Estimating a drug’s elimination rate-constant or half-life from a single blood sample: a practical approach with particular benefits for critically ill/vulnerable patients

The present investigation addresses the pharmacokinetics of human chorionic gonadotropin (hCG), intramuscularly (i.m.) administered to goats. Nine pluriparous does of the Boer goat breed, 2–6 years of age and weighing 45–60 kg, were administered 500 IU hCG (2 ml Chorulon) deep into the thigh musculature 18 h after superovulatory FSH treatment. Blood samples were drawn from the jugular vein at 2 h intervals for the first 24 h, at 6 h intervals until 42 h, and at 12 h intervals until 114 h after administration. After centrifugation, plasma hCG concentrations were determined by electrochemiluminescence immunoassay. Pharmacokinetical parameters were as follows: lag time, 0.4 (s.e.m. 0.1) h; absorption rate constant, 0.34 (s.e.m. 0.002) h; absorption half-life, 2.7 (s.e.m. 0.5) h; elimination rate constant, 0.02 (s.e.m. 0.002) h; biological half-life, 39.4 (s.e.m. 5.1) h; and apparent volume of distribution, 16.9 (s.e.m. 4.3) l. The plasma hCG profile was characterized by an absorption phase of 11.6 (s.e.m. 1.8) h and an elimination phase of 70.0 (s.e.m. 9.8) h, with considerable individual variation in bioavailability and pharmacokinetical parameters. Biological half-life was negatively correlated (P<0.05) with peak concentration (r=−0.76), absorption rate constant (r=−0.78), and elimination rate constant (r=−0.87). The results indicate that after rapid absorption, hCG remains in the circulation for an extended period. This has to be taken into account when assessing the stimulatory response to hCG treatment on an ovarian level.

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Propranolol Plasma Concentrations and Plasmapheresis

Drug Intelligence & Clinical Pharmacy ◽

10.1177/106002808101501215 ◽

1981 ◽

Vol 15 (12) ◽

pp. 993-996 ◽

Cited By ~ 17

Author(s):

Robert L. Talbert ◽

Yan Yan Wong ◽

Douglas B. Duncan

Keyword(s):

Hemolytic Uremic Syndrome ◽

Rate Constant ◽

Half Life ◽

Plasma Concentrations ◽

Elimination Rate ◽

Elimination Rate Constant ◽

Before And After ◽

Uremic Syndrome ◽

The Mean

Propranolol plasma concentrations were determined in a patient with hemolytic-uremic syndrome undergoing plasmapheresis before and after the procedure on three occasions. The mean half-life and elimination rate constant during plasmapheresis were estimated to be 25.6 percent of the values obtained without plasmapheresis. These changes suggest that plasmapheresis may influence propranolol disposition.

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Pharmacokinetics of Caspofungin in Critically Ill Patients in Relation to Liver Dysfunction: Differential Impact of Plasma Albumin and Bilirubin Levels

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02466-18 ◽

2019 ◽

Vol 63 (6) ◽

Cited By ~ 7

Author(s):

S. Kurland ◽

M. Furebring ◽

E. Löwdin ◽

E. Eliasson ◽

E. I. Nielsen ◽

...

Keyword(s):

Liver Function ◽

Critically Ill ◽

Rate Constant ◽

Negative Correlation ◽

Critically Ill Patients ◽

Elimination Rate ◽

Liver Function Tests ◽

Elimination Rate Constant ◽

Minimal Inhibitory Concentrations ◽

Function Tests

ABSTRACT Caspofungin has a liver-dependent metabolism. Reduction of the dose is recommended based on Child-Pugh (C-P) score. In critically ill patients, drug pharmacokinetics (PK) may be altered. The aim of this study was to investigate the prevalence of abnormal liver function tests, increased C-P scores, their effects on caspofungin PK, and whether pharmacokinetic-pharmacodynamic (PK/PD) targets were attained in patients with suspected candidiasis. Intensive care unit patients receiving caspofungin were prospectively included. PK parameters were determined on days 2, 5, and 10, and their correlations to the individual liver function tests and the C-P score were analyzed. Forty-six patients were included with C-P class A (n = 5), B (n = 40), and C (n = 1). On day 5 (steady state), the median and interquartile range for area under the curve from 0 to 24 h (AUC0–24), clearance (CL), and central volume of distribution (V1) were 57.8 (51.6 to 69.8) mg·h/liter, 0.88 (0.78 to 1.04) liters/h, and 11.9 (9.6 to 13.1) liters, respectively. The C-P score did not correlate with AUC0–24 (r = 0.03; P = 0.84), CL (r = −0.07; P = 0.68), or V1 (r = 0.19; P = 0.26), but there was a bilirubin-driven negative correlation with the elimination rate constant (r = −0.46; P = 0.004). Hypoalbuminemia correlated with low AUC0–24 (r = 0.45; P = 0.005) and was associated with higher clearance (r = −0.31; P = 0.062) and somewhat higher V1 (r = −0.15; P = 0.37), resulting in a negative correlation with the elimination rate constant (r = −0.34; P = 0.042). For Candida strains with minimal inhibitory concentrations of ≥0.064 μg/ml, PK/PD targets were not attained in all patients. The caspofungin dose should not be reduced in critically ill patients in the absence of cirrhosis, and we advise against the use of the C-P score in patients with trauma- or sepsis-induced liver injury.

