Concentration-to-dose Ratio Research Articles

Combined effect of CYP2C19 and CYP2D6 genotypes on escitalopram serum concentration and its metabolic ratio in a European patient population.

The aim of the present study was to investigate the impact of CYP2D6 genotype on exposure and metabolism of escitalopram in patients stratified by CYP2C19 genotype in a large real-world population. Patients were included from a therapeutic drug monitoring service if they had measured serum concentration of escitalopram and the metabolite, N-desmethyl escitalopram, and performed CYP2C19 and CYP2D6 genotyping. Patients were divided into 16 combined genotype-predicted phenotype subgroups (poor [PM], intermediate [IM], normal [NM] and ultrarapid metabolizers [UM]) of CYP2C19/CYP2D6. The concentration-to-dose (CD) ratio and metabolite-to-parent ratio (metabolic ratio) of escitalopram were compared across subgroups using the Kruskal-Wallis test followed by Dunn's test with CYP2D6 NMs as the reference group. A total of 5067 patients were included in the study. A stepwise increase in escitalopram CD ratio by decreasing CYP2D6 activity was observed in all CYP2C19 subgroups, except for in CYP2C19 UMs. The percentage differences in escitalopram CD ratio between CYP2D6 PMs and NMs were 24% in CYP2C19 NMs (P < .001), 28% in CYP2C19 IMs (P < .001) and 31% in CYP2C19 PMs (P = .04). As for the CD ratio, CYP2D6 genotype effect on metabolic ratio increased stepwise by decreasing CYP2C19 metabolism. CYP2D6 genotype is of significant importance for the individual variation in escitalopram pharmacokinetics. The most relevant increase in escitalopram concentration is seen in individuals with decreased and/or absent CYP2C19 activity. By combining CYP2C19 and CYP2D6 genotypes, the optimal dose for patients may be predicted with greater precision than for CYP2C19 genotype alone.

Impact of donor CYP3A5 genotype on pharmacokinetics of tacrolimus in South African paediatric liver transplant patients.

In the paediatric liver transplant programme in Johannesburg, South Africa (SA), tacrolimus is the calcineurin inhibitor of choice, comprising an essential component of the immunosuppression regimen. It is characterised by a narrow therapeutic index and wide interpatient variability, necessitating therapeutic drug monitoring of whole-blood concentrations. Pharmacogenetic research, although not representative of SA population groups, suggests that single-nucleotide polymorphisms within the cytochrome P450 3A5 (CYP3A5) gene contribute to the variability in tacrolimus dosing requirements. The rs776746 polymorphism, CYP3A5*3, results in a splice defect and a non-functional enzyme. Clinically, to reach the same tacrolimus concentration-to-dose ratio (CDR), expressors (CYP3A5*1/*1 and *1/*3) require a higher tacrolimus dose than non-expressors (*3/*3). To compare the pharmacokinetics of tacrolimus in paediatric liver transplant recipients with their donors' CYP3A5 genotypes, considering both donor and recipient characteristics. Blood samples from 46 living liver donors were collected, their genomic DNA was extracted, and their CYP3A5 genotype was established (polymerase chain reaction and restriction fragment length polymorphism analysis, validated by Sanger sequencing). The relationship of donor and recipient characteristics with the mean tacrolimus CDR was analysed using a general linear model. Non- confounding significant variables were included in a multiple regression model. The study showed that all expressor donors genotyped as CYP3A5*1/*1 were of black African self-reported race and ethnicity. During the first 15 days post-transplant, we found that children who received grafts from donor CYP3A5 expressors (CYP3A5*1/*1 and *1/*3) had significantly lower mean tacrolimus CDRs compared with those who received grafts from donor CYP3A5 non-expressors (*3/*3); the recipients of CYP3A5 expressor grafts therefore require higher doses of oral tacrolimus to achieve the same therapeutic target range. In addition, graft-to-recipient weight ratio and the CYP3A5 donor genotypes were independent factors that significantly (p<0.05) affected mean tacrolimus CDRs in recipients. In this study, we showed that all CYP3A5*1 homozygote donors were of black African self-reported race and ethnicity, and tacrolimus CDRs in paediatric living-donor liver transplant recipients were significantly affected by donor graft size and donor CYP3A5 genotypes. Information from this study may inform the development of an Afrocentric tacrolimus precision-medicine algorithm to optimise recipient safety and graft outcomes.

