Training-induced energy balance mismatch in Standardbred mares

AbstractThis study tested the hypothesis that exercise training would alter feed intake (FI), body composition (BC) and plasma concentrations of active ghrelin, leptin, cortisol, insulin and glucose. Eight Standardbred mares (12±2 years, 509±36 kg body weight (BW), mean±SD) were trained (EX) in an equine Equi-ciser (initially 3 days per week at 60% maximal heart rate (HRmax) for 20 min and gradually increased to 5 days per week at 70% HRmax for 30 min, with a 10-min warm-up and 10-min cool-down period at the walk). Six mares (12±2 years, 537±45 kg) served as non-exercise controls (CON). All mares were unfit and had not been subjected to conditioning for 3 years before the experiment. Pre- and post-training incremental exercise tests (GXT) were run to determine HRmax and maximal oxygen uptake (VO2max). A total mixed ration (TMR) of hay cubes was fed free choice for 16 h day-1 with the primary experiment following a 6-week diet adaptation period. Mares' FI was measured daily and reported in grams per kilogram BW of feed eaten per week. Changes in BC were assessed using BW (electronic scale) and percentage fat calculated using rump fat thickness and the Westervelt equation. Blood samples were taken every 2 weeks at 15:25, before mares were given their allotment of hay cubes on a day when they did not exercise, to measure plasma hormone and glucose concentrations. Gastroscopy for gastric ulcers was performed before, during and after the trial. VO2max increased by 7.0% (P<0.03) in EX, but did not change (P>0.05) in CON. FI decreased (P<0.001) in both groups, but was only different (P<0.02) between EX and CON at week 3. Digestible energy (DE) intake (Mcal day-1) was initially higher (P<0.001) than calculated DE requirements in EX. However, over time, DE only matched and then fell below (P<0.03) the DE intake required for training. In CON horses, DE intake was higher (P<0.001) than calculated requirements. BW and percentage body fat increased (P<0.001) over time in EX and CON. Plasma leptin concentration increased (P<0.001) over time in both groups, but was 60% higher (P<0.04) in CON compared to EX at weeks 4–8. There were no differences (P>0.05) in active ghrelin, glucose, insulin or cortisol between the groups and over time. Five out of seven EX mares developed gastric ulcers. No CON mares developed gastric ulcers. Training was associated with changes in plasma leptin concentration, an increased incidence of gastric ulcers and a disruption of the balance between required DE and actual intake.

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Oral Administration of Sodium Nitrate to Metabolic Syndrome Patients Attenuates Mild Inflammatory and Oxidative Responses to Acute Exercise

Antioxidants ◽

10.3390/antiox9070596 ◽

2020 ◽

Vol 9 (7) ◽

pp. 596

Author(s):

Xavier Capó ◽

Miguel D. Ferrer ◽

Robert A. Olek ◽

Eduardo Salaberry ◽

Rafael Suau ◽

...

Keyword(s):

Metabolic Syndrome ◽

Plasma Concentration ◽

Sodium Nitrate ◽

Vascular Function ◽

Acute Exercise ◽

Mononuclear Cells ◽

Plasma Concentrations ◽

Intercellular Adhesion Molecule ◽

Maximal Heart Rate ◽

Exercise Tests

The beneficial effects of exercise for the treatment and prevention of metabolic syndrome pathologies have been related to its anti-inflammatory and antioxidant effects. Dietary nitrate supplementation is an emerging treatment strategy to alleviate the symptoms of metabolic syndrome affections and to improve vascular function. In this double-blind crossover trial, metabolic syndrome patients performed two exercise tests for 30 min at 60–70% maximal heart rate after the intake of a placebo or a nitrate-enriched beverage. Acute exercise increased the plasma concentration of TNFα, intercellular adhesion molecule ICAM1, PGE1, PGE2 and the newly detected 16-hydroxypalmitic acid (16-HPAL) in metabolic syndrome patients. The cytokine and oxylipin production by peripheral blood mononuclear cells (PBMCs) and neutrophils could be responsible for the plasma concentrations of TNFα and IL6, but not for the plasma concentration of oxylipins nor its post-exercise increase. The intake of sodium nitrate 30 min before exercise increased the concentration of nitrate and nitrite in the oral cavity and plasma and reduced the oxygen cost of exercise. Additionally, nitrate intake prevented the enhancing effects of acute exercise on the plasma concentration of TNFα, ICAM1, PGE1, PGE2 and 16-HPAL, while reducing the capabilities of PBMCs and neutrophils to produce oxylipins.

