Single-Dose Accumulation Pharmacokinetics of Tobramycin and Netilmicin in Normal Volunteers

Transcription

1 ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Apr. 1987, p /87/465-5$2./ Copyright 1987, Americn Society for Microbiology Vol. 31, No. 4 Single-Dose Accumultion Phrmcokinetics of Tobrmycin nd Netilmicin in Norml Volunteers NANCY E. WINSLADE, MARTIN H. ADELMAN, EVAN J. EVANS, AND JEROME J. SCHENTAG* Deprtment of Phrmceutics, School of Phrmcy, Stte University of New York t Bufflo, Bufflo, New York 1426, nd The Clinicl Phrmcokinetics Lbortory, Millrd Fillmore Hospitls, Bufflo, New York 1429 Received 3 October 1986/Accepted 21 Jnury 1987 The two-comprtment tissue ccumultion phrmcokinetics of tobrmycin nd netilmicin were compred in 11 norml volunteers by using crossover design. After ech 1.-mg/kg (body weight) dose, serum ws collected for 96 h, nd complete 24-h urine collections were obtined for totl of 3 dys. Two months of wshout were required before crossover. Concentrtions in serum nd urine were mesured by rdioimmunossy, nd concentrtions in serum nd urinry excretion rtes were simultneously fitted to twocomprtment phrmcokinetic model. Netilmicin exhibited significntly lower totl body clernce (48 versus 9 ml/min) nd longer terminl elimintion hlf-life (161 versus 96 h) thn tobrmycin. As result of these phrmcokinetic differences, the predicted tissue ccumultion of netilmicin t stedy stte ws significntly higher thn tht of tobrmycin (P <.5). Reltive rtes of minoglycoside nephrotoxicity probbly depend on both the differentil tissue uptke (ccumultion) nd the concentrtion of the minoglycoside which produces intrcellulr toxicity. Becuse the stedy-stte tissue ccumultion of netilmicin is nerly 2.5 times greter thn tht of tobrmycin, its potency in the production of intrcellulr toxicity needs to be tht much less for the two gents to produce the sme incidence of clinicl nephrotoxicity. Although minoglycosides re often drugs of choice for mny grm-negtive infections, their use hs been hmpered by concerns of nephrotoxicity. For severl resons, however, it hs been difficult to cliniclly determine the true, reltive incidence of this side effect. Becuse nephrotoxicity occurs in low percentge of treted ptients, clinicl trils must enter lrge numbers of ptients to show sttisticl differences between minoglycosides. Confounding vribles which ffect the incidence of nephrotoxicity, including concurrent diseses, medictions, nd ge (23), must be considered nd blnced between popultions. Finlly, clinicl prmeters, such s elevted serum cretinine, my not be specific for minoglycoside-ssocited toxicity but my lso reflect renl injury due to vriety of other cuses (22). Recent work from our lbortory pproched this question of reltive nephrotoxic potentil by conducting crossover studies of the tissue ccumultion phrmcokinetics of minoglycosides in norml volunteers. A previous study with 1 volunteers showed significnt differences in tissue ccumultion between gentmicin nd tobrmycin (1). These differences were of the sme order nd mgnitude s noted previously in ptients (26). The mount of minoglycoside in the tissue comprtment ppers to be relted to both the mgnitude nd the extent of subsequent renl toxicity (23, 26). Work with tobrmycin (1, 25), gentmicin (1, 23), nd mikcin (8) hs supported the reltionship between the predicted mount of drug in the body t stedy stte nd reltive rtes of nephrotoxicity. Netilmicin is n minoglycoside ntibiotic which hs been widely studied in niml models (4, 9, 1, 14, 15, 18, 2), clinicl trils (3, 5, 7, 12, 19, 27, 28), nd phrmcokinetic studies in volunteers (6). Some studies rnk the nephrotoxicity of this gent s similr to tht of tobrmycin (12), wheres others suggest its nephrotoxicity profile more closely resembles tht of gentmicin (19, 28). Although in nimls netilmicin ppers to show greter tissue ccumul- * Corresponding uthor. 