Eliminacija paracetamola urinom kod pušača

The aim of this study was to evaluate the influence of smoking on the urine paracetamol elimination. Fourteen healthy female volunteers took part in this controlled study. Seven (23+/-3 years; 50 +/- 2 kg; x+/-SD) were non-smokers and seven (26 +/- 9 years; 58 +/- 8 kg) were smokers (15 cigarettes per day). After administration of 500 mg of paracetamol, urine sampling was performed at specific times (before drug administration and 1, 2, 3, 4, 6, 9, 12, 16 and 24 hours after). The bioanalytical method used for determination of hydrolyzed paracetamol conjugates in urine samples was UV-spectrometry. The obtained pharmacokinetic parameters of paracetamol, first-order elimination rate constant (â) and elimination half-life (t1/2â), were statistically compared between non-smokers and smokers. There were no significant differences in both elimination parameters (â 0.311 1/h; t1/2â 2.23 h non-smokers vs. â 0.346 1/h; t1/2â 2.19 h smokers) between the groups. However, the differences obtained in inter-individual variability in pharmacokinetic parameters (â SD 0.013 , KV 13.4 % ; t1/2â SD 0.227, KV 4.57% nonsmokers vs. â SD 0.108 , KV 90 % ; t1/2â SD 0.684 , KV 14 % smokers) indicate relatively low predictability of paracetamol elimination in smokers. That requires higher attention in dosing this drug in smokers, especially if some other factors also influence.U radu je ispitivan uticaj sastojaka duvanskog dima na brzinu eliminacije paracetamola urinom. U kontrolisanom ispitivanju je učestvovalo 14 zdravih dobrovoljaca ženskog pola. Sedam su bili nepušači (23±8 godine; 50±2 kg: X±SD), a sedam (26±9 godina; 58±8 kg; X±SD) pušači (15 cigareta dnevno). Određivan je „ukupan” paracetamol u urinu UV- spektrometrijskom metodom, posle hidrolize konjugata paracetamola i oksidacije dobijenog proizvoda, u prisustvu hipobromita, do obojenog jedinjenja - derivata indofenola. Farmakokinetičkom analizom izmerenih koncentracija u urinu izračunati su farmakokinetički parametri: konstanta brzine eliminacije (â) i poluvreme eliminacije paracetamola (t1/2â). Mada vrednosti ovih parametara kod pušača ukazuju na bržu eliminaciju paracetamola, statističkim poređenjem farmakokinetičkih parametara eliminacije kod pušača (â=0,346 1/h i t1/2â=2,19 h) i nepušača (â=0,311 1/h, t1/2â=2,23 h), nije dobijena značajna razlika ( P lt 0,05). Veće vrednosti SD=0,108 i KV=90 % za â i SD=0,684 i KV= 14, 25 % za t1/2â u grupi pušača, u poređenju sa istim parametrima u grupi nepušača (SD=0,013 i KV=13,4 % za â i SD=0,227 i KV=4,57 % za t1/2â), pokazuju veću inter-individualnu varijabilnost farmakokinetičkih parametara eliminacije paracetamola kod pušača. Posledica je relativno niska predvidivost farmakokinetike paracetamola kod pušača, pa je kod njih potrebna veća pažnja u doziranju leka, naročito ako postoji i uticaj drugih faktora farmakokinetičke varijabilnosti

Lamotrigine pharmacokinetic variability in children and adolescents on combination therapy for the treatment of epilepsy

