Search

Phenytoin elimination is a saturable process obeying Michaelis-Menten kinetics. Plasma phenytoin levels are not related linearly to dose, and small changes in enzyme activity produced by concurrent drug therapy could alter plasma levels. Two cases of phenytoin intoxication associated with simultaneous administration of diazepam are reported. Intravenous phenytoin infusions were given and the apparent K(m) and V(max) computed from the resulting plasma phenytoin levels. In one case `K(m)' and `V(max)' were 0.8 μmol/1 and 1.3 μmol/1/hour respectively during concurrent diazepam administration, and 50.3 μmol/1 and 4.4 μmol/1/hour after discontinuation of diazepam. In the second case phenytoin infusion with diazepam gave `K(m)' and `V(max)' values of 0.012 μmol/1 and 0.95 μmol/1/hour. Without diazepam these were 28.8 μmol/1 and 0.92 μmol/1/hour respectively. [ABSTRACT FROM AUTHOR]

Purpose: The safety, pharmacokinetics, and efficacy of elraglusib, a glycogen synthase kinase-3β (GSK-3β) small-molecule inhibitor, as monotherapy or combined with chemotherapy, in patients with relapsed or refractory solid tumors or hematologic malignancies was studied., Patients and Methods: Elraglusib (intravenously twice weekly in 3-week cycles) monotherapy dose escalation was followed by dose escalation with eight chemotherapy regimens (gemcitabine, doxorubicin, lomustine, carboplatin, irinotecan, gemcitabine/nab-paclitaxel, paclitaxel/carboplatin, and pemetrexed/carboplatin) in patients previously exposed to the same chemotherapy., Results: Patients received monotherapy (n = 67) or combination therapy (n = 171) elraglusib doses 1 to 15 mg/kg twice weekly. The initial recommended phase II dose (RP2D) of elraglusib was 15 mg/kg twice weekly and was defined, without dose-limiting toxicity observation, due to fluid volumes necessary for drug administration. The RP2D was subsequently reduced to 9.3 mg/kg once weekly to reduce elraglusib-associated central/peripheral vascular access catheter blockages. Other common elraglusib-related adverse events (AE) included transient visual changes and fatigue. Grade ≥3 treatment-emergent AEs occurred in 55.2% and 71.3% of patients on monotherapy and combination therapy, respectively. Part 1 monotherapy (n = 62) and part 2 combination (n = 138) patients were evaluable for response. In part 1, a patient with melanoma had a complete response, and a patient with acute T-cell leukemia/lymphoma had a partial response (PR). In part 2, seven PRs were observed, and the median progression-free survival and overall survival were 2.1 [95% confidence interval (CI), 2-2.6] and 6.9 (95% CI, 5.7-8.4) months, respectively., Conclusions: Elraglusib had a favorable toxicity profile as monotherapy and combined with chemotherapy and was associated with clinical benefit supporting further clinical evaluation in combination with chemotherapy., (©2023 American Association for Cancer Research.)

This study investigates the effect of dietary fat on the testosterone (T) pharmacokinetics in hypogonadal men following administration of a self-emulsifying capsule formulation of oral T undecanoate (TU). In an open-label, 2-center, 5-way crossover study, a single oral dose of TU containing 300-mg equivalents of T (maximum anticipated human dose per administration) was administered to 16 hypogonadal men with a washout period of at least 5 days between doses. All participants were randomized to receive the TU capsules fasting or 30 minutes after an approximately 800-calorie meal containing 10%, 20%, 30%, or 50% fat. Serial blood samples were collected from 2 hours predose to 25 hours postdose to determine serum T and dihydrotestosterone (DHT) by liquid chromatography tandem mass spectrometry. Administering TU with a meal increased serum T concentrations, with the magnitude of the increase being directly dependent on the amount of fat in the meal. Average and peak serum T concentrations and area under the curve increased as the fat content of the meal was increased. Neither the high-fat meal (50% fat) nor the lower-fat meal (20% fat) showed a significant food effect relative to the normal-fat (Western diet) meal (30% fat). However, administering TU while fasting resulted in 50% or less of the cumulative exposure obtained when administered with 20%- to 50%-fat meals (albeit still substantial). A very-low-fat meal (10% fat) showed a significant food effect relative to the normal meal, but still exceeded the fasting condition by approximately 50%. Serum DHT concentrations showed corresponding increases to the serum T. As expected with the maximum anticipated clinical dose of TU (300 mg T), oral administration of this new formulation with food containing 20% to 50% dietary fat produced T levels at or above the upper range of adult men, and T levels trended higher as dietary fat content increased. Only with a very-low-fat diet (10%) or in a fasted state did a clinically significant food effect occur, but even then sufficient TU was absorbed with the self-emulsifying TU formulation to produce average serum T concentration predicted to be in the normal reference range (10 to 35 nmol/L).

Many hypogonadal men prefer oral testosterone (T) treatment. Oral T undecanoate (TU) is available in many countries, but not in the United States. We aimed to assess the pharmacokinetics of oral TU in a new self-emulsifying drug delivery system formulation. Pharmacokinetics studies were conducted in 3 parts: 12 hypogonadal men were enrolled in 2 centers for a 1-day dosing study; 29 participants were enrolled from 3 centers for a 7-day dosing study; and 15 participants were enrolled from 1 center for a 28-day dosing study. Serial blood samples for serum sex hormone measurements by liquid chromatography-tandem mass spectrometry were drawn for up to 36 hours after oral TU administration. Mean serum T levels (C(avg)) after oral dosing of T 200 mg as TU twice daily with food were within the adult male range in most participants in the 1-, 7-, and 28-day dosing studies but were much lower in the fasting state. The dose-proportional increase in C(avg) of serum T after oral T 300 mg twice daily resulted in more participants with supraphysiologic serum T levels. In the 28-day study, trough serum T reached a steady state at day 7. Serum dihydrotestosterone and estradiol levels tracked serum T concentration. Dihydrotestosterone-testosterone ratios increased 3-fold after oral TU administration. Oral T 200 mg twice daily as TU in a new SEDDS formulation may be a viable therapy for hypogonadal men.