65 tion potentil thn even gentmicin (4, 1, 18, 2), this gent cuses less nephrotoxicity in rts (4, 14, 15, 18, 2). Less nephrotoxicity in the fce of greter tissue ccumultion rises the hypothesis tht not only ccumultion but lso the potency of the drug ginst one or more intrcellulr receptors is importnt in the pthogenesis of nephrotoxicity (4). The norml volunteer, single-dose model for tissue ccumultion phrmcokinetics hs the dvntge of reltive sfety nd obvites the need for lrge numbers of subjects in the presence of the lrge interindividul vritions in minoglycoside disposition. In this study, the norml volunteer model ws used to compre the humn tissue ccumultion profiles of netilmicin nd tobrmycin nd to determine whether the sme differences occurred s found in rts. MATERIALS AND METHODS Informed consent ws obtined from 11 norml volunteers between the ges of 2 nd 4 yers. Prestudy medicl histories, physicl exmintions, nd blood screening hemtology profiles, chemistries, urinlyses, 24-h cretinine clernces, nd (when pplicble) pregnncy tests were performed. Dosing nd blood smpling. Subjects received 1.-mg/kg (body weight) dose of either netilmicin or tobrmycin, which ws followed by 3-month intervl before the crossover phse. The drug ws dministered intrvenously in 2 ml of norml sline over 2 to 5 min. Blood smples were collected t the following times: predose, 15 nd 3 min, nd 1, 1.5, 2, 4, 6, 8, 24, 48, 72, nd 96 h fter the injection. Additionl serum smples were obtined t 12, 144, nd 168 h from severl subjects. Urine ws collected from to 4, 4 to 8, 8 to 12, nd 12 to 24 h on dy 1, nd then 24-h urine collections were done dily for 3 dys. Smples were stored frozen t -2 C until ssy. Blood screening profiles nd cretinine clernces were repeted on dys 6 nd 14 postdosing. Assys. Serum nd urine smples were nlyzed for netilmicin nd tobrmycin by rdioimmunossy (Interntionl Bioclinicl, Inc., Portlnd, Oreg.). For drug concentrtions

2 66 WINSLADE ET AL. ANTIMICROB. AGENTS CHEMOTHER. TABLE 1. Demogrphic dt of 11 norml volunteer subjects Age Wt CLCR Dose (mg) Subject (yr)/sex (kg) (mi/mi nper 1.73 inl) Tobrmycin Netilmicin 1 34/Mle /Mle /Femle /Mle /Mle /Mle /Femle /Femle /Mle /Femle /Mle CLCR, Cretinine clernce. greter thn 16,ug/ml or less thn 1.,ug/ml, ssy dilutions were modified to bring the sensitivity of the method into the desired rnges. Interdy nd intrdy coefficients of vrition verged between 3 nd 7% over the concentrtion rnge of smples ssyed. Phrmcokinetics. The concentrtions in serum nd urinry excretion rtes versus time of ech subject were simultneously fitted to n open, two-comprtment phrmcokinetic model by using the nonliner curve-fitting progrm NONLIN (16). Becuse concentrtions in serum were below ssy sensitivity within severl dys of drug dministrtion, simultneous fitting of serum nd urine dt ws necessry to obtin relible estimte of the terminl hlf-life (11). The prmeters derived from this model were