function. As a result of a recent increase in the dose being used in clinical investigations, this study was undertaken to evaluate

Transcription

1 ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Jn. 1992, p /92/1115-6$2./ Copyright C 1992, Americn Society for Microbiology Vol. 36, No. 1 Phrmcokinetics of Teicoplnin upon Multiple-Dose Intrvenous Administrtion of 3, 12, nd 3 Milligrms per Kilogrm of Body Weight to Helthy Mle Volunteers JACQUELYN A. SMITHERS,' HENRIK K. KULMALA,1 GARY A. THOMPSON,'* KELLY K. ANTONY,' ERIC W. LEWIS,1 STEPHEN J. RUBERG,1 MICHAEL T. KENNY,2 JACQUELINE K. DULWORTH,2 AND MARCIA A. BRACKMAN2 Mrion Merrell Dow Reserch Institute, Cincinnti, Ohio ,1 nd Mrion Merrell Dow Reserch Institute, Indinpolis, Indin Received 3 June 1991/Accepted 9 October 1991 Teicoplnin phrmcokinetics were evluted fter multiple-dose intrvenous dministrtion to helthy mle volunteers by using rndomied, double-blind, prllel design. Doses of 3, 12, or 3 mg of teicoplnin per kg of body weight were dministered every 24 h for 14 dys s 6-min constnt-rte intrvenous infusions. Blood nd urine smples were collected over 21 dys nd nlyed by microbiologicl ssy. Twenty-three subjects were included in the phrmcokinetic nlysis. The medin phrmcokinetic prmeters upon multiple-dose intrvenous dministrtion of 3, 12, nd 3 mg/kg included stedy-stte volumes of distribution of.94,.77, nd.68 liter/kg; totl clernces of 11.9, 12., nd 13.2 ml/h/kg; nd terminl disposition hlf-lives of 143, 166, nd 96 h, respectively. Renl clernce ccounted for pproximtely 95% of totl clernce. No dose-relted differences existed for teicoplnin totl or renl clernce. The stedy-stte volume of distribution decresed significntly with incresing doses. As result of the decrese in the volume of distribution, the terminl disposition hlf-life t 3 mg/kg ws significntly decresed. However, the decreses in the volume of distribution nd terminl disposition hlf-life re of limited clinicl importnce, since stedy-stte trough concentrtions in serum increse in proportion to dose. Combined results of ll multiple-dose studies with similr durtions of smple collection indicte no dose-relted differences for ny phrmcokinetic prmeters from 3 to 12 mg/kg. As observed in the present study, no dose-relted differences exist for teicoplnin totl nd renl clernces from 3 to 3 mg/kg. However, t 3 mg/kg, significnt decrese in the stedy-stte volume of distribution is observed. As consequence of the reduction in the volume of distribution t 3 mg/kg with no chnge in clernce, the terminl disposition hlf-life is decresed. Teicoplnin is new glycopeptide ntibiotic, chemiclly relted to vncomycin nd ristocetin. It is ctive ginst erobic nd nerobic grm-positive bcteri (4, 8, 12, 15). Its effect on susceptible bcteri is bctericidl, nd like vncomycin, it interferes with cell wll synthesis (18). In erlier studies, the phrmcokinetics of teicoplnin were determined on the bsis of plsm concentrtion-time profiles obtined over 3 to 4 dys (22, 24). A review of these studies hs recently been published (16). In more recent studies, the durtion of smple collection hs been extended up to 3 weeks, resulting in more complete chrcterition of the serum concentrtion-time profile (1, 11, 14, 21). As result of the increse in the durtion of smple collection, teicoplnin totl clernce ws found to be slightly less nd the volumes of distribution nd terminl disposition hlf-life were found to be greter thn previously reported. Results from these more recent studies indicte tht the phrmcokinetics of teicoplnin upon multiple-dose intrvenous dministrtion re liner over the rnge of 3 to 12 mg/kg of body weight (11, 14, 21). Over this rnge of doses, teicoplnin phrmcokinetics re chrcteried by the following medin prmeters: totl clernce of 13.1 ml/h/kg, renl clernce of 1.8 mlih/kg, stedy-stte volume of distribution of 1.2 liters/kg, nd terminl disposition hlf-life of 157 h. These results indicte tht totl clernce is determined * Corresponding uthor. 115 predominntly by renl clernce nd tht dosge djustments my be necessry for ptients with impired renl function. As result of recent increse in the dose being used in clinicl investigtions, this study ws undertken to evlute the phrmcokinetics of teicoplnin upon multiple-dose intrvenous dministrtion of 3, 12, nd 3 mg/kg to helthy volunteers ksIIim o U) FIG. 1. Men (± stndrd devition) serum concentrtion-time profile upon multiple-dose intrvenous dministrtion of 3 mg of teicoplnin per kg.