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Plasma Leptin in Chronic Inflammatory Bowel Disease and HIV: Implications for the Pathogenesis of Anorexia and Weight Loss

Clinical Science ◽

10.1042/cs0940479 ◽

1998 ◽

Vol 94 (5) ◽

pp. 479-483 ◽

Cited By ~ 52

Author(s):

Anne Ballinger ◽

Paul Kelly ◽

Elizabeth Hallyburton ◽

Rachel Besser ◽

Michael Farthing

Keyword(s):

Inflammatory Bowel Disease ◽

Weight Loss ◽

Body Fat ◽

Bowel Disease ◽

Plasma Concentrations ◽

Percentage Body Fat ◽

Inflammatory Bowel ◽

Plasma Leptin ◽

And Control ◽

Necrosis Factor

1. Leptin inhibits food intake and is an important regulator of long-term energy balance. In rodents, plasma concentrations of leptin are increased by administration of interleukin-1 and tumour necrosis factor. Hyperleptinaemia may mediate the anorexia and weight loss which is observed in chronic infections and inflammatory conditions. 2. Plasma leptin and soluble tumour necrosis factor receptor (sTNF-r55) concentrations were measured in patients with inflammatory bowel disease and acquired immunodeficiency syndrome (AIDS), and healthy controls. 3. The patients with AIDS were severely wasted [% body fat 12 (9–16); median (interquartile range)] compared with those with inflammatory bowel disease (25.1 (19–31.5)] and control subjects [29.4 (23.6–37.8)]. Leptin concentrations were highly correlated with percentage body fat in controls (r = 0.74, P < 0.001) and patients with IBD (r = 0.73, P < 0.001) but not in the patients with AIDS (r = −0.024). Leptin concentrations were similar in the inflammatory bowel disease (4.8 (2.6–10.1) ng/ml] and control groups [8.0 (3.1–14.1) ng/ml] but were significantly lower (P < 0.05) in patients with AIDS (1.8 (1.5–2.3) ng/ml] after 23 patients were matched for sex and percentage body fat in patients with inflammatory bowel disease (2.4 (1.8–4.1) ng/ml]. Plasma concentrations of sTNF-r55 were higher in both the patients with inflammatory bowel disease [0.19 (0.16–0.23) ng/ml] and those with AIDS [4.8 (2.8–7.3) ng/ml] compared with controls [0.14 (0.09–0.16) ng/ml] but were not correlated with either percentage body fat or plasma leptin concentrations. 4. Hyperleptinaemia does not appear to mediate the anorexia and weight loss associated with inflammatory bowel disease and AIDS. In patients with AIDS with extreme wasting there was no relationship between body fat and leptin and this may be related to the rapid weight loss which occurs in these patients.

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Regulation of plasma leptin in mice: influence of age, high-fat diet, and fasting

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1997.273.1.r113 ◽

1997 ◽

Vol 273 (1) ◽

pp. R113-R120 ◽

Cited By ~ 43

Author(s):

B. Ahren ◽

S. Mansson ◽

R. L. Gingerich ◽

P. J. Havel

Keyword(s):

Body Weight ◽

Dietary Fat ◽

High Fat Diet ◽

Plasma Insulin ◽

Plasma Concentrations ◽

Age Groups ◽

Fat Content ◽

High Fat ◽

Background Strain ◽

Plasma Leptin

Mechanisms regulating circulating leptin are incompletely understood. We developed a radioimmunoassay for mouse leptin to examine the influence of age, dietary fat content, and fasting on plasma concentrations of leptin in the background strain for the ob/ob mouse, the C57BL/6J mouse. Plasma leptin increased with age [5.3 +/- 0.6 ng/ml at 2 mo (n = 23) vs. 14.2 +/- 1.6 ng/ml at 11 mo (n = 15), P < 0.001]. Across all age groups (2-11 mo, n = 160), log plasma leptin correlated with body weight (r = 0.68, P < 0.0001), plasma insulin (r = 0.38, P < 0.001), and amount of intra-abdominal fat (r = 0.90, P < 0.001), as revealed by magnetic resonance imaging. Plasma leptin was increased by a high-fat diet (58% fat for 10 mo) and reduced by fasting for 48 h. The reduction of plasma leptin was correlated with the reduction of plasma insulin (r = 0.43, P = 0.012) but not with the initial body weight or the change in body weight. Moreover, the reduction in plasma leptin by fasting was impaired by high-fat diet. Thus plasma leptin in C57BL/6J mice 1) increases with age or a high-fat diet; 2) correlates with body weight, fat content, and plasma insulin; and 3) is reduced during fasting by an action inhibited by high-fat diet and related to changes of plasma insulin.

