Clinical pharmacokinetics (PK) of BMS-936558, a fully human anti-PD-1 monoclonal antibody.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. TPS2622-TPS2622 ◽  
Author(s):  
Shruti Agrawal ◽  
Yan Feng ◽  
Georgia Kollia ◽  
Sally Saeger ◽  
Martin Ullmann ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Body Weight ◽  
Half Life ◽  
Dose Range ◽  
Volume Of Distribution ◽  
Wide Range ◽  
Body Weights ◽  
Clinically Significant ◽  
Potentially Clinically Significant ◽  
Dose Proportional

TPS2622 Background: BMS-936558 is a fully human IgG4 monoclonal antibody targeted against human Programed Death-1 (PD1) receptor on activated T and B lymphocytes. Blocking of PD-1 prevents these activated cells from becoming anergic, thereby maintaining anti-tumor immunologic activity. Methods: The PK of BMS-936558 was characterized with data from a single ascending dose (SAD) and a multiple ascending dose (MAD) study in subjects with advanced solid malignancies. Subjects received a single IV infusion of 0.3 to 10 mg/kg BMS-936558 in the SAD study (MDX-1106-01 Study) and 0.1 to 10 mg/kg BMS-936558 every two weeks in the MAD study (MDX-1106-03/CA209003 Study). The PK of BMS-936558 was characterized by non-compartmental analysis of intensively sampled PK data from a SAD study, as well as by population PK analysis of available intensive and sparse PK data from the SAD and MAD studies, respectively. Results: The PK of BMS-936558 is linear in the studied dose range with dose-proportional increase in Cmax and AUC with low to moderate (20-44%) inter-subject variability. Geometric mean clearance ranged from 0.13 - 0.19 mL/h/kg, whereas mean volume of distribution ranged from 83 -113 mL/kg. The range of mean terminal elimination half-life of BMS-936558 is 17 to 25 days which is consistent with half-life of endogenous IgG4. BMS-936558 PK was adequately described by a linear two-compartment model, and there was no evidence of a contribution of target mediated drug disposition to drug elimination within tested dose range. Body weight and gender are potentially clinically significant covariate for both clearance and volume of distribution (> 20% effect); and baseline CRP, LDH, and albumin are potentially clinically significant covariates for CL. The body weight normalized dosing employed produces trough concentrations that are approximately constant over a wide range of body weights. Conclusions: The pharmacokinetics of BMS-936558 is dose-proportional and body weight normalized dosing is appropriate to ensure consistent exposure over a wide range of body weights.

Development of the testis and epididymis of the Clun Forest ram

1971 ◽  
Vol 76 (3) ◽  
pp. 433-441 ◽  
Author(s):  
R. J. Colyer
Keyword(s):  
Body Weight ◽  
Rate Of Increase ◽  
Wide Range ◽  
Body Weights ◽  
Close Relationship ◽  
Subsequent Phase ◽  
Dimensional Growth ◽  
Left And Right ◽  
Ram Lambs

SUMMARYObservations were made on the development of the testes and epididymides of thirty-two Clun Forest ram lambs. There were no significant differences between the weights and volumes of the left and right testes and epididymides.The rate of increase in testicular and epididymal weights was linear up to a body weight of 46 lb (20·9 kg) followed subsequently by a significantly greater rate of increase at higher body weights. Similar patterns of growth occurred in relation to age, although at a given age there was a wide range of testicular and epididymal weights. There was a close relationship between the development of the testis and the epididymis at body weights greater than 46 lb (20·9 kg).There were two distinct phases in the dimensional growth of the testis. Increases in testicular length and breadth proceeded at much the same rate at testis weights of below 20 g. During the subsequent phase testicular length increased at a significantly greater rate than testis breadth.

