The effect of age and comedication on lamotrigine clearance, tolerability, and efficacy

Abstract

SUMMARYPurpose: To compare pharmacokinetics, tolerability, and efficacy of lamotrigine (LTG) in older versus younger adults. Methods: We studied 686 adult outpatients seen at our center over 5 years. We compared apparent clearance (CL) of LTG in the youngest (16-36 years; n = 247) and oldest (55-92 years; n = 155) tertiles. We analyzed oneyear retention for younger and older adults newly started on LTG, frequency of adverse effects causing intolerability, and rates of specific adverse effects. We also investigated 6-month seizure freedom. Key Findings: Median LTG CL of older adults taking LTG in monotherapy was approximately 22% lower compared to younger adults (28.8 vs. 36.5 ml/h/kg; p < 0.001). LTG CL in older adults was lower compared to younger adults in patients on polytherapy and on polytherapy without enzyme inducers or valproate. One-year retention for LTG was comparable in older (78.1%, 121/155) and younger (72.4%, 179/247) adults. Intolerability to LTG was higher in older (34.8%) versus younger adults (24.2%; p = 0.005). Imbalance, drowsiness, and dizziness were common intolerable side effects in both groups. Older patients had higher rates of intolerability due to imbalance (16% vs. 4%), drowsiness (13% vs. 7%), and tremor (5% vs. 2%) compared with younger patients. Rates of 6-month seizure freedom were comparable, and small numbers of each group benefited from very high levels of LTG (>15 lg/ml). Significance: LTG CL in monotherapy in older adults is approximately 20% lower than in younger adults. For a given serum LTG level, older adults are twice as likely to have significant adverse effects compared to younger adults. Older patients are more likely to experience imbalance, drowsiness, and tremor than younger patients. Younger adults tolerate LTG better than older adults, but one-year retention is comparable. Some patients may benefit from high serum levels of LTG. KEY WORDS: Antiepileptic drug, Older adults, Drug interactions, Elderly, Pharmacokinetics.Lamotrigine (LTG) is a commonly used antiepileptic drug (AED) that received approval by the U.S. Food and Drug Administration (FDA) in 1994 as adjunctive therapy for partial seizures in adults and later in pediatric patients (at least 2 years of age). In addition, LTG has been approved for conversion to monotherapy in adults with partial seizures who are receiving treatment with carbamazepine (CBZ), phenytoin (PHT), phenobarbital (PB), primidone (PRM), or valproate (VPA) as the single AED (August, 2005;Gilliam et al., 1998) and for adjunctive treatment of primary generalized tonic-clonic seizures and generalized seizures of Lennox-Gastaut syndrome in adult and pediatric patients aged 2 years or older.The clinical management of seizures in older adults is often complicated by an increased likelihood of adverse effects (AEs) and potential interactions with multiple comedications. The effect of age and comedication on LTG pharmacokinetics in older adults has not been well studied. In this study we investigated drug and nondrug predictors of LTG clearan...

Pharmacokinetic Variability of Four Newer Antiepileptic Drugs, Lamotrigine, Levetiracetam, Oxcarbazepine, and Topiramate

“…14 In this study, no effects of age on pharmacokinetics were evident with lamotrigine or oxcarbazepine, but there was a large variability within the groups and too few patients in some of the subgroups for oxcarbazepine to demonstrate a significant effect. 22 The choice of comedication in various age groups may affect the results regarding the impact of age. 14,18,19 Previous studies give contradictory results regarding lamotrigine in children.…”

Treatment gaps of epilepsy and retention rates of sodium valproate in rural Guangxi, China

“…The 1-year retention for lamotrigine was comparable in older (78.1%, 121/155) and younger (72.4%, 179/247) adults in spite of the fact that younger adults tolerate lamotrigine better than older adults do. Some patients may benefit from high serum levels of lamotrigine (Arif et al, 2011). A multi-center retrospective observational study of the efficacy, tolerability, and retention rate of gabapentin use in children showed that gabapentin was well tolerated, with 55% of patients remaining on treatment beyond 1 year.…”

Lamotrigine drug interactions in combination therapy and the influence of therapeutic drug monitoring on clinical outcomes in paediatric patients

“…The only study, except our study in adults, that describes similar outcomes in triple therapy with CBZ, is Hachad et al, Perucca and Böttiger et al who mentioned that the effect of VPA was fully compensated in the presence of CBZ. Arif et al described decreased LTG clearance in combinations with VPA, +CBZ+VPA, and +TPM+VPA compared to monotherapy. Unfortunately, the difference from respective bitherapy was not statistically significant, probably due to low sample numbers.…”

“…The information about seizure type was not given in 655 (50%) request forms. The influence of the concomitant AED therapy was evaluated using the weight‐adjusted hourly apparent clearance (CL) that was calculated according to the following formula:…”