Pharmacokinetics of Imipenem-Cilastatin in Patients with Renal Insufficiency Undergoing Continuous Ambulatory Peritoneal Dialysis P

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ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Apr. 1988, p. 530-534 Vol. 32, No. 4 0066-4804/88/040530-05$02.00/0 Copyright © 1988, American Society for Microbiology Pharmacokinetics of Imipenem-Cilastatin in Patients with Renal Insufficiency Undergoing Continuous Ambulatory Peritoneal Dialysis P. SOMANI,1,2* E. H. FREIMER,1 M. L. GROSS,' AND J. T. HIGGINS, JR.' Departments of Medicine' and Pharmacology,2 Medical College of Ohio, Toledo, Ohio 43699 Received 27 July 1987/Accepted 26 January 1988

In six patients with end-stage renal disease, a single bolus of imipenem-cilastatin (500 mg each) was given either intravenously or intraperitoneaHly in a randomized crossover protocol such that each patient received the drug by both routes at a 2- to 3-week interval. Drug levels in plasma and the peritoneal dialysis fluid were analyzed at frequent intervals, and various pharmacokinetic variables were calculated for a one-compartment open model. Data obtained in the present study suggest that while no significant difference in peak plasma levels or volume of distribution were noted, the following variables were significantly different for imipenem as compared with cilastatin: elimination half-life, total plasma clearance, area under the concentration-time curve, and percent drug excretion in the peritoneal dialysis fluid. The elimination half-life of imipenem (3.28 h) or cilastatin (8.84 h) in our patients was in the same range as observed in patients with minimal renal function undergoing hemodialysis. The dose of imipenem-cilastatin should be reduced appropriately in patients with end-stage renal disease undergoing peritoneal dialysis.

Cephalosporins are usually prescribed for the treatment of 500-mg dose of commercial Primaxin (containing 500 mg bacterial peritonitis, a common problem in patients under- each of imipenem and cilastatin) given either i.v. or i.p. and going continuous ambulatory peritoneal dialysis (CAPD) (18, they were then crossed-over to receive the same dose by the 20). Since the kidneys have the most important role in alternate route at a 2- to 3-week interval (provided they did eliminating most cephalosporins from the body, the elimina- not develop any new criteria for exclusion). tion half-life (t1/2) of these drugs is usually increased in An indwelling venous catheter was placed in a forearm patients with decreased renal function and end-stage renal vein for i.v. injection of the drug over 10 min. Venous blood disease (ESRD) (2). Imipenem is a new cephalosporin which samples were collected from the contralateral arm at 0, 0.5, is commercially available as a combined formulation ofequal 1, 2, 3, 4, 6, and 8 h after injection. When the drug was given amounts of imipenem and cilastatin (a synthetic inhibitor of were taken at these intervals. renal dipeptidase in the renal tubules). The t1/2 of imipenem i.p., blood samples also and cilastatin in normal subjects is approximately 1 h (7, 14). Samples of peritoneal dialysis (PD) fluid were obtained Although both drugs have a substantial difference in renal aseptically at 0, 0.25, 0.5, 0.75, 1, 2, 3, 4, and 5 h and at the clearances when each drug is given individually (19), the end of dialysis at 6 h when the PD fluid was completely renal clearances are approximately equal (66 and 69%, exchanged. For the i.p. phase of the protocol, the drug was respectively) when imipenem and cilastatin are given to- added to a 2-liter dialysate bag containing 1.5% glucose and gether