scholarly journals Pharmacokinetics of Tedizolid in Subjects with Renal or Hepatic Impairment

2014 ◽  
Vol 58 (11) ◽  
pp. 6471-6476 ◽  
Author(s):  
S. Flanagan ◽  
S. L. Minassian ◽  
D. Morris ◽  
R. Ponnuraj ◽  
T. C. Marbury ◽  
...  
Keyword(s):  
Renal Impairment ◽  
Hepatic Impairment ◽  
Peak Concentration ◽  
Matched Control ◽  
Severe Renal Impairment ◽  
Control Group ◽  
Crossover Fashion ◽  
Severe Hepatic Impairment ◽  
Control Subjects ◽  
Before And After

ABSTRACTTwo open-label, single-dose, parallel-group studies were conducted to characterize the pharmacokinetics of the novel antibacterial tedizolid and the safety of tedizolid phosphate, its prodrug, in renally or hepatically impaired subjects. Tedizolid pharmacokinetics in subjects with severe renal impairment without dialysis support was compared with that of matched control subjects with normal renal function. Effects of hemodialysis on tedizolid pharmacokinetics were determined in a separate cohort of subjects undergoing long-term hemodialysis. Effects of hepatic impairment on tedizolid pharmacokinetics were determined in subjects with moderate or severe hepatic impairment and compared with those of matched control subjects with normal hepatic function. Each participant received a single oral (hepatic impairment) or intravenous (renal impairment) dose of tedizolid phosphate at 200 mg; hemodialysis subjects received two doses (separated by 7 days), before and after dialysis, in a crossover fashion. The pharmacokinetics of tedizolid was similar in subjects with severe renal impairment and controls (∼8% lower area under the concentration-time curve [AUC], with a nearly identical peak concentration) and in subjects undergoing hemodialysis before and after tedizolid phosphate administration (∼9% lower AUC, with a 15% higher peak concentration); <10% of the dose was removed during 4 h of hemodialysis. Tedizolid pharmacokinetics was only minimally altered in subjects with moderate or severe hepatic impairment; the AUC was increased approximately 22% and 34%, respectively, compared with that of subjects in the control group. Tedizolid phosphate was generally well tolerated in all participants. These results suggest that tedizolid phosphate dose adjustments are not necessary in patients with any degree of renal or hepatic impairment. (This study has been registered at ClinicalTrials.gov under registration numbers NCT01452828 [renal study] and NCT01431833 [hepatic study].)

The Pharmacokinetics and Safety Of Idelalisib In Subjects With Severe Renal Impairment

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5572-5572 ◽  
Author(s):  
Feng Jin ◽  
Michelle Robeson ◽  
Huafeng Zhou ◽  
Grace Hisoire ◽  
Srini Ramanathan
Keyword(s):  
Renal Impairment ◽  
Oral Dose ◽  
Least Squares ◽  
Matched Control ◽  
Severe Renal Impairment ◽  
Employment Equity ◽  
Control Subjects ◽  
Healthy Control ◽  
Equity Ownership ◽  
Oral Doses

