Paula Granić

Association between lamotrigine concentrations and ABCB1 polymorphisms in patients with epilepsy.

Background: Epilepsy is treated with a variety of anticonvulsants that are often used concomitantly. Therefore, therapeutic drug monitoring is often necessary. Along with clinical and environmental factors, genetic predisposition has been recognized to be relevant for interindividual variability in drug response. Polymorphic transporter proteins such as P-glycoprotein significantly influence pharmacokinetics and bioavailability of many structurally unrelated drugs. The aim of the study was to evaluate the impact of polymorphisms in the P-glycoprotein–encoding gene ABCB1 (C1236T, G2677T/A, C3435T) on antiepileptic drug disposition. Methods: We recruited 222 patients with epilepsy who were prescribed lamotrigine in monotherapy or polytherapy. Lamotrigine plasma concentrations were analyzed and compared with ABCB1 gene variants. The ABCB1 genotyping was performed by real-time polymerase chain reaction methods. The therapeutic drug monitoring was performed by high-performance liquid chromatography–diode array detector (DAD) and immunoassay. Results: A significant correlation was confirmed between lamotrigine concentration and additional drugs (P < 0.001). In the whole group, statistical analysis showed correlations between lamotrigine concentrations and ABCB1 C1236T variants: 10.1 and 6.5 &mgr;mol/L for CC versus CT + TT, respectively (P = 0.021), and for dose corrected lamotrigine 0.068 and 0.053 &mgr;mol·L−1·mg−1, for CC versus CT + TT, respectively (P = 0.017). Analysis of a specific haplotype showed that 1236C–2677G–3435C carriers had higher lamotrigine concentrations than 1236T–2677G–3435T carriers (P < 0.001), followed by 1236T–2677T–3435C carriers (P < 0.001). Conclusions: ABCB1 C1236T, G2677T/A, C3435T polymorphisms have an influence on lamotrigine serum concentrations.

Effect of cyclosporine on steady-state pharmacokinetics of MPA in renal transplant recipients is not affected by the MPA formulation: analysis based on therapeutic drug monitoring data.

Background: Two oral mycophenolic acid (MPA) formulations, immediate-release mycophenolate mofetil and enteric-coated mycophenolate sodium, have been shown to differ regarding some drug–drug interactions. The aim was to assess whether the effects of cyclosporine (CsA) on steady-state pharmacokinetics (PK) of MPA in renal transplant patients were affected by MPA formulation. Methods: A prospective, stratified observational study based on therapeutic drug monitoring of MPA (6 total plasma concentrations over a 12-hour dosing interval, &tgr;) in consecutive stable adult renal transplant recipients (n = 68). Results: Patients treated with enteric-coated mycophenolate sodium (n = 45) or mycophenolate mofetil (n = 23) and with either CsA (microemulsion, n = 43) or tacrolimus (Tac) (immediate release, n = 25) were comparable regarding demographics, comorbidity, renal and liver functions, comedication, corticosteroid dose, CsA or Tac dose, and trough concentrations. Based on dose-normalized MPA concentrations and with adjustment for age, sex, body mass index, estimated glomerular filtration rate, and corticosteroid dose, CsA (as compared with Tac) consistently reduced MPA area under the concentration–time curve during the dosing interval at steady state overall [geometric mean ratio (GMR), 0.78; 95% confidence interval, 0.62–0.99] and by MPA formulation (by 22% and 21%, respectively), increased CLT/F,ss overall (1.31; 1.00–1.70) and by formulation (by 25% and 36%, respectively), reduced morning predose MPA concentration overall (0.59; 0.38–0.92) and by formulation (by 34% and 47%, respectively), increased peak–trough fluctuation overall (1.51; 1.06–2.17) and by formulation (by 58% and 45%, respectively), and prolonged tmax,ss overall (adjusted median difference 0.58, 0.04–1.12 hours) and by formulation (by 0.6 and 0.5 hours, respectively). Conclusions: Qualitatively and quantitatively, the effect of CsA on steady-state PK of MPA is not conditional on MPA formulation.