used to clculte tissue ccumultion of ech minoglycoside for ech subject nd to predict the mount in the body t stedy stte (1, 16, 23, 26). Sttisticl nlysis ws performed by using pired Student t test, with significnce defined s P <.5. RESULTS Relevnt demogrphic dt for the 11 norml volunteers re shown in Tble 1. All 11 subjects completed both phses of the tril with no significnt dverse effects. Subject 7 did experience slight burning senstion during infusion of tobrmycin. There were no consistent ltertions in lbortory vlues fter dministrtion of either netilmicin or tobrmycin z.2 I...1 I-\ w z Om..2..S1.k J TIME (hr) FIG. 1. Simulted serum concentrtion-versus-time profiles for netilmicin (... ) nd tobrmycin ( ). Men vlues from the 11 subjects were used to crete the grphs. At the end of the 3-dy postdose urine collections, n verge of 11.4 ± 14% of the dministered dose hd been recovered in urine. The decline in concentrtions in serum ws biexponentil for both drugs in ll subjects. The dt were fitted to two-comprtment model. The men serum concentrtionversus-time curves for both tobrmycin nd netilmicin re shown in Fig. 1. Differences in the two-comprtment phrmcokinetics of tobrmycin nd netilmicin were pprent in the terminl phse of elimintion: netilmicin hd longer serum hlf-life nd higher postdistributive concentrtions in serum. The derived phrmcokinetic prmeters re shown in Tbles 2 nd 3. The stedy-stte volume of distribution ws consistently, lthough not significntly, TABLE 2. Two-comprtment phrmcokinetic dt for tobrmycin in 11 norml volunteer subjects Subject V1 (liter/kg) V,, (liters/kg) k12 (h-') k2l (h-1) klo (h-1) tv2 (h) CLB (mlmin) Xl) (mg) Men ± SD.245 ± ± ± ± ± ± ± 9.6 V1, Volume of distribution in the centrl comprtment; VII, volume of distribution t stedy stte; k12, k2j, nd k1o, elimintion rte constnts from centrl-peripherl comprtment, peripherl-centrl comprtment, nd centrl comprtment-urine, respectively; tv213, terminl elimintion hlf-life; CLB, totl body clernce; XI', ccumultion in body t stedy stte

3 VOL. 31, 1987 PHARMACOKINETICS OF TOBRAMYCIN AND NETILMICIN 67 TABLE 3. Two-comprtment phrmcokinetic dt for netilmicin in 11 norml volunteer subjects Subject V1 (liter/kg) V, (liters/kg) k12 (h-') k2l (h-1) klo (h-1) t1/2r (h) CLB (mlmin) XBs , ,47.9 Men.148b b.591b b ± SD ±.41 ± ±.2247 ±.171 ±.59 ± ± 1.9 ± Prmeters re defined in the footnote to Tble 2. b Significntly different from tobrmycin t P <.5. lrger for netilmicin. Netilmicin showed significntly smller centrl volume of distribution (P <.5) nd more rpid rte constnts for intercomprtmentl distribution, s well s longer terminl elimintion hlf-life. Ten of the eleven subjects hd lower clernce of netilmicin thn of tobrmycin (P <.5); these dt re shown in Fig. 2. The significntly longer terminl hlf-life of netilmicin nd overll slower totl body clernce reflect the observtion tht netilmicin showed 2.5 times lrger stedy-stte ccumultion in the body (491 versus 193 mg for tobrmycin; Tbles 2 nd 3). These differences were sttisticlly significnt t P <.5. The netilmicin phrmcokinetic prmeters for these 11 volunteers were compred with vlues from previous ptient studies (7, 25) nd previous norml volunteer studies (1). Both tobrmycin nd netilmicin showed bsolute differences between the studies in ptients nd volunteers (Tble 4). Five of the volunteers prticipted in tobrmycin studies in both 1979 nd These volunteers hd