Pharmacokinetics of intravenous cefetamet and oral cefetamet pivoxil in patients with renal insufficiency

Abstract

The pharmacokinetics of cefetamet after a short intravenous infusion of cefetamet (515 mg) and oral administration of 1,000 mg of cefetamet pivoxil were studied in 9 healthy subjects and in 38 patients with various degrees of renal impairment. The results showed that cefetamet elimination was dependent on renal function. After intravenous dosing, total body (CLs), renal (CLR), and nonrenal (CLNR) clearances were linearly related to creatinine clearance (CLCR; r = 0.95, 0.92, and 0.59, respectively). Elimination half-life (t112^) was prolonged from 2.46 ± 0.33 h in normal subjects to 29.1 13.9 h in patients with CLCR of <10 ml/min per 1.73 i2. Correspondingly, CLs and CLR decreased from 1.77 0.27 and 1.42 0.25 mI/mi per kg to 0.14 + 0.04 and 0.04 + 0.03 ml/min per kg, respectively. The volume of distribution at steady state (0.298 0.049 liter/kg) for cefetamet was not altered by renal insufficiency (P > 0.05). After oral administration, the elimination parameters, tl/2,, and CLR, were insignificantly different from the intravenous data (P > 0.05).Furthermore, the bioavailability (F) of cefetamet pivoxil (45 13%) was not altered by renal failure (P > 0.05). However, maximum concentration in plasma and the time to achieve this value were significantly increased (5.86 0.74 versus 14.8 6.14 ,ug/ml and 3.9 ± 1.1 versus 8.4 1.7 h, respectively; P < 0.05).Based on these observations, it is recommended that patients with CLCR of <10 ml/min per 1.73 m2 and between 10 and 39 ml/min per 1.73 m2 be given one-quarter of the normal daily dose either once or twice daily.Patients with CLCR between 40 and 80 ml/min per 1.73 m2 should receive one-half of the normal dose twice daily. For patients with CLCR of <10 ml/min per 1.73 m2, it would be recommended that they receive a normal standard dose as a loading dose on day 1 of treatment.Cefetamet pivoxil is the prodrug (pivaloyloxymethylester) of a new broad-spectrum cephalosporin antibiotic, cefetamet. This compound possesses a broad spectrum of antimicrobial activity against many aerobic gram-positive and gram-negative organisms (19). Previous pharmacokinetic studies in normal healthy volunteers revealed that the lowprotein-bound (22%) cefetamet is mainly eliminated by the kidneys via glomerular filtration (2, 12). This kinetic behavior is similar to that of other P-lactam antibiotics with low protein binding and high urinary recovery (e.g., carumonam [11], ceftizoxime [1,15], and ceftazidime [1,15]). Consequently, the pharmacokinetics of cefetamet are expected to be dependent on changes in renal function.The objectives of this study were to determine the pharmacokinetics of cefetamet and cefetamet pivoxil after intravenous and oral administration to patients with various degrees of impaired renal function, to compare these results with those obtained from healthy volunteers who have normal renal functions, and to determine dosage guidelines for patients with renal impairment. MATERIALS AND METHODSSubjects. Nine healthy volunteers (7 men and 2 women) and 38 patients (22 men and ...

Pharmacokinetics of intravenous cefetamet and oral cefetamet pivoxil in children

“…dose, there was a linear relationship between CLR and creatinine clearance (Fig. 3), as expected for a drug eliminated by glomerular filtration and as reported previously for cefetamet (9). The correlation between CLR and creatinine clearance (Fig.…”

“…The correlation between CLR and creatinine clearance (Fig. 3) was 0.86, which was smaller than that observed for adults (9). The smaller r value can be attributed to the destabilizing influence of anesthesia and surgery.…”

“…While the average glomerular filtration rate declines with increasing age in an adult population (6), the glomerular filtration rate of individuals does not necessarily decline as age increases (11). The ages of the comparative adults ranged from 22 to 68 years, but their creatinine clearances were between 84 and 126 ml/min/1.73 m2 (9). The influence of age on the relationship shown in Fig.…”

Future directions in antimicrobial chemotherapy

“…The bacteriological and pharmacokinetic properties of these drugs are listed in Tables 1 and 2 [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15].…”

Pharmacokinetics of intravenous cefetamet and oral cefetamet pivoxil in patients with hepatic cirrhosis

“…The pharmacokinetics of cefetamet are dose independent between 133 and 2,650 mg (14). There is a slight dosedependent bioavailability of the ester: after oral doses of between 500 and 2,000 mg of cefetamet pivoxil, the dosenormalized area under the plasma concentration-time curve kinetics of cefetamet since it is not bound appreciably in blood and it is eliminated primarily by glomerular filtration (13,14). However, because the pivoxil ester must hydrolyze to liberate cefetamet, liver disease might affect the presystemic conversion of the prodrug.…”