Abstract Abstract 5572 Background Idelalisib (IDELA) is a potent competitive inhibitor of the ATP binding site of the PI3K p110δ catalytic domain, which has been shown to be prominently expressed in cells of hematopoietic origin. Pharmacokinetics of IDELA and its major metabolite GS-563117 have been assessed in a number of clinical studies in healthy subjects and patients with hematologic malignancies. IDELA is metabolized primarily by aldehyde oxidase to form GS-563117 and to a lesser extent by CYP3A and UGT1A4. Based on a human mass balance study, renal elimination plays a minor role on elimination of IDELA (∼ 15% of dose excreted in urine). The objective of the present study was to evaluate the pharmacokinetics and safety of IDELA and GS-563117 in subjects with severe renal impairment following administration of a single oral dose of IDELA. Methods Subjects with severe renal impairment (RI) (eGFR 15 – 29 ml/min) and healthy controls (eGFR ≥ 80 ml/min) matched for age, gender, and body mass index received IDELA 150 mg single dose. Blood and urine samples for IDELA and GS-563117 were collected over 6 days post-dose and were measured using a validated LC/MS/MS method. The ratio and 90% confidence interval of the least squares geometric means of PK exposure parameters in the renal impairment group versus matched controls were calculated, with clinically relevant exposure change defined as ≥ two-fold increase. Safety assessments were performed throughout the study. Results A total of 12 subjects were enrolled in the study. The majority of subjects were female, white, and of nonHispanic/Latino ethnicity, and the median age was similar between the 2 groups (65 years of age for the severe group and 63 years for the healthy control group). Study treatments were generally well tolerated. Overall, 6 of 12 subjects (50.0%; 1 subject with severe renal impairment and 5 healthy matched control subjects) reported a total of 10 AEs; all were Grade 1 (mild) in severity. The most frequently reported AE was headache followed by nausea. No clinically significant abnormal changes were observed in vital signs (temperature, pulse, blood pressure, respiratory rate) and ECG results from baseline. Single oral doses of IDELA 150 mg were well tolerated. Following single oral administration of IDELA 150 mg, IDELA AUClast, AUCinf, and Cmax geometric least-squares mean ratio were 127%, 127%, and 105%, respectively, between subjects with severe renal impairment relative to matched control subjects (Table 1). Consistently, GS-563117 AUClast, AUCinf, and Cmax geometric least-squares mean ratio were 124%, 124%, and 96%, respectively, between subjects with severe renal impairment relative to matched control subjects. These minimal changes observed in IDELA and GS-563117 exposure in severe renal impairment vs matched control subjects are not considered to be clinically meaningful. There were no relevant relationships between IDELA or GS-563117 exposures and baseline estimated creatinine clearance. Conclusion There were no clinically relevant differences in the pharmacokinetics of IDELA or its primary metabolite GS563117 between subjects with severe renal impairment and matched healthy control subjects following a single oral dose of IDELA 150 mg. Dose adjustments for IDELA are not considered necessary in subjects with mild, moderate, or severe renal impairment following oral administration. Single oral doses of IDELA 150 mg were well tolerated. Disclosures: Jin: Gilead Sciences: Employment, Equity Ownership. Robeson:Gilead Sciences: Employment, Equity Ownership. Zhou:Gilead Sciences: Employment, Equity Ownership. Hisoire:Gilead Sciences: Employment, Equity Ownership. Ramanathan:Gilead Sciences: Employment, Equity Ownership.

scholarly journals A Phase I Study to Evaluate the Pharmacokinetics and Safety of Cabotegravir in Adults With Severe Renal Impairment and Healthy Matched Control Participants

2019 ◽  
Vol 8 (5) ◽  
pp. 674-681 ◽  
Author(s):  
Ridhi Parasrampuria ◽  
Susan L. Ford ◽  
Yu Lou ◽  
Caifeng Fu ◽  
Kalpana K. Bakshi ◽  
...  
Keyword(s):  
Renal Impairment ◽  
Phase I ◽  
Phase I Study ◽  
Matched Control ◽  
Severe Renal Impairment

Renal water excretion before and after remission of nephrotic syndrome: Relationship between free water clearance and kidney function, arginine vasopressin, angiotensin II and aldosterone in plasma before and after oral water loading

1986 ◽  
Vol 71 (1) ◽  
pp. 97-104 ◽  
Author(s):  
E. B. Pedersen ◽  
H. Danielsen ◽  
S. S. Sørensen ◽  
B. Jespersen
Keyword(s):  
Nephrotic Syndrome ◽  
Angiotensin Ii ◽  
Arginine Vasopressin ◽  
Free Water ◽  
Control Group ◽  
Ang Ii ◽  
Free Water Clearance ◽  
Water Load ◽  
Control Subjects ◽  
Before And After

