Daniela Mamoli

Topiramate pharmacokinetics in children and adults with epilepsy: A case-matched comparison based on therapeutic drug monitoring data

ObjectiveTo compare the steady-state pharmacokinetics of topiramate in a large population of children and adults with epilepsy in a therapeutic drug monitoring setting.Study designRetrospective, case-matched pharmacokinetic evaluation.PatientsSeventy children (aged 1–17 years) with epilepsy and 70 adult controls (aged 18–65 years) with epilepsy, matched for sex and comedication.MethodsTopiramate apparent oral clearance (CL/F) values were calculated from steady-state serum concentrations in children and compared with those determined in controls. Comparisons were made by means of the Mann-Whitney’s U-test, or the Kruskal-Wallis test in the case of multiple comparisons. A linear regression model was used to assess potential correlation of CL/F values with age. To investigate the influence of different variables on the variability in topiramate CL/F values, a multiple regression model was developed.ResultsIn the absence of enzyme-inducing comedication, mean topiramate CL/F was 42% higher in children than in adults (40.3 ± 21.0 vs 28.4 ± 15.3 mL/h/kg; p < 0.01). In children and adults comedicated with enzyme-inducing antiepileptic drugs (AEDs), topiramate CL/F values were approximately 1.5- to 2-fold higher than those observed in the absence of enzyme inducers, and the elevation in topiramate CL/F in children compared with adults was also present in the subgroups receiving enzyme inducers (66%; 76.6 ± 35.1 vs 46.1 ± 16.7 mL/h/kg; p < 0.0001). In the paediatric population, a negative correlation between CL/F and age was demonstrated, both in the absence (p < 0.01) and in the presence (p < 0.001) of enzyme induction. The independent influence of age and enzyme-inducing AEDs on topiramate CL/F was confirmed by multiple regression analysis.ConclusionTopiramate CL/F is highest in young children and decreases progressively with age until puberty, presumably due to age-dependent changes in the rate of drug metabolism. As a result of this, younger patients require higher dosages to achieve serum topiramate concentrations comparable with those found in older children and adults. Enzyme-inducing comedication decreases serum topiramate concentration by approximately one-half and one-third in children and adults, respectively.

Serum Carbamazepine Concentrations in Elderly Patients : A Case-matched Pharmacokinetic Evaluation Based on Therapeutic Drug Monitoring Data

Summary:  Purpose: To assess the influence of aging on the steady‐state pharmacokinetics of carbamazepine (CBZ) in a large population of patients evaluated in a therapeutic drug monitoring (TDM) setting.

Influence of aging on serum phenytoin concentrations: a pharmacokinetic analysis based on therapeutic drug monitoring data

The influence of aging on the pharmacokinetics of phenytoin at steady-state was evaluated retrospectically by comparing apparent oral clearance values (CL/F) in 75 patients aged 65-90 years (mean, 71.7 +/- 5.3 years) receiving phenytoin alone (n = 58) or in combination with phenobarbital (n = 17) and in an equal number of control patients aged 20-50 years (mean, 36.7 +/- 8.5 years) matched for gender, body weight, and comedication. All data were derived from the database of the therapeutic drug monitoring service (TDMS) of an academic neurological hospital. On average, elderly patients were found to exhibit slightly higher CL/F values compared with controls (14.6 +/- 4.7 ml h(-1) kg(-1) versus 13.1 +/- 4.2 ml h(-1) kg(-1), P < 0.05), the difference being probably related to the dose-dependent nature of phenytoin metabolism and the fact that elderly patients received lower dosages (4.4 +/- 1.1 mg kg(-1)day(-1) versus 5.3 +/- 1.1 mg kg(-1) day(-1), P < 0.001) and had lower serum phenytoin concentrations (14.1 +/- 5.7 microg ml(-1) versus 18.6 +/- 6.8 microg ml(-1), P < 0.0001). Gender and phenobarbital comedication were not found to exert any statistically significant influence on phenytoin CL/F. By contrast, in the elderly group, CL/F values were negatively correlated with age. On average, CL/F values decreased by about one-third between 65 and 85 years of age, but interindividual variability was considerable and age explained only 7.8% of the variation in CL/F in the elderly group. Overall, these findings indicate that aging is associated with a progressive decline in phenytoin clearance, presumably as a result of decreased drug metabolizing capacity. Because assessment was based on total serum phenytoin concentrations and the unbound fraction of phenytoin is known to decrease in old age, the influence of aging as quantified in this study may underestimate the magnitude of changes in the clearance of unbound, pharmacologically active drug. Based on these data, it is prudent to utilize initially smaller phenytoin dosages in old patients, and to make subsequent dose adjustments based on clinical response and serum drug level measurements. Interpretation of the latter, however, should take into account the possibility of an increase in the fraction of unbound drug.

Single-dose pharmacokinetics of lamotrigine in children: influence of age and antiepileptic comedication.