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Incidence of Duodenal Ulcers and Gastric Ulcers in a Western Population: Back to Where It Started

Canadian Journal of Gastroenterology ◽

10.1155/2009/181059 ◽

2009 ◽

Vol 23 (9) ◽

pp. 604-608 ◽

Cited By ~ 41

Author(s):

Marcel JM Groenen ◽

Ernst J Kuipers ◽

Bettina E Hansen ◽

Rob J Th Ouwendijk

Keyword(s):

Gastric Ulcers ◽

Bleeding Complications ◽

Upper Gastrointestinal Endoscopy ◽

Peptic Ulcers ◽

Duodenal Ulcers ◽

Ulcer Disease ◽

Treatment Regimens ◽

H Pylori ◽

Upper Gastrointestinal ◽

Over Time

BACKGROUND/OBJECTIVES: As recently as 40 years ago, a decline in the incidence of peptic ulcers was observed. The discovery of Helicobacter pylori had a further major impact on the incidence of ulcer disease. Our aim was to evaluate the trends in the incidence and bleeding complications of ulcer disease in the Netherlands.METHODS: From a computerized endoscopy database of a district hospital, the data of all patients who underwent upper gastrointestinal endoscopy from 1996 to 2005 were analyzed. The incidence of duodenal and gastric ulcers, with and without complications, were compared over time.RESULTS: Overall, 20,006 upper gastrointestinal endoscopies were performed. Duodenal ulcers were diagnosed in 696 (3.5%) cases, with signs of bleeding in 158 (22.7%). Forty-five (6.5%) of these ulcers were classified as Forrest I and 113 (16.2%) as Forrest II. Gastric ulcers were diagnosed in 487 cases (2.4%), with signs of bleeding in 60 (12.3%). A Forrest 1 designation was diagnosed in 19 patients (3.9%) and Forrest 2 in 41 patients (8.4%). The incidence of gastric ulcers was stable over time, while the incidence of duodenal ulcers declined.CONCLUSIONS: The incidence of duodenal ulcer disease in the Dutch population is steadily decreasing over time. Test and treatment regimens for H pylori have possibly contributed to this decline. With a further decline in the prevalence of H pylori, the incidence of gastric ulcers is likely to exceed the incidence of duodenal ulcers in the very near future, revisiting a similar situation that was present at the beginning of the previous century.

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Factors associated with vasopressin release in exercising swine

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1994.266.1.r118 ◽

1994 ◽

Vol 266 (1) ◽

pp. R118-R124 ◽

Cited By ~ 4

Author(s):

C. L. Stebbins ◽

J. D. Symons ◽

M. D. McKirnan ◽

F. F. Hwang

Keyword(s):

Plasma Volume ◽

Plasma Concentrations ◽

Plasma Osmolality ◽

Plasma Renin ◽

Treadmill Running ◽

Maximal Heart Rate ◽

Ang Ii ◽

Strong Correlations ◽

Vasopressin Release ◽

Lysine Vasopressin

This study examined the effect of dynamic exercise on vasopressin release in the miniswine and factors that may elicit this response (n = 15). Thus lysine vasopressin (LVP), the catecholamines epinephrine and norepinephrine (EPI and NE), plasma renin activity (PRA), and plasma volume, Na+, and osmolality were measured before and during treadmill running at work intensities of 60, 80, and 100% of each swine's maximal heart rate reserve (HRR). LVP increased in a progressive manner similar to that of humans, ranging from 5.9 +/- 0.4 pg/ml before exercise to 30.1 +/- 4.5 pg/ml during maximal exercise. EPI, NE, and PRA [an index of angiotensin II (ANG II) activity] demonstrated a pattern of response comparable to LVP. Although these hormones can influence the release of LVP, only PRA displayed a strong correlation with LVP (r = 0.84). When ANG II synthesis was blocked (captopril, 1-3 mg/kg, intra-atrial injection) during exercise (80% HRR), plasma LVP was reduced from 9.9 +/- 0.6 to 7.5 +/- 0.6 pg/ml (P < 0.05). In addition, moderate-to-strong correlations were found between plasma concentrations of LVP and plasma osmolality (r = 0.79) and body temperature (r = 0.78). Plasma LVP also correlated with decreases in plasma volume (r = 0.84). These data suggest that the miniswine model is a good one for studying vasopressin effects during exercise and that ANG II appears to be a particularly strong stimulus for the release of this hormone.