Lamotrigin (LTG) se kod dece i adolescenata često koristi kao adjuvantna terapija parcijalnih i generalizovanih napada, uključujući kloničko-toničke napade i napade udružene sa Lennox-Gastaut-ovim sindromom. Njegov potencijal za farmakokinetičke interakcije je manji od potencijala antiepileptičkih lekova starije generacije. Ipak, i karbamazepin (CBZ) i valproinska kiselina (VPA), svojom sposobnošću da indukuju, odnosno inhibiraju izoenzime uridin-difosfo-glukuronoziltransferaze (UGT), odgovorne za metabolizam LTG, mogu dovesti do klinički značajnih interakcija. Iako su mnogi faktori koji utiču na farmakokinetiku LTG identifikovani, neki od izvora farmakokinetičke varijabilnosti su i dalje nepoznati ili su podaci o njima nekoherentni. Cilj ovog istraživanja je bio identifikacija i kvantifikacija faktora farmakokinetičke varijabilnosti LTG u kombinovanoj terapiji. Materijali i metode. Korišćeni su podaci dobijeni od 70 pacijenata, koji su bili na kombinovanoj terapiji sa CBZ i/ili VPA, tokom standardnog praćenja LTG u Institutu za mentalno zdravlje u Beogradu. Koncentracije LTG su izmerene validiranom metodom visoko efikasne tečne hromatografije. Podaci dobijeni od pacijenata, koji su ispunili kriterijume za uključivanje u studiju, uvršteni su u farmakokinetičku analizu. Analiza podataka izvršena je korišćenjem metoda višestruke regresione analize i nelinearnog modelovanja kombinovanih efekata inkorporiranog u softver NONMEM®. Rezultati i diskusija. Uticaj faktora varijabilnosti na oralni klirens LTG prikazan je u vidu finalnog modela, koji sumira uticaj godina pacijenta i primenjene komedikacije. CBZ je prouzrokovao dozno-zavisni porast, a VPA dozno-zavisno smanjenje brzine metabolizma LTG, pri čemu je efekt CBZ bio izraženiji od efekta VPA. Sa porastom godina starosti pacijenta, smanjivao se klirens LTG, pa se očekuje da će deca metabolizovati LTG brže nego odrasli. Razvijen je i validiran populacioni model LTG koji daje kvantitativne uticaje faktora pacijenata i terapije na oralni klirens LTG u ispitivanoj populaciji. Deo varijabilnosti LTG može se opisati koterapijom sa CBZ i/ili VPA, kao i telesnom masom. Pacijent koji je na koterapiji CBZ + VPA, imaće smanjen klirens LTG u proseku za 69,5% u poređenju sa pacijentom koji je na koterapiji CBZ. Klirens LTG pacijenta koji je na koterapiji VPA biće u proseku smanjen za 87,6% u poređenju sa pacijentom koji je na koterapiji samo CBZ. Telesna masa utiče na klirens LTG u ispitivanoj populaciji kao kategorička varijabla sa dve kategorije: 25 kg i 60 kg. Zaključci. Ispitivanje faktora varijabilnosti pokazalo je da uzrast pacijenta i primenjena doza CBZ i VPA značajno utiču na farmakokinetiku LTG. Primenjena doza CBZ imala je najveći uticaj na vrednosti farmakokinetičkih parametara LTG. Pomoću populacionog pristupa opisana je interindividualna varijabilnost u vrednostima oralnog klirensa LTG: koterapija sa CBZ i/ili VPA, kao i telesna masa pacijenta imaju signifikantan uticaj na ovaj parametar u ispitivanoj populaciji. Primena dobijenog populacionog modela za LTG omogućava izračunavanje individualnih vrednosti oralnog klirensa, farmakokinetičkog parametra koji predstavlja osnovu individualnih režima doziranja. Populacioni pristup zajedno sa standardnim praćenjem LTG u terapiji doprinosi postizanju efikasne i bezbedne primene leka u pacijenata sa epilepsijom.Lamotrigine (LTG) is often used as adjunctive treatment of partial and generalized seizures, including tonic-clonic seizures and seizures associated with Lennox-Gastaut syndrome in children and adolescents. LTG has lower potential for pharmacokinetic interactions than the older antiepileptic drugs. Yet it has been reported that both carbamazepine (CBZ), a potent inducer and valproic acid (VPA), an inhibitor of isoenzymes uridine diphospho-glucuronosyltransferase (UGT), involved in LTG metabolism, can lead to clinically important drug interactions. Although many factors that influence the pharmacokinetics of LTG are identified, some of them remain unknown or the data are incoherent. Theferefore, the aim of this study was to identify and quantify the sources of pharmacokinetic variability of LTG applied for adjunctive treatment of epilepsy. Materials and methods. Data from standard monitoring of 70 patients with epilepsy in Institute for Mental Health in Belgrade, concomitantly treated with CBZ and/or VPA, were gathered. LTG concentrations were measured by a validated high-performance liquid chromatography method. Pharmacokinetic analysis was performed with the results from the patients that fullfilled the inclusion/exclusion criteria. Methods of multiple regression analysis and nonlinear mixed effects modelling incorporated in software NONMEM® were used for the data analysis. Results and discussion. The LTG variabilty factors were summed up in the final model, which describes the influence of age and comedication. CBZ was associated with a dose-dependent increase and VPA with dose-dependant decrease of LTG metabolism rate. The effect of CBZ was more pronounced. The LTG clearance decreased with age and younger patients are expected to metabolize LTG more rapidly. The LTG populatiom model was developed and validated. It defines quantitative relationships in patients’ and therapy characteristics and LTG apparent clearance. The part of LTG variability can be explained by body weight and CBZ and/or VPA co-therapy. If a patient was concomitantly treated with CBZ and VPA, the clearance decreased on average 69.5% relative to LTG and CBZ therapy. VPA was found to decrease the LTG clearance by 87.6% compared to co-therapy with only CBZ. Body mass influences LTG oral clearance in the population as a categorical covariate with two categories: 25 kg and 60 kg. Conclusions. Age and comedication with CBZ and VPA had significant influence on LTG pharmacokinetics in the study of pharmacokinetic variability. CBZ dose had the greatest impact on LTG pharmacokinetic parameters. The population model included the effects of concomitant drugs and patients’ weight in order to describe interindividual variability in LTG oral clearance. This model can be used for estimation of individual values of clearance, a pharmacokinetic parameter which is valuable for reliable individualisation of the LTG dosage regimen. Along with therapeutic drug monitoring, the population approach may contribute to the effective and safe epilepsy treatment

