Comparative analysis of safety and efficacy between brand and generic lamotrigine products in the Saudi market

Abstract

Background

Epilepsy is one of the most chronic neurological disorders worldwide. In 2023, the World Health Organization (WHO) estimates that approximately 50 million individuals globally would be affected by epilepsy. Furthermore, it was suggested that as many as 70% of patients could experience a life without seizure if they received appropriate treatment. Lamotrigine (LTG) is one of the newer antiepileptic drugs. It has been globally marketed under the name Lamictal^00AE. Due to the increasing demand for transformation between brand and generic products, this study aims to evaluate the product safety and efficacy on liver enzymes, as well as the behavioral effects and pharmacokinetics of lamotrigine, specifically the brand Lamictal^00AE and its generics available in the Saudi market.

Methods

Male albino mice with an average weight of 24 g will be randomly divided into groups (n = 6) for pharmacokinetic study, liver enzyme analysis, and behavioral evaluation of brand Lamictal^00AE and generics. One-way ANOVA and Bonferroni’s post hoc test will be used to compare results in the different animal groups. Statistical significance p-values will be determined at P < 0.05.

Results

The study found that generics had a significant difference PK parameters were compared to those of Lamictal^00AE, which was mostly found in generics 1 and 2. Liver analysis revealed liver enzyme elevation in all generics compared to the brand Lamictal^00AE, which was primarily pronounced in AST and GGT with generic 2, and an increase in ALT, ALP, and GGT was primarily found in generic 1. The behavioral study indicates higher seizure attacks in generics compared to the brand Lamictal^00AE, with an increase in mortality rates mainly observed with generics 1 and 2.

Conclusions

This research finds that there is a significant difference in safety and efficacy between brand and generic lamotrigine products in terms of liver enzyme tests, behavioral analysis, and PK parameters. Future studies to evaluate lamotrigine brand and generic drugs in humans are recommended.

Supplementary Information

The online version contains supplementary material available at 10.1186/s40360-025-00963-7.

Introduction

Epilepsy is one of the most chronic neurological disorders worldwide that influences men and women of different ages. It is characterized by generating transitory changes in the electrical function of the brain that cause recurrent seizures [1]. In 2023, the World Health Organization (WHO) estimated that approximately 50 million individuals globally would be affected by epilepsy [2]. Furthermore, it was suggested that as many as 70% of patients could experience a life without seizure if they received appropriate treatment. According to the International League Against Epilepsy (ILAE) classification, epilepsy is classified into four major categories with different types of seizures. The first type is generalized epilepsies, which affect both sides of the brain lobe and include absence, myoclonic, atonic, tonic, and tonic-clonic seizures); focal epilepsies that affect one lobe of the brain, including focal aware seizures, focal impaired awareness seizures, focal motor seizures, focal non-motor seizures, and focal to bilateral tonic-clonic seizures; combined generalized and focal epilepsy and also an unknown epilepsy group [3]. Epilepsy is a disorder that cannot be cured but typically necessitates taking medication called antiepileptic drugs (AEDs) to control and manage seizures [4].

