Factors Influencing the Steady-State Plasma Concentration of Imatinib Mesylate in Patients With Gastrointestinal Stromal Tumors and Chronic Myeloid Leukemia

Imatinib mesylate (IM) is the standard treatment for advanced, metastatic gastrointestinal stromal tumors (GISTs) and chronic myeloid leukemia (CML) with a fixed daily standard dosage via the oral route. Interindividual and intraindividual variability in plasma concentrations have been closely linked to the efficacy of IM therapy. Therefore, this review identifies and describes the key factors influencing the plasma concentration of IM in patients with GISTs and CML. We used the following keywords to search the PubMed, EMBASE, Ovid, Wangfang, and CNKI databases to identify published reports: IM, plasma concentration, GISTs, CML, drug combination/interaction, pathology, and genotype/genetic polymorphism, either alone or in combination. This literature review revealed that only 10 countries have reported the mean concentrations of IM in GISTs or CML patients and the clinical outcomes in different ethnic groups and populations. There were totally 24 different gene polymorphisms, which were examined for any potential influence on the steady-state plasma concentration of IM. As a result, some genotype locus made discrepant conclusion. Herein, the more sample capacity, multicenter, long-term study was worthy to carry out. Eleven reports were enumerated on clinical drug interactions with IM, while there is not sufficient information on the pharmacokinetic parameters altered by drug combinations with IM that could help in investigating the actual drug interactions. The drug interaction with IM should be paid more attention in the future research.

Drug–drug interaction of rivaroxaban and calcium channel blockers in patients aged 80 years and older with nonvalvular atrial fibrillation

ObjectivesFor revealing the peculiarities of the drug–drug interaction of rivaroxaban (substrate CYP3A4 and P-gp) and calcium channel blockers (CCBs) (verapamil – inhibitor CYP3A4 and P-gp and amlodipine – substrate CYP3A4) in patients 80 years and older with nonvalvular atrial fibrillation (NAF) we studied 128 patients.MethodsAll patients were divided into groups depending on the therapy taken: the 1st – rivaroxaban + amlodipine (n=51), the 2nd – rivaroxaban + verapamil (n=30), the control group – rivaroxaban without CCBs (n=47). A trough steady-state plasma concentration (Cmin,ss) of rivaroxaban, prothrombin time (PT) in the blood plasma and the event of clinically relevant non-major (CRNM) bleeding were assessed for each patient.ResultsPatient in group 2 had higher Cmin,ss of rivaroxaban, PT and CRNM than subjects in the control group (Me 73.8 [50.6–108.8] ng/mL vs. 40.5 [25.6–74.3] ng/mL; Me 14.8 [13.4–17.3] s vs. 13.8 [12.6–14.4] s; 34% vs. 13%, respectively, p<0.05 for all). When compared, the PT and complication rate in group 1 with the control group Cmin,ss of rivaroxaban were practically the same (p>0.05 for all).ConclusionsIn patients ≥80 years with NAF, the use of rivaroxaban in combination with verapamil may not be safe and can lead to CRNM bleeding.

Utility of In Vitro Bioactivity as a Lower Bound Estimate of In Vivo Adverse Effect Levels and in Risk-Based Prioritization

Use of high-throughput, in vitro bioactivity data in setting a point-of-departure (POD) has the potential to accelerate the pace of human health safety evaluation by informing screening-level assessments. The primary objective of this work was to compare PODs based on high-throughput predictions of bioactivity, exposure predictions, and traditional hazard information for 448 chemicals. PODs derived from new approach methodologies (NAMs) were obtained for this comparison using the 50th (PODNAM, 50) and the 95th (PODNAM, 95) percentile credible interval estimates for the steady-state plasma concentration used in in vitro to in vivo extrapolation of administered equivalent doses. Of the 448 substances, 89% had a PODNAM, 95 that was less than the traditional POD (PODtraditional) value. For the 48 substances for which PODtraditional &lt; PODNAM, 95, the PODNAM and PODtraditional were typically within a factor of 10 of each other, and there was an enrichment of chemical structural features associated with organophosphate and carbamate insecticides. When PODtraditional &lt; PODNAM, 95, it did not appear to result from an enrichment of PODtraditional based on a particular study type (eg, developmental, reproductive, and chronic studies). Bioactivity:exposure ratios, useful for identification of substances with potential priority, demonstrated that high-throughput exposure predictions were greater than the PODNAM, 95 for 11 substances. When compared with threshold of toxicological concern (TTC) values, the PODNAM, 95 was greater than the corresponding TTC value 90% of the time. This work demonstrates the feasibility, and continuing challenges, of using in vitro bioactivity as a protective estimate of POD in screening-level assessments via a case study.

