Evaluation of the population pharmacokinetic properties of lidocaine and its metabolites, MEGX, GX, and 2,6-xylidine, after application of lidocaine 5% medicated plaster.
J. Grevel1, E. Fuseau1, C. Crepin1, M. Vernaz-Gris1, M. Marchand1, D. Huntjens2
1EMF Consulting, Aix-en-Provence, France, 2GrŁnenthal Research and Development, Aachen, Germany
Background/Aims: Patients suffering from postherpetic neuralgia were treated with medicated plasters after healing of the herpes zoster skin rash. Lidocaine acts locally in the skin and only a very small portion of the topically applied lidocaine with a maximum number of three plasters reaches the circulation. This systemic exposure was quantified.
Methods: 1989 serum concentrations of lidocaine and its metabolites MEGX, GX, and 2,6-xylidine were measured in 212 patients participating in two clinical trials for up to one year. Population PK analysis was carried out with NONMEM, V, using a linear model with 4 compartments, one for each chemical entity. The influence of study design parameters and patient covariates on PK parameters was investigated with categorical models (cut-off at the 70th percentile). Models were evaluated with visual performance predictive checks. Monte Carlo simulations demonstrated the variability in exposure.
Results: The serum concentrations were best modelled with a zero order input into the central compartment which lasted for as long as the plaster was applied (12 h). Repeated applications every 24 h did not change the kinetics. The application of more than 2 plasters simultaneously led to lower than expected concentrations of lidocaine MEGX, GX, and 2,6-Xylidine. Statistically significant covariate effects were found, but their influence on steady state concentrations was altogether weak. Median individual predictions of serum concentrations ranged from 29.4 to 35.8 ng/mL and 10.3 ng/mL (not influenced by covariates) and from 5.6 to 9.6 ng/mL and from 5.2 to 7.1 ng/mL for lidocaine, MEGX, GX, and 2,6-xylidine, respectively, after repeated application of 3 plasters with and without the influence of covariates. These steady state concentrations were reached already by the 4th day of treatment.
Conclusions: Systemic exposure to lidocaine and its metabolites in patients treated for neuropathic pain associated with postherpetic neuralgia with topically applied 5% medicated plasters was very low in comparison to the therapeutic range of systemically applied lidocaine.