2007 - KÝbenhavn - Denmark

PAGE 2007: Applications- Other topics
Roger Jelliffe

A Population Model of Epidural Lidocaine

Andrea Kwa, Pharm.D1, Juraj Sprung, M.D., Ph.D.2, Michael Van Guilder, Ph.D3., Roger W. Jelliffe, M.D.3

USC School of Medicine

Objectives: To examine the population behavior of epidural lidocaine in geriatric patients, and to search for any difference in the PK behavior of epidural lidocaine when dopamine is given concurrently.

Methods: Twenty patients over age 65, undergoing peripheral vascular surgery under continuous lidocaine epidural anesthesia, were studied. Ten received an intravenous (IV) infusion of placebo (normal saline), while ten other patients received an IV infusion of dopamine at 2 mg/kg/min. Total arterial plasma lidocaine concentrations (gas-chromatographic assay) were measured just before injecting the first epidural dose (baseline) and then at 5, 15, 30, 60, 90, 120 min and hourly thereafter.  Samples were also taken when the lidocaine infusion was stopped at the end of the surgery, and at 30min, 60min, 90min, 2h, 3h, 4h, and 5h after surgery. The nonparametric adaptive grid (NPAG) computer program in the MM-USC*PACK collection was utilized for population PK modeling to obtain the entire discrete maximum likelihood joint parameter distribution [1-3]. The assay error polynomial was determined to be 0.2 + 0.05*C. The structural population PK model was linear, and had 3 compartments, each with first order transfer kinetics.

Results: Lidocaine had a very fast transfer rate constant (Ka part + K2-0) from the epidural space to the serum compartment, and this rate was slowed, by about 40%, probably significantly, by dopamine. The rate constant of elimination from the serum compartment (K2-0) was somewhat increased by dopamine. The rate constant for drug movement from central to peripheral compartment (K2-3) was also somewhat increased in the dopamine patients. The rate constant back from the peripheral to the central compartment (K3-2) was somewhat slowed by dopamine. There was no obvious difference in the apparent volume of distribution of the central compartment between the placebo and the dopamine patients.

Table 1.  Mean, median, standard deviation, and % coefficient of variation (CV) of pharmacokinetic parameters for the placebo, dopamine, and combined placebo and dopamine groups.

Parameter

Mean

Median

SD

% CV

Ka part

 

 

 

 

Placebo

37.791

22.723

42.232

111.751

Dopamine

16.604

13.394

11.078

  66.719

All patients

33.569

18.840

42.250

125.860

K20

 

 

 

 

Placebo

0.3098

0.3379

0.0644

20.788

Dopamine

0.3399

0.3041

0.0985

28.979

All patients

0.3189

0.2995

0.0703

22.044

K23

 

 

 

 

Placebo

0.9377

0.2024

1.6024

170.886

Dopamine

1.3784

0.6295

2.4894

180.600

All patients

1.2736

0.5847

2.0960

164.572

K32

 

 

 

 

Placebo

2.8161

0.5581

4.3401

154.117

Dopamine

1.5237

0.4125

3.2954

216.276

All patients

2.1861

0.4389

3.9000

178.400

Volume of Distribution of Compartment 2

Placebo

106.2905

88.7317

40.6795

 38.2720

Dopamine

94.6621

91.0094

32.7763

 34.6245

All patients

98.8996

90.7130

34.4857

 34.8694

Conclusions: In this first population model of epidural lidocaine, to our knowledge, low-dose dopamine appears to decrease the rate of transfer of lidocaine from the epidural to the serum compartment, and also to increase both the rate of elimination of lidocaine and its transfer between the central (serum) and peripheral compartment, presumably by increasing tissue perfusion. Serum lidocaine concentrations were slightly less in the dopamine patients. Dosage requirements (overall infusion rates) were also similar for the two groups, though they were slightly less for the dopamine patients, consistent with the slower removal of lidocaine from the epidural compartment. This model may be useful in the future to design more optimal epidural infusion protocols.

References:
[1] Schumitzky A. Nonparametric EM algorithms for estimating prior distributions. App. Math Computation 1991;45:143-57.
[2] Leary R, Jelliffe R, Schumitzky A, and Van Guilder M: A Unified Parametric/Nonparametric Approach to Population PK/PD Modeling. Presented at the Annual Meeting of the Population Approach Group in Europe, Paris, France, June 6-7, 2002.
[3] Bustad A, Terziivanov D, Leary R, Port R, Schumitzky A, and Jelliffe R: Parametric and Nonparametric Population Methods: Their Comparative Performance in Analysing a Clinical Data Set and Two Monte Carlo Simulation Studies. Clin. Pharmacokinet.,45: 365-383, 2006.




Reference: PAGE 16 (2007) Abstr 1072 [www.page-meeting.org/?abstract=1072]
Poster: Applications- Other topics
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