Avian Egg Morphometrics - Allometric Models of Egg Volume, Clutch Volume and Shape

1994 ◽  
Vol 42 (3) ◽  
pp. 307 ◽  
Author(s):  
PD Olsen ◽  
RB Cunningham ◽  
CF Donnelly
Keyword(s):  
Body Weight ◽  
Body Size ◽  
Sexual Dimorphism ◽  
Clutch Size ◽  
Egg Volume ◽  
Simple Power ◽  
Wide Range ◽  
Body Weights ◽  
Body Sizes ◽  
Simple Power Function

This paper describes three comprehensive new models of the allometric relationships between egg volume, clutch volume and shape, and body weight. Mean egg dimensions, clutch sizes and adult body weights were obtained for 326 species, mainly of four bird types: raptors (including owls), shorebirds, frogmouths (including nightjars), and storks (including the New World vultures). These are groups in which there is a wide range of body sizes and of sexual dimorphism in body size (in direction and degree). Female body weight alone accounted for 92% of the variation in egg volume. Sexual dimorphism in body size, phylogenetic relationship, and clutch size were significant contributors to the model of egg volume; their addition increased the explained variance to over 98%. The model was curvilinear (quadratic) in form, rather than linear as assumed in previous models. Larger species laid smaller eggs than expected under a simple power function. For the fitted model, within bird types, generic groupings had parallel curvilinear slopes but differing intercepts. Between bird types, the slopes differed. Clutch volume was scaled to body weight; all the bird types had a common slope, which was curvilinear. Body weight and dimorphism accounted for 89.5% of the variation in clutch volume. For all bird types, eggs became proportionally longer in shape as body weight increased, according to a simple power law. The relevance of these relationships to hypotheses on the evolution and adaptive significance of sexual dimorphism and to the trade-off between egg size and clutch size is discussed briefly.

Volume of Distribution and Fractional Clearance of Urea in Amputees on Continuous Ambulatory Peritoneal Dialysis

1994 ◽  
Vol 14 (4) ◽  
pp. 356-361 ◽  
Author(s):  
Antonios H. Tzamaloukas ◽  
Mark S. Saddler ◽  
Gayle Murphy ◽  
Kelley Morgan ◽  
Richard S. Goldman ◽  
...  
Keyword(s):  
Mathematical Model ◽  
Body Weight ◽  
Peritoneal Dialysis ◽  
Actual Body ◽  
Continuous Ambulatory Peritoneal Dialysis ◽  
Volume Of Distribution ◽  
Actual Body Weight ◽  
Leg Length ◽  
Body Weights ◽  
The Mathematical Model

Objectives To demonstrate the effects of amputation on the estimates of urea volume of distribution (V) and KTN urea in continuous ambulatory peritoneal dialysis (CAPD) patients and to present a method for correcting the errors created by the uncorrected anthropometric formulas estimating V. Design (1) A mathematical analysis of the error and the correction proposed was performed. (2) Urea kinetic modeling with uncorrected and corrected estimates utilizing both the Watson and the Hume anthropometric formulas was performed in amputees on CAPD. Setting Subjects were recruited from four dialysis units in one city: one Veterans Affairs unit, one university-affiliated unit, and two community units. Patients Fourteen amputees on CAPD: 12 with unilateralleg amputation and 2 with bilateral leg amputation, at the same length of the leg, were studied. Interventions Urea kinetic studies were performed in 24-hour drained dialysate and urine specimens. Main Outcome Measures Uncorrected and corrected estimates of V and KTN urea were compared to each other and to the predictions of the mathematical model. Body weights corresponding to uncorrected and correct ed V estimates were compared to the actual body weights. Results (1) The mathematical model predicts that uncorrected estimates by the anthropometric formulas will falsely characterize unilateral amputees as leaner than they are and bilateral amputees as more obese than they are. (2) In unilateral amputees studied with the Watson formulas, uncorrected V was 0.546±0.023 L/kg and corrected V was 0.520±0.023 L/kg (p < 0.001). Corresponding weekly KTN urea values were 1.97±0.14 and 2.07±0.14, respectively (p < 0.001). Similar results were obtained with the Humeformulas. In bilateral leg amputees studied with the Watson formulas, uncorrected V was 0.479±0.022 L/kg and corrected V was 0.514±0.023 L/kg. Corresponding KT N estimates were 2.11 ±0.45 and 1.96±0. 14, respectively. The differences were even greater with the Hume formulas. Estimates of body weight calculated from corrected V values were equal to actual weight measurements, whereas those calculated from uncorrected V values were lower than actual body weight measurements in unilateral amputees, and much higher than actual body weight measurements in bilateral amputees. Conclusion Uncorrected anthropometric estimates falsely characterize unilateral amputees as leaner than they actually are and bilateral amputees, amputated at the same leg length, as more obese than they actually are. Uncorrected KTN estimates are, therefore, falsely low in unilateral amputees, and falsely high in bilateral amputees. The proposed correction of the anthropometric formulas provides estimates agreeing closely with dietary estimates of body composition. Further studies are needed to define the accuracy of the corrected formulas.