UGT1A polymorphism rs4148324 associated with topiramate plasma concentration to dose ratio in children with epilepsy.

The objective of this study is to evaluate the association between genetic polymorphisms and the concentration to dose ratio of topiramate in children with epilepsy. A cohort of 163 pediatric patients with epilepsy receiving topiramate therapy were enrolled. The ultra-performance liquid chromatography-tandem mass spectrometry method was employed to measure the trough plasma concentration of topiramate at steady-state. These concentrations were normalized by dividing them by the ratio of total daily dose to body weight, yielding the concentration to dose ratio (CDR) of topiramate. MassArray system identified 30 single nucleotide polymorphisms associated with the pharmacokinetics and pharmacodynamics of topiramate. The CDR values were logarithmic transformed (lnCDR) for normal distribution. The association between the identified genetic polymorphisms and lnCDR was assessed using the PLINK software, employing linear regression analysis with adjustments by epilepsy types, estimated glomerular filtration rate, alanine aminotransferase, valproic acid, phenobarbital, and oxcarbazepine. Variant rs4148324 (UGT1A1/3/4/5/6/7/8/9/10, BETA=0.182, P = 0.010) was significantly associated with lnCDR of topiramate. Patients carrying the G allele exhibited higher normalized topiramate plasma concentrations. No other significant associations were found. In pediatric patients receiving topiramate therapy, rs4148324 was associated with normalized topiramate plasma concentration. Further studies are warranted to validate and confirm the findings.

Effect of Age, Comedications, and CYP3A4/5 Polymorphisms on Perampanel Exposure in Chinese Pediatric Patients With Epilepsy.

Perampanel (PER) is a new type of antiseizure medication used for partial or generalized seizures. However, the plasma concentration shows obvious individual variability in children. The present study aims to ascertain the effect of age, comedications, and cytochrome P450 (CYP) 3A4/5 polymorphisms on PER exposure in Chinese pediatric patients with epilepsy. Clinical data were retrospectively collected in a tertiary children's hospital medical records system from January 2021 to December 2022. The influence factors on the daily dose, plasma concentration, and concentration-to-dose ratio (CDR) of PER were investigated. A total of 135 pediatric patients with 178 blood samples were involved. With a median daily dose of 4.0 mg (interquartile range, 3.0-5.0 mg), the median plasma concentration was 409.4 ng/mL (interquartile range, 251.7-639.4 ng/mL). The CDR in patients aged less than 4 years was significantly decreased by 48.0% and 39.1% compared with those aged 4-11 years and 12 years or older, respectively. Enzyme inducers significantly decreased the CDR of PER by 34.5%, while valproic acid showed an increase of 71.7%. In addition, genotype CYP3A5*3/*3 carriers presented a significant increase of 21.5% compared to the CYP3A5*1/*3 expresser. No correlations were observed between the CDR and CYP3A4∗1G polymorphism. PER showed high variations in individual plasma concentrations. Age younger than 4 years, comedication with enzyme inducers or valproic acid, and possession of the CYP3A5*3 genotype potentially predicted PER exposure in pediatric patients with epilepsy.

Methadone pharmacokinetics in opioid agonist treatment: Influencing factors and clinical implications.

A considerable inter-individual variability has been reported in the relationship between methadone doses applied and serum concentrations achieved in methadone maintenance treatment. However, the underlying causes for this variability are not fully understood. We investigated the influence of genetic, pathophysiological and pharmacological factors on serum methadone concentration-to-dose ratio (CDR) and discussed the clinical implications of the findings. We used data from two retrospective laboratory databases and a prospective cohort study to investigate the impact on methadone CDR of hepatic cytochrome P450 enzyme system (CYP) genetic polymorphisms, age, sex, concomitant medication, liver fibrosis and body mass index through linear mixed model analyses. A positive association was found between CDR and the homozygous CYP2B6*6 genotype, concurrent treatment with CYP3A4 inhibitors and body mass index. CDR was lower among women and during concomitant use of CYP inducers. CDR was not associated with age or the degree of liver fibrosis in our investigations. This research work supports the need for individually tailored dosage considering the various factors that influence methadone CDR. The gained knowledge can contribute to reducing the risks associated with the treatment and optimizing the desired outcomes.