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A microcomputer program to determine the precision of elimination rate constant and half-life estimates when sampling time is short

Fundamental and Clinical Pharmacology ◽

10.1111/j.1472-8206.1993.tb00223.x ◽

1993 ◽

Vol 7 (2) ◽

pp. 103-108

Author(s):

JP Guédès ◽

W. Couet

Keyword(s):

Rate Constant ◽

Half Life ◽

Elimination Rate ◽

Sampling Time ◽

Elimination Rate Constant ◽

Microcomputer Program

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Theoretical consideration for the cases where absorption rate constant approaches elimination rate constant in the linear one-compartment open models

International Journal of Pharmaceutics ◽

10.1016/0378-5173(82)90106-5 ◽

1982 ◽

Vol 12 (4) ◽

pp. 351-354 ◽

Cited By ~ 6

Author(s):

M. Barzegar-Jalali ◽

M. Toomanian

Keyword(s):

Rate Constant ◽

Theoretical Consideration ◽

Absorption Rate ◽

Elimination Rate ◽

Elimination Rate Constant ◽

Absorption Rate Constant

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Semiparametric approach to pharmacokinetic-pharmacodynamic data

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1989.256.4.r1005 ◽

1989 ◽

Vol 256 (4) ◽

pp. R1005-R1010

Author(s):

D. Verotta ◽

S. L. Beal ◽

L. B. Sheiner

Keyword(s):

Steady State ◽

Rate Constant ◽

Drug Concentration ◽

Venous Blood ◽

Time Lag ◽

Elimination Rate ◽

Hysteresis Loops ◽

Real Data ◽

Elimination Rate Constant ◽

Arterial Blood

A semiparametric model for analysis of pharmacokinetic (PK) and pharmacodynamic (PD) data arising from non-steady-state experiments is presented. The model describes time lag between drug concentration in a sampling compartment, e.g., venous blood (Cv), and drug effect (E). If drug concentration at the effect site (Ce) equilibrates with arterial blood concentration (Ca) slower than with Cv, a non-steady-state experiment yields E vs. Cv data describing a counterclockwise hysteresis loop. If Ce equilibrates with Ca faster than with Cv, clockwise hysteresis is observed. To model hysteresis, a parametric model is proposed linking (unobserved) Ca to Cv with elimination rate constant kappa ov and also linking Ca to Ce with elimination rate constant kappa oe. When kappa oe is greater than (or less than) kappa ov clockwise (or counterclockwise) hysteresis occurs. Given kappa oe and kappa ov, numerical (constrained) deconvolution is used to obtain the disposition function of the arterial compartment (Ha), and convolution is used to calculate Ce given Ha. The values of kappa oe and kappa ov are chosen to collapse the hysteresis loops to single curves representing the Ce-E (steady-state) concentration-response curve. Simulations, and an application to real data, are reported.

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Cefamandole Distribution in Serum, Adipose Tissue, and Wound Drainage in Morbidly Obese Patients

Drug Intelligence & Clinical Pharmacy ◽

10.1177/106002808602001109 ◽

1986 ◽

Vol 20 (11) ◽

pp. 869-873 ◽

Cited By ~ 20

Author(s):

Henry J. Mann ◽

Henry Buchwald

Keyword(s):

Adipose Tissue ◽

Rate Constant ◽

Subcutaneous Adipose Tissue ◽

Elimination Rate ◽

Elimination Rate Constant ◽

Morbidly Obese ◽

Obese Patients ◽

Tissue Concentrations ◽

Wound Drainage ◽

Subcutaneous Adipose

Distribution and elimination of cefamandole 2 g iv were studied in 11 morbidly obese patients during a gastric bypass operation and again on the first postoperative day. Serum, subcutaneous adipose tissue, wound drainage, and urine were analyzed by high performance liquid chromatography for cefamandole and pharmacokinetic parameters from the intraoperative period were compared to those obtained postoperatively. Total body clearance was significantly greater (p < 0.001) postoperatively (297 ml/min) than intraoperatively (254 ml/min). Volume changes were unpredictable but the elimination rate constant tended to increase postoperatively. Renal clearance and percentage of urinary recovery were significantly increased (p < 0.01) postoperatively. The patients had a mean (± SD) volume of the central compartment of 10.3 (± 2.3) L, volume at steady state of 18.3 (± 3.9) L, and elimination rate constant of 1.67 (± 0.63) h−1. Tissue concentrations of cefamandole were highest during the first hour after drug administration and were < 1 μg/g after 3.5 hours. Mean wound drainage concentrations ranged between 10 and 12 μg/ml during a dosing interval and dropped to 7 μg/ml 12 hours after the last dose. Intraoperative dosing of cefamandole is required to maintain subcutaneous adipose tissue concentrations > 1 μg/g during procedures longer than three hours in morbidly obese patients. A postoperative dose of cefamandole 2 g iv q6h will provide sustained and therapeutic concentrations in the wound drainage of morbidly obese patients.