Furthermore, there are several types of AEDs. Lamotrigine (LTG) is one of the most common medications used to treat epilepsy. Lamotrigine is a phenothiazine derivative, a second-generation AED use, used to manage epilepsy. It was approved by the FDA in 1994 and was commonly used worldwide; LTG can be used as a monotherapy or in combination with other AEDs to treat seizures [4, 5]. Another indication of LTG is the treatment of bipolar disorder and mood stabilizers [6]. Additionally, LTG is only one of two drugs from newer AEDs that are used for epilepsy (during pregnancy) because of having a lower risk of major congenital malformation in the fetus when compared to the older AEDs such as valproic acid, phenytoin, and phenobarbital [7, 8]. Furthermore, when comparing LTG with other antiepileptic treatments, it can be observed that it induces less cognitive impairment and less sedation effect [9]. Following oral administration of LTG, its bioavailability is estimated to be 98%, with peak plasma concentrations occurring 1.4–4.8 h after dosing and a half-life of 24 h hours [10]. The absorption rate is slightly reduced when administered with food, but the extent of absorption remains unchanged [11]. Also, there are no apparent first-pass metabolic effects on LTG. The volume of distribution in adults is between 0.9 and 1.4 L/kg, and plasma protein binding is about 55% [12]. LTG is mainly metabolized through the liver by glucuronidation, which is an inactive conjugation reaction via uridine-diphosphate glucuronosyltransferase (UGT), mostly UGT1A4 and UGT2B7, the most metabolite,2-N-glucuronide is eliminated by the kidney and pharmacologically inactive metabolite [13]. Moreover, LTG is excreted in both the urine and feces; about 94% of the total drug and its metabolites administered are recovered in the urine, and 2% is recovered in the feces [14]. LTG works by binding and inhibiting voltage-gated sodium channels, presynaptic neuronal membrane stabilization, and inhibition of presynaptic glutamate and aspartate release [15]. One of the severe side effects of LTG is a rash that can develop to cause Stevens-Johnson syndrome, toxic epidermal necrolysis, and epidermal necrolysis risk is increased when taking it with other AEDs; consequently, allergic reactions are the most significant side effect that happens with LTG, other side effects that are associated with LTG like headache, nausea, vomiting, constipation, insomnia, blurred vision, dizziness, visual disturbance and weight changes [9, 16, 17]. The impact of using generic products on side effects is uncertain, as it is unclear whether they could exacerbate or diminish them.

Recently, many newer AEDs prescribed for patients as generic products interchangeable with the brand of LTG drug [18]; this also applies to Lamictal^® which is the brand name of LTG by GlaxoSmithKline company is substituted with three generic products available in the Saudi market. Because of price disparity and competitiveness between brands and generic drugs, there is an excellent drive for the transformation of prescribed generic products rather than the trade ones [18]. The global health care system supports transformation from brand to generic formulation approach because generic drugs are less expensive than brand drugs as long as they are bioequivalent, meaning that they have the same dosage form, safety, strength, route of administration, quality, and intended use [19]. Although seizure control should be considered a priority before cost, many patients and health care report to the FDA about the rising incidence of breakthrough seizures and adverse effects after the substitution of a brand to a generic drug [18]. This could be due to differences in pharmacokinetic or bioequivalence [20]. Earlier studies were conducted on LTG to evaluate bioequivalence between brand and generic products on humans and also on animals in global markets [21–23]. While it is correct that many studies showed that no significant differences exist between trade and generic drugs in terms of safety and efficacy, a clinical study conducted by Ting et al., 2015 showed that seizure patients went through exacerbated seizure attacks or toleration issues after switching lamotrigine from brand to generic [21].

Therefore, this study aims to evaluate the product safety and efficacy of liver enzymes, as well as the behavioral effects and pharmacokinetics of the lamotrigine brand Lamictal^® and generics available in the Saudi market.

Materials and methods

Chemicals and reagents

Standard of LTG with (purity > 99.3%) was obtained from Merck KGaA in (Darmstadt, Germany). An internal standard (IS) of Lidocaine with (purity > 99.8%). The grade ammonium formate with (a purity of 99.99%) was purchased from SIGMA-ALDRICH in (the USA), while acetonitrile with (a purity of 99.9%) was purchased from Pabreac AppliChem in (Spain). Ultrapure water was obtained from the Ultrapure water Milli-Q Advantage A10 water purification system, utilizing a 0.22 m filter from Millipore in (Molsheim, France). The brand LTG, known as Lamictal, was purchased from Glaxo Saudi Arabia Ltd, while LTG generics were purchased from the Saudi Market. Pentylenetetrazol-PTZ was purchased from Sichuan Benepure Pharmaceutical Co., Ltd in (Chania). Liver enzyme UV/Kinetic kits for AST, ALT, GGT, and ALP were purchased from the United Diagnostic Industry in (Dammam, Saudi Arabia).