Pharmacokinetics (PK) of the chimeric anti-GD2 antibody, ch14.18, in children with high-risk neuroblastoma.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 9576-9576
Author(s):  
Ami Vijay Desai ◽  
Elizabeth Fox ◽  
Theresa C. DiSipio ◽  
L. Mary Smith ◽  
Allison Lim ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
High Risk ◽  
Half Life ◽  
Limit Of Detection ◽  
Sampling Strategy ◽  
Volume Of Distribution ◽  
Plasma Samples ◽  
Limited Sampling ◽  
Dosing Strategies ◽  
Pre Treatment

9576 Background: The PK of ch14.18, a chimeric monoclonal antibody (cMoAb) that significantly improves survival in high-risk neuroblastoma, was previously reported to be highly variable in children, and its clearance (CL, 130 mL/h · m2) and volume of distribution (Vdss, 32 L/m2) were >10-fold higher than the CL and Vdss of other cMoAbs. Characterizing the PK of ch14.18 and the factors responsible for its variability could lead to alternative dosing strategies that reduce toxicity. Methods: Detailed PK sampling was performed prior to, during and for 25 d after 4 daily 10 h infusions of 25 mg/m2 of ch14.18 administered with sargramostim (ANBL0032) in children enrolled on an IRB-approved institutional correlative protocol supported by United Therapeutics Corp. Ch14.18 concentrations were measured with a validated ELISA with a lower limit of detection of 0.44 mcg/mL. PK parameters were derived using non-compartmental methods and reported as median (range). Results: 5 males and 4 females, median (range) age 3.5 (1-7) yrs, have been enrolled. Six were studied on cycle 1 (C1), 2 on C5 and 1 on C3; 3 of 6 patients studied on C1 were re-studied on C3. Data from 3 patients are not included because pre-treatment plasma samples contained a substance that interfered with the ELISA. The Cmax after the 4th daily infusion was 14 (10-24) mcg/mL, and ch14.8 was undetectable at day 25 in 3/6 patients. The half-life was 220 (120-390) h, and the CL was 11 (3.8-16) mL/h · m2, which is similar to the average CL of 4 other cMoAbs (11 mL/h · m2). The Vdss of 2.8 (1.2-3.9) L/m2 approximated blood volume and was similar to the Vdss of other cMoAbs (1.7 L/m2) and humanized MoAbs (2.8 L/m2). AUC0-∞ in 2 patients studied twice were 3440 and 1540 mcg · h/mL on C1 and 2760 and 2690 mcg · h/mL on C3. Conclusions: Ch14.18 CL, Vdss and half-life in children are similar to those in adults receiving ch14.18 at the same dose and similar to other cMoAbs. Ch14.18 PK in children was less variable than previously reported. The identity of the interfering substance in the plasma of some patients requires further investigation. A limited sampling strategy will be developed from these data for use in larger multi-institutional PK studies of ch14.18.

scholarly journals Pharmacokinetics and Safety Profile of the Human Anti-Pseudomonas aeruginosa Serotype O11 Immunoglobulin M Monoclonal Antibody KBPA-101 in Healthy Volunteers