1. An oral water load of 20 ml/kg body wt. was given to eight patients with nephrotic syndrome before and after remission of the syndrome, and to 13 healthy control subjects. Urine volume (D), free water clearance (Cwater), plasma concentrations of arginine vasopressin (AVP), angiotensin II (ANG II) and aldosterone (Aldo), were determined before and three times during the first 4 h after loading. 2. D and Cwater increased to a significantly lower level (P < 0.01) after water loading in patients with nephrotic syndrome than in control subjects, but D and Cwater were normal after remission of the syndrome. The maximum increase in Cwater (ΔCwater max.) was 1.07 ml/min (median) before remission and 7.93 ml/min after, compared with 8.01 ml/min in the control group. 3. Creatinine clearance (Ccr) increased significantly after remission (63 ml/min to 88 ml/min, P < 0.01), and the fractional excretion of sodium was enhanced. AVP was higher in the nephrotic syndrome both before (2.9 pmol/l) and after remission (2.9 pmol/l) compared with the control group (1.8 pmol/l). ANG II and Aldo did not change after remission and remained at the same level as in the control group. 4. The elevation in ΔCwatermax after remission was accompanied by an increase in Ccr in all patients and ΔCwatermax. and Ccr were significantly correlated (ρ = 0.600, n = 16, P < 0.05). No relationship was found between the change in ΔCwater max. and ANG II and Aldo. 5. AVP was significantly suppressed in patients with nephrotic syndrome before remission, but not after remission nor in control subjects, so that although AVP did not differ in nephrotic patients before and after remission, AVP cannot be excluded as a contributory factor to the reduction in Cwater in the nephrotic syndrome. 6. It is concluded that patients with nephrotic syndrome excrete an oral water load slower than control subjects and that the excretion rate is normal after remission of the syndrome. It is suggested that the normalization of Cwater may be attributed to an increase in glomerular filtration rate or a decrease in proximal tubular sodium reabsorption, although a possible role for AVP has not been excluded.

Changes in perceptions and emotions before and after refeeding in anorexia nervosa: a pilot study

1994 ◽  
Vol 11 (2) ◽  
pp. 57-63 ◽  
Author(s):  
Sidney H Kennedy ◽  
Randy Katz ◽  
Christine G Ford ◽  
Elizabeth Ralevski
Keyword(s):  
Anorexia Nervosa ◽  
Hospital Treatment ◽  
Control Group ◽  
Food Cravings ◽  
Standard Meal ◽  
Group Of Seven ◽  
Control Subjects ◽  
Before And After ◽  
Patient Groups ◽  
Clinically Significant

AbstractObjective: Physiological and psychological distortions associated with eating are recognised within the syndrome of anorexia nervosa. The purpose of this study was to compare subgroups of restricting and bulimic anorexic patients (AN-R and AN-B) with control subjects, and with themselves after six weeks of refeeding and weight gain, on a series of indices before and after a standard meal. Method: Nineteen consecutively admitted female AN patients completed visual analogue ratings of hunger, satiety, depression, urge to binge, urge to vomit and food craving during the first week and sixth week of hospitalisation. A female control group of seven subjects completed similar ratings for one week. The patient ratings were compared to those of the control subjects at baseline before and after a meal. Further comparisons between the two patient groups were also carried out six weeks after treatment. Results: As expected, AN patients reported significantly higher ratings of depression, urges to vomit, urges to binge and higher satiety levels when compared to controls. Comparisons between the patient subgroups revealed that at baseline AN-B patients had significantly higher urges to vomit that AN-R patients after meals, and reported significantly less satiety both before and after eating. Also, an increase in depression after the meal, at baseline, was reported by both groups although after six weeks higher levels of depression were recorded before rather than after the meal. There was also a significant decrease in food cravings after six weeks compared to baseline for both patient groups.Conclusions: The findings in this study provide further evidence that clinically significant differences exist between subtypes of patients suffering from anorexia nervosa, and highlight the differential, change in various symptoms during intense hospital treatment.

