AIMThis study evaluated the influence of CYP2C19 polymorphisms on the pharmacokinetics of nelfinavir and its metabolite M8 in patients with pancreatic cancer.
METHODSNelfinavir was administered orally to patients for over 10 days. The plasma concentrations of nelfinavir and M8 were measured by HPLC. The genotypes of CYP2C19*1, CYP2C19*2 and CYP2C19*3 were determined by the polymerase chain reaction-restriction fragment length polymorphism method.
RESULTSPharmacokinetic profiles of nelfinavir and M8 were characterized by wide interindividual variability. The mean C max of nelfinavir in CYP2C19*1/*1 patients was 3.89 ± 0.40 (n = 3) and 5.12 ± 0.41 (n = 30) μg ml -1 , while that of CYP2C19*1/*2 patients was 3.60 (n = 1) and 6.14 ± 0.31 (n = 5) μg ml -1 at the doses of 625 and 1250 mg nelfinavir twice daily, respectively. For the M8 metabolite, the mean C max of CYP2C19*1/*1 patients was 1.06 ± 0.06 (n = 3) and 1.58 ± 0.27 (n = 30) μg ml -1 , while those of CYP2C19*1/*2 patients were 1.01 (n = 1) and 1.23 ± 0.15 (n = 5) μg ml -1 at the doses of 625 and 1250 mg nelfinavir twice daily, respectively. The area under the plasma concentrationtime curve (AUC(0,12 h)) values of nelfinavir for CYP2C19*1/*1 patients were 28.90 ± 1.27 and 38.90 ± 4.99 μg ml -1 ·h and for CYP2C19*1/*2 patients, AUC(0,12 h) was 28.20 (n = 1) and 40.22 ± 3.17 (n = 5) μg ml -1 ·h at the doses of 625 and 1250 mg nelfinavir twice daily, respectively. The
BACKGROUND: Pralatrexate (PDX) is an inhibitor of dihydrofolate reductase that was rationally designed to improve cellular uptake and retention of the drug. Preclinical data have shown synergy with the sequential administration of a dihydrofolate reductase inhibitor followed 24 hours later by 5-fluorouracil (5-FU). METHODS: Twenty-seven patients were enrolled at 1 of 5 PDX dose levels from 75 to 185 mg/m 2 on day 1 followed 24 hours later by 5-FU at a dose of 3000 mg/m 2 /48 hours every 2 weeks with folic acid and vitamin B12 supplementation. Baseline blood was collected for pharmacogenetic analysis of polymorphisms of methylenetetrahydrofolate reductase and thymidylate synthase. RESULTS: Mucositis was the most common dose-limiting toxicity. When the worst toxicities across all cycles were considered, grade 3 to 4 neutropenia, anemia, and thrombocytopenia were found to have occurred in 14.8%, 14.8%, and 0% of patients, respectively. Grade 2 to 3 toxicities included mucositis (66.6%), dehydration (33.3%), fatigue (25.9%), and diarrhea (22.2%). Version 3.0 of the National Cancer Institute Common Toxicity Criteria was used to grade toxicities The median progression-free survival (PFS) was 112 days (range, 28-588 days). Seven patients (26%) had a PFS of >180 days (5 patients with colorectal cancer, 1 patient with pancreatic cancer, and 1 patient with non-small cell lung cancer). Polymorphisms in methylenetetrahydrofolate reductase and thymidylate synthase did not correlate with toxicity. CONCLUSIONS: The recommended dose of PDX was 148 mg/m 2 . A subset of heavily pretreated patients had PFS durations of 6 months with this regimen. Cancer 2015;121:3862-8. INTRODUCTION 5-fluorouracil (5-FU) and folate inhibitors of dihydrofolate reductase (DHFR), including methotrexate (MTX), are active in a variety of malignancies. There is strong preclinical evidence that the optimal sequence for combining DHFR inhibitors with 5-FU involves pretreatment with the DHFR inhibitor followed by 5-FU. 1-4 Administration of 5-FU followed by MTX is antagonistic in both in vitro and in vivo studies. The antipurine action of MTX is believed to result from 2 factors: 1) partial depletion of 10-formyl-tetrahydrofolate, which is required for purine synthesis; and 2) buildup of dihydrofolate, which is an inhibitor of de novo purine synthesis. Ongoing thymidylate synthesis is required to deplete the cellular reduced-folate pool. Pretreatment with 5-FU inhibits thymidylate synthase (TS) thereby blocking the conversion of reduced folates to dihydrofolate. The reduced-folate pool is thus spared for purine synthesis, and the dihydrofolate pool does not expand. When MTX precedes 5-FU, ongoing thymidylate synthesis depletes reduced folates and dihydrofolate pools accumulate, thus allowing blockade of purine biosynthesis. Inhibition of de novo purine synthesis expands the intracellular pool of phosphoribosyl pyrophosphate, which is then available for the anabolism of 5-FU to fluorouridine monophosphate by orotate phosphoribosyl transferase. Enhancement o...
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