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Pharmacokinetics of Intermittent Intraperitoneal Cefazolin in Continuous Ambulatory Peritoneal Dialysis Patients

Peritoneal Dialysis International ◽

10.1177/089686089901900111 ◽

1999 ◽

Vol 19 (1) ◽

pp. 65-70 ◽

Cited By ~ 28

Author(s):

Harold J. Manley ◽

George R. Bailie ◽

Rupesh D. Asher ◽

George Eisele ◽

Reginald F. Frye

Keyword(s):

Body Weight ◽

Peritoneal Dialysis ◽

Continuous Ambulatory Peritoneal Dialysis ◽

Rate Constant ◽

Half Life ◽

Elimination Rate ◽

Pharmacokinetic Parameters ◽

Number Of Patients ◽

The Mean ◽

Concentration Levels

Objective To investigate the pharmacokinetic parameters of intermittent intraperitoneal (IP) cefazolin, and recommend a cefazolin dosing regimen in continuous ambulatory peritoneal dialysis (CAPD) patients. Design Prospective nonrandomized open study. Setting CAPD outpatient clinic in Albany, New York. Patients Seven volunteer CAPD patients without peritonitis. Three of the patients were nonanuric while 4 were anuric. Interventions Cefazolin (15 mg/kg total body weight) was given to each patient during the first peritoneal exchange. Blood and dialysate samples were collected at times 0, 0.5, 1, 2, 3, 6 (end of the first antibiotic-containing dwell), 24, and 48 hours after the administration of IP cefazolin. Urine samples were collected in nonanuric patients over the study period. Results The mean ± SD amount of cefazolin dose absorbed from the dialysate after the 6-hour dwell was 69.7% ± 8.0% of the administered dose. The cefazolin absorption rate constant from dialysate to serum was 0.21 ± 0.1 /hr (absorption half-life 3.5 ± 0.8 hr). The mean serum concentrations reached at 24 and 48 hours were 52.4 ± 3.7 mg/L and 30.3 ± 5.9 mg/L, respectively. The mean dialysate cefazolin concentrations reached at 24 and 48 hours were 15.1 ± 3.4 mg/L and 7.9 ± 1.4 mg/L, respectively. The cefazolin serum elimination rate constant was 0.02 ± 0.01 /hr (elimination half-life 31.5 ± 8.8 hr). The total cefazolin body clearance was 3.4 ± 0.6 mL/min. In the 3 nonanuric patients the mean renal clearance of cefazolin was 0.6 ± 0.4 mL/min. The peritoneal clearance of cefazolin was 1.0 ± 0.3 mL/min. The systemic volume of distribution of cefazolin was 0.2 ± 0.05 L/kg. No statistical difference was detected in pharmacokinetic parameters between anuric and nonanuric patients, although this may be due to the small number of patients in each group. Conclusion A single daily dose of cefazolin dosed at 15 mg/kg actual body weight in CAPD patients is effective in achieving serum concentration levels greater than the minimum inhibitory concentration for sensitive organisms over 48 hours, and dialysate concentration levels over 24 hours. Caution is warranted in extrapolation of dosing recommendations to patients who maintain a significant degree of residual renal function.

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Kinetic simulation method of C-reactive protein in beagle dogs during acute inflammation

European Journal of Inflammation ◽

10.1177/1721727x17712048 ◽

2017 ◽

Vol 15 (2) ◽

pp. 120-123

Author(s):

Takashi Kuribayashi

Keyword(s):

Rate Constant ◽

Inflammatory Responses ◽

Elimination Rate ◽

Simulation Method ◽

Elimination Rate Constant ◽

Enzyme Linked Immunosorbent Assay ◽

Serum Concentrations ◽

Beagle Dogs ◽

C Reactive Protein ◽

Reactive Protein

The half-life ( t1/2) of C-reactive protein (CRP) and its ability to stimulate weak inflammatory responses were investigated in beagle dogs. Four beagle dogs were administered 20 mg/kg indomethacin and blood was collected from the cephalic vein pre-dosing and at 24, 48, 72, 96, 144, 192, 240, 312, and 360 h post-administration. The serum concentrations of CRP were measured by enzyme-linked immunosorbent assay. The serum t1/2 was calculated using the equation 0.693/elimination rate constant. The serum concentration of CRP beyond 192 h post-administration declined to levels in the normal range. The t1/2 was 148.3 h, which is considered to be the essential t1/2 of CRP. The simulation of CRP serum concentrations at arbitrary times using the elimination rate constant obtained in this study became possible.

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