in a 1:1 ratio (500 mg each) (19). In patients with the PD fluid was instilled into the peritoneal cavity over a decreased creatinine clearance, the t1/2 of both imipenem 15-min period. and cilastatin is increased; however, the t1/2 of imipenem is Plasma and PD fluid samples were processed within 30 increased to 3.4 to 4.8 h, whereas the t112 of cilastatin is min, and a stabilizer was added immediately after collection increased to 12.0 to 16 h (8, 19). Both imipenem and to prevent breakdown of the drugs. The stabilizer consisted cilastatin are almost completely removed by hemodialysis of a 1:1 (vol/vol) mixture of ethylene glycol and 1 M (3, 8), the t1/2s during hemodialysis being 1.2 and 2.2 h, 4-morpholinoethanesulfonate. The amount of stabilizer respectively. No information is available about the handling added to either plasma or PD fluid was 1:1 (vol/vol). Samples of either imipenem or cilastatin given to patients undergoing were split and rapidly frozen to -70°C until analysis by a CAPD, although it is now being used in such patients to treat highly sensitive and specific high-pressure liquid chromato- serious infections. In the present study, we investigated the graphic method for cilastatin (6) or by a microbiological pharmacokinetics of imipenem-cilastatin given by either the assay for imipenem (19) in the pharmacokinetic laboratory of intravenous (i.v.) or intraperitoneal (i.p.) route to six pa- Merck Sharp & Dohme. The sensitivity, specificity, repro- tients undergoing chronic CAPD. ducibility, and relative recovery of imipenem and cilastatin MATERIALS AND METHODS have been described in detail previously (6, 19). The pharmacokinetics of imipenem-cilastatin were calcu- Six patients undergoing CAPD for 6 to 24 months were lated by the PC-NONLIN program (Statistical Consultants, enrolled in the protocol after signing an informed consent Lexington, Ky.) on an IBM-PC computer with a one- approved by the Institutional Review Board. Patients with model: C = Ae7K , where C known allergy to cephalosporins, active peritonitis within compartment linear regression the 2 weeks before the study, severe cardiac failure or is the drug concentration in plasma, A is the intercept at time hepatic dysfunction, or a history of convulsive disorders zero, and K is the elimination rate constant based on a were excluded. Patients were randomized to receive a single one-compartment open model. Area under the curve was calculated by the trapezoidal rule; total plasma clearance (CL) was calculated by the equation Ke V; volume of * Corresponding author. 530 VOL. 32, 1988 PHARMACOKINETICS OF IMIPENEM-CILASTATIN 531 distribution (V) was calculated from the dose/CO; and plasma standard deviation) compared with 3.2 + 0.47% for imipe- t1/2 was calculated from the equation t1/2 = 0.693/K; QPD is nem over the same dwell time. An explanation for this the amount of drug removed in PD at 6 h. The total amount apparent discrepancy may be that the concentration of of peritoneal fluid at the end of the 6-h dwell time remained imipenem in the PD fluid reached a plateau around 3 h in approximately 2 liters since we were using 1.5% glucose in most patients, and therefore, no additional transfer of the the PD fluid. In addition, when the drug was given i.p., drug would occur between plasma and the PD fluid beyond percent absorption of the drug for each patient was calcu- this time, although the total dwell time was 6 h. lated (9) from the equation: percent absorption = [(amount After imipenem-cilastatin was given i.p., the drug concen- injected - amount recovered)/amount injected] x 100. tration in the dialysate decreased gradually over the 6-h dwell