Chemical formula: C₉H₇Cl₂N₅ Molecular mass: 256.091 g/mol PubChem compound: 3878
The results of pharmacological studies suggest that lamotrigine is a use- and voltage dependent blocker of voltage gated sodium channels. It inhibits sustained repetitive firing of neurones and inhibits release of glutamate (the neurotransmitter which plays a key role in the generation of epileptic seizures). These effects are likely to contribute to the anticonvulsant properties of lamotrigine.
In contrast, the mechanisms by which lamotrigine exerts its therapeutic action in bipolar disorder have not been established, although interaction with voltage gated sodium channels is likely to be important.
In tests designed to evaluate the central nervous system effects of medicinal products, the results obtained using doses of 240 mg lamotrigine administered to healthy volunteers did not differ from placebo, whereas both 1000 mg phenytoin and 10 mg diazepam each significantly impaired fine visual motor co ordination and eye movements, increased body sway and produced subjective sedative effects.
In another study, single oral doses of 600 mg carbamazepine significantly impaired fine visual motor co ordination and eye movements, while increasing both body sway and heart rate, whereas results with lamotrigine at doses of 150 mg and 300 mg did not differ from placebo.
Lamotrigine is rapidly and completely absorbed from the gut with no significant first pass metabolism. Peak plasma concentrations occur approximately 2.5 hours after oral administration of lamotrigine. Time to maximum concentration is slightly delayed after food but the extent of absorption is unaffected. There is considerable inter-individual variation in steady state maximum concentrations but within an individual, concentrations rarely vary.
Binding to plasma proteins is about 55%; it is very unlikely that displacement from plasma proteins would result in toxicity.
The volume of distribution is 0.92 to 1.22 L/kg.
UDP-glucuronyl transferases have been identified as the enzymes responsible for metabolism of lamotrigine.
Lamotrigine induces its own metabolism to a modest extent depending on dose. However, there is no evidence that lamotrigine affects the pharmacokinetics of other AEDs and data suggest that interactions between lamotrigine and medicinal products metabolised by cytochrome P450 enzymes are unlikely to occur.
The apparent plasma clearance in healthy subjects is approximately 30 mL/min. Clearance of lamotrigine is primarily metabolic with subsequent elimination of glucuronide conjugated material in urine. Less than 10% is excreted unchanged in the urine. Only about 2% of lamotrigine related material is excreted in faeces. Clearance and half life are independent of dose. The apparent plasma half life in healthy subjects is estimated to be approximately 33 hours (range 14 to 103 hours). In a study of subjects with Gilbert’s Syndrome, mean apparent clearance was reduced by 32% compared with normal controls but the values are within the range for the general population.
The half life of lamotrigine is greatly affected by concomitant medicinal products. Mean half life is reduced to approximately 14 hours when given with glucuronidation inducing medicinal products such as carbamazepine and phenytoin and is increased to a mean of approximately 70 hours when co administered with valproate alone.
The pharmacokinetics of lamotrigine are linear up to 450 mg, the highest single dose tested.
Clearance adjusted for body weight is higher in children than in adults with the highest values in children under five years. The half life of lamotrigine is generally shorter in children than in adults with a mean value of approximately 7 hours when given with enzyme inducing medicinal products such as carbamazepine and phenytoin and increasing to mean values of 45 to 50 hours when co administered with valproate alone.
In 143 paediatric patients aged 2 to 26 months, weighing 3 to 16 kg, clearance was reduced compared to older children with the same body weight, receiving similar oral doses per kg body weight as children older than 2 years. The mean half life was estimated at 23 hours in infants younger than 26 months on enzyme inducing therapy, 136 hours when co administered with valproate and 38 hours in subjects treated without enzyme inducers/inhibitors. The inter individual variability for oral clearance was high in the group of paediatric patients of 2 to 26 months (47%). The predicted serum concentration levels in children of 2 to 26 months were in general in the same range as those in older children, though higher Cmax levels are likely to be observed in some children with a body weight below 10 kg.
Results of a population pharmacokinetic analysis including both young and elderly patients with epilepsy, enrolled in the same trials, indicated that the clearance of lamotrigine did not change to a clinically relevant extent. After single doses apparent clearance decreased by 12% from 35 mL/min at age 20 to 31 mL/min at 70 years. The decrease after 48 weeks of treatment was 10% from 41 to 37 mL/min between the young and elderly groups. In addition, pharmacokinetics of lamotrigine was studied in 12 healthy elderly subjects following a 150 mg single dose. The mean clearance in the elderly (0.39 mL/min/kg) lies within the range of the mean clearance values (0.31 to 0.65 mL/min/kg) obtained in nine studies with non elderly adults after single doses of 30 to 450 mg.
Twelve volunteers with chronic renal failure and another six individuals undergoing haemodialysis were each given a single 100 mg dose of lamotrigine. Mean clearances were 0.42 mL/min/kg (chronic renal failure), 0.33 mL/min/kg (between haemodialysis) and 1.57 mL/min/kg (during haemodialysis), compared with 0.58 mL/min/kg in healthy volunteers. Mean plasma half lives were 42.9 hours (chronic renal failure), 57.4 hours (between haemodialysis) and 13.0 hours (during haemodialysis), compared with 26.2 hours in healthy volunteers. On average, approximately 20% (range = 5.6 to 35.1) of the amount of lamotrigine present in the body was eliminated during a 4 hour haemodialysis session. For this patient population, initial doses of lamotrigine should be based on the patient’s concomitant medicinal products; reduced maintenance doses may be effective for patients with significant renal functional impairment.
A single dose pharmacokinetic study was performed in 24 subjects with various degrees of hepatic impairment and 12 healthy subjects as controls. The median apparent clearance of lamotrigine was 0.31, 0.24 or 0.10 mL/min/kg in patients with Grade A, B, or C (Child Pugh Classification) hepatic impairment, respectively, compared with 0.34 mL/min/kg in the healthy controls. Initial, escalation and maintenance doses should generally be reduced in patients with moderate or severe hepatic impairment.
Non-clinical data reveal no special hazard for humans based on studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential.
In reproductive and developmental toxicity studies in rodents and rabbits, no teratogenic effects but reduced foetal weight and retarded skeletal ossification were observed, at exposure levels below or similar to the expected clinical exposure. Since higher exposure levels could not be tested in animals due to the severity of maternal toxicity, the teratogenic potential of lamotrigine has not been characterised above clinical exposure.
In rats, enhanced foetal as well as post-natal mortality was observed when lamotrigine was administered during late gestation and through the early post-natal period. These effects were observed at the expected clinical exposure.
In juvenile rats, an effect on learning in the Biel maze test, a slight delay in balanopreputial separation and vaginal patency and a decreased postnatal body weight gain in F1 animals were observed at exposures approximately two-times higher than the therapeutic exposures in human adults.
Animal experiments did not reveal impairment of fertility by lamotrigine. Lamotrigine reduced foetal folic acid levels in rats. Folic acid deficiency is assumed to be associated with an enhanced risk of congenital malformations in animals as well as in humans.
Lamotrigine caused a dose-related inhibition of the hERG channel tail current in human embryonic kidney cells. The IC50 was approximately nine-times above the maximum therapeutic free concentration. Lamotrigine did not cause QT prolongation in animals at exposures up to approximately two-times the maximum therapeutic free concentration. In a clinical study, there was no clinically significant effect of lamotrigine on QT interval in healthy adult volunteers.
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