Pharmacokinetics of LB80331 and LB80317 following Oral Administration of LB80380, a New Antiviral Agent for Chronic Hepatitis B (CHB), in Healthy Adult Subjects, CHB Patients, and Mice

ABSTRACT LB80380, a dipivoxil ester prodrug of LB80331 (metabolite, LB80317), is a novel antiviral agent for chronic hepatitis B (CHB). The pharmacokinetics of LB80331/LB80317 were evaluated in two clinical studies and a study with mice. The clinical studies were dose-escalating pharmacokinetic studies with six healthy subjects per single-dose group and six CHB patients per repeated-dose group. The mouse study was designed to measure the amounts of the phosphorylated portions of LB80331 and LB80317 in the liver. In healthy subjects receiving a single dose of LB80380, the plasma level of LB80331 increased as the dose increased. Although a high-fat diet delayed the time to the maximum concentration in plasma (T max) of LB80331, the area under the concentration-time curve from time zero to infinity was similar between the subjects in the fasted group and those in the group who consumed a high-fat diet. In CHB patients, the mean T max of LB80331 was 1.0 to 2.0 h postdosing at steady state. The steady-state plasma concentration of LB80331 declined in a monoexponential manner, and the apparent elimination half-life was 2.5 to 3.3 h. The steady-state plasma concentration of LB80317 was maximum at 3 to 8 h postdoing and declined in a monoexponential manner; the apparent elimination half-life was 45 to 62 h at the 30- to 240-mg doses, while LB80317 was measurable in plasma only at higher doses of 120 and 240 mg after the administration of the first dose of LB80380. Forty percent of the amount of LB80331/LB80317 in the mouse liver was detected as the phosphorylated form. In conclusion, LB80380 is rapidly absorbed and converted to LB80331. LB80317 has a long half-life at steady-state, supporting the use of a once-daily dosing regimen. The ingestion of a high-fat diet delays the rate of absorption of LB80380 without affecting the extent of absorption.

Current clinical evidence on topiramate pharmacokinetics

Topiramate is biochemically classified as a fructopyranose sulphamate. Discovered as early as 1979, during middle 1980's it was approved in many countries for the treatment of epilepsies and migraine prevention. More recently, in the experimental stage, possible new indications have been disclosed: treatment of obesity, bipolar disorder, also cessation of smoking, neuropathic pain, cerebral pseudotumour, bulimia, periventricular leucomalatia in preterm infants and alcohol addiction. Most epileptologists consider it to be the first choice antiepileptic drug in severe pharmacoresistant epilepsies. A substantial corpus of evidence in paediatric population has been accumulated that confirms its efficiency in the treatment of generalised tonic-clonic seizures, Lenox-Gestaut syndrome, partial, absence and combined seizures. Having a unique monosaccharide chemical structure among other anticonvulsant drugs, characterizes it with special pharmacokinetic features. This substance exhibits a low interindividual variability in plasma levels and hence it features predictable pharmacokinetics. A steady state plasma concentration of topiramate increases linearly with higher dosages. Serum protein binding is approximately 15%, and biologic half-life in healthy volunteers is considered to range from 20 to 30 hours. Mean expected distribution volume rates from 0.55-0.8 l/kg, and accordingly, the drug shows a low and saturable binding capacity toward erythrocytes. It has not been present at the market for a sufficiently long time that would enable us to speak about a significant accumulation of data on its metabolism based on post-registration 4th stage clinical trials. For this purpose, we have done a literature review in order to summarise so far reported experience on topiramate pharmacokinetics in patients and healthy adults. Deeper understanding of its pharmacokinetic profile could enable a better technological design of the produced drug and the choice of the adequate route of its administration, and accordingly a more rational treatment of severe epilepsies resistant to other drugs.

