Concentration-to-dose Ratio Research Articles

Interaction between sulthiame and clobazam: Sulthiame inhibits the metabolism of clobazam, possibly via an action on CYP2C19

The aim of this study was to investigate the effect of sulthiame (STM) on the pharmacokinetics of clobazam (CLB) by determining the concentration to dose (CD) ratio (serum level (ng/ml) divided by dose (mg/kg)) of CLB and that of N-desmethyl-clobazam (DMCLB).We evaluated five patients (an adult and four children) whose serum CLB and DMCLB concentrations were monitored after the addition or discontinuation of STM. Four of the five patients were CYP2C19 intermediate metabolizers, and one patient was an extensive metabolizer. When the patients were taking STM (100–275mg/day), the mean CD ratio of DMCLB increased by 82.6 to 248.5%, which was higher than when they were not using STM. The increase was dose-dependent. In contrast, the CD ratio of CLB remained stable after addition or discontinuation of STM.These data suggest that STM has the potential to inhibit CYP2C19 enzyme activity. During combination therapy with STM and CLB in patients with CYP2C19 intermediate or extensive metabolizer phenotypes, monitoring of DMCLB concentrations may be helpful in ascertaining CLB-related adverse effects.

Factors Influencing Serum Topiramate Concentrations in Routine Therapeutic Drug Monitoring in Korean Adult Patients With Epilepsy

Topiramate (TPM) is a broad-spectrum anticonvulsant used both as an adjunctive treatment and as monotherapy. In this study, the results from a routine therapeutic drug monitoring (TDM) service for TPM are summarized. In addition, factors influencing the variability in serum concentration of TPM and the effects of comedication on serum TPM concentration were investigated. Serum measurements of TPM from a routine TDM database were analyzed retrospectively. Concentration-to-dose ratio (CDR) was calculated to assess pharmacokinetic variability. We compared CDRs for patients receiving TPM monotherapy and patients receiving TPM with other antiepileptic drugs, together with the effects of each comedication on TPM concentration were studied. There were 510 samples from 476 adult patients. Serum TPM was below 2.0 mg/L or above 10.0 mg/L in 28.2% and 5.9% of samples, respectively. Although serum TPM was broadly related to prescribed dose, there was wide variation. Most patients using TPM were treated in combination with other anticonvulsants (90.8%). TPM-CDR in patients receiving TPM monotherapy was not significantly different from those receiving TPM in combination with nonenzyme inducers, but TPM-CDR was lower in patients who were taking inducers (P < 0.0001, Kruskal-Wallis test, Dunnett method). A large interindividual variability in TPM serum concentrations was observed in this cohort of patients. TDM of TPM is useful in selected patients such as those suspected of poor compliance/absorption and those who may experience pharmacokinetic changes because of comedication or physiological changes.

Concentrations of Stiripentol in Children and Adults With Epilepsy

Stiripentol (STP) was approved as an orphan drug in 2007 in Europe as adjunctive therapy with valproic acid (VPA) and clobazam (CLB) for Dravet syndrome. Dravet syndrome is a highly pharmacoresistant form of epilepsy, which starts in early childhood. Data about STP pharmacokinetics and interactions are still limited and in part inconsistent. The aim of our study was to analyze the effect of age, gender, daily STP dose per body weight (milligrams per kilogram), VPA, CLB, and enzyme-inducing antiepileptic drugs on STP concentration-to-dose ratio (CDR), STP clearance, and STP trough concentrations. Retrospectively, 220 STP serum concentrations in 75 patients from 3 German Epilepsy Centers were analyzed. Analysis of variance, regression analysis, and generalized estimating equations were used for statistical analysis. Our findings confirm the nonlinear STP pharmacokinetics. At steady state, STP CDR increased with daily STP doses. Compared with patients older than 12 years, STP concentrations were decreased by 39.6% in children aged 6-12 years (P < 0.001) and by 57.5% in children younger than 6 years (P < 0.001). Phenobarbital and phenytoin decreased STP concentrations by 63.2%. This effect was highly significant (P < 0.001), despite the small number of patients (n = 7) treated with phenobarbital or phenytoin. VPA had no significant effect on STP serum concentrations, whereas STP serum concentrations were moderately but significantly increased by CLB (24.6%, P = 0.011). Therapeutic drug monitoring of STP seems to be useful because of the wide variation of STP CDR, the nonlinear concentration-to-dose relationship, age-dependent pharmacokinetics, and drug-drug interactions.