Therapeutic Drug Monitoring of Perampanel in Children With Refractory Epilepsy: Focus on Influencing Factors on the Free-Perampanel Concentration.

This study aimed to assess the effect of perampanel dose, age, sex, and antiseizure medication cotherapy on steady-state free-perampanel concentration in children with refractory epilepsy, as well as the relationship between inflammation and the pharmacokinetics of perampanel. This prospective study in China included 87 children with refractory epilepsy treated with adjunctive perampanel therapy. Free and total perampanel concentrations in plasma were determined using liquid chromatography-tandem mass spectrometry. Free-perampanel concentration was compared among patients with various potential influencing factors. A total of 87 pediatric patients (44 female children) aged 2-14 years were enrolled. The mean free-perampanel concentration and free concentration-to-dose (CD) ratio in plasma were 5.7 ± 2.7 ng/mL (16.3 ± 7.7 nmol/L) and 45.3 ± 21.0 (ng/mL)/(mg/kg) [129.6 ± 60.1 (nmol/L)/(mg/kg)], respectively. The protein binding of perampanel in plasma was 97.98%. A linear relationship was observed between perampanel dose and free concentration in plasma, and a positive relationship was found between the total and free-perampanel concentrations. Concomitant use of oxcarbazepine reduced the free CD ratio by 37%. Concomitant use of valproic acid increased the free CD ratio by 52%. Five patients had a plasma high-sensitivity C-reactive protein (Hs-CRP) level of >5.0 mg/L (Hs-CRP positive). The total and free CD ratios of perampanel were increased in patients with inflammation. Two patients with inflammation developed adverse events, which disappeared as the Hs-CRP level returned to normal, and neither required perampanel dose reduction. Age and sex did not influence the free-perampanel concentration. This study found complex drug interactions between perampanel and other concomitant antiseizure medications, providing valuable information to enable clinicians to apply perampanel in the future reasonably. In addition, it may be important to quantify both the total and free concentrations of perampanel to assess complex pharmacokinetic interactions.

A retrospective non-interventional study evaluating the pharmacokinetic interactions between cenobamate and clobazam.

Cenobamate is an antiseizure medication (ASM) approved for the treatment of partial-onset seizures in adults. As both an inductor and an inhibitor of hepatic enzymes, cenobamate affects the metabolism of other ASMs, among which is clobazam. To our knowledge, the extent of interaction between cenobamate and clobazam and its clinical significance have not been studied yet. In this retrospective study we assessed serum concentrations of clobazam and N-desmethylclobazam (NCLB)in five patients before and after co-medication with cenobamate and calculated the percentage increase in concentration-to-dose ratio (CDR) of both. We were able to demonstrate that the addition of cenobamate resulted in an increase in serum concentration and consequently in CDR of NCLB in all patients. However this occurred in variable degrees: NCLB concentration showed an increase of 1208 μg/L (CDR145%) in one patient and between 1691 μ/L (CDR 819%) and 3995 μ/L (CDR 1852%) in the other four. This resulted in fatigue, which improved after dose reduction of CLB. Therefore, it is to be concluded that concomitant administration of cenobamate and clobazam can lead to a substantial increase in serum concentrations of NCLB. This can have a positive therapeutic effect on one hand; however, on the other hand, this can lead to unwanted fatigue.

Clinical value of therapeutic drug monitoring for levetiracetam in pediatric patients with epilepsy

PurposeTo identify pediatric patients who require therapeutic drug monitoring (TDM) of levetiracetam (LEV). MethodsWe retrospectively investigated 2413 routine therapeutic drug monitoring data on serum LEV concentration from 1398 pediatric patients (age, 0–15 years). Samples were grouped by age (infants, < 1 year; preschool children, 1–5 years; primary school children, 6–11 years; and adolescents, 12–15 years), and the LEV concentration-to-dose (CD) ratio was calculated. ResultsThe mean CD ratio was highest in adolescents (analysis of variance, p < 0.001); 22.5 % and 15.7 % higher in adolescents than in preschool children and school children, respectively (Scheffé test, p < 0.001); and higher in infants than in preschool children. Preschool children had the lowest ratio and tended to show an increase in the ratio from age 2 to 5 years. Use of enzyme-inducing antiseizure medication reduced the CD ratio by 6.1 % in infants, 12.2 % in preschool children, 5.9 % in primary school children, and 9.4 % in adolescents. The mean CD ratio was 2.7 %, 26.9 %, and 39.3 % higher in preschool children, primary school children, and adolescents with defined chronic kidney disease (CKD) than in the respective age group of patients without CKD. The therapeutic concentration range for a long-term LEV therapy was 11 to 32 μg/mL. ConclusionsLEV pharmacokinetics are significantly different between infant and preschool children, so TDM of LEV is clinically useful in these patients. In pediatric patients at higher risk for CKD, glomerular filtration rate and LEV levels should be carefully monitored.

