Importance of within subject variation in levodopa pharmacokinetics: A 4 year cohort study in Parkinson's disease

被引:21
作者
Chan, PLS [1 ]
Nutt, JG
Holford, NHG
机构
[1] Univ Auckland, Dept Pharmacol & Clin Pharmacol, Auckland 1, New Zealand
[2] Oregon Hlth & Sci Univ, Portland, OR 97201 USA
[3] Portland VA Med Ctr, Dept Neurobiol Physiol & Pharmacol, Portland, OR USA
[4] Pfizer Inc, Ann Arbor, MI 48105 USA
关键词
levodopa; within subject variability; pharmacokinetics; Parkinson's disease; population approach;
D O I
10.1007/s10928-005-0039-x
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
The purpose of the study was to describe the population pharmacokinetics of levodopa in patients with Parkinson's disease studied in 5 trials (10 occasions) over 4 years. Twenty previously untreated Parkinsonian patients were investigated. Each trial consisted of a 2-hr IV infusion of levodopa (1 mg/kg/h) with concomitant oral carbidopa given on two occasions separated by 72hr with no levodopa in between. This trial design was repeated at 6, 12, 24 and 48 months. A two-compartment pharmacokinetic model with central volume (V-1), peripheral volume (V-2), clearance (CL) and inter-compartmental clearance (CLic) was used to fit plasma levodopa concentrations. The model accounted for levodopa dosing prior to each trial and endogenous levodopa synthesis. Population parameter estimates (geometric mean) and population parameter variability (PPV; SD of normal distribution) were V-1 11.4 l/70 kg (0.44), CL 30.9 l/h/70 kg (0.25), V-2 27.3 l/70 kg (0.27), and CLic 34.6 l/h/70 kg (0.48). PPV was partitioned into between subject variability (BSV) which was 0.12 V-1, 0.13 CL, 0.15 V-2, 0.28 CLic, within trial variability (WTV) which was 0.16 V-1, 0.13 CL, 0.08 V-2, 0.18 CLic and between trial variability (BTV) which was 0.40 V-1, 0.17 CL, 0.21 V-2, 0.34 CLic. Neither structural nor random levodopa pharmacokinetic parameters were associated with the time course of development of fluctuation in motor response. Variability in levodopa pharmacokinetic parameters (particularly V-1) may result in variability in plasma levodopa concentrations that could contribute to fluctuations in motor response.
引用
收藏
页码:307 / 331
页数:25
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