time in a linear manner (Fig. 2). However, the slopes of decline in PD concentration for the two drugs were RESULTS significantly different. After a 6-h dwell, the calculated absorptions of imipenem and cilastatin were 79 ± 8 and 62 + Imipenem-cilastatin injection was well tolerated by all six 13% (mean ± standard deviation), respectively. It may be patients. After a single i.v. bolus of 500 mg of the drug, data seen (Fig. 2) that the concentration of both imipenem and were obtained for plasma (Fig. 1A) and PD fluid (Fig. 1B) cilastatin in plasma increased rapidly beginning at 0.5 h; concentrations of the two individual drugs. In most patients, however, the peak concentrations of the two drugs in plasma the first data point (at 0.5 h) for cilastatin (Fig. 1B) and were significantly different (Fig. 2). occasionally for imipenem suggested an early distribution phase and was excluded from the pharmacokinetic calcula- tion. The data obtained for the pharmacokinetic variables DISCUSSION are summarized in Table 1. Statistically significant differences (group t test) between the two drugs were found for It is now well recognized that the t1/2 of most antibiotics, Ke, t1/2, area under the curve, CL, QPD, and percent including cephalosporins, is increased in proportion to the excretion in CAPD fluid (Table 1). The most important decline in creatinine clearance, and in patients with ESRD, a findings are that whereas both imipenem and cilastatin had significant adjustment in the dosing frequency must be made similar peak plasma concentrations and V, the t1/2 of imipe- (2, 16). Patients with ESRD undergoing hemodialysis are nem (3.28 h) was significantly shorter than that of cilastatin quite different from those undergoing CAPD since in the (8.84 h). Both imipenem and cilastatin diffused readily from former a highly dialyzable drug is removed extensively the central blood compartment into the peritoneal compart- during hemodialysis, and after completion of the procedure, ment, the levels in PD fluid being detectable as early as 0.25 a supplemental dose may be necessary to reestablish thera- h. The peak levels of imipenem in PD fluid were at or near peutic drug levels, whereas in patients on CAPD, a contin- plateau by the end of 3 h after the i.v. dose (Fig. 1A). On the uous exchange of drug may occur throughout the 24-h period other hand, the concentration of cilastatin in PD fluid in- and the drug excretion via this route would depend on the creased slowly over the 6-h dwell time (Fig. 1B), the rate of transperitoneal movement and the number of ex- maximum PD/plasma ratio being only 0.73 at the end of 6 h. changes per day. Results of previous investigations (1, 4, 11, However, the percent excretion of cilastatin over the 6-h 17) with single drugs showed that some drugs such as dwell time via the PD fluid was 5.4 ± 0.38% (mean + gentamicin (22), tobramycin (5, 23), moxalactam (12, 21),

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1 2 3 4 5 6 1 2 3 4 5 6 DWELL TIME (hours) DWELL TIME (hours) FIG. 1. Data showing the time course of plasma (0, l) and PD (0, *) concentration of imipenem (A) or cilastatin (B) after a single i.v. bolus injection of 500 mg each of the two drugs. Data represent mean + standard deviation (bars) from six patients; solid line for plasma data indicates best fit by linear regression analysis for a one-compartment model. IP/IV ratio of the drug concentration at 3, 4, and 6 h shows that imipenem, but not cilastatin, achieves near equilibration by the end of 6-h dwell time. 532 SOMANI IET AL. ANTIMICROB. AGENTS CHEMOTHER.