2009 ◽  
Vol 53 (8) ◽  
pp. 3442-3446 ◽  
Author(s):  
Hedvika Lazar ◽  
Michael P. Horn ◽  
Adrian W. Zuercher ◽  
Martin A. Imboden ◽  
Peter Durrer ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Pseudomonas Aeruginosa ◽  
Body Weight ◽  
Healthy Volunteers ◽  
Human Monoclonal Antibody ◽  
Dose Range ◽  
Plasma Concentrations ◽  
Immunoglobulin M ◽  
Serious Adverse Events ◽  
The Mean

ABSTRACT KBPA-101 is a human monoclonal antibody of the immunoglobulin M isotype, which is directed against the O-polysaccharide moiety of Pseudomonas aeruginosa serotype O11. This double-blind, dose escalation study evaluated the safety and pharmacokinetics of KBPA-101 in 32 healthy volunteers aged 19 to 46 years. Each subject received a single intravenous infusion of KBPA-101 at a dose of 0.1, 0.4, 1.2, or 4 mg/kg of body weight or placebo infused over 2 h. Plasma samples for pharmacokinetic assessments were taken before infusion as well as 0.25, 0.5, 1, 2, 2.5, 4, 6, 8, 12, 24, 36, and 48 h and 4, 7, 10, and 14 days after start of dosing. Plasma concentrations of KBPA-101 were detected with mean maximum concentrations of drug in plasma of 1,877, 7,571, 24,923, and 83,197 ng/ml following doses of 0.1, 0.4, 1.2, and 4.0 mg/kg body weight, respectively. The mean elimination half-life was between 70 and 95 h. The mean volume of distribution was between 4.76 and 5.47 liters. Clearance ranged between 0.039 and 0.120 liters/h. At the highest dose of 4.0 mg/kg, plasma KBPA-101 levels were greater than 5,000 ng/ml for 14 days. KBPA-101 exhibited linear kinetics across all doses. No anti-KBPA-101 antibodies were detected after dosing in any subject. Overall, the human monoclonal antibody KBPA-101 was well tolerated over the entire dose range in healthy volunteers, and no serious adverse events have been reported.

Doxorubicin clearance in the obese.

1988 ◽  
Vol 6 (8) ◽  
pp. 1321-1327 ◽  
Author(s):  
K A Rodvold ◽  
D A Rushing ◽  
D A Tewksbury
Keyword(s):  
Body Weight ◽  
Half Life ◽  
High Performance ◽  
Area Under The Curve ◽  
Ideal Body Weight ◽  
Apparent Volume ◽  
Volume Of Distribution ◽  
Obese Patients ◽  
Elimination Half Life ◽  
Elimination Half

A study was carried out to examine the effect, if any, of obesity on doxorubicin pharmacokinetics. Body weight was found to be significantly related to doxorubicin clearance (r = -.75; P less than .001) and elimination half-life (r = .62; P = .003). Thus, the contribution of obesity on pharmacokinetics of antineoplastic agents should be taken into consideration in the analysis of clinical data with respect to toxicity and tumor response. Twenty-one patients were studied with their first course of doxorubicin (50 to 70 mg/m2) administered as a 60-minute intravenous (IV) infusion. Patients were divided into three groups on the basis of percentage of ideal body weight (IBW): normal (less than 115% IBW), mildly obese (115% to 130% IBW), and obese (greater than 130% IBW). Blood samples were collected up to 48 hours after the infusion and analyzed for doxorubicin and its metabolite, doxorubicinol, by high performance liquid chromatography. Doxorubicin area under the curve (AUC) was greater in obese than in normal patients (2,209 v 1,190 ng h/mL; P less than .05), yielding correspondingly reduced systemic clearance of the agent in obese patients (891 v 1,569 mL/min; P less than .001). The mean elimination half-life (T1/2) was 20.4 hours in the obese patients and 13.0 hours in the normal patients. The apparent volume of distribution (Vss) was not significantly different among the three groups of patients, indicating that the prolonged T1/2 in the obese patients is due to the reduction in clearance. The AUC and T1/2 of doxorubicinol were similar among all patient groups.