similr kinetic prmeters on both occsions (Tble 5). DISCUSSION Erly studies with gentmicin, tobrmycin, netilmicin, nd mikcin proposed tht minoglycosides re similr when studied using one-comprtment phrmcokinetic model (6, 21, 28). Recent studies demonstrted significnt differences between these gents when their two-comprtment phrmcokinetic prmeters re compred (1, 7, 8, 15, 23). The lower totl body clernce for netilmicin (48 versus 9 ml/min for tobrmycin) could be explined by differences in filtrtion or tissue binding. However, becuse netilmicin nd tobrmycin hve similr moleculr weights nd neither is highly protein bound, it is unlikely tht differences in glomerulr filtrtion could ccount for the observed differences. The volunteers did not show differences in cretinine clernce, so the lower totl body clernce reltive to cretinine clernce reflects more vid netilmicin rebsorption nd binding in the proximl convoluted tubulr cells. This binding ffinity differentil presumbly exists in ll tissues which bind minoglycosides. Bsed on previous studies of postmortem tissue concentrtion mesurement, most body tissues vidly bind minoglycosides (24). The tobrmycin volunteer dt on tissue ccumultion in this tril differ somewht from those of our previous study in norml volunteers (1; Tble 4). In similr tril compring gentmicin nd tobrmycin given s 1.-mg/kg doses to norml volunteers, Adelmn et l. (1) reported significntly smller vlues for tobrmycin elimintion rte constnts from centrl-peripherl comprtment nd from peripherlcentrl comprtment, volume of distribution t stedy stte, nd predicted mount in the body t stedy stte. Our two studies, lthough conducted 4 yers prt, hd five subjects in common. If the results for these five subjects common to both trils re compred, there re no significnt differences between the predicted phrmcokinetic prmeters (Tble 5). This observtion points to the stbility of intrindividul minoglycoside disposition, nd the study differences produced by dding new volunteers to the popultion demonstrte the consequences of wide intersubject vribility on smll-smple comprisons of the multicomprtment phrmcokinetics of minoglycosides. Crossover design is 1_ E w z < -J -J z l S TOBRAMYCIN CLEARANCE ml/min FIG. 2. Clculted netilmicin clernce versus clculted tobrmycin clernce. The line of unity is drwn for reference.

4 68 WINSLADE ET AL. ANTIMICROB. AGENTS CHEMOTHER. TABLE 4. Comprison of predicted phrmcokinetic prmeters with previous vlues from both ptient nd norml volunteer studies Study drug nd reference No. of VI sss prticipnts (liter/kg) (liters/kg) t4/21 (h) CLB XB (ml/min) (mg) Tobrmycin Schentg et l. (25) Adelmn et l. (1) Winslde et l. (this study) b 96 9C 193b Netilmicin Edwrds et l. (7) Winslde et l. (this study) 11 O.15d d 491d Prmeters re defined in the footnote to Tble 2. bsignificntly different (P <.5) from tobrmycin volunteer dt of Adelmn et l. (1). c Significntly different (P <.5) from tobrmycin ptient dt (25). d Significntly different (P <.5) from netilmicin ptient dt of Edwrds (7). TABLE 5. Sequentil phrmcokinetic prmeters for five subjects given tobrmycin in 1979 nd gin in 1984 Subject Yr V, (liter/kg) V (liters/kg) ti/2 (h) CLB (ml/min) XBS (mg/kg) A B C D E Men + SD" ± ± ± ± ± ± ± ± ± ± 1.3 Prmeters re defined in the footnote to Tble 2. b1979 versus 1984: P =.43 for V1, P =.13 for Vss, P =.35 for t11, P =.54 for CLB, nd P =.6 for X'SB. essentil to