Experimental animals

Healthy male Balb/c mice weighing (20-28 g) were acquired from the animal house at the College of Pharmacy, King Saud University in Riyadh, Saudi Arabia. The animals were maintained in a climate-controlled environment with controlled light/dark cycles, a temperature range of 20–25o C, 50% humidity, and easy access to food and water. Continuous monitoring of all mice was necessary to guarantee the well-being of the animals. Our sample size was calculated according to the “resource equation” method which relies on the law of diminishing return because the main goal is to determine any degree of variation between groups. In accordance with this method, we used the following formula: E = Total number of animals − Total number of groups. “E” which is nothing but the degree of freedom of analysis of variance (ANOVA). The “E” value must range from 10–20; if a value is less than 10 increasing the number of animals will increase the likelihood of obtaining significant results, while if a value is more than 20 increasing the number of animals will not increase the likelihood to obtain significant.

At the end of the study, Animals were euthanized through asphyxiation in a controlled saturated CO2 chamber. All methods were carried out in accordance with guidelines and regulations. We ensured that all studies involving animals adhered to the guidelines established by the Ethical Committee for conducting studies on animals at King Saud University in Riyadh, Saudi Arabia, and ethical approval number KSU-SE-24-11. All methods are reported in accordance with ARRIVE guidelines. It is noteworthy to mention that the use of separate cohorts of animals in each experiment (liver safety, efficacy, and PK analysis) was a strategic decision to avoid confounding stress responses and drug accumulation effects across assessments.

Instrumentation

Ultra-high-performance liquid chromatography (UHPLC) was purchased from ACQUITY Waters Company in (Singapore). Spectrophotometer were purchased from SprctraMax^®M5 in (China).

LTG chromatographic conditions

Ultra-high-performance liquid chromatography (UHPLC) grade was utilized to assess the LTG concentration in mice plasma, using lidocaine as an internal standard (IS). Analytes and internal standards are extracted from mice plasma through protein precipitation extraction. The chromatography procedure involved the usage of an ACQUITY UPLC^® BEH C18 1.7 μm 2.1 mm X 50 mm Column, which will be obtained from Waters Company in (Ireland). To ensure its protection, a security guard precolumn (ACQUITY Waters Quality Parts, USA) equipped with a graphite filter will be used. The mobile phase utilized in the analysis will be comprised of a mixture of acetonitrile 570.1 mM ammonium formate solution in a ratio of 90:10 (v/v). The flow rate will be adjusted to 0.500 mL/min, with an injection volume of 10 µl and a total runtime of 3 min. The samples will be subjected to analysis using a quadrupole mass spectrometer. The analytes will be detected using tandem mass spectrometry by using multiple reaction monitoring (MRM). The MRM involved precursor-product ion transitions with 200 ms dwell time at (m/z 256.1/211) for LTG and (m/z 235.2/87) for Lidocaine. The critical source/gas parameters of the mass spectrometer will be optimized and kept at specific values throughout the analysis. These parameters will include a collision-activated dissociation (CAD) gas setting of 10; a curtain gas,8; a nebulizer gas,12; turbo ion spray (IS) voltage, 2000 V; and a source temperature maintained at 450 °C [24]. Data collection and handling were carried out using MassLynx software version 4.1. Quantitative measurement of LTG concentration was obtained from a calibration curve by analysis of standard plots with seven points with a correlation coefficient r = 0. 99. In method validation analyte peak of the lower limit of quantification LLOQ sample should be identifiable separate from other peaks and consistently reproducible with accuracy and precision (15,20%) respectively. MRM graphs and parameters of method validation are found in (supplementary material figures S.1, Tables S.1, 2, and 3).

Table 2.

