a Department of Pharmacology, Gifu University School of Medicine, 40 Tsukasa-machi, Gifu 500-8705, b Shitoro Clinic, Hamamatsu 432-8066, c Department of Orthopedic Surgery, Nagoya City University School of Medicine, Nagoya 467-8601 and d Wyeth-Lederle Japan Ltd, Tokyo 175-0082, Japan
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Abstract |
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Introduction |
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Single and repeated iv doses of biapenem have been reported to be well tolerated by healthy young volunteers, showing linear pharmacokinetics within the dosage range of 20600 mg.3 This tolerability has been also demonstrated in the elderly.4 In normal subjects, biapenem is cleared mainly by urinary excretion. However, the predominant concern in terms of adverse reactions to imipenem/cilastatin is the increased tendency to cause seizures compared with other ß-lactams, and the risk of producing a seizure is highly associated with inadequate dose adjustment in relation to renal function.5 Although Koeppe et al.6 reported the pharmacokinetics of biapenem in patients with various degrees of reduced renal function, those on the days on and off haemodialysis were compared between the different patient groups. Thus the present study was conducted to compare them within the same patients.
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Methods |
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The safety and pharmacokinetics were examined after a single 1 h iv infusion of 300 mg biapenem in 100 mL saline. Biapenem was administered first on the day of haemodialysis and then on a day off haemodialysis at a 1 month interval. On the first dosing occasion, the patients underwent regular haemodialysis treatment, which was started immediately after the end of biapenem infusion. Haemodialysis was performed for 4 h using a double-needle access in the arteriovenous fistula and a hollow-fibre polysulfone high-flux dialyser with a filter surface area of 1.52.0 m2. The dialysate flow was 500 mL/min and the blood flow was 200 mL/min. On the second dosing occasion, the patients underwent their usual haemodialysis 24 h after the end of biapenem infusion.
Blood samples (4 mL each) were collected before and 1, 1.5, 2, 3, 5, 9, 12 and 24 h after the beginning of 1 h iv administration, before and after the next haemodialysis session, and at the follow-up examination after 10 days. Blood samples were also taken at the inlet and outlet of haemodialysis apparatus 1 h post-infusion. Plasma concentrations of biapenem were measured by high-performance liquid chromatography according to previously reported methods.3,4 The calibration curve generated by measuring the plasma solution adjusted to the concentrations of 2.0, 4.9, 9.9, 19.7, 49.3 and 98.5 µg/mL biapenem was linear (r = 0.999). Its coefficient of variation (CV) was 1.38%. The mean recovery (n = 6) of biapenem was 99.5%. The detection limit was 0.l µg/mL in plasma.
The elimination profile of biapenem concentrations from blood on the first dosing occasion apparently showed two phases, i.e. one during and the other after haemodialysis. Therefore, the log-transformed plasma concentrations measured at 1.5, 2, 3 and 5 h after the beginning of infusion and those measured at 5, 9 and 12 h, and 24 h if measurable, were fitted separately by a linear least-squares method. The plasma drug concentrations obtained on the second dosing occasion were fitted in the same manner (Table I). The area under the plasma concentrationtime curve (AUC0
) was calculated by use of the trapezoidal rule and estimated to infinity by using quotient of the last measurable concentration to the terminal-phase rate constant. The maximum concentration in plasma (Cmax) was obtained from the observed value at l h. Total body clearance (CLtot) was calculated by dividing the dose by the AUC0
.
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Results |
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The elimination profile of biapenem from blood apparently exhibited two phases, the half-lives of which were 1.16 ± 0.12 and 3.33 ± 0.91 h, respectively. On the day off haemodialysis, the biapenem concentrations in plasma appeared to be eliminated mono-exponentially with an elimination half-life of 4.4 ± 1.3 h (Table I). On the day off haemodialysis, the volume of distribution of water-soluble biapenem would be different between the time periods with and without haemodialysis (VdHD and VdnonHD) to reveal some influence of haemodialysis treatment on the kinetics of this drug. The volume of distribution was calculated to have decreased from 16.0 ± 3.6 L (VdHD) to 10.8 ± 7.3 L (VdnonHD) after haemodialysis. The clearance of biapenem was also decreased from 9.60 ± 1.70 to 2.14 ± 0.91 L/h. On the day off haemodialysis the total body clearance was 2.6 ± 0.6 L/h (Table II
).
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Discussion |
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The intrinsic non-renal clearance of biapenem evaluated in anuric patients on the day off haemodialysis was 2.6 L/h, which was exactly the same as the value calculated by subtracting CLdia from CLHD during haemodialysis. The fact that this value is slightly smaller than that obtained in the subjects having no apparent renal dysfunction may be due to the overhydration during the interval of haemodialysis treatment, but CLHD and CLnonHD were similar to that reported by Koeppe et al.6 When prescribing an antibiotic such as a ß-lactam, the main excretion route of which is renal, for such patients with reduced renal function, precautions should be taken with regard to the changes in pharmacokinetic properties.10 In the anuric patients the plasma concentration of biapenem was 2.4 ± 0.5 and 0.5 ± 0.4 mg/L at 12 and 24 h after dosing, respectively, which exceed the MICs of biapenem for most pathogens except Pseudomonas aeruginosa. It is known that carbapenem antibiotics exhibit significant postantibiotic effects against the majority of Gram-negative organisms and Gram-positive aerobes. Taken together, we recommend that dosing intervals be prolonged to 24 h in anuric patients to avoid unnecessary accumulation of biapenem and to minimize the risk of possible side-effects.
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Notes |
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References |
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2 . Hikida, M., Kawashima, K., Nishiki, K., Furukawa, Y., Nishizawa, K., Saito, I. et al. (1992). Renal dehydropeptidase-I stability of LJC10,627, a new carbapenem antibiotic. Antimicrobial Agents and Chemotherapy 36, 4813.[Abstract]
3 . Nakashima, M., Uematsu, T., Ueno, K., Nagashima, S., Inaba, H., Nakano, M. et al. (1993). Phase I study of L-627, biapenem, a new parenteral carbapenem antibiotic. International Journal of Clinical Pharmacology, Therapy and Toxicology 31, 706.[Medline]
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Kozawa, O., Uematsu, T., Matsuno, H., Niwa, M., Takiguchi, Y., Matsumoto, S. et al. (1998). Pharmacokinetics and safety of a new parenteral carbapenem antibiotic, biapenem (L-627), in elderly subjects. Antimicrobial Agents and Chemotherapy 42, 14336.
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7 . Schaedeli, F. & Uehlinger, D. E. (1998). Urea kinetics and dialysis treatment time predict vancomycin elimination during high-flux haemodialysis. Clinical Pharmacology and Therapeutics 63, 2638.[ISI][Medline]
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Received 14 February 2000; returned 5 May 2000; revised 23 June 2000; accepted 3 August 2000