the evlution of reltive tissue ccumultion, becuse it elimintes the impct of interindividul vrince. Most two-comprtment prmeters for netilmicin re lso significntly different from the ptient dt reported by Edwrds et l. (7; Tble 4). In this ptient study, renl function differed from tht of the volunteers, nd the durtion of smpling ws shorter in the ptient study. Netilmicin ccumultes within the kidney to much greter degree thn either gentmicin or tobrmycin (4, 1, 18, 2). Although this my led to the conclusion tht netilmicin is more nephrotoxic thn either gentmicin or tobrmycin, most niml studies indicte tht netilmicin ppers to cuse little nephrotoxicity when compred with similr doses of gentmicin or tobrmycin (1, 14, 15, 18, 2). In humns, the reported incidence of netilmicin-induced renl dysfunction vries gretly (3, 5, 12, 27). Vlues rnge from 3% (12) to 38% (3). In these studies, netilmicin does not pper to be more nephrotoxic thn tobrmycin. Thus, its 2.5-foldgreter tissue ccumultion does not predict 2.5-foldgreter degree of clinicl nephrotoxicity. Whenever one prmeter (such s tissue ccumultion) does not explin ll fcets of problem such s reltive minoglycoside nephrotoxicity, then other fctors (such s intrcellulr toxicity) must be considered. Intrcellulr dmge to vrious orgnelles or sites hs been extensively studied but lso does not precisely rnk these drugs. Thus, it seems necessry to ccount for nephrotoxicity s n event prtilly dependent on tissue ccumultion nd prtly dependent on potency in the production of intrcellulr dmge. One possibility is tht surfce binding or cellulr uptke is greter for netilmicin, while netilmicin hs lower potency ginst the intrcellulr site(s) of nephrotoxicity. Although dt on the reltive toxicity of netilmicin in lysosomes (17, 29), mitochondri (2), nd phospholipid binding sites (13) fvor lesser toxic potentil for netilmicin thn gentmicin t these sites, netilmicin invribly ppers similr to tobrmycin. LITERATURE CITED 1. Adelmn, M., E. Evns, nd J. J. Schentg Twocomprtment comprison of gentmicin nd tobrmycin in norml volunteers. Antimicrob. Agents Chemother. 22: Bendirdjin, J. P., J. P. Fillstre, nd B. Foucher Mitochondril modifiction with the minoglycosides, p In A. Whelton nd H. Neu (ed.), The minoglycosides. Mrcel Dekker, Inc., New York. 3. Bock, B. V., P. H. Edelstein, nd R. D. Meyer Prospective comprtive study of efficcy nd toxicity of netilmicin nd mikcin. Antimicrob. Agents Chemother. 17: Brier, M. E., P. R. Myer, R. A. Brier, D. Visscher, F. C. Luft, nd G. R. Aronoff Reltionship between rt renl ccumultion of gentmicin, tobrmycin, nd netilmicin nd their nephrotoxicities. Antimicrob. Agents Chemother. 27: Buckwold, F. J., A. R. Ronld, B. Lnk, L. Thompson, C. Rox, nd G. K. M. Hrding Clinicl efficcy nd toxicity of netilmicin in the tretment of grm-negtive infections. Cn. Med. Assoc. J. 12: Chung, M., R. Costello, nd S. Symchowicz Comprison