Shows statistical significance (control vs. brand and generics) and (brand vs. generics) for liver enzymes over a duration of 4 weeks

4 WEEK	ALT	ALP	AST	GGT
(Control vs. Generic 1) (Brand vs. Generic 1)	****	****	***	****
(Control vs. Brand)	ns	ns	ns	ns
(Control vs. Generic 2) (Brand vs. Generic 2)	***	****	****	****
(Control vs. Generic 3) (Brand vs. Generic 3)	***	***	**	***

p-values of 0.05 were considered statistically significance, where * p < 0.05, ** p < 0.005, *** p < 0.001, and **** p < 0.0001

Table 3.

Shows the statistical significance of behavioral analysis of (control vs. brand and generics) and (brand vs. generics)

	Death rate	Seizure latency	Seizure duration	Last attack	Number of attacks
(Control vs. Generic 1) (Brand vs. Generic 1)	***	****	**	***	****
(Control vs. Brand)	****	****	***	***	***
(Control vs. Generic 2) (Brand vs. Generic 2)	**	**	**	**	**
(Control vs. Generic 3) (Brand vs. Generic 3)	****	****	****	***	***

p-values of 0.05 were considered statistically significance, where * p < 0.05, ** p < 0.005, *** p < 0.001, and **** p < 0.0001

Liver functions study and histological evaluation of mice tissues

Sixty male Balb/c mice weighing (20–28 g) were divided randomly into 10 groups, each group consisting of (n = 6). Each animal within the groups was administered a 20 mg/kg dose of either brand or generic LTG oral tablets dissolved in a 0.2 ml aqueous solution [25]. For a duration of 2 weeks, 4 groups received LTG while 1 group received normal saline, which was considered the control group. Then, for a duration of 4 weeks, 4 additional groups received LTG while 1 group received normal saline, which was regarded as the control group for that period. The administration of LTG will performed once daily through oral gavage using an oral needle. Subsequently, animals were sacrificed, and blood samples were collected by centrifugation at 1500 rpm, four °C for 10 min. Liver enzyme analysis, including Alanine Aminotransferase (ALT), Alkaline Phosphatase (ALP), Aspartate Aminotransferase (AST), and Gamma Glutamyl Transpeptidase (GGT), was conducted using the ELISA and spectrophotometer, SoftMax Pro 6.3 software [26]. Furthermore, the liver samples were trimmed, prepared for fixation, and sent to King Khalid University Hospital (KKUH), Saudi Arabia, for histological analysis. The evaluation involved staining the samples with Hematoxylin and Eosin (H&E) to assess their microstructural characteristics.

Behavioral study

Another set of animals, male Balb/c mice weighing (20–28 g), were divided randomly into 5 groups (n = 6); the study lasted for one day, and then the behavior of each group was observed [27]. Each group from 1 to 4 received LTG brand (Lamictal^®) or generic products at a dose of 20 mg /kg orally, while group 5 received normal saline, which is considered group control. All groups from 1 to 5 will receive (PTZ) 50 mg/kg intraperitoneally (IP) and were observed and recorded by the camera (SONY AVCHD full HD 1080 Camera in Japan) for 30 min pointed towards the animal with 60 cm space [25]. Different seizure activities were monitored, including seizure latency, seizure duration, number of attacks, last attack, and death rate [28].

Pharmacokinetic study

A new group of 24 animals was randomly divided into 4 groups (n = 6). Every group received a single dose of LTG 20 mg/kg, either brand (Lamictal^®) or generic products. The tablet was dissolved in an aqueous solution of 0.2 ml, and at a prearranged time point, LTG was administered by oral gavage with an oral needle [25]. Mice were sacrificed as described above, and blood samples were collected from the tail vein at 0,0.15,0.30,1,2,4,6,8,24,48, and 72 h to plot the concertation time curve (Supplementary Fig. 2) [24, 26].

