Pharmacokinetics of intravenous amdinocillin in healthy subjects and patients with renal insufficiency

Abstract

Five healthy volunteers and 31 patients with various degrees of renal impairment received a 10-mg/kg intravenous dose of amdinocillin by infusion over 15 min to establish the disposition profile of the drug in plasma and urine. Both clearance from plasma and elimination rate constant showed a linear relationship with creatinine clearance. It was noted that in subjects with creatinine clearances of greater than 50 ml/min, the elimination half-life remained relatively constant; however, as the creatinine clearance decreased from 50 to 5 ml/min, there was a progressive rise in the elimination half-life. Despite the removal of the drug by hemodialysis (32 to 72% of the dose), concentrations of amdinocillin in plasma remained in the therapeutic range. In patients undergoing peritoneal dialysis, less than 4.0% of the infused dose was removed by dialysis during the hourly exchanges over a 14-to 18-h period. Although the clearance from plasma and the half-life of amdinocllin were altered up to fourfold in patients with creatinine clearances of less than 15 ml/min, the amdinocillin dosage per se may not need to be reduced for these patients if the frequency of dosing is reduced from six to three or four times daily. This is based on drug accumulation estimates of 56% from a regimen of 10 mg/kg every 8 h in these patients as compared with less than 10% from a regimen of 10 mg/kg every 4 h in subjects with normal renal function. In addition, supplemental doses may not be necessary during or at the end of hemodialysis for patients undergoing hemodialysis.Amdinocillin (also known as mecillinam) (recently approved by the Food and Drug Administration for clinical use and soon to be available under the trade name of Coactin) is an amdino penicillinate (6) which is active against a broad range of gram-negative bacteria and acts synergistically with other ,B-lactam antibiotics (2, 9, 12, 13). The pharmacokinetics of amdinocillin in healthy human volunteers have been defined by several investigators (3,4,7,8,10). According to these studies, amdinocillin has a relatively short elimination half-life (t1/20; 47 to 59 min), a small volume of distribution (V; 0.22 to 0.53 liter/kg), and a low clearance from plasma (CLp; 3.0 to 5.3 ml/min per kg). In addition, the fraction of a dose of amdinocillin excreted unchanged in urine (fe) is 50 to 70%, whereas biliary excretion and metabolism represent two minor pathways of elimination for amdinocillin in humans. Preliminary studies, which were limited to patients with severe-to-end-stage renal insufficiency, have shown that t1/2P of amdinocillin is prolonged in such patients (1, 11).

Pharmacokinetics of ticarcillin and clavulanic acid (timentin) in relation to renal function

“…Various pharmacokinetic parameters of ticarcillin and clavulanic acid determined in this study (Tables 1 and 2) were similar to values reported in subjects with normal or impaired renal function (1-3, 6, 14 (8), cefotaxime (11), and amdinocillin (15). The reason for this is not known, but it may be the result of changes in hepatic or biliary function secondary to the presence of renal malfunction undetectable by typical nonspecific clinical evaluations of liver enzymes and blood chemistries.…”

“…The C ,s values showed greater variability because of the additional dependence of the terminal slope on renal and metabolic clearances. However, the C X and C 15 values were similar at all levels of renal function, confirming the suitability of the dosage recommendations based on extending T to attain similar Cmax and Cmjn, as well as equal AUC values. This also indicates that, to whatever extent the 30:1 ratio of ticarcillin:clavulanic acid is effective in patients with normal renal function, the same ratio will be maintained over the dosage interval as renal function lessens.…”

“…Venous blood samples (3 to 5 ml) were drawn into lithium heparin tubes from the arm contralateral to that used for drug administration. Samples were taken before drug infusion and at 5,10,15,20,30, and 40 min and 1, 2, 3, 4, 6, 8, and 12 h after infusion from subjects with CLCR of >60 ml min-1. Additional samples were taken at 10, 24, and 36 h (excluding the 12-h sample) from subjects with CLCR of <60 ml min-'.…”

Removal of Doripenem During Hemodialysis and the Optimum Dosing Regimen for Patients Undergoing Hemodialysis

“…In this study, the RDD was calculated to be 56.12 ± 8.11%. With other β‐lactam antibiotics, the RDD ranged from 46–53% for hemodialysis for 4–6 h (12–19). The RDDs for imipenem and meropenem in particular, which are carbapenem antibiotics like doripenem, were reported to be 54.8% (20) and 52% (21), respectively.…”

Pharmacokinetic/Pharmacodynamic Determination of Systemic MIC Breakpoints for Intermittent, Extended, and Continuous Infusion Dosage Regimens of Mecillinam

“…Previous studies have presented PK parameters and excretion characteristics of mecillinam after i.v. administration in healthy subjects ( 4 , 8 , 15 ). According to their findings, mecillinam has a relatively short elimination half-life, a small volume of distribution, and a low clearance from plasma.…”