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Research Article Open Access
Pharmacokinetic Modelling of Lamotrigine from Plasma Concentrations in Healthy Volunteers
Ilbeyi Agabeyoglu*, Tuba Incecayir
Dept.Pharmaceutical Technology, Faculty of Pharmacy, Gazi University, Ankara, TURKEY
*Corresponding author: Prof.Dr.Ilbeyi Agabeyoglu,
Gazi Univ. Ecz. Fak.
Etiler 06330 Ankara/TURKEY,
Tel: +90 (532) 262 99 39,
Fax: +90 (312) 212 79 58,
E-mail: ilbeyi@tr.net
 
Received December 06, 2009; Accepted December 28, 2009; Published December 28, 2009
 
Citation: Agabeyoglu I, Incecayir T (2009) Pharmacokinetic Modelling of Lamotrigine from Plasma Concentrations in Healthy Volunteers. J Bioanal Biomed 1: 041-045. doi:10.4172/1948-593X.1000009
 
Copyright: © 2009 Agabeyoglu I, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
 
Abstract
 
The pharmacokinetics of the antiepileptic agent lamotrigine (CAS 84057-84-1) was investigated after
single oral doses in 14 healthy volunteers. After the administration of single oral doses of 2x100 mg lamotrigine chewable/soluble tablets to healthy volunteers, blood samples were collected for the next 96 h. The pharmacokinetic modelling of lamotrigine showed that the drug exhibited two compartment open model with regard to the goodness of fits, Residual Sum of Squares (RSS), Akaike’s Information Criteria (AIC), Schwartz Criteria (SC), standard deviation of the regression (Sr), and determination coefficient (r2). The time-concentration curves showed a mean time to reach peak plasma concentration, Cmax (tmax) of 2.0 h. The pharmacokinetic parameters were calculated based on the plasma curves. Area under the curve of concentration versus time from zero to infinity ( img), systemic clearance (Cl), apparent volume of distribution (Vdarea), apparent volume of distribution at steady state (Vdss), apparent volume of distribution for I.V. (Vdext), and mean residence time (MRT) were found to be 128±31 μg.h/ mL, 1.63±0.39 L/h, 88.5±28.6 L, 83.2±23.6 L, 93.2±35.6 L, and 62.6±13.7 h (mean±SD), respectively. Compartmental analysis demonstrated that oral lamotrigine tablets obey two compartment open model with rapid absorption and a relatively long half life.
 
Keywords
 
Lamotrigine; Pharmacokinetics; Modelling
 
Introduction
 
Being a member of the phenyltriazine class, lamotrigine (6- (2, 3-dichlorophenyl)-1, 2, 4-triazine-3, 5-diamine, CAS 84057- 84-1) is an anticonvulsant, that has a novel chemical structure and mechanism of action (Goa et al., 1993). It exerts its antiepileptic effects by blocking the voltage-sensitive sodium channels and inhibiting the release of glutamate (LaRoche, 2007; Stefan et al., 2007). Lamotrigine exhibits a broad spectrum of efficacy, being active against partial seizures with or without secondary generalization, primarily generalized tonic-clonic seizures, absence seizures, and drop attacks associated with the Lennox-Gastaut Syndrome (Perucca, 1996; Frank et al., 1999; Motte et al., 1997). The present study is designed to carry out the pharmacokinetic modelling of lamotrigine in plasma after the administration of a single oral dose to 14 healthy volunteers.
 
Materials and Methods
 
Clinical protocol
 
The study was an open-label, single period, single-dose study. 14 healthy volunteers, nine males and five females within 10 % of their ideal body weight participated in the study. Their mean age was 23±2 years. After the administration of single oral doses of 2x×100 mg lamotr igine chewable/soluble tablets (LAMICTAL™ DC 100mg chewable/soluble tablets, GlaxoWellcome, Istanbul, Turkey, batch no. B117131) to volunteers, blood samples were collected at 0, 0.25, 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 48, 72 and 96 h. Study design and drug analysis details can be found in the previous paper by the authors (Incecayir et al., 2007).
 
Data analysis
 
Most of the plasma concentration data were modelled by the program KINETICA™ (Version 3.1; Philadelphia, USA). Some of the data were stripped with the programme ESTRIP (Brown et al., 1978), while two were fit manually (Wagner, 1979). Both ESTRIP and manual fits were further optimized by nonlinear regression, using the program SPSS v.11.5.
 