Ethinyl Estradiol, Not Progestogens, Reduces Lamotrigine Serum Concentrations

To study the interaction between lamotrigine (LTG) and hormonal contraception. LTG serum concentrations of female patients using either no hormonal contraception (n=18), an ethinyl estradiol (EE)-containing (n=11), or a progestogen (PG)-only-containing compound (n=16) were analyzed. Patients were recruited prospectively, and blood samples were drawn during drug fasting and at steady-state conditions. Comedication with enzyme inducers, valproate, topiramate, or sertraline was not allowed. Some patients changed groups and thus served as their own controls. Samples were analyzed by a gas chromatography/ mass spectroscopy method. The Mann-Whitney U test was used for statistical comparison of the groups. The LTG serum concentration-to-dose ratio (CDR), expressed as (mg/L)/(mg/d) was significantly lower in women using EE than in the control group (mean+/-SD, 0.010+/-0.004 vs. 0.017+/-0.006; p=0.003). The CDR in women using PG was 0.02+/-0.007, which was not statistically different from controls. No difference was found in CDR between women using either oral, topical, or parenteral PG. Five women switched from the control to the EE group and experienced a considerable reduction in CDR. An increase of the CDR toward control level was seen in the two women who changed from EE to PG. It is the EE component of oral contraceptives that interacts with LTG. The PG-only compounds did not alter LTG serum concentrations in this study. These findings should be considered when counselling women with epilepsy in the childbearing ages.

10-Hydroxycarbazepine Serum Concentration-to-Oxcarbazepine Dose Ratio

This study was done to evaluate the association between patient age and the concomitant use of enzyme-inducing antiepileptic drugs (AEDs) and oxcarbazepine (OXC) concentration-to-dose ratio (CDR) by a multivariate analysis. The influence of patient age and concomitant AEDs on the trough steady-state serum concentration of 10-hydroxycarbazepine (OHC) normalized to 1 mg/kg body weight of OXC or concentration-to-dose ratio (OHC-OXC-CDR) was assessed by analysis of covariance. Samples were collected from 106 patients (90% outpatients), aged 1-80, who were receiving OXC either alone (n = 41) or in combination with other AEDs (n = 65). The average OHC-OXC CDR was 0.70 +/- 0.26 (mean +/- SD). Analysis of covariance showed that patient age was influential (P < 0.001) and that there was a difference between the noninducers group (OXC or OXC + lamotrigine, topiramate, or valproate) and the inducers group (OXC + phenobarbital or phenytoin) (P < 0.001). The OHC-OXC CDR increased with age (r = 0.14, P < 0.001) and was approximately 48% lower in children aged 6 or less than in patients over 45, and approximately 32% lower in the inducers group than in patients receiving OXC alone. The correlation between OHC-OXC CDR and the age of the patients concerned with OXC alone was r = 0.48, P < 0.001. In the noninducers group the OHC-OXC CDR was 0.59 +/- 0.24 in patients aged 11 or less (n = 16), and 0.81 +/- 0.23 in patients over 11 years (n = 62). In the inducers group it was 0.25 +/- 0.11 in patients aged 11 or less (n = 3) and 0.57 +/- 0.18 in patients over the age of 11 (n = 25). The OHC-OXC CDR increased with patient age and decreased in the presence of enzyme-inducing AEDs in epileptic patients chronically treated with OXC. These influences may be clinically relevant, and, therefore, patient age and the presence of inducers should be considered in estimating either compliance or the OXC dose needed to achieve a desired OHC concentration.

Association Between Patient Age and Gabapentin Serum Concentration-to-Dose Ratio

To evaluate the association between patient age and gabapentin (GBP) concentration-to-dose ratio by a multivariate analysis. The association between patient age and the trough steady-state serum concentration of gabapentin (GBP) normalized to 1 mg/kg body weight or concentration-to-dose ratio (CDR) was retrospectively assessed by analysis of covariance. Potential confounding factors considered were GBP dosage, the number of GBP doses per day, and the presence of concomitant antiepileptic drugs (AEDs). Concentrations that had been measured in predose "trough" samples collected from 66 patients, aged 5-84 years, with partial seizures or neuropathic pain chronically receiving GBP BID (n = 21) or TID (n = 45), alone (n = 15) or in combination with other AEDs (n = 51) were used in this retrospective analysis. Average GBP CDR was 0.23 +/- 0.18 (mean +/- SD). The GBP CDR increased with age (r2 = 0.46, P < 0.001), and the correlation was improved when only samples from patients taking GBP BID were separately considered (r2 = 0.68, P < 0.001). The ratio was lower in the 10 children younger than 11 years of age (0.07 +/- 0.05) than in 8 adolescents aged 12 to 18 years (0.14 +/- 0.04), lower than in 35 adults aged 19 to 65 years (0.22 +/- 0.13), and lower than in 13 patients older than 65 years of age (0.45 +/- 0.20) by 1-way analysis of variance (F = 19.4, P < 0.001). Analysis of covariance showed a significant influence on GBP CDR of patient age (P < 0.001) and the number of GBP daily doses (P < 0.01), but GBP daily dosage or concomitant AEDs had no significant influence on the ratio. In this retrospective study of a small, select group of patients, (1) the GBP CDR increased significantly with age when potential confounding factors such as GBP dosage, number of GBP doses per day, and concomitant AEDs were considered by analysis of covariance, and (2) patients older than 65 years, even without any known renal disease, may have double GBP CDR than younger adults and, therefore, may need half of the GBP dose per body weight to achieve a similar concentration.