Statistics analysis

GraphPad Prism 8 edition was used for statistical analysis (GraphPad Software company, USA). Data were represented as mean and ± SEM. One-way ANOVA and Bonferroni’s post hoc test were used to compare results in the different animal groups. Statistical significance p-values were determined at P < 0.05.

Results and discussion

The global healthcare system supports transformation from brand to generic formulation approach because generic medications are less expensive than brand drugs as long as they are bioequivalent, meaning that they have the same safety and efficacy profile [19]. The bioequivalence of LTG was earlier assessed by [21, 22]; results show similar bioequivalence in both brand and generic products in the global market. Therefore, this study aims to evaluate the product safety and efficacy of liver enzymes, the behavioral effects and pharmacokinetics of the lamotrigine brand (Lamictal^®), and generics available in the Saudi market.

Liver enzymes and histological analysis of mice tissue

LTG is primarily metabolized in the liver through glucuronidation, a process where it is converted into inactive compounds by uridine-diphosphate glucuronosyltransferase (UGT). Approximately 55% of LTG binds to plasma proteins. During clinical trials, the breakdown of LTG was observed as follows: 10% unchanged drug, 76% converted into a 2-N-glucuronide, 10% converted into a 5-N-glucuronide, 0.14% transformed into a 2-N-methyl metabolite, and 4% formed various other minor metabolites [29]. Prospective studies indicate that fewer than 1% of individuals develop increased aminotransferase serum during long-term treatment, despite the fact that LTG is known to its potential to cause clinically evident hepatotoxicity with approximated incidence of 1 in 2000 to 10,000 patients receiving LTG [30]. This study aimed to compare the safety profile of brand and generic products of LTG by evaluating their effect on liver enzymes. Testing liver function involves the measurement of serum biomarkers, which include alanine aminotransferase ALT, alkaline phosphatase ALP, aspartate aminotransferase AST, and glutamyl transpeptidase GGT [31]. Liver enzyme test results show no significant difference between the brand and control groups; on the other hand, there was an increase in all four enzymes after 2 and 4 weeks of monitoring for all three generics. Generic 1 shows the highest increase in ALT, ALP, and GGT levels, while generic 2 has a notable elevation in all enzymes and mainly was seen with AST and GGT, whereas generic 3 represents elevated enzyme levels but to a lesser extent than other generic groups (Fig. 1; Tables 1 and 2). Furthermore, after the sacrifice and dissection of mice, it appeared that animals in group 1 exhibited hepatomegaly (Supp Fig. 3). The change in body weight during the 4 weeks of liver enzyme evaluation, which was used to monitor the well-being and normal growth pattern of animals, dropped with generic 1 and 3. However, the increase in body weight of generic 2 exhibited in similar pattern to the animal receiving brand.

Fig. 1.

All generics caused an increase in liver enzyme apparent at 2 weeks post-drug administration (top) and continued until 4 weeks of drug administration (bottom), while no significant difference existed between the brand and control group. (n = 6) where * p < 0.05, ** p < 0.005, *** p < 0.001, and **** p < 0.0001

Table 1.

Statistical significance (control vs. brand and generics) and (brand vs. generics) for liver enzyme over a duration two week

2 WEEk	ALT	ALP	AST	GGT
(Control vs. Generic 1) (Brand vs. Generic 1)	****	****	***	****
(Control vs. Brand)	ns	ns	ns	ns
(Control vs. Generic 2) (Brand vs. Generic 2)	***	***	****	****
(Control vs. Generic 3) (Brand vs. Generic 3)	****	***	**	***

p-values of 0.05 were considered statistically significance, where * p < 0.05, ** p < 0.005, *** p < 0.001, and **** p < 0.0001

Fig. 3.