Lamotrigine pharmacokinetic variability in children and adolescents on combination therapy for the treatment of epilepsy

Lamotrigin (LTG) se kod dece i adolescenata često koristi kao adjuvantna terapija parcijalnih i generalizovanih napada, uključujući kloničko-toničke napade i napade udružene sa Lennox-Gastaut-ovim sindromom. Njegov potencijal za farmakokinetičke interakcije je manji od potencijala antiepileptičkih lekova starije generacije. Ipak, i karbamazepin (CBZ) i valproinska kiselina (VPA), svojom sposobnošću da indukuju, odnosno inhibiraju izoenzime uridin-difosfo-glukuronoziltransferaze (UGT), odgovorne za metabolizam LTG, mogu dovesti do klinički značajnih interakcija. Iako su mnogi faktori koji utiču na farmakokinetiku LTG identifikovani, neki od izvora farmakokinetičke varijabilnosti su i dalje nepoznati ili su podaci o njima nekoherentni. Cilj ovog istraživanja je bio identifikacija i kvantifikacija faktora farmakokinetičke varijabilnosti LTG u kombinovanoj terapiji. Materijali i metode. Korišćeni su podaci dobijeni od 70 pacijenata, koji su bili na kombinovanoj terapiji sa CBZ i/ili VPA, tokom standardnog praćenja LTG u Institutu za mentalno zdravlje u Beogradu. Koncentracije LTG su izmerene validiranom metodom visoko efikasne tečne hromatografije. Podaci dobijeni od pacijenata, koji su ispunili kriterijume za uključivanje u studiju, uvršteni su u farmakokinetičku analizu. Analiza podataka izvršena je korišćenjem metoda višestruke regresione analize i nelinearnog modelovanja kombinovanih efekata inkorporiranog u softver NONMEM®. Rezultati i diskusija. Uticaj faktora varijabilnosti na oralni klirens LTG prikazan je u vidu finalnog modela, koji sumira uticaj godina pacijenta i primenjene komedikacije. CBZ je prouzrokovao dozno-zavisni porast, a VPA dozno-zavisno smanjenje brzine metabolizma LTG, pri čemu je efekt CBZ bio izraženiji od efekta VPA. Sa porastom godina starosti pacijenta, smanjivao se klirens LTG, pa se očekuje da će deca metabolizovati LTG brže nego odrasli. Razvijen je i validiran populacioni model LTG koji daje kvantitativne uticaje faktora pacijenata i terapije na oralni klirens LTG u ispitivanoj populaciji. Deo varijabilnosti LTG može se opisati koterapijom sa CBZ i/ili VPA, kao i telesnom masom. Pacijent koji je na koterapiji CBZ + VPA, imaće smanjen klirens LTG u proseku za 69,5% u poređenju sa pacijentom koji je na koterapiji CBZ. Klirens LTG pacijenta koji je na koterapiji VPA biće u proseku smanjen za 87,6% u poređenju sa pacijentom koji je na koterapiji samo CBZ. Telesna masa utiče na klirens LTG u ispitivanoj populaciji kao kategorička varijabla sa dve kategorije: 25 kg i 60 kg. Zaključci. Ispitivanje faktora varijabilnosti pokazalo je da uzrast pacijenta i primenjena doza CBZ i VPA značajno utiču na farmakokinetiku LTG. Primenjena doza CBZ imala je najveći uticaj na vrednosti farmakokinetičkih parametara LTG. Pomoću populacionog pristupa opisana je interindividualna varijabilnost u vrednostima oralnog klirensa LTG: koterapija sa CBZ i/ili VPA, kao i telesna masa pacijenta imaju signifikantan uticaj na ovaj parametar u ispitivanoj populaciji. Primena dobijenog populacionog modela za LTG omogućava izračunavanje individualnih vrednosti oralnog klirensa, farmakokinetičkog parametra koji predstavlja osnovu individualnih režima doziranja. Populacioni pristup zajedno sa standardnim praćenjem LTG u terapiji doprinosi postizanju efikasne i bezbedne primene leka u pacijenata sa epilepsijom.Lamotrigine (LTG) is often used as adjunctive treatment of partial and generalized seizures, including tonic-clonic seizures and seizures associated with Lennox-Gastaut syndrome in children and adolescents. LTG has lower potential for pharmacokinetic interactions than the older antiepileptic drugs. Yet it has been reported that both carbamazepine (CBZ), a potent inducer and valproic acid (VPA), an inhibitor of isoenzymes uridine diphospho-glucuronosyltransferase (UGT), involved in LTG metabolism, can lead to clinically important drug interactions. Although many factors that influence the pharmacokinetics of LTG are identified, some of them remain unknown or the data are incoherent. Theferefore, the aim of this study was to identify and quantify the sources of pharmacokinetic variability of LTG applied for adjunctive treatment of epilepsy. Materials and methods. Data from standard monitoring of 70 patients with epilepsy in Institute for Mental Health in Belgrade, concomitantly treated with CBZ and/or VPA, were gathered. LTG concentrations were measured by a validated high-performance liquid chromatography method. Pharmacokinetic analysis was performed with the results from the patients that fullfilled the inclusion/exclusion criteria. Methods of multiple regression analysis and nonlinear mixed effects modelling incorporated in software NONMEM® were used for the data analysis. Results and discussion. The LTG variabilty factors were summed up in the final model, which describes the influence of age and comedication. CBZ was associated with a dose-dependent increase and VPA with dose-dependant decrease of LTG metabolism rate. The effect of CBZ was more pronounced. The LTG clearance decreased with age and younger patients are expected to metabolize LTG more rapidly. The LTG populatiom model was developed and validated. It defines quantitative relationships in patients’ and therapy characteristics and LTG apparent clearance. The part of LTG variability can be explained by body weight and CBZ and/or VPA co-therapy. If a patient was concomitantly treated with CBZ and VPA, the clearance decreased on average 69.5% relative to LTG and CBZ therapy. VPA was found to decrease the LTG clearance by 87.6% compared to co-therapy with only CBZ. Body mass influences LTG oral clearance in the population as a categorical covariate with two categories: 25 kg and 60 kg. Conclusions. Age and comedication with CBZ and VPA had significant influence on LTG pharmacokinetics in the study of pharmacokinetic variability. CBZ dose had the greatest impact on LTG pharmacokinetic parameters. The population model included the effects of concomitant drugs and patients’ weight in order to describe interindividual variability in LTG oral clearance. This model can be used for estimation of individual values of clearance, a pharmacokinetic parameter which is valuable for reliable individualisation of the LTG dosage regimen. Along with therapeutic drug monitoring, the population approach may contribute to the effective and safe epilepsy treatment

