Identifikacija i kvantifikacija faktora varijabilnosti topiramata kod odraskih pacijenata sa epilepsijom

Abstract

Cilj doktorske disertacije je bio da se istraže, otkriju i kvantitativno izraze uticaji faktora koji doprinose varijabilnosti topiramata (TPM) kod odraslih pacijenata sa epilepsijom. Prvi deo istraživanja je bio fokusiran na razvoj populacionog farmakokinetičkog modela TPM primenom nelinearnog modelovanja kombinovanih efekata uz program NONMEM®. Podaci su dobijeni od 78 pacijenata koji su bili na mono ili koterapiji TPM i drugim antiepilepticima. Koncentracije TPM u stanju ravnoteže su određene u uzorcima krvi visoko efikasnom tečnom hromatografijom. Jednoprostorni model sa resorpcijom i eliminacijom prvog reda je korišćen za fitovanje podataka o koncentraciji i vremenu. Razmatrano je ispitivanje uticaja demografskih, biohemijskih i karakteristika terapije na oralni klirens leka (CL/F). Volumen distribucije je procenjen na 0.575 l/kg. Finalni model ukazuje da je povećanje CL/F pod uticajem doze karbamazepina i renalne funkcije najbolje opisano linearnim i eksponencijalnim modelima. Validacija je potvrdila stabilnost i adekvatne prediktivne karakteristike modela. Dobijeni model pruža mogućnost individualizacije režima doziranja TPM u rutinskoj kliničkoj praksi. U drugom delu istraživanja je ispitan uticaj različitih faktora na nivo bikarbonata i kalijuma. Podaci su dobijeni od 59 pacijenata koji su bili na mono ili koterapiji TPM i drugim antiepilepticima, dok su iz uzorka pre primene doze bile dostupne ravnotežne koncentracije TPM kod 54. Analiza podataka je vršena SPSS® programom. Primećena je statistički značajna razlika u vrednosti bikarbonata (p < 0.05) između pacijenata koji su na terapiji TPM duže od 5 godina i onih koji su kraće (ili jednako). Regresiona analiza je potvrdila da nivo bikarbonata opada linearno sa dužinom terapije. Nije primećena značajna veza između doze, nivoa TPM ili starosti pacijenta sa nivoom ispitivanih elektrolita, kao ni između trajanja terapije i nivoa kalijuma. Rezultati ove studije naglašavaju moguću pojavu nižeg nivoa bikarbonata i kod dužeg trajanja terapije TPM, što ukazuje na značaj praćenja.

The objective of the doctoral dissertation was to investigate, detect and quantitatively express influence of factors that contribute to topiramate (TPM) variability in adult patients with epilepsy. The first part of the research was focused on developing population pharmacokinetic model of TPM using nonlinear mixed effects modelling approach with NONMEM® program. Data were collected from 78 patients on mono or co-therapy with TPM and other antiepileptic drugs. Steady-state TPM concentrations were determined in blood samples by high performance liquid chromatography. A onecompartment model with first order absorption and elimination was used to fit the concentration-time data. The influence of demographic, biochemical parameters and therapy characteristics on oral clearance (CL/F) was considered for evaluation. Volume of distribution was estimated at 0.575 l/kg. Final model showed that increase of CL/F with carbamazepine dose and renal function was the best described by linear and exponential models. Validation confirmed stability and adequate predictive performance of the model. This model allows individualization of TPM dosing during routine patient care. In the second part of the research effect of different factors on bicarbonate and potassium levels was examined. Data were collected from 59 patients on mono- or cotherapy with TPM and other antiepileptic drugs, while steady-state TPM trough levels were available from 54. Data analysis was performed by SPSS® program. Significant difference (p < 0.05) in bicarbonate levels was observed between groups of patients treated with TPM longer and shorter than (or equal to) 5 years. Regression analysis showed that bicarbonate levels linearly decreases with therapy duration. No significant association was noted between the TPM dose, level or patient age and investigated electrolytes, as well as between therapy duration and potassium level. The findings of this study highlight possible occurrence of lower bicarbonate level associated also with longer TPM therapy duration, indicating usefulness of monitoring.