Behavioral Analysis (A) death rate, (B) seizure latency, (C) last attack, (D) number of attacks, (E) seizure duration. A statistically significant difference between the control group and all treatment groups. Moreover, Brand and Generic 3 showed comparable outcomes. (n = 6) where * p < 0.05, ** p < 0.005, *** p < 0.001, and **** p < 0.0001

According to histopathological sections of liver tissues of mice in the groups receiving generic 1 and generic 2 mild periportal lymphocytic inflammation was apparent. On the other hand, groups receiving brand and generic 3 showed scattered foci of spotty necrosis (Fig. 2).

Fig. 2.

Histopathological evaluation of mice in different treatment groups. (A) Generic 2, (B) Generic 1 shows (mild lymphocytic periportal inflammation). Figures (C, J) Generic 3, fig (D, I) brand shows the focus of spotty necrosis (arrow). Figure (E) Generic 2 shows (normally distributed hepatocytes and portal tracts), Similar results in Fig (F)Generic1, Fig (H)Brand

Numerous studies have pointed out that although bioequivalence studies try to ensure that pharmacokinetic parameters, such as Cmax and AUC are as similar as possible, other factors that could cause discrepancies in pharmacodynamic parameters are not much considered [32]. Moreover, it is documented in the literature that generics could cause adverse events such as hepatotoxicity due to excipients which can impact metabolism, especially in vulnerable populations. For example, it was found that liquid acetaminophen is less toxic than the sold form, the main response for hepatotoxicity in the USA and Europe [33]. It was then discovered that this is due to the presence of polyethylene glycol in acetaminophen liquid form, which acts as a competitive antagonist to CYP2E1 which decreased the AUC of metabolites by 16%. This concludes that excipients can have an effect on APIs PK [34] Thus, further investigation of the excipients used in the different generics in this study is needed to rule out factors that contributed to the elevation of hepatic enzymes.

Behavioral analysis

In behavioral analysis, results show significant differences between the control group and all treatment groups. Brand and generic 3 showed comparable outcomes, which are represented in (Fig. 3). Regarding the percentage of death rate, it showed a high mortality rate in the control group, generic one and generic 2 (100%, 33.3%, 66.6%), respectively, and the brand and generic 3, which show zero incidences of death. This result indicates that brand and generic 3 are better at reducing seizure-related mortality (Fig. 3. A). Even though the consequence shows a difference in seizure latency, which means seizure onset or first attack between brand, generic 1, and 3, it is considered not statistically significant. However, the attack was significantly different with the control group and generic 2 when compared with the brand (Fig. 3. B). In addition, seizure durations measure time per minute short attack duration means better protection; seizure length was decreased and statistically significant in brand and generic 3 when compared to the control group, which indicates generic 3 has a shorter duration, which provides good protection. Seizure durations were highest in the control group, generic 1 and generic 2 (Fig. 3. C). In terms of the last attack, which measures time free from seizure after the previous attack, the result shows better protection with brand and generic 3 compared to the control group and generic 2, which was significantly different. When comparing generic 1 with brand and generic 3, there was no significant difference (Fig. 3.D). Finally looking at the number of attacks that were observed on animals 30 min after being treated with PTZ, there was a significant difference in attack numbers between brand and generic 1, while there was no significant difference between the control group and generic 2 compared to the brand, which might be ought to the increase in animal death in the control group and generic 2 (100%, 66.6%) which hindered drawing any significance. Brand and generic 3 on the other hand, were slightly similar in terms of the number of attacks (Fig. 3. E) (Table 3). Death because of seizures can be caused by prolonged convulsions i.e. status epilepticus or physical trauma. The absence of death in the control group and generic 3 suggest better control of seizures and neuroprotection while generics 1 and 2 showed less protection against attacks [35].