To evaluate the influence of pediatric age and antiepileptic comedication on the single-dose pharmacokinetics of lamotrigine, 19 patients with epilepsy (10 comedicated with enzyme inducers and 9 comedicated with valproic acid) aged 8 months to 30 years received a single oral dose of lamotrigine (0.6 to 2.2 mg/kg) after an overnight fast. Blood samples were collected for at least 36 hours and plasma lamotrigine concentrations were determined by high-performance liquid chromatography. Pharmacokinetic parameters were calculated by noncompartmental analysis. Lamotrigine half-life (T1/2) and oral clearance (Cl/F) values were significantly lower and significantly higher, respectively, in patients comedicated with enzyme inducers than in those receiving valproic acid (T1/2 = 8.1 vs. 41.7 hours respectively, P < 0.001; Cl/F = 0.11 vs. 0.04 L/h per kg respectively, P < 0.005, geometric means), whereas Cmax and Tmax values were comparable in the two groups. The differences in pharmacokinetic parameters persisted when comparisons were made within subgroups stratified according to age. Within groups of patients homogeneous for type of comedication, Cmax and AUC values tended to be lower in children aged less than 12 years than in older patients. There was no significant relationship between half-life values and age. The authors conclude that both age and type of comedication influence lamotrigine pharmacokinetics. The reduction in lamotrigine concentrations caused by enzyme inducers and the elevation caused by valproic acid can be explained by stimulation and inhibition, respectively, of lamotrigine glucuronidation. On the other hand, the lower plasma lamotrigine levels in children than in adolescents and older patients may not be explainable solely by differences in metabolic rate.

The influence of old age and enzyme inducing comedication on the pharmacokinetics of valproic acid at steady-state: A case-matched evaluation based on therapeutic drug monitoring data

PURPOSE To evaluate the influence of aging on the pharmacokinetics of valproic acid (VPA) at steady-state and on the susceptibility of VPA metabolism to enzyme induction by antiepileptic comedication. METHODS The database of the therapeutic drug monitoring service of a large neurological hospital was searched to identify patients aged > or = 65 years stabilized on VPA therapy. Apparent VPA oral clearance (CL/F) calculated for each elderly patient was compared with that determined in an equal number of VPA-treated controls aged 20-50 years and matched for gender, body weight and antiepileptic drug (AED) comedication. RESULTS A total of 71 elderly patients aged 70.0+/-4.4 years, including 20 receiving enzyme inducing AEDs, was included in the main evaluation. In the absence of enzyme inducing comedication, VPA CL/F in the elderly was similar to that found in non-elderly controls (9.7+/-4.6 versus 10.2+/-4.6mlh(-1)kg(-1)). Elderly patients on enzyme inducing comedication, on the other hand, had lower CL/F values than enzyme induced younger controls (11.7+/-5.4 versus 16.0+/-6.3mlh(-1)kg(-1), p<0.05). Since VPA CL/F is known to increase with increasing dosage, a lower VPA dosage in elderly patients comedicated with enzyme inducers compared with controls may have contributed to differences in CL/F between the two groups. CONCLUSIONS In the absence of enzyme inducing comedication, VPA clearance in the elderly was comparable to that observed in controls. VPA clearance in elderly patients receiving enzyme inducing AEDs was lower than in controls, the difference being probably due to an influence of age as well as to the fact that mean VPA dosage was lower in these patients than in controls. Since our measurements of clearance were based on total serum VPA concentrations and VPA binding to plasma proteins is known to be reduced in old age, it is likely that the clearance of unbound, pharmacologically active, VPA was decreased to an important extent in the elderly, presumably as a result of a decline in drug metabolizing capacity.

Italian Consensus Conference on Epilepsy and Pregnancy, Labor and Puerperium

To facilitate an integrated and rational approach to the care of women with epilepsy of childbearing potential, a group of experts appointed by Italian scientific societies in the fields of epileptology, neonatology, pediatrics, neuropediatrics, child neuropsychiatry, obstetrics, and gynecology held a joint meeting in Santa Trada di Cannitello, Reggio Calabria, Italy, on October 15–16, 2004, with the aim of reaching consensus on the optimal management of these women. An ad hoc system for the classification of available published evidence and the opinions of experts was developed and used to grade recommendations on different aspects related to counseling, diagnostic, and treatment issues. The present document summarizes available evidence on the reciprocal interactions between epilepsy, antiepileptic drugs, fertility, contraception, pregnancy, delivery, breastfeeding, and the offspring. Recommendations are made concerning the information and counseling that should be provided to women with epilepsy with respect to issues related to contraception, conception, pregnancy, labour, and puerperium. More detailed recommendations on the same issues are provided to physicians and other healthcare professionals involved in the care of these women, with special reference to choice of effective contraception, optimization of antiepileptic drug therapy, use of prenatal diagnostic tests and other monitoring procedures, and appropriate management practices in relation to childbirth, puerperium, and the care of the child.

Phenobarbital Pharmacokinetics in Old Age: A Case-matched Evaluation Based on Therapeutic Drug Monitoring Data

Summary:  Purpose: To assess the influence of aging on the pharmacokinetics of phenobarbital (PB) at steady state in patients receiving long‐term therapy.