Pharmacokinetics of lamotrigine in paediatric and young adult epileptic patients-nonlinear mixed effects modelling approach

The purpose of the study was to examine and describe adjunctive lamotrigine (LTG) pharmacokinetics in paediatric and young adult patients using a nonlinear mixed effects modelling (NONMEM) approach. The study included 53 patients (age range 3-35 years) who were concomitantly treated with carbamazepine (CBZ) and/or valproic acid (VPA). A total of 70 blood samples corresponding to trough levels were available for analysis. Data were modelled, and the final model was evaluated using NONMEM and auxiliary software tools. The final LTG population model included the effects of concomitant drugs and patient's weight (WT) which stratified the population into three groups: a parts per thousand currency sign25 kg, > 25 to lt 60 kg and a parts per thousand yen60 kg. Based on the final model, the estimated LTG oral clearance (CL/F) for a typical patient weighing a parts per thousand currency sign25 kg, > 25 to lt 60 kg or a parts per thousand yen60 kg who was concomitantly treated with CBZ was estimated to be 3.28, 4.23, or 7.15 l/h, respectively. If a patient was concomitantly treated with CBZ + VPA, the CL/F decreased on average by 69.5 % relative to LTG + CBZ co-therapy. VPA was found to decrease the LTG CL/F by 87.6 % compared to co-therapy with only CBZ. The LTG population pharmacokinetic model developed in this study may be a reliable method for individualising the LTG dosing regimen in paediatric and young adult patients on combination therapy during therapeutic drug monitoring