In addition, case classification of seizure was utilized to evaluate the difference between LTG brand and generic products in terms of effectiveness in protecting against seizure attacks. Cases classified as case: immobilization, case 2: head nodding partial myoclonus, case 3: continuous whole body myoclonus, case 4: rearing tonic seizure, case 5: tonic-clonic seizure and jumping, case 6: death [35]. The results for case 1 showed a significant difference between the control group and the brand with generic 3. Also, case 2 exhibits significant differences between the control group and other groups, mainly observed in generic 1 and 3. However, case 3 shows comparable outcomes within all treatment groups. Cases 4 and 5 indicated a significant difference between the control group, brand, and all generics. Generic 1 and 2 revealed no significant difference with control, while generic 3 was mostly similar to brand. Lastly, case 6 represents a significant difference between brand and generic 3 when compared to the control group and generic 1, and 2 (Fig. 4; Table 4).

Fig. 4.

Behavioral analysis of cases shows a significant difference between the brand and three generics, (n = 6) where * p < 0.05, ** p < 0.005, *** p < 0.001, and **** p < 0.0001

Table 4.

Shows the statistical significance of behavioral analysis cases of (control vs. brand and generics) and (brand vs. generics)

	Case 1	Case 2	Case 3	Case 4	Case 5
(Control vs. Generic 1) (Brand vs. Generic1)	**	****	****	**	**
(Control vs. Brand)	***	**	****	***	****
(Control vs. Generic 2) (Brand vs. Generic 2)	**	***	****	**	**
(Control vs. Generic 3)	***	***	***	****	***
(Brand vs. Generic 3)	***	***	***	****	****

p-values of 0.05 were considered statistically significance, where * p < 0.05, ** p < 0.005, *** p < 0.001, and **** p < 0.0001

Pharmacokinetic analysis

Pharmacokinetic analysis was conducted to investigate the drug disposition in the body following administration. The PK parameters were determined using a PK Solver Add-In Excel 2010 The PK parameters that were determined included the highest concentration of the drug in the bloodstream (Cmax), the duration it took to reach that maximum concentration (Tmax), the time it takes for half of the drug to be eliminated from the body (T1/2), the area under the concentration-time curve from 0 to the last sampling time (AUC0-72), the area under the concentration-time curve from 0 to infinity (AUC0-∞), and the rate at which the drug is cleared from the body after administration (CL/F) [36]. The PK parameters showed significant differences and notable variations between brands and other generic products. The brand had the highest peak concentration (Cmax), while generics had significantly lower values, which might indicate insufficient dosing. For the time taken to reach the maximum concentration (Tmax), generics 1,3 demonstrated a significant decrease in (Tmax), while brand and generic 2 showed similar results. The brand has the most extended half-life (T1/2), which is associated with the prolonged presence of the drug in the body, while the three generics have substantially shorter half-life (duration in the body), mostly seen with generic 2. However, there is a significant difference in the area under the curve from 0 to 72 h (AUC0-72) and infinite time (AUC0-∞) between the brand and generic 1,2,3, which manifests less protection from seizure attacks due to insufficient drug exposure by generics. Also, the brand had the lowest oral clearance rate (CL/F), while the three generics had similar rates (Fig. 5), which were significantly higher than the brand.

Fig. 5.

PK parameters of animals in different treatment groups. Significant differences existed between brands and all three generics used in this study. (n = 6) where * p < 0.05, ** p < 0.005, *** p < 0.001, and **** p < 0.0001

Brands and generics are not necessarily identical when it comes to excipients [32]. In light of this, it is noteworthy to mention that literature indicated that it is not unusual for generics to have lower absorption (exposure) yet exhibit higher side effects [32, 37]. One explanation can be due to excipients which are thought to be pharmacologically inert, yet studies showed that excipients can have effects on drug transporters and/or metabolic enzymes [37]. Therefore, the modulation of transport and metabolism from the included excipients may change the pharmacokinetics (absorption, distribution, metabolism, and elimination) of active pharmaceutical ingredients [37]. A study by Zhang et al., 2016 showed that excipients can cause an induction of hepatic function and increase liver enzymes with lower drug exposure [38]. This indicates that excipients can induce toxicity independent of drug absorption. Not to neglect that this observation was more pronounced in our study since it is possible that animals have a higher sensitivity to excipients than humans.