Effects of Renal Impairment on the Pharmacology of Rivaroxaban (BAY 59-7939) - An Oral, Direct, Factor Xa Inhibitor.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 913-913 ◽  
Author(s):  
Atef Halabi ◽  
Haidar Maatouk ◽  
Norbert Klause ◽  
Volkmar Lufft ◽  
Dagmar Kubitza ◽  
...  
Keyword(s):  
Renal Impairment ◽  
Dose Adjustment ◽  
Severe Renal Impairment ◽  
Plasma Concentrations ◽  
Factor Xa ◽  
Direct Factor ◽  
Pharmacokinetics And Pharmacodynamics ◽  
Control Subjects ◽  
Severe Impairment ◽  
Mild Impairment

Abstract Rivaroxaban (BAY 59-7939) is an oral, direct Factor Xa (FXa) inhibitor in advanced clinical development for the prevention and treatment of thromboembolic disorders. It has predictable pharmacokinetics and pharmacodynamics in healthy subjects. Approximately 30% of rivaroxaban is excreted unchanged in the urine; therefore, renal excretion is an important route of elimination. This multicenter study was performed to evaluate the effect of renal impairment on the tolerability, pharmacokinetics, and pharmacodynamics of a single oral 10 mg dose of rivaroxaban. Subjects (N=32) were allocated to one of four groups (matched by age and gender), based on calculated creatinine clearance (CrCL): ≥80 mL/min (control); 50–79 mL/min (mild impairment); 30–49 mL/min (moderate impairment); and <30 mL/min (severe impairment). Rivaroxaban was well tolerated; treatment-emergent adverse events occurred in 62.5% of control subjects, and 12.5%, 12.5%, and 37.5% of those with mild, moderate, and severe renal impairment, respectively. All adverse events were mild to moderate in severity, and resolved by the end of the study. Decreased CrCL led to increased rivaroxaban plasma concentrations: AUC was 44%, 52%, and 64% higher in subjects with mild, moderate, and severe renal impairment, respectively, compared with control subjects (p<0.05); Cmax was relatively unaffected, and tmax was delayed in subjects with CrCL <50 mL/min (3 hours vs 2 hours for control). Renal clearance of rivaroxaban decreased with decreasing renal function; 29% of rivaroxaban was excreted via the urine in control subjects, compared with 20%, 13%, and 10% in those with mild, moderate, and severe renal impairment, respectively. The pharmacodynamic effects of rivaroxaban (inhibition of FXa activity and prolongation of prothrombin time [PT]) were increased with decreasing renal function. The AUC for inhibition of FXa activity increased by 50% (mild impairment), 86% (moderate impairment), and 100% (severe impairment) (p<0.01; Pearson’s correlation coefficient −0.49), and the AUC for prolongation of PT increased by 33%, 116%, and 144%, respectively (p<0.001; correlation −0.56), compared with control. The maximum effects (Emax) of rivaroxaban on inhibition of FXa activity or prolongation of PT did not differ to a relevant extent among the different groups. In conclusion, rivaroxaban plasma concentrations and, as a result, inhibition of FXa activity and prolongation of PT, are inversely correlated with CrCL. In phase II clinical studies of rivaroxaban, patients with mild or moderate renal impairment were included without dose adjustment. However, whether dose adjustment is necessary in patients with renal impairment will require investigation in future clinical trials.

A Pilot Study on the Effect of Rapport on the Task Performance of an Elderly Confused Population

1988 ◽  
Vol 55 (5) ◽  
pp. 255-258 ◽  
Author(s):  
Linda Porszt-Miron ◽  
Majka Florian ◽  
Jean Burton
Keyword(s):  
Task Performance ◽  
Effective Interaction ◽  
Control Group ◽  
Helping Professions ◽  
Group Leaders ◽  
Control Subjects ◽  
Clinical Observations ◽  
Before And After ◽  
Experimental Subjects ◽  
Positive Effect

Rapport has been viewed traditionally by the helping professions as a prerequisite to effective interaction between therapist and patient. Clinical observations indicate that confused elderly residents of a Home for the Aged have the capacity to establish warm personal relationships with their therapists and caregivers. In order to determine if this apparent rapport has a positive effect on task performance, six confused subjects were assigned either to an experimental or control group. They were administered the Picture Identification Task before and after receiving a program designed to establish rapport with their respective leaders. All testing was done by the experimental group leaders. Thus the experimental subjects had rapport with the administrators, while the control subjects did not. The data indicated that experimental subjects decreased their inappropriate behaviours, were able to respond quicker, and made better use of nonverbal test cues at posttest. Control subjects did not demonstrate these changes. It was concluded that rapport can facilitate some task behaviours despite cognitive impairment.

