A pharmacokinetic-pharmacodynamic model for intrathecal baclofen in patients with severe spasticity

Abstract

Aims: Intrathecal baclofen (ITB) has proven to be an effective and safe treatment for severe spasticity. However, although ITB is used extensively, clinical decisions are based on very scarce pharmacokinetic-pharmacodynamic (PKPD) data. The aim of this study was to measure baclofen CSF concentrations and clinical effects after administration of various ITB boluses in patients with spasticity and to create a PKPD model for ITB.

Methods: Twelve patients with severe spasticity received four different bolus doses of ITB (0, 25, 50, 75 μg and an optional dose of 100 μg), administered via a catheter with the tip at thoracic level (Th) 10. After each bolus, 10 CSF samples were taken at fixed time intervals, using a catheter with the tip located at Th12. Clinical effect was assessed by measuring spasticity with the Modified Ashworth Scale (MAS). These data were used to develop a PKPD model.

Results: All patients achieved an adequate spasmolytic effect with ITB doses varying from 50 to 100 μg. No serious side effects were observed. CSF baclofen concentrations, as well as the clinical effects, correlated significantly with ITB doses. The PK model predicted a steep spinal concentration gradient of ITB along the spinal axis. The clinical effect could be predicted using a delayed-effect model.

Conclusions: ITB is an effective and safe therapy with, however, a steep concentration gradient along the spinal axis. This means that the administered baclofen is staying mainly around the catheter tip, which stresses the importance to position the ITB catheter tip closely to the targeted spinal level.

Figure 1

Pharmacokinetic model for intrathecal baclofen, based on the diffusion–distribution model from Shafer & Shafer 8. The intrathecal space (V1) is distributed in a series of 57 connected compartments. Each compartment communicates with the adjacent tissue (V2). The caudal end of the model is closed, the rostral end is open

Figure 2

CSF baclofen concentration vs. time after the administration of different doses of ITB

Figure 3

MAS vs. time after the administration of different doses of ITB

Figure 4

CSF baclofen concentration (upper) and MAS (lower) vs. time after administration of three doses of ITB in two patients. The dotted line represents the observed concentration (upper) and MAS (lower), the solid line the individual predicted fit and the dashed line the population predicted fit

Figure 5

Predicted CSF baclofen concentration–time profile at different distances below the catheter tip after administration of 50 μg for patient 4 and 10. — 0 cm (administration), – – 6 cm (sample), ‐‐‐ 12 cm, ‐‐‐‐‐ 18 cm, ········· 24 cm

Figure 6

Population prediction for PK (baclofen concentration in sample compartment) and PD (MAS) after four doses of baclofen, based on the PKPD model for ITB. — population predicted PK, ‐‐‐ population predicted PD