Transcript Pharmacokinetics, induction of anaesthesia and safety

Population pharmacokinetics and pharmacodynamics of
Propofol in morbidly obese patients
Jeroen Diepstraten (1), Simone van Kralingen (2), Mariska Y.M. Peeters (1), Eric P.A. van Dongen (2), Bert
van Ramshorst (3), Vera H. Deneer (1), Meindert Danhof (4) and Catherijne A.J. Knibbe(1,4)
(1) Department of Clinical Pharmacy, St. Antonius Hospital, Nieuwegein, The Netherlands; (2) Department of Anaesthesiology and Intensive Care, St. Antonius Hospital,
Nieuwegein, The Netherlands; (3) Department of Surgery, St. Antonius Hospital, Nieuwegein, The Netherlands; (4) Division of Pharmacology, Leiden/ Amsterdam Center for
Drug Research, Leiden University, Leiden, The Netherlands
INTRODUCTION
The number of morbidly obese patients (BMI > 40 kg/m 2)
undergoing (weightreducing) surgery increases. However, the dose
of anesthetics is unknown because of the lack of evidence of the
exact pharmacokinetics and -dynamics. We therefore developed a
population PK-PD model of propofol used for anesthesia in
morbidly obese patients, thereby studying the influence of
covariates.
Tabel 1.
Covariate analysis in
morbidly obese patients:
Total Body Weight (TBW)
Lean Body Weight (LBW)
Ideal Body Weight (IBW)
Body Mass Index (BMI)
Model
Covariate
Simple
Lineair
LBW on
clearance
IBW on
clearance
BMI on
clearance
TBW on
clearance
Lineair
Allometric
fixed
Allometric
fixed
Objective No. of
function
structural
parameters
-643
6
-638
7
-641
7
-651
7
-653
7
METHODS
In morbidly obese patients induction and maintenance of
anesthesia was performed using propofol with use of the Bispectral
index (BIS). Population PK-PD modelling was performed using
NONMEM VI. A step-wise covariate analysis was performed for
TBW, LBW, IBW, BMI, age, sex, creatinine, bilirubin, PEEP and
remifentanil. The analysis was repeated with inclusion of 44 nonobese patients [1,2]. Bootstrap resampling (250 times) method was
used to assess the stability of the parameter estimates and the
robustness of the final model.
Figure 1. Diagnostic plots for propofol pharmacokinetics and effect (BIS)
in morbidly obese patients including observations versus individualpredictions (A) and observations versus population-predictions (B).
PK-Final Total Body Weight model
PD-Final model
Pop. parameters (CV%):
EC50 = 1,41 mg/L (20,36)
Hill coefficient = 7,17
Emax = 59.1 BIS units(7,34)
Baseline = 91,8 BIS units
Keo = 0.071 min-1 (36,80)
REFERENCES
Tabel 2. Population parameter estimates of the pharmacokinetic model and
the stability of the parameters using the bootstrap validation.
Obese
Obese
Obese
Parameter
Simple model
(CV%)
Total Body
Weight model
(CV%)
Final Total
Body Weight
model (CV%)
Obese
Number of
patients
Cl (L/min)
CL 70 kg (Lmin)
b
V1 (L)
V2 (L)
V3 (L)
Q1 (L/min)
Q2 (L/min)
20
20
20
3,58 (4,83)
4,52 (13,03)
22,20 (18,92)
106,00 (12,64)
2,56 (14,26)
1,41 (15,46)
2,33 (14,08)
0,72 (34,40)
4,52 (13,10)
22,20 (19,68)
107,00 (12,80)
2,55 (14,82)
1,41 (15,39)
2,29 (3,31)
0,75 FIX
4,52 (13,05)
22,20 (19,64)
107,00 (12,90)
2,55 (14,78)
1,41 (15,25)
Obese and
Non-Obese [1, 2]
Bootstrap Final Final Total Body
Total Body
Weight model
Weight model
(CV%)
250 x (%)
64
98,3%
2,17 (2,60)
0,75 FIX
98,2%
3,10 (9,65)
104,5%
5,52 (10,74)
115,0%
120 (7,61)
100,8%
1,90 (5,47)
100,0%
1,66 (8,43)
OF
-643
-653
-653
97,4%
-1836
Omega CL (%)
Omega V1 (%)
Omega V3 (%)
16,13 (36,05)
45,35 (42,12)
30,04 (46,94)
11,87 (28,86)
44,68 (46,76)
28,92 (47,57)
11,96 (28,72)
44,68 (47,14)
28,90 (47,13)
97,5%
116,3%
123,6%
18,23% (18,78)
44,41% (43,06)
27,36% (22,99)
Sigma (%)
29,38 (15,36)
29,44 (15,52)
29,44 (15,52)
134,8%
27,77 (20,05)
30,51 (15,96)
19,86 (18,58)
RESULTS
90
70
BIS
Figure 2.
Individual concentrationeffect relationship for BIS
as a function of the
propofol effect
concentration.
The thick black line
represents the population
effect curve.
Figure 3.
Individual posthoc values
of propofol clearance
versus IBW, LBW, TBW
and BMI from the simple
pharmacokinetic model of
morbidly obese patients.
50
30
10
1
3
5
7
Propofol concentration (mg/L)
[1] Knibbe C.A., Eur J Clin Pharmacol 2000; 56: 89-95
[2] Knibbe C.A., Br J Clin Pharmacol 1999; 47: 653-660
9
11
In twenty morbidly obese patients (TBW 98-167 kg, BMI 38-60 kg/m2)
517 propofol samples were collected. In the three-compartment
model, TBW was the only significant covariate (p< 0.001). Its
influence was best characterised using an allometric equation with an
estimated exponential scaling factor of 0.72. In the final model, Cl was
(2.29*(TBW/70)** 0.75)) and no other covariates proved to be
significant for any of the parameters. When the non-obese data sets
were added, similar pharmacokinetic parameters were obtained,
including the estimated allometric function for clearance. Depth of
sedation using the BIS could be described by an indirect sigmoid E max
model.
CONCLUSIONS
In morbidly obese patients, propofol clearance is significantly affected
by TBW in a 0.75 allometric function. The model can be used for
extrapolation to patients outside the study population.