The mean time to reach peak plasma concentration, Cmax, (tmax) for a three exponential function cannot be determined directly, as for a two exponential model. Iterative techniques as described by Wagner, (1979) has been employed for this purpose for each subject equation. Cmax’s have then been calculated by substitution in the respective equations.
 
Results
 
The semilogarithmic mean plasma concentration-time profile of lamotrigine during 96 h. in 14 healthy volunteers are shown in Figure 1.
 
fig
 Figure 1: Semilogarithmic mean plasma concentration-time profiles of lamotrigine in 14 healthy volunteers(with standard deviations).
 
The data were fit both to one compartment and two compartment open models. The equations describing the compartments are as follows:
 
fig
 
formula2
 
where, Cp is the plasma concentration (μg/mL); kd, β, disposition rate constants(h-1); ka, absorption rate constant(h-1); α, distribution rate constant(h-1); and Ci’s, coefficients(μg/mL). α, β, C1, C2 and C3 are the macrorate constants. Obtained macro parameters for one and two compartment models are depicted in Tables 1 and 2.
 
Table 1: One compartment macroparameters. a, bmacrorate constants; cdisposition rate constants (h-1); dabsorption rate const . (h-1); eStandard deviation; fCoefficient of variation.
 
Table 2: Two compartment macroparameters. a, b, cmacrorate constants; ddisposition rate constants (h-1); eabsorption rate const. (h-1); fabsorption rate const.(h-1); gStandard deviation; hCoefficient of variation.
 
Goodness of fits were assessed with Residual Sum of Squares (RSS), Akaike’s Information Criteria (AIC), Schwartz Criteria (SC), standard deviation of the regression (Sr) and determination coefficient (r2). Fits for one and two compartment models are given in Tables 3 and 4.
 
Table 3: One compartment fits. aResidual sum of squares; bAkaike’s Information Criteria; cSchwartz Criterion; dStandard deviation of the regression; eDetermination Coefficient; fStandard deviation.
 
Table 4: Two compartment fits. aResidual sum of squares; bAkaike’s Information Criteria; cSchwartz Criteria; dStandard deviation of the regression; eDetermination Coefficient; fStandard deviation.
 
Microrate constants calculated from two compartment model are given in Table 5 and other pharmacokinetic parameters in Table 6.
 
Table 5: Microrate constants for the two compartment open model. aApparent distribution volume with bioavailability coefficient; bRate constant from the central to the peripheral compartment; cRate constant for elimination from the central compartment; dRate constant from the peripheral to central compartment; eStandard deviation; fCoefficient of variation.
 
Table 6: Other pharmacokinetic parameters flor the two compartment open model. aBiological half-life; bMean Residence Time; cEstimated time to reach maximum plasma concentration; dEstimated maximum plasma concentration; eArea under the curve to infinity; fSystemic clearance; gApparent volume of distribution from area; hApparent volume of distribution at steady state; iApparent volume of distribution for I.V.; jStandard deviation; kCoefficient of variation.
 
Discussion
 
In pharmacokinetic data analysis, it is necessary to select the correct model, allowing estimation of pharmacokinetic parameters with small bias and good precision, and to select a model, allowing precise predictions of concentrations. Therefore, the present study was designed to carry out plasma pharmacokinetics of lamotrigine in 14 healthy volunteers after the administration of single oral doses of 200 mg. In our previous paper (Incecayir et al., 2007), only noncompartmental approach was employed to data, whereas full pharmacokinetic modelling is employed in this paper. It was seen that two compartment fits gave better results than one compartment fits with regard to all five criteria, RSS, AIC, SC, Sr and r2 (Figure 2). From Figure 1, which is a semilogarithmic plot, the two phase disposition is also apparent.
 
fig
 Figure 2: The two compartmental open model of lamotrigine in healthy volunteers (Cp: Plasma concentration (μg/mL), V: Apparent distribution volume(L), ka: Absorption rate const.(h-1), kel: Rate constant for elimination from the central compartment(h-1), k12: Rate constant from the central to the peripheral compartment(h-1), k21: Rate constant from the peripheral to central compartment(h-1)).
 
