Association of NUDT15*3 and FPGS 2572C>T Variants with the Risk of Early Hematologic Toxicity During 6-MP and Low-Dose Methotrexate-Based Maintenance Therapy in Indian Patients with Acute Lymphoblastic Leukemia.

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 NUDT15*3 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) carrier status along with NUDT15*3 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. NUDT15*3 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.

Comparative Effect of Divided Doses of Adult Solid and Liquid Oral Formulations of Antiepileptic Drugs in the Management of Pediatric Epilepsy.

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.

Tablet Splitting of Antiepileptic Drugs in Pediatric Epilepsy: Potential Effect on Plasma Drug Concentrations.

INTRODUCTION: Tablet splitting is the process of dividing a tablet into portions to obtain a prescribed dose of medication. Very few studies have investigated whether split parts of a tablet deliver the expected amount of drug to patients. OBJECTIVE: Our objectives were to evaluate the split parts of adult-dose tablet formulations for percentage of weight deviation, weight uniformity, weight loss, drug content, and the content uniformity of four antiepileptic drugs (AEDs) prescribed to pediatric patients. We also measured AED plasma concentrations in the children. METHODS: We chose to study first-line AEDs (phenytoin sodium [PHE], sodium valproate [SVA], carbamazepine, and phenobarbitone) as they are routinely prescribed in India. We asked caregivers to perform the same splitting process they follow in their homes on three whole tablets during their routine visit to the outpatient department. After caregivers split the tablets, we studied the weight and content of the split parts. We also used high-performance liquid chromatography to study plasma drug concentrations in children who had received split AEDs for at least 4 months. RESULTS: A total of 168 caregivers participated in the study, and we analyzed 1098 split tablet parts. In total, 539 (49.0 %) split parts were above the specified limit of the 2010 Indian Pharmacopeia (IP) acceptable percentage weight deviation (PHE 169 [48.8 %], SVA 187 [51.9 %], carbamazepine 56 [41.1 %], phenobarbitone 127 [49.6 %]); 456 (41.5 %) split parts were outside the proxy IP specification for drug content (PHE 135 [39.0 %], SVA 140 [38.8 %], carbamazepine 51 [37.5 %], phenobarbitone 130 [50.7 %]), and 253 split parts were outside the acceptable content uniformity range of <85 % and >115 % (PHE 85 [24.5 %], SVA 98 [27.2 %], carbamazepine 14 [10.2 %], phenobarbitone 56 [21.8 %]). In total, 130 (72.2 %) patients had plasma drug concentrations outside the therapeutic range (PHE 36 [72.0 %], SVA 39 [78.0 %], carbamazepine 34 [68.0 %], phenobarbitone 21 [70.0 %]). CONCLUSIONS: 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.