Work performance of trained rats as affected by corticoadrenal steroids and by adrenalectomy

1960 ◽  
Vol 199 (5) ◽  
pp. 863-866
Author(s):  
Charles A. Winter ◽  
Lars Flataker
Keyword(s):  
Skeletal Muscle ◽  
Body Weight ◽  
Adrenal Insufficiency ◽  
Work Performance ◽  
Skeletal Muscle Mass ◽  
Food Reward ◽  
Narrow Range ◽  
Wide Range ◽  
Body Weights ◽  
Fasted Rats

Fasted rats trained to climb a rope for a food reward were capable of carrying added weights approximately equal to their own body weights. The logclimbing time in seconds was linearly related to the total weight of the animal plus added load within a narrow range of body weight. When correction was made for skeletal muscle mass, the rate of work performance in gram-meters per long second per gram muscle was essentially the same over a wide range of body weights and of added load. Work performance as measured by this preparation was sensitive to changes in glucocorticoid levels, and was increased by cortisone or hydrocortisone in either intact or adrenalectomized animals, and was decreased by adrenal insufficiency.

scholarly journals Pharmacokinetics and Tolerability of Daptomycin at Doses up to 12 Milligrams per Kilogram of Body Weight Once Daily in Healthy Volunteers

2006 ◽  
Vol 50 (10) ◽  
pp. 3245-3249 ◽  
Author(s):  
Mark Benvenuto ◽  
David P. Benziger ◽  
Sara Yankelev ◽  
Gloria Vigliani
Keyword(s):  
Body Weight ◽  
Healthy Volunteers ◽  
Bloodstream Infections ◽  
Volume Of Distribution ◽  
Pharmacokinetic Parameters ◽  
Time Curve ◽  
Once Daily ◽  
Complicated Skin ◽  
Multiple Dose Pharmacokinetics ◽  
Dose Proportional

ABSTRACT Daptomycin, a novel lipopeptide, is bactericidal against a broad range of gram-positive strains, including methicillin- (MRSA) and vancomycin-resistant Staphylococcus aureus. Daptomycin is approved at 4 mg/kg of body weight given intravenously once daily for the treatment of complicated skin and skin structure infections and at 6 mg/kg for the treatment of S. aureus bloodstream infections (bacteremia), including right-sided endocarditis caused by methicillin-susceptible S. aureus and MRSA. The present study was designed to evaluate the multiple-dose pharmacokinetics and safety of daptomycin at doses of 6 to 12 mg/kg in healthy volunteers. Three cohorts of 12 subjects each were given daptomycin (10 mg/kg) or placebo once daily for 14 days, daptomycin (12 mg/kg) or placebo once daily for 14 days, or daptomycin (6 or 8 mg/kg) once daily for 4 days. Daptomycin produced dose-proportional increases in the area under the plasma concentration-time curve and in trough daptomycin levels and nearly dose-proportional increases in peak daptomycin concentrations. Other pharmacokinetic parameters measured on day 1 and at steady state were independent of the dose, including the half-life (approximately 8 h), weight-normalized plasma clearance (9 to 10 ml/h/kg), and volume of distribution (approximately 100 ml/kg). Plasma protein binding was 90% to 93% and was independent of the daptomycin concentration. Daptomycin did not produce electrocardiographic abnormalities or electrophysiological evidence of muscle or nerve toxicity. Daptomycin was well tolerated in subjects dosed with up to 12 mg/kg intravenously for 14 days. Doses of daptomycin higher than 6 mg/kg once daily may be considered in further studies to evaluate the safety and efficacy of daptomycin in difficult-to-treat infections.

