Klaus Stoeckel

Effects of concentration‐dependent plasma protein binding on ceftriaxone kinetics

The kinetics of ceftriaxone, a cephalosporin, was studied in six healthy subjects who received bolus injections of 150, 500, and 1,500 mg intravenously in a random crossover fashion. Although total drug concentration time profiles after all doses could be described by biexponential equation, simple compartment analysis was inappropriate because a disproportional increase in the area under the total drug concentration time curves occurred with dose. This resulted in a dose‐dependent increase in total systemic clearance (ClTS) from 9.7 ml/min at the 150‐mg dose to 13 ml/min at the 1500‐mg dose. The dose‐dependent changes in ClTS could be explained in terms of the concentration‐dependent plasma protein binding of ceftriaxone (fplasma ranging from 0.04 to 0.167), because the area under the free drug concentration time curves (AUCF0–∞) increased proportionately to dose. Mean total clearance with reference to free (unbound) ceftriaxone (CIFR) was constant at 255 ml/min. Calculated mean renal clearance with reference to free ceftriaxone (CIFR) was 173 ml/min, or slightly more than the average glomerular filtration rate in humans. Mean plasma ceftriaxone t½ was not influenced by dose and averaged 8 hr. This biologic t½ is by far the longest ever for a cephalosporin in healthy subjects.

Pharmacokinetics of Rocephin®, a Highly Active New Cephalosporin with an Exceptionally Long Biological Half-Life

The total (bound and unbound) plasma concentration time profiles following the three intravenous doses of Rocephin (150, 500 and 1,500 mg) declined in a biphasic manner. A simple compartment analysis was inappropriate since a dose-disproportional increase in the area under the total drug concentration time curve (AUCT,0(-8)) occurred. This resulted in unstable, dose-dependent total systemic clearance (9.7-13.0 ml/min) and volume of distribution (7.0-8.6 litres) values. The dose-dependent pharmacokinetic changes could be completely explained in terms of the concentration-dependent plasma protein binding (fp ranging from 0.04 to 0.17 in the concentration range from 0.5 to 300 micrograms/ml). Hence, the pharmacokinetics of free (unbound) Rocephin was linear and dose-independent. With reference to free (unbound) drug the mean total clearance was 255 ml/min and the mean renal clearance about 160 ml/min. The renal clearance was therewith slightly higher than the average glomerular filtration rate in man (approximately 125 ml/min). Consequently the coadministration of probenecid (1 g) had no effect on the pharmacokinetics of Rocephin. The mean plasma half-life of Rocephin was not influenced by dose and averaged 8 h. It was therewith the longest ever reported one for a cephalosporin in healthy volunteers.

Pharmacokinetics of ceftriaxone following intravenous administration of a 3 g dose

SummaryThe pharmacokinetic parameters of total (bound and unbound) and free (unbound) ceftriaxone in six healthy volunteers after intravenous injection of 39 were compared with low-dose data from a previous study. The dose-dependent behaviour of total drug was considerably more pronounced after the 3 gram dose. In contrast, total body clearance (ClSF=258 ml/min), renal clearance (ClRF=170 ml/min) and volume of distribution (VD(β)F=168 l) of free (unbound) drug did not differ from the data reported earlier. There was no significant change in biological half-life (t1/2(β)=7.8 h) or in the fraction excreted unchanged in urine (fu=0.67).

Age-associated changes in ceftriaxone pharmacokinetics.

SummaryCeftriaxone pharmacokinetic parameters were compiled from recent publications. The subjects (27 female, 93 male) were from 1 day to 92 years old and appeared to have normal renal and hepatic function. In 1- to 8-day-old neonates, the half-life averaged 19 hours; it declined to 6.3 hours in 1- to 6-year-old subjects and then increased gradually throughout the remainder of the life-span to 14 hours in 75- to 92-year-old subjects. The age-associated changes in half-life appeared to result from changes in systemic clearance. The fraction of the dose eliminated renally averaged 70% in neonates and declined throughout childhood to 40 to 60% in adults, in whom it was age invariant. No clinically significant differences between males and females were detected in ceftriaxone kinetic parameter values. Plasma protein binding of ceftriaxone (100 mg/L) was about 70% in neonates and it increased throughout childhood to the adult value of 90 to 95%. To achieve a given free concentration of ceftriaxone, the same dosage per unit surface area can be used for children and adults, provided glomerular filtration and biliary secretion function are normal for age. Dosage should be reduced by as much as a factor of 5 in neonates less than 1 week of age and perhaps by a factor of 2 in the very old.

Ceftriaxone binding to human serum albumin: Indirect displacement by probenecid and diazepam

In vitro protein binding studies were conducted to examine the interaction between ceftriaxone (CEF), probenecid (PROB) and diazepam (DIAZ). The presence of PROB and DIAZ at concentrations equal to molar albumin concentration caused a decrease in CEF affinity from 3.7 x 10(4) M-1 (control) to 1.1 x 10(4) (PROB) and 2.6 x 10(4) (DIAZ) M-1, but not in binding capacity in pooled human plasma. PROB and DIAZ at five times the molar albumin concentration also caused a decrease in CEF affinity from 4.5 x 10(4) M-1 (control) to 0.45 x 10(4) (PROB) and 3.0 x 10(4) (DIAZ) M-1 in isolated human serum albumin. DIAZ and PROB displaced one another, confirming their common binding site (Site II, the benzodiazepine site) on serum albumin. By contrast, CEF was unable to displace either PROB or DIAZ from defatted albumin. In the presence of elevated free fatty acid concentrations (four times the albumin concentration), CEF decreased the binding of both drugs. CEF free fraction (fp) in isolated human serum albumin (CEF fp = 7.7%) was increased by drugs which bind to Site I: sulfisoxazole (CEF fp = 68.1%), warfarin (CEF fp = 56.0%) and furosemide (CEF fp = 55.0%). At ten times the molar concentration of albumin, CEF displaced both warfarin (warfarin fp from 0.99 to 2.20%) and phenytoin (phenytoin fp from 17.7 to 23.4%) from defatted albumin. CEF appeared to bind to Site I (the warfarin site) on human serum albumin, and was displaced by PROB and DIAZ via a mechanism which did not involve direct competition at a common binding site.

Volume of distribution terms for a drug (ceftriaxone) exhibiting concentration-dependent protein binding I. Theoretical considerations

SummaryWe have theoretically examined the influence of plasma protein binding (specifically the fraction unbound, fp) on the pharmacokinetic parameters following rapid injection of a drug undergoing concentration-dependent binding. Particular emphasis was placed on the apparent volume of distribution terms based on both total and unbound drug concentrations. Computer simulations were performed to establish the validity and utility of such relationships. The following observations were made: a) distributional parameters based on total drug (both Vβ and the model-independent VSS) were inaccurate/invalid; b) Vβ based on unbound drug was misleading; c) the model-independent VSS for unbound drug accurately predicted the steady state situation. Furthermore, two new terms (

Single‐dose ceftriaxone kinetics in functionally anephric patients

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Effect of probenecid on the elimination and protein binding of ceftriaxone

and