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Increased plasma leptin attenuates adaptive metabolism in early lactating dairy cows

Journal of Endocrinology ◽

10.1530/joe-16-0031 ◽

2016 ◽

Vol 229 (2) ◽

pp. 145-157 ◽

Cited By ~ 12

Author(s):

Richard A Ehrhardt ◽

Andreas Foskolos ◽

Sarah L Giesy ◽

Stephanie R Wesolowski ◽

Christopher S Krumm ◽

...

Keyword(s):

Dairy Cow ◽

Feed Intake ◽

Plasma Levels ◽

Plasma Concentrations ◽

Body Weight Loss ◽

Energy Output ◽

Glucose Disposal ◽

Hepatic Glycogen ◽

Metabolic Efficiency ◽

Plasma Leptin

Mammals meet the increased nutritional demands of lactation through a combination of increased feed intake and a collection of adaptations known as adaptive metabolism (e.g., glucose sparing via insulin resistance, mobilization of endogenous reserves, and increased metabolic efficiency via reduced thyroid hormones). In the modern dairy cow, adaptive metabolism predominates over increased feed intake at the onset of lactation and develops concurrently with a reduction in plasma leptin. To address the role of leptin in the adaptive metabolism of early lactation, we asked which adaptations could be countered by a constant 96-h intravenous infusion of human leptin (hLeptin) starting on day 8 of lactation. Compared to saline infusion (Control), hLeptin did not alter energy intake or milk energy output but caused a modest increase in body weight loss. hLeptin reduced plasma glucose by 9% and hepatic glycogen content by 73%, and these effects were associated with a 17% increase in glucose disposal during an insulin tolerance test. hLeptin attenuated the accumulation of triglyceride in the liver by 28% in the absence of effects on plasma levels of the anti-lipolytic hormone insulin or plasma levels of free fatty acids, a marker of lipid mobilization from adipose tissue. Finally, hLeptin increased the plasma concentrations of T4and T3by nearly 50% without affecting other neurally regulated hormones (i.e., cortisol and luteinizing hormone (LH)). Overall these data implicate the periparturient reduction in plasma leptin as one of the signals promoting conservation of glucose and energy at the onset of lactation in the energy-deficient dairy cow.

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Effects of a dietary supplement on gastric ulcer number and severity in exercising horses1

Translational Animal Science ◽

10.1093/tas/txy005 ◽

2018 ◽

Vol 2 (2) ◽

pp. 119-124

Author(s):

Alysia L Conner ◽

Amanda J Davis ◽

Cheryl A Porr

Keyword(s):

Gastric Ulcer ◽

Dietary Supplement ◽

Fixed Effects ◽

Gastric Lesion ◽

Gastric Ulcers ◽

Experimental Unit ◽

Adaptation Period ◽

Feeding Period ◽

Gastric Lesions ◽

Dependent Variables

Abstract This study evaluated the effect of a dietary supplement on the treatment of equine gastric ulcer syndrome (EGUS). Gastroscopy was performed on university riding horses of mixed breeds at two locations and only horses exhibiting gastric ulcers were selected to participate in this study (location A, n = 13; location B, n = 15). Gastric ulcer severity was assessed using two different methods depending on location before treatment (Pre). After gastroscopy, horses were fed the supplement in addition to their regular diet for 44 d (14-d adaptation period followed by 30-d feeding period). All horses were subjected to gastroscopy again at the end of the feeding period (Post) to evaluate changes in gastric lesions. Statistical analysis was performed using SAS. Individual horses were the experimental unit with dependent variables including severity and number of gastric ulcers. At location A, dependent variable included severity of gastric lesions with fixed effects of time (Pre and Post) and location (stall or pasture). For location B, dependent variables included severity and number of gastric lesions with fixed effects of time. Severity of gastric ulcers decreased at both locations in horses following the feeding period. Gastric lesion scores decreased from 2.2990 to 1.3760 (P = 0.0015) at location A and gastric lesion severity from 3.8000 to 2.5667 (P = 0.0322) at location B. No differences were found in gastric lesion scores at location A between horses housed in stalls or pastures (1.8750 and 1.8000; P = 0.7783). The number of gastric ulcers observed at location B were similar Pre and Post treatment (3.4667 and 3.5333; P = 0.8363). There were no changes in body condition score (P ≥ 0.2607), BW (P ≥ 0.4551), or behavior at either location. Results suggest that oral supplementation may decrease severity of gastric ulcers in horses participating in university riding programs.

