Netilmicin Pharmacokinetics After Single Intravenous Doses to Elderly Male Patients

Abstract

The pharmacokinetics of the new aminoglycoside antibiotic netilmicin were examined after single intravenous injections at two different dose levels to elderly male patients. The drug obeyed two-compartment model kinetics in serum, and elimination was monoexponential from 1 to 2 h after dosing. Netilmicin levels in serum were above minimum inhibitory concentration values for most susceptible organisms for up to 8 h after dosing in normal individuals and for at least 12 h in uremic patients. Urine levels of netilmicin were uniformly above minimum inhibitory concentration values throughout 24 h after dosing. Netilmicin distribution characteristics were largely independent of both dose level and renal function. Netilmicin elimination kinetics were independent of dose level but were markedly influenced by renal function. Relationships are described between netilmicin elimination and renal function indicators, which provide a basis for dosage adjustment in individuals with renal function impairment.Netilmicin, the 1-N-ethyl derivative of sisomicin, is a new aminoglycoside which is effective against gram-negative bacteria, including strains resistant to gentamicin, sisomicin, and tobramycin (5,6,9).In a previous study at this institution, netilmicin was shown to be clinically effective and free from toxic side effects when given intramuscularly to elderly male patients at doses of 1.0 to 2.5 mg/kg every 8 h for 7 days (A. Baumueller and P. 0. Madsen, submitted for publication). A preliminary study in a similar patient population showed that after rapid intravenous irjection, netilmicin had a serum halflife of about 4.5 h, and the half-life was linearly related to serum creatinine (Baumueller and Madsen, submitted for publication).Here we report on the pharmacokinetics of netilmicin after single intravenous doses to elderly male patients with normal and impaired renal function. MATERIALS AND METHODSSubjects and protocols. Subjects were 42 patients in the urology ward of the Veterans Administration Hospital, Madison, Wis. Details of subjects' ages, weights, creatinine clearances, and serum creatinine values are described in Table 1. Almost all of the patients were suffering from lower urinary tract obstruction, infections associated with lower urinary tract obstruction, urethral stricture, carcinoma or hyperplasia of the prostate, or bladder tumor. Some patients had indwelling bladder catheters; most of them were not bedridden during the study.For analysis, patients were divided into three groups based on creatinine clearances. Groups 1, 2 and 3 had creatinine clearances greater than 100 ml/ min, between 50 and 100 ml/min, and less than 50 ml/min, respectively. Creatinine clearances were obtained from 12-h urine collections, except in the case of some severely uremic patients where 24-h urine clearances were obtained. Patients received netilmicin by rapid intravenous injection into a forearm vein at dose levels of 1 or 2 mg/kg. The injection was administered in 5 ml of physiological saline, and the injection time was 2 m...

Quantitative Structure – Pharmacokinetics Relationships Analysis of Basic Drugs: Volume of Distribution

“…The VD ss value of netilmicin in the Obach's database (5) is 0.073 L/kg. However, the value in the original reference is 0.2 -0.3 L/kg (36) which is close to our prediction of 0.42 L/kg. An even higher value of 0.68 L/kg was announced by Wenk et al (37).…”

Pharmacokinetic Properties of Netilmicin in Newborn Infants

“…The average terminal half-life of 62.4 h is within the range determined for gentamicin by Schentag et al (25). This value is somewhat longer than that found after single-dose studies with netilmicin (17,30) and may be explained by our ability to measure serum concentrations as low as 0.02 ,ug/ml by utilizing the well diffusion assay technique. In spite of this long terminal half-life and tissue accumulation, dosing intervals of two to three times the half-life appear to be appropriate for most neonates.…”

“…To our knowledge, two-compartment model pharmacokinetics have not been applied to aminoglycosides in the neonate, although there have been reports of this model for netilmicin (17,20,30), sisomicin (20), tobramycin (20), and gentamicin (3,25) in adults and older children. We analyzed the serum concentrations obtained during the steady state by both the one-and two-compartment models and found that the former model provided the best fit.…”

“…We have also measured netilmicin in serum and/or urine for as long as 12 days after discontinuation of therapy and have fit these data to a two-compartment model as has been described for aminoglycosides in older children and adults (3,17,20,25,30).…”

Clinical Pharmacokinetics, Toxicity and Cost Effectiveness Analysis of Aminoglycosides and Aminoglycoside Dosing Services

“…The approximate half-lives of the aminoglycosides in patients with normal renal function are: gentamicin 2-4 h (1315), tobramycin 2-3 h (2, 16), amikacin 2-4 h (2,8) and netilmicin 2-3 h (17,18).…”