While some investigators (Yuen et al., 1987) declared that lamotrigine pharmacokinetics can be described by the one-compartment open model, the detailed statistical analysis conducted in this study with 14 volunteers’ single dose data demonstrated that two compartmental open model was the correct pharmacokinetic model for lamotrigine. It is certainly known that lamotrigine is widely distributed to all organs and tissues, including brain tissue (Ramsay et al., 1991). In a study, a mean
brain:serum ratio of 2.8 was found in 11 patients with brain tumors who had received lamotrigine 100-400 mg/day from one day to 17 months (Goldsmith et al., 2003). Such a good distribution of lamotrigine in the brain is certainly a result of the basic and lipophilic properties of the molecule, which permits it to cross the blood-brain barrier easily and have high affinity to the brain tissue (Castel-Branco et al., 2003). Also, a study (Garnett, 1997) assessed the ability of lamotrigine and its glucuronide metabolite to penetrate the blood-brain barrier in a 10-year-old epileptic patient, who underwent a frontal topectomy to remove seizure-causing foci in the cerebral cortex, approximately four hours after the last dose. The concentration of lamotrigine in the brain was higher than the unbound concentration in plasma. On the other hand, concentrations of lamotrigine glucuronide were very low in the brain. On the basis of this result, the good transport of lamotrigine to the brain might explain the data obeying two compartment open model in the present study. Moreover, brain seems to play a role as a peripheral compartment in the two-comparment open model of lamotrigine, which is needed to be proven in future researches.
 
Previous investigations (Btaiche et al., 1995; Perucca, 1999) in healthy individuals demonstrated that lamotrigine is rapidly absorbed from the gastrointestinal tract. After an oral dose Cmax occurs within 1 to 3 hours. This study also showed that absorption of lamotrigine appeared rapid with a tmax of 2.0 h.
 
The biological half-life (t½) of lamotrigine was approximately 38 h, which is longer than those reported as 24.1 to 31.2 h following single oral doses in healthy adults by other researchers (Yuen et al., 1987; Cohen et al., 1987; Goa et al., 1993). Mean residence time (MRT) of lamotrigine after oral administration, was 62.6 ± 13.7 h. It was shown that long t½ and MRT allows once or twice-daily administration of lamotrigine, which has been already used in this dosage regimen in clinical situations. Yau et al., (1991) indicated the dose proportionality of lamotrigine at single oral doses of 50, 200, 400 mg in 20 subjects. The area under the curve of concentration versus time (AUC) for 200 mg dose was 109.4±36.6 μg.h/mL, which is very close to the AUC value of 128±31 μg.h /mL found in the present study.
 
Systemic clearance (Cl) of 1.63±0.39 L/h and apparent volume of distribution (Vdarea) of 88.5±28.6 L found in this study are comparable to the others reported by most investigators (Yuen et al., 1987; Cohen et al., 1987; Goa et al., 1993; Elwes et al., 1996). No lag time was demonstrated in this study. As a result, it is known that lamotrigine is well absorbed; there is negligible first pass effect and bioavailability is virtually 100 % (Yuen et al., 1987; Gram, 1996).
 
Researchers have conducted several investigations on the pharmacokinetics of single and multiple doses of lamotrigine, influence of age, comedication, and disease state on lamotrigine pharmacokinetics in both healthy individuals and patients. However, the present study conducted in healthy volunteers receiving single oral dose of lamotrigine, approaches to the pharmacokinetics of lamotrigine in a different perspective of mathematical modelling.
 
Overall, on the basis of the detailed compartmental analysis, the results of this single dose study demonstrated that oral lamotrigine tablets obey two compartment open model with rapid absorption and a relatively long half life.
 
Acknowledgement
 
This study was supported by the research grant (02/2003-18) from Gazi University, Ankara, Turkey.
 
References
 
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  14. Perucca E (1996) The new generation of antiepileptic drugs: advantages and disadvantages. Br J Clin Pharmacol 42: 531-543. » PubMed  »  Google Scholar

  15. Perucca E (1999) The clinical pharmacokinetics of the new antiepileptic drugs. Epilepsia 40: S7-S13. » PubMed  »  Google Scholar

  16. Ramsay RE, Pellock JM, Garnett WR, Sanchez RM, Valakas AM, et al. (1991) Pharmacokinetics and safety of lamotrigine (Lamictal®) in patients with epilepsy. Epilepsy Res 10: 191-200. » PubMed  »  Google Scholar

  17. Stefan H, Feuerstein TJ (2007) Novel anticonvulsant drugs. Pharmacol Ther 113: 165-183. » CrossRef » PubMed  »  Google Scholar