TABLE 1. Pharmacokinetic data for imipenem and cilastatin after a single i.v. bolus in patients undergoing CAPD' Drug and Dose Cmax K. 1/2 AUC V CL QPD % Excretion patient no. (mg) (mg/liter) (h-') (h) (mg/liter* h-1) (liters) (mUmin) (mg/6 h) Imipenem 1 500 19.3 0.209 3.3 92 25.9 91 14.8 3.0 2 500 19.7 0.167 4.1 117 25.4 71 15.2 3.0 3 500 28.1 0.179 3.86 157 17.8 53 20.6 4.1 4 500 23.4 0.232 2.98 100 21.4 83 14.0 2.8 5 500 35.4 0.249 2.78 142 14.1 59 15.2 3.0 6 500 49.9 0.261 2.66 192 10.0 44 15.8 3.2 Mean 29.3 0.216 3.28 133 19.1 66.8 15.9 3.2 SD 10.5 0.04 0.59 38 6.4 18.1 2.4 0.5 Cilastatin 1 500 29.5 0.184 3.75 160 16.9 52 24.0 4.8 2 500 29.0 0.073 9.45 399 17.2 21 28.6 5.7 3 500 46.1 0.107 6.45 430 10.8 19 28.9 5.8 4 500 29.3 0.097 7.11 300 17.1 28 26.1 5.2 5 500 33.9 0.051 13.52 669 14.7 13 25.4 5.1 6 500 40.7 0.054 12.78 751 12.3 11 23.0 4.6 Mean 34.8 0.094 8.84 452 14.8 24.0 26.0 5.2 SD 6.5 0.05 3.80 223 2.8 14.9 2.4 0.5 P value' NS <0.001 0.005 0.005 NS <0.001 <0.001 <0.001 a Cmax, Calculated peak concentration in plasma; K,, elimination rate constant; AUC, area under the curve for plasma drug concentration; V, apparent volume of distribution in central compartment; CL, total plasma clearance; QPD. total amount of drug in the dialysate after 6-h dwell time; % excretion, percentage of the injected drug removed by peritoneal dialysis in 6 h. b Data for imipenem and cilastatin were compared by Student's group t test; NS, not significant. cefamandole (15; G. D. Morse, P. E. Lieveld, D.M. Janicke, 19) and in patients with normal renal function (19). Data M. A. Apicella, and J. J. Walshe, Clin. Pharmacol. Ther. obtained in the present study in patients with impaired renal 37:214, 1986), or cefonicid (13) are poorly eliminated by PD function undergoing CAPD demonstrate that both imipenem although they are rapidly absorbed when given i.p. How- and cilastatin are eliminated at a slower rate than in patients ever, only 3 to 10% of the highly dialyzable drugs (e.g., with normal renal function. However, there are significant ceftizoxime) are eliminated by this route (9, 10). differences in the absorption and peritoneal elimination of Primaxin is a combination of the antibiotic imipenem and the two drugs. Thus, whereas approximately 78% of imipe- the renal dipeptidase inhibitor cilastatin; both drugs are nem is absorbed over a 6-h dwell time, only 52% of cilastatin rapidly excreted by the kidney in normal volunteers (7, 14, is absorbed over a comparable time. Even more signifi-

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0 1 2 3 4 5 6 0 1 2 3 4 5 6 DWELL TIME (hours) DWELL TIME (hours) FIG. 2. Data showing the time course of PD (0, *) and plasma (0, l) concentration of imipenem (A) or cilastatin (B) after a single i.p. bolus of 500 mg each of the two drugs. Data represent mean ± standard deviation (bars) from six subjects; solid line of peritoneal concentration represents best fit by linear regression analysis for a one-compartment model. VOL. 32, 1988 PHARMACOKINETICS OF IMIPENEM-CILASTATIN 533 cantly, the plasma t1/2 of cilastatin after an i.v. dose is travenous and intraperitoneal cefotaxime in chronic ambulatory increased to 8.84 h as compared with 3.28 h for imipenem in peritoneal dialysis. Clin. Pharmacol. Ther. 38:285-289. such patients. The exact reason for the difference in the rate 2. Bennett, W. M., G. R. Aronoff, G. Morrison, T. A. Golper, J. Pullian, M. Wolfson, and I. Singer. 1983. Drug prescribing in of transperitoneal exchange of the two drugs is not known, renal failure. Dosing guidelines for adults. Am. J. Kidney Dis. 3: although in view of previous information for other antibiot- 155-193. ics, different drug molecules are handled differently through 3. Berman, S. J., J. G. Sugihara, J. M. Nakamura, K. K. Kawa- the peritoneal membrane. Differences in molecular weight hara, E. G. C. Wong, J. E. Musgrave, L. M. F. Wong, and cannot explain this difference since both imipenem (molec- A. M. Siemsen. 