Impact of ABCC2 1249G>A and -24C>T Polymorphisms on Lacosamide Efficacy and Plasma Concentrations in Uygur Pediatric Patients With Epilepsy in China.

We aimed to evaluate the effect of the ABCC2 1249G>A (rs2273697) and -24C>T (rs717620) polymorphisms on lacosamide (LCM) plasma concentrations and the efficacy of LCM in Uygur pediatric patients with epilepsy. We analyzed 231 pediatric patients with epilepsy, among which 166 were considered to be LCM responsive. For drug assays, 2-3 mL of venous blood was collected from each patient just before the morning LCM dose was administered (approximately 12 hours after the evening dose, steady-state LCM concentrations). The remaining samples after routine therapeutic drug monitoring were used for genotyping analysis. The χ 2 test and Fisher exact test were utilized for comparative analysis of the allelic and genotypic distribution of ABCC2 polymorphisms between the LCM-resistant and LCM-responsive groups. The Student t test or Mann-Whitney U test was conducted to analyze differences in plasma LCM concentration among pediatric patients with epilepsy with different genotypes. Patients with the ABCC2 1249G>A GA genotype (0.7 ± 0.3 mcg/mL per kg/mg) and AA genotype (0.5 ± 0.3 mcg/mL per kg/mg) showed significantly ( P < 0.001) lower LCM concentration-to-dose (CD) ratios than patients with the GG genotype (1.0 ± 0.4 mcg/mL per kg/mg). Moreover, patients with the ABCC2 -24C>T CT genotype (0.6 ± 0.2 mcg/mL per kg/mg) and TT genotype (0.6 ± 0.3 mcg/mL per kg/mg) presented a significantly ( P < 0.001) lower LCM CD ratio than patients with the CC genotype (1.1 ± 0.4 mcg/mL per kg/mg). The ABCC2 1249G>A (rs2273697) and ABCC2 -24C>T (rs717620) polymorphisms can affect plasma LCM concentrations and treatment efficacy among a population of Uygur pediatric patients with epilepsy, causing these patients to become resistant to LCM. In clinical practice, ABCC2 polymorphisms should be identified before LCM treatment, and then, the dosage should be adjusted for pediatric patients with epilepsy accordingly.

Combined impact of the inter and intra-patient variability of tacrolimus blood level on allograft outcomes in kidney transplantation.

Tacrolimus (TAC) has been widely used as an immunosuppressant after kidney transplantation (KT); however, the combined effects of intra-patient variability (IPV) and inter-patient variability of TAC-trough level (C0) in blood remain controversial. This study aimed to determine the combined impact of TAC-IPV and TAC inter-patient variability on allograft outcomes of KT. In total, 1,080 immunologically low-risk patients who were not sensitized to donor human leukocyte antigen (HLA) were enrolled. TAC-IPV was calculated using the time-weighted coefficient variation (TWCV) of TAC-C0, and values > 30% were classified as high IPV. Concentration-to-dose ratio (CDR) was used for calculating TAC inter-patient variability, and CDR < 1.05 ng•mg/mL was classified as rapid metabolizers (RM). TWCV was calculated based on TAC-C0 up to 1 year after KT, and CDR was calculated based on TAC-C0 up to 3 months after KT. Patients were classified into four groups according to TWCV and CDR: low IPV/non-rapid metabolizer (NRM), high IPV/NRM, low IPV/RM, and high IPV/RM. Subgroup analysis was performed for pre-transplant panel reactive antibody (PRA)-positive and -negative patients (presence or absence of non-donor-specific HLA-antibodies). Allograft outcomes, including deathcensored graft loss (DCGL) and biopsy-proven allograft rejection (BPAR), were compared. The incidences of DCGL, BPAR, and overall graft loss were the highest in the high-IPV/RM group. In addition, a high IPV/RM was identified as an independent risk factor for DCGL. The hazard ratio of high IPV/RM for DCGL and the incidence of active antibody-mediated rejection were considerably increased in the PRA-positive subgroup. High IPV combined with RM (inter-patient variability) was closely related to adverse allograft outcomes, and hence, more attention must be given to pre-transplant PRA-positive patients.

