Splitting adult-dosage formulations of AEDs results in patients not receiving the optimal dose. Plasma drug concentrations are also not optimal. Pediatric dosage formulations should be preferred to splitting adult-dosage formulations in pediatric epilepsy.

Genetic variants influencing the pharmacokinetics and/or pharmacodynamics of the chemotherapeutic drugs used in Acute Lymphoblastic Leukemia (ALL) therapy often contribute to the occurrence of treatment related toxicity (TRT). In this study, we explored the association of candidate genetic variants with early hematological TRT (grade 3–4) occurring within the first 100 days of low-dose methotrexate and 6-mercaptopurine based maintenance therapy (n = 73). Fourteen variants in the following candidate genes were genotyped using allele discrimination assay by real-time PCR: ABCB1, DHFR, GGH, FPGS, MTHFR, RFC1, SLCO1B1, TPMT, and NUDT15. Methotrexate polyglutamate (MTXPG3-5) levels in red blood cells were measured by LC-MS/MS. Early hematological TRT (grade 3–4) was seen in 54.9% of patients. The NUDT15c.415T allele was associated with early TRT occurrence [HR: 3.04 (95% CI: 1.5–6.1); p = 0.007]. Sensitivity of early TRT prediction improved (from 30.7% to 89.7%) by considering FPGS variant (rs1544105’T’) carrier status along with NUDT15c.415T allele [HR = 2.7 (1.5–4.7, p = 0.008)]. None of the considered genetic variants were associated with MTXPG3-5 levels, which in turn were not associated with early TRT. NUDT15c.415T allele carrier status could be used as a stratifying marker for Indian ALL patients to distinguish patients at high or low risk of developing early hematological TRT.

Objective:To compare the differences in the efficacy and safety of the commonly prescribed AEDs in the management of epilepsy in children when using divided doses of adult solid oral formulations (DDSF) with the liquid oral formulations (LFs).Materials and Methods:Patients who had one or more seizures per month and prescribed with DDSF were recruited. Initially the patients were continued on DDSF for 4 months following which they were switched over to LF for the subsequent 4 months. Seizure frequencies and adverse drug effects (ADRs) were recorded every month for 8 months and plasma AED levels were estimated at the end of 4th and 8th months.Results:A total of 200 patients completed the study protocol. The median seizure frequencies per month with DDSF and LF were: partial seizures (20.5, 9.0; P < 0.001), generalized tonic-clonic seizures (6.5, 2.0; P < 0.001), myoclonic seizures (58.5, 29.0; P < 0.001). Mean plasma drug levels ± SD (μg/ml) with DDSF and LF were: sodium valproate (48.2 ± 13.7, 69.1 ± 16.3; P < 0.001), phenytoin sodium (5.0 ± 2.4, 12.8 ± 3.8; P < 0.001), carbamazepine (4.5 ± 2.0, 11.5 ± 4.8; P < 0.001) and phenobarbitone (14.1 ± 5.2, 25.4 ± 12.3, P < 0.001). The incidence of treatment emergent ADRs was poor scholastic performance (25.5%), behavioral problems and dizziness/sedation (21.0%), somnolence/sleep disorders (19.5%).Conclusion:Patients treated with LF had better seizure control and optimal therapeutic drug levels and less adverse effects when compared to DDSF.

Background and Objectives: Globally the survival of ALL has increased tremendously with the five-year overall survival (OS) reaching 90% in high-income countries (HICs) (1, 2). However, in India, the five-year OS has been reported to be 30-70 %( 3) and deaths due to treatment related toxicity (TRT) in ALL were ranged from 2-24 % (4), which is ten times higher compared to HICs suggesting increased susceptibility to the toxicity of the chemotherapeutic drugs. This could be due to frequent variants in candidate genes determining the pharmacodynamic response or pharmacokinetics of the chemotherapeutic drugs used during maintenance therapy of ALL. Variations in the patient management, supportive care therapy are the other possible reasons of this increased incidence of TRT. Many patients are lost to follow-up due to the TRT, and eventually will die of the disease progression. The present study aimed to explore the association of common genetic variants in the candidate genes with early treatment related hematological toxicities (grade 3-4) in patients with Acute Lymphoblastic Leukemia (ALL) receiving low-dose MTX (LDMTX) and 6-Mercaptopurine (6-MP) based maintenance therapy. Materials and Methods: This prospective study was conducted between August 2011 and May 2016 and approved by institutional scientific and ethics committees. A total of 71 patients (43 males and 28 females aged between 1-51 years) with ALL were enrolled in the study after obtaining written informed consent and in the case of children, from legally accepted guardians. Patients below 25 years of age were treated using protocol-841 (MCP) I2A and those older than 25 years were treated with modified GMALL-84 protocols. MTX and 6-MP doses did not differ across both the protocols during maintenance therapy. Germline DNA samples collected at the time of remission from peripheral mononuclear cells was used to genotype15 selected variants frequent in the following candidate genes : ABCB1, DHFR, GGH, FPGS, MTHFR, RFC1, SLCO1B1, TPMT, and NUDT15 using allele discrimination assay by real-time PCR. LC-MS/MS method was used to measure methotrexate polyglutamate (MTXPG3-5) levels in RBC's.Toxicities were graded according to the Common Terminology Criteria for Adverse Events (CTCAE-version 4.03). Early grade 3-4 hematological toxicities occurring within first 100 days of the maintenance therapy was studied for its association with the genetic variants and other risk factors. Cumulative incidence curves were plotted and a risk factor analysis was performed using multivariate Cox regression. Co-linearity between variables was assessed. We used a back-ward selection method, retaining those variables with P-values<0.05 in the final model. Data analysis was done using statistical software « R ». Results: The cumulative incidences of early hematological TRT (grade 3-4) and relapse were 54.9 %, and 38.0 %, respectively. The relapse free survival was 59.2 %. The median follow-up of all patients from the start of maintenance was 1018 days. In multivariate analysis including all genetic variants, age, and WBC counts at diagnosis, we observed a significant increase in the risk of TRT in carriers of NUDT15*3 allele(rs116855232 ; p=0.002 ; univariate Hazards ratio : 2.81 (95% CI : 1.41-5.59). 3435C>T variant in ABCB1 gene showed a trend of association with that of relapse free survival. Neither the genetic variants studied were associated with the methotrexate polyglutamate levels, nor were the levels associated with the clinical outcomes. Conclusion: The NUDT15*3 allele carriers status could be used as one of the stratifying markers in South Indian ALL patients at the time of diagnosis to distinguish high and low-risk patients to develop early hematological toxicity, especially related to 6-mercaptopurine based ALL maintenance therapy protocols. Disclosures No relevant conflicts of interest to declare.