Sex Differences in the Limb Tremor of Morbidly Anxious Patients

1967 ◽  
Vol 113 (504) ◽  
pp. 1265-1266 ◽  
Author(s):  
J. R. G. Carrie
Keyword(s):  
Sex Differences ◽  
Normal Control ◽  
Matched Control ◽  
Control Group ◽  
Normal Male ◽  
Male And Female ◽  
Matched Control Group ◽  
Control Subjects ◽  
The Mean ◽  
Female Subjects

In several previous studies it has been shown that the mean tremor amplitude displayed by morbidly anxious patients is greater than that of normal control subjects. The most detailed experiments were those carried out by Redfearn (1957). He compared the findings obtained in groups of male morbidly anxious patients and controls, and in addition to confirming the existence of a difference in tremor amplitude, he reported that the tremor of male anxious patients showed a greater degree of accentuation of the 8–10 c/sec. components than the tremor of a matched control group. Halliday and Redfearn (1956) compared the tremor spectra obtained from normal male and female subjects, and found that the curve for men was similar to that for women.

The Pharmacokinetics and Safety Of Idelalisib In Subjects With Moderate Or Severe Hepatic Impairment

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5571-5571 ◽  
Author(s):  
Feng Jin ◽  
Michelle Robeson ◽  
Huafeng Zhou ◽  
Grace Hisoire ◽  
Srini Ramanathan
Keyword(s):  
Oral Dose ◽  
Hepatic Impairment ◽  
Healthy Subjects ◽  
Severe Hepatic Impairment ◽  
Employment Equity ◽  
Control Subjects ◽  
Matched Healthy Control ◽  
Healthy Control ◽  
Equity Ownership ◽  
Oral Doses

Abstract Background Idelalisib (IDELA) is a potent competitive inhibitor of the ATP binding site of the PI3K p110s catalytic domain, which has been shown to be prominently expressed in cells of hematopoietic origin. IDELA is metabolized primarily by aldehyde oxidase to form GS-563117 and to a lesser extent by CYP3A and UGT1A4. Based on mass balance study of IDELA, the majority of the radioactive dose administered in healthy subjects was recovered in feces (∼78%).  The objective of the present study was to evaluate the pharmacokinetics and safety of IDELA and GS-563117 in subjects with moderate or severe hepatic impairment following administration of a single oral dose of IDELA. Methods Eligible subjects were enrolled into 2 cohorts that included subjects with moderate or severe hepatic dysfunction as categorized by the ChildPugh-Turcotte (CPT) classification system and healthy controls matched for age, gender, and body mass index. Each subject received a single oral dose of IDELA at 150 mg under fed condition. Blood samples for IDELA and GS-563117 were collected over 6 days post-dose and were measured using a validated LC/MS/MS method. The ratio and 90% confidence interval of the least squares geometric means of PK exposure parameters in the hepatic impairment group(s) versus matched controls were calculated, with clinically relevant exposure change defined as ≥ two-fold increase. Safety assessments were performed throughout the study. Results A total of 32 subjects were enrolled in the study. The majority of subjects were white (87.5%) males (71.9%) and median age was 52 years. Study treatments were generally well tolerated. The majority of the treatment-emergent AEs (TEAE) were assessed as Grade 1 in severity. The only TEAE reported in more than 1 subject was headache (5 subjects overall; 2 subjects with moderate hepatic impairment and 3 healthy subjects). Most treatmentemergent laboratory abnormalities were Grade 1 or 2 in severity. Single oral doses of IDELA 150 mg were well tolerated in subjects with hepatic impairment and in healthy matched controls. IDELA Cmax was generally comparable in the subjects with moderate (CPT Class B) or severe (CPT Class C) hepatic impairment relative to healthy matched control subjects, while mean AUC was higher (58% to 60%). GS-563117 exposures were lower in subjects with moderate and severe hepatic impairment relative to matched healthy control subjects, likely due to lower formation in the setting of liver impairment. Overall, the observed changes in mean exposures of IDELA and GS-563117 are not considered to be clinically relevant. Exploratory analyses indicated no relevant relationships between the IDELA or GS-563117 plasma exposures and CPT score for subjects with moderate or severe hepatic impairment. Conclusion No clinically relevant changes in IDELA and GS-563117 exposures were observed in subjects with moderate or severe hepatic impairment versus matched healthy control subjects. Single oral doses of IDELA 150 mg were well tolerated. Disclosures: Jin: Gilead Sciences: Employment, Equity Ownership. Robeson:Gilead Sciences: Employment, Equity Ownership. Zhou:Gilead Sciences: Employment, Equity Ownership. Hisoire:Gilead Sciences: Employment, Equity Ownership. Ramanathan:Gilead Sciences: Employment, Equity Ownership.