The brand Lamictal^® contains excipients (Lactose monohydrate, Microcrystalline cellulose, Povidone, Sodium starch glycolate, Iron oxide yellow(E172), and Magnesium stearate) [39]. Generic 1 contains excipients (Lactose, Avicel PH 101, Povidone 30, Sodium starch glycolate, Iron oxide yellow, Magnesium stearate, Purified water, Avicel PH 102, Colloidal silicon dioxide) [39]. Generic 2 contains excipients (Lactose, Microcrystalline cellulose, Povidone, Sodium starch glycolate, Magnesium stearate, FD&C yellow no.6 lake) [39]. Generic 3 contains excipients (Lactose monohydrate, Microcrystalline cellulose, Povidone, Sodium starch glycolate, Iron oxide yellow(E172), and Magnesium stearate) [39]. This may explain the similarity in results between brand and generic 3. Thus, further investigation of the excipients used in the different generics that could contribute to differences in PK and toxicity is recommended.

The limitations of this study include, first, that it is conducted on an animal model, which may not entirely replicate the pharmacokinetics and safety profile of lamotrigine in humans. Further validation through clinical trials in human subjects is necessary to confirm whether the observed effects in mice would occur in humans. Second, while the study shows significant differences in pharmacokinetics and safety between the brand and generic of Lamotrigine, the scope of the study did not include investigating the impact of excipients which can have an impact on the result. Third, the relatively short duration of the study conducted over 2-4-week duration might not have captured long-term effects, and its focus on liver enzymes, behavioral effects, and basic pharmacokinetic parameters provided a limited scope of safety evaluation. A more comprehensive assessment involving other organ systems and biochemical markers would offer a broader understanding.

Conclusion

After all, this study found that there is a significant difference between Lamotrigine (LTG) brand and generic products, especially seen with generic 1 and generic 2. The only product that is relatively close to Lamictal^® in terms of safety and efficacy is generic 3, however, significant differences in PKs were apparent. Therefore, when taking Lamotrigine it is worthwhile to closely evaluate liver enzyme function especially (AST and ALT) and monitor seizure activity, regardless of whether receive brand or generic products. Moreover, we recommend future studies for the evaluation of the lamotrigine brand Lamictal^® and generic products on humans.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Author contributions

Conceptualization, Haya Alotaibi, Sarah Sulaiman Alenazi, and Aliyah Almomen; data curation, Haya Alotaibi, Sarah Sulaiman Alenazi and Maria Arafah; formal analysis, Aliyah Almomen, Maria Arafah and Sarah Megren Alrubia; funding acquisition, Aliyah Almolmen and, Nourah Alzoman; investigation, Haya Alotaibi and Sarah Sulaiman Alenazi; methodology, Haya Alotaibi, Sarah Sulaiman Alenazi, and Aliyah Almomen; project administration, Aliyah Almolmen and, Nourah Alzoman; resources, Alikyah Almolmen; supervision, Aliyah Almolmen, Sarah Megren Alrubia, and Nourah Alzoman; validation, Aliyah Almomen; writing original draft Haya Alotaibi, Sarah Sulaiman Alenazi, Sarah Megren Alrubi, and Aliyah Almomen; writing review and editing, Haya Alotaibi, Sarah Sulaiman Alenazi, Sarah Megren Alrubi, and Aliyah Almomen. All authors have read and agreed to the published version of the manuscript.

Funding

This research was supported by funding from the Ongoing Researcher Funding Program (ORF-2025-1125), King Saud University, Riyadh, Saudi Arabia.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Institutional review board

The research adhered to the guidelines established by the ethical committee for conducting studies that involve animals at King Saud University, Riyadh, Saudi Arabia, protocol number (KSU-SE-24-11).

Competing interests

The authors declare no competing interests.