1985. Multiple-dose study of imipenem/ci- ular weight, 317) and cilastatin (molecular weight, 384) are lastatin in patients with end-stage renal disease undergoing small molecules. Our data also demonstrate that while the long-term hemodialysis. Am. J. Med. 78:113-116. two individual drugs in a commercial preparation may have 4. Bunke, C. M., G. R. Aronoff, M. E. Brier, R. S. Sloan, and F. C. similar pharmacokinetic profiles in patients with normal Luft. 1983. Cefazolin and cephalexin kinetics in continuous ambulatory peritoneal dialysis. Clin. Pharmacol. Ther. 33:66- renal function, it does not necessarily follow that the same 72. would be true for patients with ESRD undergoing CAPD. 5. Bunke, C. M., G. R. Aronoff, M. E. Brier, R. S. Sloan, and F. C. These observations are consistent with those of Gibson et al. Luft. 1983. Tobramycin kinetics during continuous ambulatory (8) and Rogers et al. (19) who found that the tl2 of cilastatin peritoneal dialysis. Clin. Pharmacol. Ther. 34:110-106. (12 to 16 h) was increased much more than that of imipenem 6. Demetriades, J. L., P. R. Sonder, L. N. Entwistle, W. C. Vincek, (3.4 to 4.8 h) in patients with complete renal failure during D. G. Musson, W. F. Bayne. 1986. High-performance liquid the interdialysis period. Since patients on hemodialysis have chromatographic determination of cilastatin in biological fluids. low renal clearance of the drug, the CL of cilastatin and J. Chromatogr. 382:225-231. imipenem was reduced to 61.8 and 13.1 ml/min, respectively, 7. Drusano, G. L., and H. C. Standiford. 1985. Pharmacokinetic profile of imipenem/cilastatin in normal volunteers. Am. J. Med. as compared with 224 and 212 ml/min, respectively, in 78:47-52. normal volunteers (7). Data obtained in the present study 8. Gibson, T. P., J. L. Demetriades, and R. A. Bland. 1984. suggest that in patients undergoing CAPD, the CL of both Imipenem/cilastatin: pharmacokinetic profile in renal insuffi- drugs also was reduced (Table 1) compared with that in ciency. Am. J. Med. 78:54-61. normal volunteers. Unlike hemodialysis, however, the 9. Gross, M. L., P. Somani, B. S. Ribner, R. Raeder, E. H. amount of drug removed in a single 6-h peritoneal dwell was Freimer, and J. T. Higgins. 1983. Ceftizoxime elimination kinet- small (Table 1). ics in continuous ambulatory peritoneal dialysis. Clin. Pharma- Although no data are currently available on the pharmacol. Ther. 34:673-680. cokinetics of or cilastatin after doses in 10. Janicke, D. M., G. D. Morse, M. A. Apicella, W. J. Jusko, and imipenem multiple of bidirectional CAPD with or without J. J. Walshe. 1986. Pharmacokinetic modeling patients with ESRD undergoing transfer during peritoneal dialysis. Clin. Pharmacol. Ther. 40: peritonitis, results of the present study may have significant 209-218. implications if this drug combination is to be used clinically 11. Keller, E., A. Jansen, K. Pelz, G. Hoppe-Seyler, and P. Schol- in treating peritonitis or systemic infections in such patients meyer. 1984. Intraperitoneal and intravenous cefoperazone ki- (2, 16). Thus, if 500 mg each of imipenem and cilastatin was netics during continuous ambulatory peritoneal dialysis. Clin. to be given at a fixed dosing interval of 6 h, the same as the Pharmacol. Ther. 35:208-213. 6-h dwell time, then the concentration of cilastatin in plasma 12. Morse, G. D., D. M. Janicke, R. Cafarell, K. Piontek, M. would continue to increase significantly more than that of Apicella, W. J. Jusko, and J. J. Walshe. 