Plasma N-POMC, ACTH and Cortisol Concentrations in a Psychogeriatric Population

1990 ◽  
Vol 156 (5) ◽  
pp. 676-679 ◽  
Author(s):  
A. Leake ◽  
B. G. Charlton ◽  
P. J. Lowry ◽  
S. Jackson ◽  
A. Fairbairn ◽  
...  
Keyword(s):  
Elderly Patients ◽  
Diurnal Variation ◽  
Matched Control ◽  
Cortisol Secretion ◽  
Adrenocorticotrophic Hormone ◽  
Alzheimer Type ◽  
Control Subjects ◽  
Depressed Patients ◽  
Alzheimer Type Dementia ◽  
Before And After

Elderly patients with depression and Alzheimer-type dementia (ATD) were compared with age-matched control subjects using a protocol which measured Cortisol, adrenocorticotrophic hormone (ACTH) and N-terminal pro-opiomelanocortin (N-POMC) to determine diurnal variation and the effect of dexamethasone administration. Depressed patients had significantly elevated Cortisol concentrations both before and after dexamethasone administration. Basal ACTH and N-POMC concentrations were normal in depressed patients but were both elevated, compared with controls, after dexamethasone. By contrast, in ATD patients, Cortisol was elevated only after dexamethasone, as was ACTH, but not N-POMC. This may imply that the pattern of secretion of POMC-derived peptides underlying increased Cortisol secretion is different in ATD from that in depression.

scholarly journals Movement strategies for maintaining standing balance during arm tracking in people with multiple sclerosis

2014 ◽  
Vol 112 (7) ◽  
pp. 1656-1666 ◽  
Author(s):  
Matthew C. Chua ◽  
Allison S. Hyngstrom ◽  
Alexander V. Ng ◽  
Brian D. Schmit
Keyword(s):  
Multiple Sclerosis ◽  
Matched Control ◽  
Berg Balance Scale ◽  
Control Group ◽  
Dominant Hand ◽  
Balance Performance ◽  
Kinetic Measurements ◽  
Control Subjects ◽  
Movement Strategies ◽  
Arm Tracking

The purpose of this study was to quantify hip and ankle movement strategies during a standing arm tracking task in people with multiple sclerosis (MS). Full-body kinematics and kinetics were assessed with motion analysis cameras and force plates in nine MS and nine age-matched control subjects. While standing, participants used their dominant hand to track a target moving around a large horizontal or vertical figure eight on a screen in front of them. The target moved at constant speed, or linearly increasing speeds, with a frequency between 0.05 Hz and 0.35 Hz. Hip and ankle moments and angles during tracking were calculated from kinematic and kinetic measurements. Ratios of peak-to-peak (PP) hip/ankle moments (kinetics) and angles (kinematics) were calculated to determine the strategies of the hips and ankles used to maintain balance during arm movements. Center of mass (CoM) root mean square (RMS) acceleration was calculated as a measure of overall balance performance. The MS group produced larger PP hip/ankle moments at all speeds compared with the control group ( P < 0.05). The CoM RMS acceleration increased with tracking speed for both groups but was not significantly different between groups. Additionally, the ratios of hip to ankle moments were highly correlated with the Berg Balance Scale during horizontal steady-speed tracking in MS. These results suggest that people with MS increase the use of the hip during standing arm tracking compared with age-matched control subjects. This adapted strategy might allow people with MS to achieve balance performance similar to control subjects, possibly increasing the importance of the hip in maintaining balance during voluntary movements.

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