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  20. Yuen WC, Peck AW (1987) Lamotrigine pharmacokinetics: oral and I.V infusion in man. Epilepsia 28: 582.
  21. Brown RD, Manno JE (1978) ESTRIP, a BASIC computer program for obtaining initial polyexponential parameter estimates. J Pharm Sci 67: 1687- 1691. » PubMed  »  Google Scholar

  22. Btaiche IF, Woster PS (1995) Gabapentin and lamotrigine: novel antiepileptic drugs. Am J Health Syst Pharm 52: 61-69.  » PubMed  »  Google Scholar

  23. Castel-Branco M, Lebre V, Falcão A, Figueiredo I, Caramona M (2003) Relationship between plasma and brain levels and the anticonvulsant effect of lamotrigine in rats. Eur J Pharmacol 482: 163-168.  » CrossRef » PubMed  »  Google Scholar

  24. Cohen AF, Land GS, Breimer DD, Yuen WC, Winton C, et al. (1987) Lamotrigine, a new anticonvulsant: pharmacokinetics in normal humans. Clin Pharmacol Ther 42: 535-541. » PubMed  »  Google Scholar

  25. Elwes RDC, Binnie CD (1996) Clinical pharmacokinetics of newer antiepileptic drugs-lamotrigine, vigabatrin, gabapentin and oxcarbazepine. Clin Pharmacokinet 30: 403-415.   » PubMed  »  Google Scholar

  26. Frank LM, Enlow T, Holmes GL, Manasco P, Concannon S, et al. (1999) Lamictal (lamotrigine) monotherapy for typical absence seizures in children. Epilepsia 40: 973-979. » PubMed  »  Google Scholar

  27. Garnett WR (1997) Lamotrigine: Pharmacokinetics. J Child Neurol 12: S10- S15.  » PubMed »  Google Scholar

  28. Goa KL, Ross SR, Chrisp P (1993) Lamotrigine: a review of its pharmacological properties and clinical efficacy in epilepsy. Drugs 46: 152-176. » PubMed »  Google Scholar

  29. Goldsmith DR, Wagstaff AJ, Ibbotson T, Perry CM (2003) Lamotrigine: A review of its use in bipolar disorder. Drugs 63: 2029-2050. » PubMed  »  Google Scholar

  30. Gram L (1996) Pharmacokinetics of new antiepileptic drugs. Epilepsia 37: S12-S16. » PubMed  »  Google Scholar

  31. Incecayir T, Agabeyoglu I, Gucuyener K (2007) Comparison of plasma and saliva concentrations of lamotrigine in healthy volunteers. Arzneimittelforschung 57: 517-521. » PubMed  »  Google Scholar

  32. LaRoche SM (2007) A new look at the second-generation antiepileptic drugs: a decade of experience. Neurologist 13: 133-139. » CrossRef » PubMed  »  Google Scholar

  33. Motte J, Trevathan E, Arvidsson JF, Barrera MN, Mullens EL, et al. (1997) Lamotrigine for generalized seizures associated with the lennox-gastaut syndrome. N Engl J Med 337: 1807-1812. » CrossRef » PubMed  »  Google Scholar

  34. Perucca E (1996) The new generation of antiepileptic drugs: advantages and disadvantages. Br J Clin Pharmacol 42: 531-543. » PubMed  »  Google Scholar

  35. Perucca E (1999) The clinical pharmacokinetics of the new antiepileptic drugs. Epilepsia 40: S7-S13. » PubMed  »  Google Scholar

  36. Ramsay RE, Pellock JM, Garnett WR, Sanchez RM, Valakas AM, et al. (1991) Pharmacokinetics and safety of lamotrigine (Lamictal®) in patients with epilepsy. Epilepsy Res 10: 191-200. » PubMed  »  Google Scholar

  37. Stefan H, Feuerstein TJ (2007) Novel anticonvulsant drugs. Pharmacol Ther 113: 165-183. » CrossRef » PubMed  »  Google Scholar

  38. Wagner JG (1979) Fundamentals of Clinical Pharmacokinetics. 2nd ed Hamilton, Illinois.  »  Google Scholar

  39. Yau MK, Garnett WR, Wargin WA, Pellock JM (1991) A single dose, dose proportionality, and bioequivalence study of lamotrigine in normal volunteers. Epilepsia 32: 3-8.  »  Google Scholar

  40. Yuen WC, Peck AW (1987) Lamotrigine pharmacokinetics: oral and I.V infusion in man. Epilepsia 28: 582.

 
 
 
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