1985. Moxalac- imipenem. Although one can make theoretical projections of tam epimer disposition in patients undergoing continuous am- the steady-state concentrations of imipenem or cilastatin in bulatory peritoneal dialysis. Clin. Pharmacol. Ther. 38:150- plasma after multiple doses, further investigation in such 156. 13. Morse, G. D., T. Lane, D. K. Nairn, J. Deterding, J. Curry, and patients will be necessary to provide actual data. Berman et P. Gal. 1987. Peritoneal transport of cefonicid. Antimicrob. al. (3) gave multiple doses of imipenem-cilastatin (500 mg Agents Chemother. 31:292-294. every 12 h) to patients with minimal creatinine clearance and 14. Norrby, S. R., J. D. Rogers, and F. Ferber. 1984. Disposition of found trough levels of cilastatin in plasma as high as 122 radiolabeled imipenem and cilastatin in normal human volun- ,ug/ml in some patients. Such high concentrations of cilasta- teers. Antimicrob. Agents Chemother. 26:707-714. tin did not produce any untoward side effects in their study. 15. Pancorbo, S., and C. Comty. 1983. Pharmacokinetics of cefa- Since peritoneal excretion of either drug is limited, the usual mandole in patients undergoing continuous ambulatory perito- daily dose should not exceed 1 g by the i.v. route in patients neal dialysis. Peritoneal Dialysis Bull. 3:135-137. with ESRD undergoing CAPD. Although we detected the 16. Paton, W. T., W. R. Cornish, M. A. Manuel, and B. G. Hardy. 1985. Drug therapy in patients undergoing peritoneal dialysis: presence of a metabolite of imipenem (which has been clinical pharmacokinetics considerations. Clin. Pharmacokinet. implicated in causing convulsions) in some of our patients, 10:404 426. the concentration after a single dose was very low. Further 17. Petersen, J., R. D. M. Stewart, G. R. D. Catto, and N. Edward. studies will be necessary to determine whether this metab- 1985. Pharmacokinetics of intraperitoneal cefotaxime treatment olite will continue to accumulate after multiple doses of of peritonitis in patients on continuous ambulatory peritoneal imipenem-cilastatin in such patients. dialysis. Nephron 40:79-82. 18. Prowant, B., K. D. Nolph, L. Ryan, Z. Twardowski, and R. Khanna. 1986. Peritonitis in continuous ACKNOWLEDGMENTS ambulatory peritoneal dialysis: analysis of an 8 year experience. Nephron 43:105- 109. We thank Maureen McDermott and Lois Barnett-Coy for their 19. Rogers, J. D., M. A. P. Meisinger, F. Ferber, G. B. Calandra, invaluable help in performing this study. J. L. Demetriades, and J. A. Bland. 1985. Pharmacokinetics of imipenem and cilastatin in volunteers. Rev. Infect. Dis. 7:S435- LITERATURE CITED S446. 20. Rubin, J., W. Rogers, H. Taylor, E. Everette, B. Prowant, L. 1. Albin, H. C., F. M. Demotes-Mainard, J. L. Bouchet, G. A. Fruto, and K. D. Nolph. 1980. Peritonitis during continuous Vincon, and C. Martin-Dupont. 1985. Pharmacokinetics of in- ambulatory peritoneal dialysis. Ann. Intern. Med. 92:7-13. 534 SOMANI ET AL. ANTIMICROB. AGENTS CHEMOTHER.

21. Singlas, E., H. F. Boutron, H. Merdjan, J. F. Brocard, M. neum during continuous ambulatory peritoneal dialysis. Clin. Pocheville, and D. Fries. 1983. Moxalactam kinetics during Pharmacol. Ther. 32:111-121. chronic ambulatory peritoneal dialysis. Clin. Pharmacol. Ther. 23. Walshe, J. J., G. D. Morse, D. M. Janicke, and M. A. ApicelHa. 34:403-407. 1986. Cross-over pharmacokinetic analysis comparing intrave- 22. Somani, P., R. S. Shapiro, H. Stockard, and J. T. Higgins, Jr. nous and intraperitoneal administration oftobramycin. J. Infect. 1982. Unidirectional absorption of gentamicin from the perito- Dis. 153:170-177.