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A time-series effect of phytase supplementation on phosphorus utilization in growing and finishing pigs fed a low-phosphorus diet

Journal of Animal Science ◽

10.1093/jas/skab350 ◽

2021 ◽

Vol 100 (1) ◽

Author(s):

Olufemi Oluwaseun Babatunde ◽

Olayiwola Adeola

Keyword(s):

Time Series ◽

Growth Performance ◽

Block Design ◽

Average Daily Gain ◽

Plasma Concentrations ◽

Growing Pigs ◽

Water Soluble ◽

Feed Ratio ◽

Finishing Pigs ◽

Over Time

Abstract Two experiments were carried out to determine a time-series effect of phytase on phosphorus (P) utilization in growing and finishing pigs using growth performance, apparent total tract digestibility (ATTD) of nutrients, P excretion, and plasma concentrations of minerals as the response criteria for evaluation. In both experiments, treatments were arranged as a 3 × 4 factorial in a randomized complete block design with 3 corn–soybean meal-based diets including a P-adequate positive control (PC), a low-P negative control (NC; no inorganic P), and NC supplemented with phytase at 1,000 FYT/kg (NC + 1,000); and 4 sampling time points at days 7, 14, 21, and 28 in experiment 1, and days 14, 26, 42, and 55 in experiment 2. In both trials, 96 growing pigs with average body weight (BW) of 19.8 ± 1.16 and 49.8 ± 3.21 kg, respectively, were allocated to the 3 diets with 8 replicates pens (4 barrows and 4 gilts) and 4 pigs per pen. In experiment 1, pigs fed the PC had higher (P < 0.01) BW, average daily gain (ADG), average daily feed intake (ADFI), and gain-to-feed ratio (G:F) when compared with pigs fed the NC. There was an interaction (P < 0.01) between time and diet on the BW and ADG of pigs while a linear and quadratic increase (P < 0.01) was observed with the ADFI and G:F, respectively, over time. Phytase supplementation improved (P < 0.01) all growth performance responses. Pigs fed the PC had greater (P < 0.01) ATTD of P and Ca than pigs fed the NC. There was no interaction effect on the ATTD of nutrients. Phytase addition improved the ATTD of P and Ca over pigs fed the NC. There was an interaction (P < 0.01) between diet and time on the total and water-soluble P (WSP) excreted. There was a quadratic decrease (P < 0.01) in plasma concentration of Ca in pigs over time. In experiment 2, there was a quadratic increase (P < 0.01) in BW, ADG, and G:F of pigs over time. Similarly, the inclusion of phytase improved (P < 0.05) all growth performance parameters except ADFI. A linear increase (P < 0.05) in the ATTD of DM, P, and Ca occurred over time. Phytase inclusion improved (P < 0.01) the ATTD of P and Ca. Plasma concentrations of P were improved by phytase addition. Phytase supplementation of the NC reduced WSP excretion by 45%, 32%, and 35% over the growing, finishing, and entire grow-finish period, respectively. In conclusion, phytase improves the utilization of P in growing and finishing pigs; however, the magnitude of effect on responses may vary over time.

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Abstract P119: Non-exercise Cardiorespiratory Fitness Prediction Equations: Accuracy Over Time in Apparently Healthy Adults

Circulation ◽

10.1161/circ.141.suppl_1.p119 ◽

2020 ◽

Vol 141 (Suppl_1) ◽

Author(s):

James E Peterman ◽

Matthew Harber ◽

Mary Imboden ◽

Mitchell Whaley ◽

bradley fleenor ◽

...

