Six patients with human immunodeficiency virus were given foscarnet in oral solution, 4000 mg every 6 hours for 3 days, followed by a washout period for 2 days and continuous intravenous infusion of 16,000 mg/24 hr over 72 hours. After oral foscarnet, plasma concentrations were less than 33 mumol/L in four patients; two had occasional concentrations of 35 to 50 mumol/L. The extent of absorption varied between 12% and 22%. During intravenous infusion, plasma concentrations ranged between 75 and 265 mumol/L. The disposition of foscarnet was triphasic, with mean half-lives of 0.45, 3.3, and 18 hours. Excretion data suggested elimination was by tubular secretion and glomerular filtration. Renal clearance was 176 ml/min 1.73 m2. The apparent nonrenal clearance, 40 ml/min 1.73 m2, probably reflects sequestration of foscarnet into bone. Ten percent to 28% of the cumulative dose may have been deposited in bone 2 days after infusion. A slight increase in serum calcium levels and changes in serum phosphate values may reflect the uptake of foscarnet in bone. Five patients had diarrhea (oral) and two had thrombophlebitis (intravenous).

To investigate the pharmacokinetics and effects of intravenous foscarnet, 13 relatively healthy male patients with human immunodeficiency virus infection and a mean CD4+ lymphocyte value of 0.45 x 10-9 cells per liter were given a continuous intravenous infusion of foscarnet (0.14 to 0.19 mg/kg per min) for 8 to 21 days. Blood and urine samples were taken during and after drug administration to monitor foscarnet concentrations. Lumbar puncture was performed during the infusion in five patients. The concentrations in plasma showed large variations both within and between patients. The disposition of foscarnet could be explained by a triexponential equation (tl2,1, 0.40 to 2.52 h; t112X, 3.20 to 16.7 h; tl/2J3, 36 to 196 h). Renal clearance accounted for most of the plasma clearance, the dilerence probably reflecting the passage of foscarnet into bone. Up to 20% of the cumulative dose may have been deposited in bone 7 days postinfusion. Foscarnet was distributed to the cerebrospinal fluid in a concentration varying from 13 to 68% of the simultaneous concentration in plasma. Polyuria and polydipsia were recorded in all patients. There appears to be an association between the degree of malaise, including symptoms such as nausea, vomiting, fatigue, and headache, and concentrations in plasma above 350 ,umol/liter.

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IMPORTANCEPlinabulin is a novel, non-granulocyte colony-stimulating factor (GCSF) small molecule with both anticancer and neutropenia-prevention effects.OBJECTIVE To assess the efficacy and safety of plinabulin compared with pegfilgrastim for the prevention of chemotherapy-induced neutropenia following docetaxel chemotherapy in patients with non-small lung cancer. DESIGN, SETTING, AND PARTICIPANTS This was a randomized, open-label, phase 2 clinical trial of 4 treatment arms that was conducted in 19 cancer treatment centers in the United States, China, Russia, and Ukraine. Participants were adult patients with non-small cell lung cancer whose cancer had progressed after platinum-based chemotherapy. Data were collected from April 2017 through March 2018 and analyzed from August 2019 through February 2020.INTERVENTIONS All patients received docetaxel 75 mg/m 2 on day 1 and were randomly assigned to 1 of 3 doses of plinabulin (5, 10, or 20 mg/m 2 ) on day 1 or to pegfilgrastim 6 mg on day 2. Patients were treated every 21 days for 4 chemotherapy cycles. MAIN OUTCOMES AND MEASURESThe primary end point was the determination of the recommended phase 3 dose of plinabulin based on the days of severe neutropenia during chemotherapy cycle 1. Daily complete blood cell counts and absolute neutrophil counts were drawn during times of anticipated neutropenia during cycle 1. RESULTSOf the 55 patients randomized and evaluated, the mean (SD) age was 61.3 (10.2) years, and 38 (69.1%) were men. With each escalation of the plinabulin dose, the incidence of any grade of neutropenia decreased. There were no significant differences in mean (SD) days of severe neutropenia among those treated with pegfilgrastim (0.15 [0.38] days) when dosed at day 2 vs plinabulin 20 mg/m 2 (0.36 [0.93] days; P = .76) when dosed at day 1, and no safety signals were detected.CONCLUSIONS AND RELEVANCE Single dose-per-cycle plinabulin has a similar neutropenia protection benefit as pegfilgrastim. Plinabulin 40 mg fixed dose, which is pharmacologically equivalent to 20 mg/m 2 , will be compared with pegfilgrastim 6 mg in the phase 3 portion of this trial. Noninferior days of severe neutropenia will be the primary end point, and bone pain reduction, thrombocytopenia reduction, and quality of life maintenance will be secondary end points.

Exercise and physical labor in extreme environmental conditions causes transient decreases in immune cell and cytokine concentrations, likely increasing the susceptibility to opportunistic infection. Baker's yeast beta glucan (BYBG) has been previously demonstrated to be an effective countermeasure in athletes, but its effectiveness in individuals of average fitness under similar physical stress is unknown. The purpose of this study was to determine if 10 days of oral supplementation with BYBG could modify previously observed suppression of monocytes, T cells, circulating and whole blood LPS-stimulated cytokines due to strenuous exercise. Venous blood samples were collected from 109 healthy volunteers prior to, immediately after, 2 and 4 h post-exercise. Monocyte and T cell concentration, cell-surface receptor expression and serum and LPS-stimulated cytokines were assessed. BYBG significantly (P < 0.05) altered total and classic monocyte concentration and expression of CD38, CD80, CD86, TLR2, and TLR4 on monocyte subsets. BYBG also significantly increased CD4+ and CD8+ T cell concentration and the exercise response of CCR7+/CD45RA- central memory (TCM) cells. Likewise, BYBG significantly (P < 0.05) altered serum IFN-γ and IL-2, and LPS-stimulated IFN-γ, IL-2, IL-4, and IL-7. Taken together these data support the hypothesis that oral BYBG supplementation modulates the expected exercise response for individuals of average fitness. This may result in a decrease in susceptibility to opportunistic infections after strenuous exercise.