Effect of CYP3A4 and PPARA polymorphism on concentration-to-dose ratio and adverse effects of tacrolimus in Pakistani liver transplant recipients.

Objectives:Polymorphism in cytochrome P450 3A4 (CYP3A4) and its regulatory gene peroxisome proliferator activated receptor (PPARA) may significantly affect the metabolism of tacrolimus. This study aims to explore the effect of the single nucleotide polymorphisms (SNP) of cytochrome P450 3A4 and PPARA on the pharmacological variables of adverse effects and the concentration-to-dose ratio (CDR) of the immune suppressant drug tacrolimus in Pakistani liver transplant recipients.Methods:Eighty-one liver transplant patients were included and their demographic and clinical data were recorded. Dosages and trough levels of tacrolimus measured by electrochemiluminescence (ECLIA) were recorded daily. Genotyping for transplant recipients was performed for CYP3A4 rs35599367, PPARA rs4253728 and rs4823613. Incidence of sepsis, acute cellular rejection (ACR) and other adverse effects were recorded.Results:Liver transplant recipients with CYP3A4 rs35599367 CT and TT genotype reported higher tacrolimus CDR compared to the CC genotype during week-1 (p<0.001) and week-2 (p =0.03) post-transplantation period. CYP3A4 rs35599367 polymorphism presented a significant association with nephrotoxicity, sepsis, seizures and psychosis. Significant association of PPARA rs4253728 and PPAARA rs4823613 polymorphism with ACR was observed.Conclusion:Genotyping for CYP3A4 rs35599367 polymorphism during dose titration may shorten the duration to reach optimal tacrolimus trough levels and may help predict adverse events in transplant recipients receiving tacrolimus; genotyping for PPARA rs4253728 and rs4823613 may predict the incidence of ACR.

Influence of UGT2B7 and UGT1A6 polymorphisms on plasma concentration to dose ratio of valproic acid in Chinese epileptic children

We explored the potential effects of genetic variations on the concentration to dose ratio (CDR) of valproic acid (VPA) in paediatric epilepsy patients. Two hundred and twenty-nine epileptic children on VPA monotherapy were included, and the VPA trough concentrations at steady-state of all subjects were determined. Nineteen single nucleotide polymorphisms (SNPs) of seven selected genes related to the metabolising enzymes and transporters of VPA were identified, and their influences on CDRVPA (a logarithmic transformation was performed if abnormally distributed) were evaluated. UGT2B7 rs7668258 (C>T) TT genotype was associated with a decrease in lnCDRVPA among epileptic children receiving VPA monotherapy (β=–0.191, p = 0.036). Significantly lower lnCDRVPA was also observed in paediatric patients with UGT1A6 rs2070959 (A>G) GG genotype compared to those AA genotype (β=–0.270, p = 0.021). This research indicated that UGT2B7 rs7668258 (C>T) and UGT1A6 rs2070959 (A>G) polymorphisms may be correlated to the normalised plasma concentrations of VPA in Chinese epileptic children. The associations could be abolished after Bonferroni's correction and our findings need to be validated in further and larger investigations.

Management and tolerability of glecaprevir-pibrentasvir pharmacotherapy in hepatitis C viremic heart and lung transplant recipients.

