Pharmacokinetics of a parenteral carbapenem, biapenem, in patients with end-stage renal disease and influence of haemodialysis

Satoru Nagashimaa,b, Osamu Kozawaa, Takanobu Otsukac, Ken-ichi Kohnoa,b, Masahiko Minamotod, Masahiro Yokokawad, Mitsutaka Kanamarub and Toshihiko Uematsua,*

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


    Abstract
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 Abstract
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 Methods
 Results
 Discussion
 References
 
The effects of haemodialysis on the pharmacokinetics of a carbapenem, biapenem, were evaluated in five patients with end-stage renal disease, who received 1 h iv infusions of 300 mg biapenem on both the days on and off 4 h haemodialysis. With haemodialysis, plasma biapenem exhibited two elimination phases, one during and the other after haemodialysis with half-lives of 1.16 ± 0.12 and 3.33 ± 0.91 h, respectively. Ninety percent of biapenem was removed from blood to dialysate. Without haemodialysis, plasma biapenem was mono-exponentially eliminated with a half-life of 4.35 ± 1.30 h.


    Introduction
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Biapenem (L-627) [Lederle (Japan), Ltd] is a parenteral carbapenem that possesses antibacterial activities against a wide range of Gram-positive and -negative bacteria.1 It is stable to human renal dehydropeptidase-I (DHP-I) and therefore does not require the co-administration of a DHP-I enzyme inhibitor.2

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 20–600 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.


    Methods
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 Methods
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Five patients aged 39–62 years and weighing 46.1–67.5 kg, with end-stage renal disease, i.e. either chronic glomerulonephritis (n = 2) or diabetic nephropathy (n = 3), undergoing long-term haemodialysis treatment (duration: 0.9–17.4 years) participated in the study after giving their informed consent, with the approval of the local Ethics Committee.

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 1.5–2.0 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 IGo). The area under the plasma concentration–time curve (AUC0–{infty}) 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–{infty}.


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Table I. Pharmacokinetic parameters of biapenem (300 mg), as administered iv over 1 h, in patients with end-stage renal disease on the days on and off of haemodialysis treatment
 

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 Methods
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 Discussion
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Biapenem was well tolerated by the patients with end-stage renal disease on both occasions. No adverse clinical effects were noted, and none of the subjects developed any laboratory abnormalities definitely attributable to the test drug.

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 IGo). 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 IIGo).


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Table II. Intrinsic (non-renal) and haemodialysis clearances of biapenem derived for each patient
 
The plasma biapenem concentrations, measured at the inlet and outlet of haemodialysis apparatus l h after the commencement of the treatment, were analysed to obtain the biapenem clearance through the dialyser (CLdia) corrected by the haematocrit with the assumption of protein-unbound fraction of biapenem as 0.934. CLdia was thus calculated as 7.0 ± 0.4 L/h. Since biapenem clearance during haemodialysis was the sum of CLdia and non-renal intrinsic clearance (CLnr), the latter was calculated as 2.6 ± 1.6 L/h. Biapenem was removed by 89.6 ± 3.5% from blood to dialysate.


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The elimination half-life in healthy adult volunteers was 1.0–1.8 h, while that in the anuric patients was increased, by a factor of 2.6, up to 4.4 h. During the haemodialysis, however, it was 1.2 h, even shorter than that in healthy adults. Biapenem was, in fact, removed from blood to dialysate 90% through the high-flux membrane of dialyser. Because protein binding of biapenem in serum is small (c. 7%) and the mol. wt is 350.4, the ratio of biapenem clearance through dialyser to that of blood–urea–nitrogen (BUN) was 0.909. In general, haemodialysis prescription guidelines are based on BUN kinetics. Schaedeli & Uehlinger7 have reported that urea kinetics and dialysis treatment time can predict vancomycin elimination during high-flux haemodialysis. The relative mol. wt of vancomycin is 1448, and therefore it is not significantly cleared during haemodialysis with cuprophane dialysers,8 but it is cleared through high-flux dialysers with larger pore sizes. The present findings suggest that biapenem clearance during haemodialysis can be easily predicted by urea kinetics. On the other hand, the clearance of ceftriaxone during haemodialysis is reported to be influenced by the type of membranes used, i.e. cuprophane, haemophane and polysulfone.9 Therefore, an increase in the dose of biapenem might be recommended in dialysis patients with large surface and area highly permeable membranes.

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.


    Notes
 
* Corresponding author. Tel: +81-58-267-2231; Fax: +81-58-267-2959; E-mail: uematsu{at}cc.gifu-u.ac.jp Back


    References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
1 . Ubukata, K., Hikida, M., Yoshida, M., Nishiki, K., Furukawa, Y., Tashiro, K. et al. (1990). In vitro activity of LJCl0,627, a new carbapenem antibiotic with high stability to dehydropeptidase-I. Antimicrobial Agents and Chemotherapy 34, 994–1000.[ISI][Medline]

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, 481–3.[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, 70–6.[Medline]

4 . 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, 1433–6.[Abstract/Free Full Text]

5 . Alvan, G. & Nord, C. E. (1995). Adverse effects of monobactams and carbapenem. Drug Safety 12, 305–13.[ISI][Medline]

6 . Koeppe, P., Hoeffler, D. & Fitzen, B. (1997). Biapenem pharmacokinetics in healthy volunteers and in patients with impaired renal function. Arznelmittel-Forschung 47, 1250–6.

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, 26–38.[ISI][Medline]

8 . Tan, C. C., Lee, H. S., Ti, T. Y. & Lee, E. J. (1990). Pharmacokinetics of intravenous vancomycin in patients with end-stage renal failure. Therapeutic Drug Monitoring 12, 29–34.[ISI][Medline]

9 . Gabutti, L., Taminelli-Beltraminelli, L. & Marone, C. (1997). Clearance of ceftriaxone during haemodialysis using cuprophane, haemophane and polysulfone dialyzers. European Journal of Clinical Pharmacology 53, 123–6.[ISI][Medline]

10 . Regazzi, M. B., Rondanelli, R. & Calvi, M. (1993). The need for pharmacokinetics protocols in special cases. Pharmacological Research 27, 21–31.[ISI][Medline]

Received 14 February 2000; returned 5 May 2000; revised 23 June 2000; accepted 3 August 2000





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