S. Rietbrock, S. Harder, H. Baas
Dept. Clinical Phamacology, University Hospital, Frankfurt/Main, Germany
Apomorphine (AM) is an agonist of dopaminergic receptors in the
striatum. We investigated the influence of AM given in a low,
subclinical dose (1 mg/h s.c. over 6 h) on the PK/PD-
relationship of a single dose of oral levodopa (LD, 100mg+25mg
benserazide) in 10 patients with advanced Parkinson's disease.
The Columbia Rating Scale (CURS
) was used for assessment
of effects. The PK/PD-analysis was caried out using a
conventional two-step-approach and based on a sigmoidal
Emax-model with a semiparametric approach for the effect-site
equilibrium (Teq=ln2/ke0). The analysis was then reevaluated
using NONMEM IV to compare the performance of these two methods
in a data-rich situation and under consideration of a complex
PK/PD model. Post-hoc estimates (first order) were obtained. The
structure of the NONMEM-model was as follows:
Table: PK/PD-parameters of LD alone and other with AM
Results:
The concentration/time profile of LD suggested no significant PK
interaction between LD and AM. Clinically, a 30%-increase in the
duration of the on-period was seen, due to a significant decrease
in the EC50 of LD as seen by the two step procedure (table).
Hysteresis (Teq) was not present or significantly shortened under
AM when individual curves were analyzed. NONMEM analysis proves
the significant reduction in LD potency and the reduction in Teq
when the treatment phase (AM-coadministration) was introduced in
a basic PK/PD model. Paramters of both methods (i.e. the mean of
the individual curves and the population mean 
) as well as the
extend of the left shift and the reduced Teq were found in good
agreement. We conclude that NONMEM is a suitable method for PK/PD
modeling and might be used instead the two step procedure.