We conducted a retrospective review of thoracic transplant recipients (22 heart and 16 lung transplant recipients) prospectively enrolled in a single-center observational study of HCV NAT+ organ transplantation in HCV NAT- recipients. All recipients were treated with 8weeks of glecaprevir-pibrentasvir (GP) for HCV viremia in addition to standard triple immunosuppression post-transplant. Thoracic transplant recipients of HCV NAT- organs were used as a control (24 heart and 22 lung transplant recipients). Our primary outcome was to assess the effect of GP on tacrolimus dose requirements. Secondary objectives included assessing drug interactions with common post-transplant medications, adverse effects, and the need to hold or discontinue GP therapy. The median tacrolimus concentration-to-dose ratio (CDR) in the cohort was 184 (99-260) during GP therapy and 154 (78-304) over the first month after GP (P=.79). Trends in median tacrolimus CDR were similar on a per-week basis and per-patient basis. In three instances, concomitant posaconazole and GP led to hyperbilirubinemia and interruption of posaconazole. GP therapy was held in one heart transplant recipient and discontinued in another due to unresolving hyperbilirubinemia. Utilization of GP to treat HCV viremia post-thoracic transplant is feasible and safe, but requires modifications to post-transplant pharmacotherapy and careful monitoring for adverse effects.

Therapeutic Monitoring of Lacosamide in Japanese Patients With Epilepsy: Clinical Response, Tolerability, and Optimal Therapeutic Range.

Lacosamide is a novel anticonvulsant that acts by enhancing sodium channel slow inactivation. The aims of this study were to evaluate the influence of concomitant antiepileptic drugs (AEDs) on serum lacosamide concentration and explore the relationship between lacosamide serum concentration and both clinical response and adverse effects. The authors analyzed 649 serum samples from 426 Japanese patients with epilepsy. The concentration-to-dose (CD) ratio of lacosamide was compared among patients on various AED regimens. Clinical information about seizure frequency and adverse events was obtained from clinical records. In patients who did not receive enzyme-inducing AEDs, the CD ratio (mean ± SD) of lacosamide was 1.84 ± 0.68. By contrast, the CD ratio in patients who received phenytoin, carbamazepine, and phenobarbital was 1.42 ± 0.66 (22.8% lower), 1.46 ± 0.40 (20.7% lower), and 1.36 ± 0.38 (26.1% lower), respectively. Seventy-four patients (17.3%) achieved >50% seizure reduction. The median lacosamide concentration in patients who received and did not receive a sodium channel blocker was 6.6 mcg/mL (26.4 μmol/L) and 8.4 mcg/mL (33.6 μmol/L), respectively. Adverse events, including dizziness, somnolence, diplopia, and anorexia, were reported by 70 patients (16.4%). The incidence rate in patients treated with sodium channel blockers was significantly higher than that in patients not treated with these drugs (21.1% vs. 10.3%; P < 0.005), and the median lacosamide concentration in these patient groups was 5.1 (20.4 μmol/L) and 7.5 mcg/mL (30 μmol/L), respectively. Therapeutic drug monitoring of lacosamide is clinically useful because it allows physicians to estimate the extent of drug interactions and adjust the dose in individual AED regimens.

Methadone serum concentrations and influencing factors: A naturalistic observational study

Although methadone maintenance treatment (MMT) has long been used for opioid addiction, our knowledge on its pharmacokinetics is still limited. We aimed to investigate effects of age, gender, and various co-medications on methadone serum concentration-to-dose ratio (CDR) in a naturalistic setting. In total, 4425 routine serum methadone concentrations obtained from 1691 MMT patients in the period October 1999 to July 2017 were included. Information about doses, age, gender, and concurrent medications was available in the laboratory database at the Department of Clinical Pharmacology at St. Olav University Hospital in Trondheim, Norway. A log-linear mixed model was used when analyzing the data. Mean age was 38.4 (range, 21-78) years and 70% were men. Mean CDR was 332 (range, 7-1776) (ng/mL)/(100mg/d). Concomitant medication with at least one out of totally 170 drugs was recorded in 26% of the samples. CDRs were significantly lower in women (- 9%; confidence interval (CI), - 13%, - 4%; p= 0.001) and with concurrent use of CYP inducers (- 36%; CI, - 44%, - 28%; p< 0.001), but higher using CYP3A4 inhibitors as co-medications (+ 36%; CI, + 10%, + 68%; p = 0.005). Our results warrant taking into consideration gender differences in methadone metabolism as well as the impact of potential drug-drug interactions to obtain an optimal therapeutic effect and avoid adverse effects in MMT. Although the clinical implications of the altered drug levels require further study, our results call for close clinical monitoring of all patients undergoing MMT, preferably along with laboratory measurements of methadone serum concentrations.