5 VOL. 31, 1987 PHARMACOKINETICS OF TOBRAMYCIN AND NETILMICIN 69 of netilmicin nd gentmicin phrmcokinetics in humns. Antimicrob. Agents Chemother. 17: Edwrds, D. J., A. Mngione, T. J. Cumbo, nd J. J. Schentg Predicted tissue ccumultion of netilmicin in ptients. Antimicrob. Agents Chemother. 2: French, M. A., F. B. Cerr, M. E. Plut, nd J. J. Schentg Amikcin nd gentmicin ccumultion phrmcokinetics nd nephrotoxicity in criticlly ill ptients. Antimicrob. Agents Chemother. 19: Giulino, R. A., G. A. Verpooten, L. Verbist, R. P. Wedeen, nd M. E. BeBroe In vivo uptke kinetics of minoglycosides in the kidney cortex of rts. J. Phrmcol. Exp. Ther. 236: Hottendorf, G. H., D. Brnett, L. L. Gordon, E. F. Christensen, nd H. Mdissoo Nonprllel nephrotoxicity doseresponse curves of minoglycosides. Antimicrob. Agents Chemother. 19: Jusko, W. J Guidelines for collection nd phrmcokinetic nlysis of drug disposition dt, p In W. E. Evns, J. J. Schentg, nd W. J. Jusko (ed.), Applied phrmcokinetics. Applied Therpeutics Inc., Sn Frncisco. 12. Lerner, A. M., M. P. Reyes, L. A. Cone, D. C. Blir, W. Jnsen, G. E. Wright, nd R. R. Lorber Rndomized controlled tril of the comprtive efficcy, uditory toxicity, nd nephrotoxicity of tobrmycin nd netilmicin. Lncet i: Lipsky, J. J., nd P. S. Lietmn Aminoglycoside inhibition of renl phosphtidylinositol phospholipse Cl. J. Phrmcol. Exp. Ther. 22: Luft, F. C., R. Bloch, R. S. Slon, M. N. Yum, R. Costello, nd D. R. Mxwell Comprtive nephrotoxicity of minoglycoside ntibiotics in rts. J. Infect. Dis. 138: Luft, F. C., M. N. Yum, nd S. A. Kleit Comprtive nephrotoxicities of netilmicin nd gentmicin in rts. Antimicrob. Agents Chemother. 1: Metzler, C. M NONLIN: computer progrm for prmeter estimtion in nonliner situtions. Technicl report 792/69/7292/5. The Upjohn Co., Klmzoo, Mich. 17. Morin, J. P., nd J. P. Fillstre Aminoglycoside induced lysosoml dysfunctions in kidney, p In A. Whelton nd H. C. Neu (ed.), The minoglycosides. Mrcel Dekker, Inc., New York. 18. Ormsby, A. M., R. A. Prker, C. E. Plmp, P. Stevens, D. C. Houghton, D. N. Gilbert, nd W. M. Bennett Comprison of the nephrotoxic potentil of gentmicin, tobrmycin nd netilmicin in the rt. Curr. Ther. Res. Clin. Exp. 25: Pnwlker, A. P., J. B. Mlow, V. M. Zimelis, nd G. G. Jckson Netilmicin: clinicl efficcy, tolernce, nd toxicity. Antimicrob. Agents Chemother. 13: Prker, R. A., D. N. Gilbert, D. C. Houghton, G. A. Porter, nd W. M. Bennett Comprtive nephrotoxicities of highdose netilmicin nd tobrmycin in rts. Antimicrob. Agents Chemother. 18: Regmey, C., R. C. Gordon, nd W. M. M. Kirby Comprtive phrmcokinetics of tobrmycin nd gentmicin. Clin. Phrmcol. Ther. 14: Schentg, J. J Specificity of renl tubulr dmge criteri for minoglycoside nephrotoxicity in criticlly ill ptients. J. Clin. Phrmcol. 23: Schentg, J. J., T. J. Cumbo, W. J. Jusko, nd M. E. Plut Gentmicin tissue ccumultion nd nephrotoxic rections. J. Am. Med. Assoc. 24: Schentg, J. J., W. J. Jusko, J. W. Vnce, T. J. Cumbo, E. Abrutyn, M. DeLttre, nd L. M. Gerbrcht Gentmicin disposition nd tissue ccumultion on multiple dosing. J. Phrmcokinet. Biophrm. 5: Schentg, J. J., G. Lsezky, T. J. Cumbo, M. E. Plut, nd W. J. Jusko Accumultion phrmcokinetics of tobrmycin. Antimicrob. Agents Chemother. 13: Schentg, J. J., M. E. Plut, nd F. B. Cerr Comprtive nephrotoxicity of gentmicin nd tobrmycin: phrmcokinetic nd clinicl studies in 21 ptients. Antimicrob. Agents Chemother. 19: Snydmn, D. R., F. P. Tlly, S. H. Lndesmn, M. Brz, nd S. L. Gorbch Netilmicin in grm-negtive bcteril infections. Antimicrob. Agents Chemother. 15: Trestmn, I., J. Prsons, J. Sntoro, G. Goodhrt, nd D. Kye Phrmcology nd efficcy of netilmicin. Antimicrob. Agents Chemother. 13: Tulkens, P. M., M. E. DeBroe, P. Lldgue, nd J. A. Heuson- Stiennon Lysosoml ltertions in minoglycoside induced cute renl filure, p In K. Solez nd A. Whelton (ed.), Acute renl filure. Mrcel Dekker, Inc., New York.