Effect of Deferasirox (Exjade®) on Labile Plasma Iron Levels in Heavily Iron-Overloaded Patients with Transfusion-Dependent Anemias Enrolled in the Large-Scale, Prospective 1-Year EPIC Trial

Background: Labile plasma iron (LPI) is a toxic, directly chelatable form of non-transferrin- bound iron that is produced continually in conditions of iron overload and, due to rapid uptake into hepatocytes, myocardium and endocrine tissues, leads to secondary expansion of the cellular iron pool. The sustained presence of an iron chelator in the plasma may help avoid accumulation of LPI, thereby minimizing iron-related morbidity and mortality. This analysis evaluates the effect of deferasirox on LPI levels in patients (pts) with transfusion-dependent anemias enrolled in the large-scale, prospective, 1-yr multicenter EPIC trial. Methods: Enrolled pts were aged ≥2 yrs, had transfusion-dependent anemia and serum ferritin (SF) levels of ≥1000 ng/mL, or <1000 ng/mL with a history of multiple transfusions (>20 transfusion episodes or >100 mL/kg of RBCs) and an R2 MRI-confirmed LIC >2 mg Fe/g dry weight (dw). Deferasirox starting dose was determined based on blood transfusion frequency. Dose adjustments in steps of 5–10 mg/kg/day (in the range 0–40 mg/kg/day) were based on SF trends and safety markers. Blood samples to measure LPI and assess the deferasirox pharmacokinetic profile were taken pre-administration and 2 hrs post administration at baseline and wks 12, 28 and 52. Results: LPI data are available from 1602 pts (825 M, 777 F; mean 30.4±23.0 yrs). Underlying anemias were: β-thalassemia (n=1029), myelodysplastic syndromes (MDS; n=305), aplastic anemia (AA; n=104), sickle cell disease (SCD; n=79), rare anemias (mostly hemolytic in nature) (n=42), and other conditions associated with anemias requiring transfusion (n=43). Mean LPI, pre and post deferasirox administration, at baseline and wks 12, 28 and 52 are shown in Table 1. Table 1. Mean LPI, pre and post deferasirox administration, at baseline and after repeat doses Baseline Week 12 Week 28 Week 52 Pre Post Pre Post Pre Post Pre Post NOTE: Data are mean LPI±SD (μmol/L); normal levels are 0–0.40 μmol/L All pts 0.89 ±1.84 0.33 ±1.59 0.30 ±0.90 0.11 ±0.56 0.27 ±0.87 0.11 ±0.62 0.47 ±1.35 0.30 ±1.33 β-thalassemia 1.25 ±2.34 0.58 ±2.10 0.40 ±1.07 0.15 ±0.67 0.34 ±0.94 0.13 ±0.72 0.60 ±1.55 0.39 ±1.52 MDS 0.53 ±0.63 0.02 ±0.11 0.08 ±0.28 0.02 ±0.10 0.15 ±0.88 0.03 ±0.18 0.14 ±0.32 0.02 ±0.07 AA 0.23 ±0.34 0.01 ±0.02 0.08 ±0.20 0.01 ±0.04 0.06 ±0.20 0.01 ±0.03 0.04 ±0.10 0.03 ±0.10 SCD 0.11 ±0.54 0.04 ±0.29 0.09 ±0.42 0.06 ±0.31 0.11 ±0.28 0.14 ±0.46 0.10 ±0.21 0.07 ±0.19 Rare anemias 0.50 ±0.55 0.01 ±0.04 0.05 ±0.13 0.01 ±0.03 0.06 ±0.18 0.01 ±0.03 0.29 ±0.52 0.02 ±0.03 Overall mean deferasirox dose during the 1-yr treatment period was 22.4±6.0 mg/kg/day (β-thalassemia, MDS, AA, SCD and rare anemias: 24.3±5.5, 19.3±5.7, 17.8±4.7, 20.2±3.8 and 18.6±5.6 mg/kg/day, respectively). At each time point, peak LPI levels observed just before deferasirox dosing were decreased compared with baseline and were mostly within the normal range from week 12 onwards in each underlying anemia. A small rebound at 52 wks was seen in the thalassemia sub-group: this could be associated with decreased compliance or other reasons, to be investigated further. In all pts, mean steady-state plasma concentration (ie pre-administration value) of deferasirox at wks 12, 28 and 52 was 32.9, 35.9 and 39.4 μmol/L, respectively. At each time point this was approximately half of the concentration value observed at 2 hrs post administration (84.4, 89.3 and 97.0 μmol/L, respectively). Conclusions: The results from this 1-yr study confirm the ability of once-daily deferasirox to provide sustained reduction in toxic LPI levels across various transfusion-dependent anemias, supporting previous data in pts with β-thalassemia. This is likely due to trough levels of deferasirox being within the therapeutic range, thereby preventing LPI levels rebounding between doses. Deferasirox therapy may therefore reduce unregulated tissue iron loading and prevent further end-organ damage in these pts.