Clinical profiles associated with serum perampanel concentrations in children with refractory epilepsy

BackgroundPerampanel (PER) is a new antiepileptic drug (AED) with a novel mechanism of action. Investigations of the efficacy and safety of PER in pediatric and adult patients have increased recently. Although the clinical usefulness and pharmacokinetics of PER have been investigated in adolescent and adult populations, similar studies have not been performed in children. Patients and methodsWe retrospectively reviewed the medical records of patients treated with PER for more than 6 months in the Department of Pediatrics, Hiroshima University Hospital, between September 2016 and November 2018. We obtained demographic and clinical data including age, sex, epilepsy type, seizure type, seizure frequency before and after treatment initiation, adverse events, reasons for discontinuing PER treatment, doses at evaluation points, serum concentrations, concomitant AEDs, intellectual status, and epilepsy etiology. Seizure types and epilepsy syndromes were classified according to the criteria of the International League Against Epilepsy. ResultsThe study included 44 patients (22 males) between the ages of 6 months and 16 years. Of those, 10 patients discontinued PER therapy. The 50% response rate was 52.3% in patients treated with PER, and four patients achieved complete seizure control. Perampanel was highly effective in patients with generalized and focal epilepsy (50% responder rates, 52.9% and 50.0%, respectively). Favorable response rates were observed for tonic–clonic, focal nonmotor, and absence seizures with 50% response rates of 54.5%, 50.0%, and 66.7%, respectively. The 50% responder rate was 31.3 for epileptic spasms (ES). Treatment-emergent adverse events (TEAEs) included somnolence (n = 8), irritability (n = 2), ataxia (n = 2), and one case each of dizziness, compulsiveness, and enuresis. Serum concentrations of PER were compared in patients taking concomitant enzyme-inducing antiepileptic drugs (EIAEDs; carbamazepine, phenytoin, and phenobarbital) and those taking concomitant non-EIAEDs. Serum PER concentrations were correlated with dose per body weight in both groups (EIAED: r = 0.765, p = 0.00000212; non-EIAED: r = 0.71, p = 0.0000158). The mean concentration-to-dose (CD) ratio was 2398.4 ng mL−1 mg−1 kg−1 (range: 800–4524.7) in the non-EIAED group and 693.7 ng mL−1 mg−1 kg−1 (range: 344–1309.7) in the EIAED group. Serum PER levels were lower in the EIAED group than in the non-EIAED group. All patients with serum PER concentrations above 400 ng/mL experienced somnolence. ConclusionsPerampanel is effective against various types of seizures, including ES, in pediatric patients with refractory epilepsy. Furthermore, PER has good tolerability when the dose is adjusted based on serum concentrations. The PER CD ratio was lower in pediatric patients than in adolescents and adults; therefore, clinicians must consider the CD ratio when treating children with PER.

Meta-analysis of the Influence of UGT Genetic Polymorphisms on Lamotrigine Concentration.

Uridine 5'-diphospho-glucuronosyltransferases (UGTs) are involved in the metabolism of lamotrigine, but whether the UGT1A4 and UGT2B7 genetic polymorphisms affect lamotrigine concentration remains controversial. Thus, the objective of this meta-analysis was to analyse the influence of UGT1A4 and UGT2B7 genetic polymorphisms on lamotrigine concentration. Through searching, screening, selection, data extraction and quantitative analyses, the influence of UGT1A4 and UGT2B7 genetic polymorphisms on lamotrigine concentration-to-dose ratio (CDR) was assessed by meta-analysis of nine studies. Neither UGT1A4 70C>A nor 142T>G significantly affected lamotrigine CDR values (standardized difference in means [SDM]=0.433, 95% confidence interval [CI]=-0.380-1.302; SDM=-0.458, 95% CI=-1.141-0.224, respectively). Only the UGT2B7 -161C>T homozygous variant had significantly higher CDR values than the wild-type (WT) and heterozygous variant (SDM=0.634, 95% CI= 0.056-1.222). In conclusion, CDR of lamotrigine was significantly higher for the UGT2B7 -161C>T homozygous variant than for the WT and heterozygous variant. Thus, UGT2B7 -161C>T homozygous variant needs to receive reduced dose.