The Clinical Pharmacokinetics of Quinapril

Angiology ◽  
1989 ◽  
Vol 40 (4_part_2) ◽  
pp. 351-359 ◽  
Author(s):  
Stephen C. Olson ◽  
Ann Marie Horvath ◽  
Barbara M. Michniewicz ◽  
Allen J. Sedman ◽  
Wayne A. Colburn ◽  
...  
Keyword(s):  
Half Life ◽  
Peak Plasma ◽  
Dose Range ◽  
Plasma Concentrations ◽  
Area Under The Curve ◽  
Clinical Pharmacokinetics ◽  
Q 61 ◽  
Dose Proportional

Quinapril (Q) and quinaprilat (QT) pharmacokinetics are dose pro portional following single oral 2.5- to 80-mg Q doses. Q absorption and hy drolysis to QT is rapid with peak Q and QT concentrations occurring one and two hours postdose, respectively. Peak plasma QT concentrations were approximately fourfold higher than those of Q (923 vs 207 ng/mL follow ing 40-mg Q). Dose-proportional QT area under the curve and dose-inde pendent percent of dose excreted in urine as QT demonstrate that the ex tent of Q conversion to QT is con stant over the dose range studied. Q and QT were eliminated from plasma with apparent half-lives of 0.8 and 1.9 hours and apparent plasma clear ances of 1,850 and 220 mL/min, re spectively, over the 2.5- to 80-mg dose range. Following oral 14C-Q, 61% and 37% of radiolabel was recovered in urine and feces, respectively. Q plus QT accounted for 46% of radioactiv ity circulating in plasma and 56% of that excreted in urine. Metabolism to compounds other than QT is not extensive. Two diketo piperazine metabolites of Q have been identified in plasma and urine, with approximately 6% of an admin istered dose excreted in urine as each of these metabolites. Peak plasma concentrations of these metabolites are similar to that of Q, and each is eliminated rapidly with a half-life of approximately one hour. Urinary ex cretion profiles indicate the presence of other minor metabolites. In summary, the absorption of Q and conversion to QT is rapid and dose-proportional, subsequent clear ance of both Q and QT is independ ent of dose, and metabolism to compounds other than QT is not ex tensive.

scholarly journals Neurotoxicity and Toxicokinetics of Artelinic Acid Following Repeated Oral Administration in Rats

2007 ◽  
Vol 26 (5) ◽  
pp. 401-410 ◽  
Author(s):  
Yuanzheng Si ◽  
Qigui Li ◽  
Lisa Xie ◽  
Kent Bennett ◽  
Peter J. Weina ◽  
...  
Keyword(s):  
Body Weight ◽  
Exposure Time ◽  
Drug Exposure ◽  
Neuronal Degeneration ◽  
Neuronal Damage ◽  
Dose Range ◽  
Volume Of Distribution ◽  
The Body ◽  
Water Soluble ◽  
Dosing Regimens

Neurotoxicity secondary to oil-soluble artemisinins has been reported in various animal species. The onset of neurotoxicity and toxicokinetics of oral artelinic acid (AL), a water-soluble artemisinin, were investigated. After dose range study, rats were dosed at either 160 mg/kg daily for 9 consecutive days or at 288 mg/kg once every other day for five doses, so that the total dose (1440 mg/kg) and duration (9 days) were identical. Neuronal damage of varying severity was identified beginning as early as 1 day after completing dosing and continued for up to 10 days post dosing. Neuronal injury was most severe 7 days after the last treatment in each of the two dosing regimens. The rats dosed with 160 mg/kg of AL daily showed moderate neurotoxicity and lost 22% of their body weight during treatment. Compared with the first dose, the toxicokinetic profile of this regimen changed significantly, with the elimination half-life increasing 3.82-fold and the volume of distribution increasing 5.23-fold on the last day of dosing. In the animals treated with AL at 288 mg/kg every other day for 5 doses, minimal neuronal degeneration (severity score 1.17) was identified and the body weight was only 8% loss. Furthermore, there were no obvious differences in the pharniacokinetic parameters between first and last dosing days with this regimen. Additionally, a progressively drug retention in stomach and drug accretion in blood were only found in rats treated with 160 mg/kg daily for 9 days. These results imply that delayed gastric emptying resulted in AL accumulation in blood and prolonged a neurotoxic exposure time (186 h) in 160 mg/kg rats when compared to that (75 h) in 288 mg/kg animals. Therefore, the drug exposure time is a key factor in the neurotoxicity induced by AL.

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