Keyword(s):

Cardiorespiratory Fitness ◽

Heart Association ◽

Healthy Adults ◽

Prediction Equations ◽

Exercise Tests ◽

Average Percentage ◽

The Impact ◽

Over Time ◽

Apparently Healthy

Introduction: Mortality risk predictions are improved with routine assessment of cardiorespiratory fitness (CRF). Accordingly, an American Heart Association Scientific Statement suggests routine clinical assessment of CRF in apparently healthy adults minimally using non-exercise prediction equations, which can be calculated from common health metrics. However, no study has assessed the ability of non-exercise CRF prediction equations to accurately detect longitudinal changes. Hypothesis: Changes in estimated CRF (eCRF) would be related to directly-measured changes, yet appreciable misclassification would occur at the individual level. Methods: The sample included 987 apparently healthy adults (324 females; mean±SD age 43.1±10.4 years) who completed 2 cardiopulmonary exercise tests (CPX) at least 3 months apart (3.2±5.4 years follow-up). The change in eCRF from 27 distinct non-exercise prediction equations was compared to the change in directly-measured CRF determined from CPX. A change of ≥5% was used to classify participants as having a directional increase or decrease in CRF. Analysis included Pearson product moment correlations, standard error of estimate (SEE) values, the Benjamini-Hochberg procedure to compare eCRF with directly-measured CRF, and chi-squared tests to examine the impact of follow-up time on the percentage of participants correctly identified as having a directional increase or decrease in CRF. Results: The change in eCRF from each equation was correlated to the change in directly-measured CRF ( P <0.001) with R 2 values ranging from 0.06-0.43 and SEE values ranging from 0.9-5.9 ml·kg -1 ·min -1 . For 16 of the 27 equations, the change in eCRF was significantly different from the change in directly-measured CRF. When classifying directional changes, the prediction equations correctly categorized an average of 54% of individuals as having increased, decreased, or no change in CRF. When examining the influence of follow-up time, the average percentage of individuals correctly classified as having a directional increase in CRF was greater when the time between tests was ≤8months (54%) compared to ≥2years (28%). In contrast, the average percentage correctly classified as having a directional decrease in CRF was lower with tests ≤8months apart (8%) compared to ≥2years (73%). Conclusions: As hypothesized, discernible variability was found in the accuracy between non-exercise prediction equations and the ability of equations to accurately assess changes in directly-measured CRF over time. Considering the appreciable error that prediction equations had with detecting even directional changes in CRF, these results suggest eCRF may have limited clinical utility.

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Population Pharmacokinetic Modeling of VL-2397, a Novel Systemic Antifungal Agent: Analysis of a Single- and Multiple-Ascending-Dose Study in Healthy Subjects

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00163-19 ◽

2019 ◽

Vol 63 (6) ◽

Cited By ~ 3

Author(s):

Laura L. Kovanda ◽

Sean M. Sullivan ◽

Larry R. Smith ◽

Amit V. Desai ◽

Pete L. Bonate ◽

...

Keyword(s):

Antifungal Agent ◽

Healthy Subjects ◽

Phase 1 ◽

Plasma Concentrations ◽

Population Pharmacokinetic ◽

Binding Model ◽

Saturable Binding ◽

Drug Concentrations ◽

Over Time

ABSTRACT VL-2397, a novel, systemic antifungal agent, has potent in vitro and in vivo fungicidal activity against Aspergillus species. Plasma concentrations from a phase 1 study were used to construct a population pharmacokinetic (PPK) model for VL-2397. Healthy subjects aged 18 to 55 years received single doses of VL-2397, ranging from 3 to 1,200 mg, multiple daily doses of 300, 600, or 1,200 mg for 7 days, or 300 mg three times/day for 7 days followed by 600 mg daily for 21 days. Plasma samples were collected throughout the dosing intervals. Sixty-six subjects provided 1,908 concentrations. Drug concentrations over time were increased less than dose proportionally for doses above 30 mg. Dose-normalized concentrations plotted over time did not overlap. A 3-compartment nonlinear saturable binding model fit the data well. Clearance increased with dose, and mean values ranged from 0.4 liters/h at 3 mg to 8.5 liters/h at 1,200 mg. Mean volume in the central compartment ranged from 4.8 to 6.9 liters across doses. In the first 24 h, once-daily dosing results in a rapid decrease in concentrations by hour 16 to approximately 1 mg/liter, regardless of dose, with slow clearance over time. Administration of 300 mg every 8 h achieved concentrations above 1 mg/liter over an entire 24-h period. There was a significant relationship between body surface area and clearance. The data suggest that VL-2397 has nonlinear saturable binding kinetics. Protein binding is the likely primary source of the nonlinearity. The PPK model can now be used to optimize dosing by bridging the kinetics to efficacious pharmacodynamic targets.

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