Annual Report of Activities CNC 2008 - Center for Neuroscience and ...

Pharmacometrics | Head: Amílcar Falcão FerreiraObjectivesPharmacometrics is the science of developing andapplying mathematical and statistical methods tocharacterize, understand, and predict a drugs’spharmacokinetic, pharmacodynamic, andbiomarker‐outcomes behaviour. In effect,pharmacometrics is the science of interpreting anddescribing pharmacology in a quantitative fashion.We explored methods to predict early in the drugdevelopment the ADME (Absorption, Distribution,Metabolism and Excretion) as well as drug‐druginteractions of new chemical entities (NCEs).Model‐based drug development is characterised bythe development and application ofpharmacostatistical models of drug efficacy andsafety from non‐clinical and clinical data toimprove drug development knowledgemanagement and decision making.Main AchievementsThe Pharmacometrics Group as a new group(started in 2007), has a small experience to share atthe present time. Therefore, some individualongoing projects were incorporated in the groupand some of our achievements can be easily foundanalysing the productivity section. Nevertheless,our preclinical research studies in new drugdevelopment process focused on eslicarbazepineacetate could be the considered the main structuredachievement in 2008.Eslicarbazepine acetate (ESL) is a promising centralnervous system‐active compound recentlyaccepted by the authorities to be put on theEuropean market for the treatment of epilepsy(submission to FDA are going on). In the last years,we have been involved in the ESL developmentprogram to complete the pharmacokinetic dataobtained from preceding and ongoing ESL clinicaltrials. Since pharmacokinetic studies imply theevaluation of drug concentrations over the time inthe biological matrices of interest, we developedand validated the first chiral liquidchromatographic method with ultraviolet detection(LC‐UV) to determine ESL and its metabolites [Slicarbazepine(S‐Lic), R‐licarbazepine (R‐Lic) andoxcarbazepine (OXC)] in mouse plasma and brain,liver and kidney tissue homogenates. Additionally,a similar LC‐UV method was also developed inhuman plasma, making available a useful tool notonly to support ESL clinical research but also to theroutine therapeutic drug monitoring assays.Recently we characterized the pharmacokineticsand the oral biodisposition of ESL in adult maleCD‐1 mice, and then we studied thepharmacokinetics and the enantioselectivedisposition of S‐Lic and R‐Lic (pharmacologicallyactive metabolites of ESL).ESL is rapidly and extensively metabolised in miceto S‐Lic (major metabolite), which is then oxidisedto OXC to a small extent. R‐Lic was not found inmeasurable amounts in all matrices. On the otherhand, following the oral administration to mice ofeach licarbazepine enantiomer separately, it wasnoted that S‐Lic and R‐Lic were rapidly absorbedand immediately distributed, at least, to the highlyperfused tissues. Both licarbazepine enantiomerswere metabolized to a small extent but, even so, thebi‐directional chiral inversion was observed and itoccurred preferentially in the R→S direction.52OOCH 3NONH 2ESLHOONONH2S-LicNO NH 2OXCHONTrans-diolONH2R-LicProposed metabolism of ESL, S‐Lic and R‐Lic in CD‐1 mice.The thickness of the arrows indicates the relative extent ofthe metabolic pathways.