2) in renal tubular secretion was considered. Plasma concentration-time profiles of pramipexole were predicted and validated, first in healthy populations and then in PD patients with varied renal function. Finally, the pharmacokinetics of PD patients with different degrees of renal impairment were predicted. The simulated pharmacokinetic parameters, including maximum plasma concentration (Cmax ), area under the plasma concentration-time curve (AUC), time to maximum plasma concentration (tmax ), and steady-state trough plasma concentration values, obtained using the PBPK model were validated using fold error values, which were all smaller than 2. The successfully validated model supported that OCT2-mediated tubular secretion was affected proportionally to changes in glomerular filtration for various degrees of renal impairment. The predicted AUC0-inf values were increased 1.16-, 1.76-, 3.26-, and 9.48-fold in mild, moderate, and severe renal impairment and end-stage renal disease (ESRD) subjects, resepctively, compared with PD patients with normal renal function. It appears that PD patients with mild renal impairment are unlikely to require dose adjustment (0.125 mg 3 times a day). The pramipexole dose should be reduced to approximately 0.125 mg twice daily, 0.125 mg once daily, and 0.0375 mg once daily in PD patients with moderate renal impairment, severe renal impairment, and ESRD, respectively.
Assuntos
Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Pramipexol/farmacocinética , Insuficiência Renal/metabolismo , Administração Oral , Adulto , Idoso , Área Sob a Curva , Simulação por Computador , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Transportador 2 de Cátion Orgânico/metabolismo , Pramipexol/administração & dosagem , Pramipexol/sangue , Eliminação Renal , Distribuição Tecidual , Adulto JovemRESUMO
An efficient, selective, sensitive, and rapid ultra-performance liquid chromatography tandem mass spectrometry method was established and validated for the quantification of pramipexole dihydrochloride monohydrate and levodopa simultaneously in human plasma with the aid of diphenhydramine as an internal standard. A simple protein precipitation technique with HPLC grade acetonitrile was efficiently utilized for the cleanup of plasma. The analysis was performed using a Hypersil gold 50 mm × 2.1 mm (1.9 µm) column and a mobile phase of 0.2% formic acid and methanol (90: 10 v/v). The triple-quadrupole mass spectrometer equipped with an electrospray source operated in the positive mode was set up in the selective reaction monitoring mode (SRM) to detect the ion transitions m/z 212.15 â153.01, m/z 198.10â 135.16, and m/z 255.75 â 166.16 for pramipexole dihydrochloride monohydrate, levodopa, and diphenhydramine, respectively. The method was thoroughly validated according to FDA guidelines and proved to be linear, accurate, and precise over the range 100-4000 pg/mL for pramipexole dihydrochloride monohydrate and 60-4000 ng/mL for levodopa. The proposed method was effectively applied for monitoring both drugs in plasma samples of healthy volunteers.