Add-on stiripentol elevates serum valproate levels in patients with or without concomitant topiramate therapy

ObjectiveStiripentol (STP), valproate (VPA) and topiramate (TPM) are reported to have efficacy for Dravet syndrome. In this study, we sought to elucidate the mechanisms underlying the increased serum VPA concentrations following STP adjunctive therapy in patients with Dravet syndrome. MethodsTwenty-eight patients with Dravet syndrome (age range, 1–35 years) undergoing combination therapy with VPA and STP were included in this study. We evaluated VPA and clobazam (CLB) serum concentrations before and after add-on STP. We also investigated potential factors impacting VPA metabolism during add-on STP therapy, including add-on TPM and CYP2C9 and CYP2C19 gene polymorphisms. The effect of STP on the metabolism of concomitantly administered CLB was also investigated. ResultsAdd-on STP was significantly associated with the serum concentration-to-dose (CD) ratio of VPA. Two patients, who were concomitantly treated with TPM, developed severe anorexia and thrombocytopenia because of marked increases in serum VPA concentrations. Further analysis revealed that the rate of increase in the VPA CD ratio was positively correlated with TPM dose. In patients not receiving TPM, STP enhanced the rate of increase in the VPA CD ratio to a significantly greater extent in CYP2C19 extensive metabolizers than in CYP2C19 poor metabolizers. Add-on STP was also associated with significant increases in CLB and N-desmethyl-CLB serum concentrations. ConclusionOur findings suggest that serum VPA concentrations should be carefully monitored during STP adjunctive therapy, particularly in patients receiving concomitant TPM therapy.

UGT1A6- and UGT2B7-related valproic acid pharmacogenomics according to age groups and total drug concentration levels.

The role of UGT1A6 and UGT2B7 polymorphisms and the impact of total drug plasma concentration in valproic acid (VPA) pharmacogenomics. A total of 134 Greek patients were recruited (76 adults). Patients were genotyped for UGT1A6 19T>G, 541A>G and 552A>C and UGT2B7 802T>C polymorphisms. Patients' demographic and clinical data were registered. Natural logarithm of concentration-to-dose ratio (CDR) was also calculated as the final outcome. No significant genotype-related differences in VPA metabolism were noted among various subgroups. An increased lnCDR ratio was noted in children patients compared with adults suggesting increased metabolic capability in younger ages. UGT1A6 and UGT2B7 genotypes were not related to significant changes in VPA metabolism, even after controlling for total drug concentration levels. Younger ages were associated with increased VPA clearance rate.

Impact of cytochrome P450 inducers with or without inhibitors on the serum clobazam level in patients with antiepileptic polypharmacy.

The aim of this study was to evaluate the effect of cytochrome P450 (CYP) inducers/inhibitors on the pharmacokinetics of clobazam (CLB) in patients receiving antiepileptic polypharmacy. A total of 2,504 samples obtained from 1,280 patients for routine therapeutic drug monitoring were retrospectively reviewed. These samples were grouped according to the antiepileptic drug regimens or age, and then the concentration to dose (CD) ratio (serum level (ng/ml) divided by dose (mg/kg)) of CLB was calculated for comparison. The mean CD ratio of CLB in adult patients using enzyme inducers (phenytoin (PHT), carbamazepine (CBZ), and phenobarbital (PB) alone or in combination) was 60.8% lower than the ratio in patients without inducers. Among the inducers, patients using PHT had a significantly lower CD ratio than patients using PB or CBZ (p < 0.001). When PHT was combined with CBZ and/or PB, no additive or synergetic interactions was observed. The CD ratio of CLB in pediatric patients using inducers was 44.3% lower than in patients without inducers. The influence of inducers was unchanged regardless of the child's age, and the effect was stronger in adults than in pediatric patients. Other than inducers, valproic acid (VPA) additively reduced the CD ratio, whereas concomitant use of stiripentol significantly elevated the CD ratio in patients receiving VPA. In contrast, CYP3A4 substrates, such as zonisamide and topiramate, had little influence on the CD ratio of CLB. We identified an impact of CYP inducers/inhibitors on the CLB concentration. Our findings demonstrated that clinically relevant interactions occur between CLB and concomitant antiepileptic drugs.