2 116 SMITHERS ET AL. ANTIMICROB. AGENTS CHEMOTHER. 1. O 1. Ni 1.- S Z 11- co FIG. 2. Men (+ stndrd devition) serum concentrtion-time profile upon multiple-dose intrvenous dministrtion of 12 mg of teicoplnin per kg. MATERIALS AND METHODS Study design. This ws rndomied, double-blind, prllel study consisting of three different dosge regimens. Inclusion criteri included tht volunteers be helthy mles of ny rce, between 21 nd 45 yers of ge, nd without cliniclly significnt bnormlities upon physicl exmintion, lbortory evlution, or electrocrdiogrm. Exclusion criteri included cute or chronic illness, cute or chronic mediction, tobcco use within the pst 3 months, nd lcohol or drug buse. Institutionl Review Bord pprovl nd written informed consent were obtined prior to the strt of the study. Doses of 3, 12, or 3 mg of teicoplnin (lot IC-4198; Mrion Merrell Dow Inc.) per kg were dministered every 24 h for 14 dys. All doses were dministered s 6-min constnt-rte intrvenous infusions. Blood smples were obtined for the following doses t the indicted times: dose 1,, 6, 65, 7, 75, 9, nd 12 min nd 3, 4, 6, 8, 1, 12, nd 16 h fter the strt of the infusion; doses 2 through 13, (immeditely prior to dosing) nd 6 min fter the strt of the infusion; nd dose 14,, 6, 65, 7, 75, 9, nd 12 min nd 3, 4, 6, 8, 1, 12, 16, 24, 36, 48, 6, 72, 84, 96, 18, 12, 132, 144, 156, 168, 18, nd 192 h fter the strt of the infusion. Urine specimens were pooled every 24 h for 21 dys. Anlyticl methods. Serum smples (hrvested from blood smples) nd urine smples were nlyed for teicoplnin by vlidted microbiologicl ssy (5) which is liner over the cc FIG. 4. Observed (circles) nd predicted (line) serum concentrtion-time profiles upon multiple-dose intrvenous dministrtion of 3 mg of teicoplnin per kg (subject 118). rnge of.2 to 96 mg/liter. Smples with concentrtions bove the upper rnge of the stndrd curve were diluted nd renlyed. Within- nd between-dy coefficients of vrition were less thn 1%. The lower limits of quntittion for serum nd urine smples were.2 nd 2. mg/liter, respectively. Phrmcokinetic nlysis. Serum concentrtion-time dt obtined throughout multiple dosing were nlyed with NONLIN84 (19) nd the following eqution: k n C = E E{[DJ/Dj] [CJI(-Li TI1)] [1 - e(li bj)] * [e-(li t-)]} j=1 i=1 where k is the number of doses dministered; n is the number of exponentils necessry to chrcterie the serum concentrtion-time profile; Dj is the sie of the jth dose (in milligrms per kilogrm); D1 is the sie of the initil dose (in milligrms per kilogrm); Ci is the ith coefficient which corresponds to 3, 12, or 3 mg/kg; Li is the ith exponent; TI is the durtion of the jth infusion; bj is second independent vrible, equl to tj during the jth infusion nd equl to TbI fter the jth infusion; nd tj is the time fter the strt of the jth infusion. Initil prmeter estimtes were obtined from previous study conducted with helthy volunteers (11). Vrious weightings of the observed concentrtions in serum (1, 11C'-5, 1/C, nd 1/C2) were used in the dt nlysis. Decisions bout the pproprite weighting nd the number of 15 -I - J Ul 2 Uj LU 12 g 9 i FIG. 3. Men (t stndrd devition) serum concentrtion-time profile upon multiple-dose intrvenous dministrtion of 3 mg of teicoplnin per kg FIG. 5. Teicoplnin totl clernce (CL) versus dose (D) upon multiple-dose intrvenous dministrtion of 3, 12, nd 3 mg/kg to norml volunteers. Circles re the observed dt; the line is the predicted reltionship from liner regression [CL = (.36. D); r2 =.12; slope, P =.2; intercept, P <.1]. 3

3 VOL. 36, 1992 PHARMACOKINETICS OF TEICOPLANIN UPON MULTIPLE DOSING 117 TABLE 1. Teicoplnin phrmcokinetic prmeters upon multiple-dose intrvenous dministrtion of 3 mg/kg to helthy volunteers Sub Age Wt Ht VC Vss V CL CLR MRT ti/2 (yr) (kg) (cm) (liters/kg) (liters/kg) (liters/kg) (mi/h/kg) (mi/h/kg) (h) (h) b b b " " Medin Men SD Sub, subject; Vc, volume of the centrl comprtment; Vss, volume of distribution t stedy stte; V, terminl phse volume of distribution; CL, totl clernce; CLR, renl clernce; MRT, men residence time; t2, terminl disposition hlf-life. btheoreticlly, CLR is smller thn or equl to CL; since CL is determined primrily by CLR, norml vribility in dt results in CLR being slightly lrger thn CL. exponentils required to chrcterie the serum concentrtion-time dt were bsed on visul inspection of the rndomness of sctter of the observed dt bout the fitted line, the sum of weighted squred residuls, nd the F-test rtio (3). Renl clernce ws determined s the rtio of the totl mount of teicoplnin recovered from urine to the re under the predicted serum concentrtion-time profile (determined over the sme time intervl). Are under the predicted serum concentrtion-time profile ws determined with the liner trpeoidl rule (with concentrtions predicted every.1 h). Volumes of distribution, totl clernce, men residence time, nd terminl disposition hlf-life were obtined from the coefficients nd exponents by stndrd equtions (6, 9, 25) Ṡttisticl nlysis. Subject demogrphics for ech dose were compred by one-wy nlysis of vrince. Robust liner regression (M estimtion) ws used to ssess the influence of dose on the phrmcokinetic prmeters. Huber's T function ws used with cutoff (tuning constnt) of 1 (7). When there ws significnt trend with ll doses, the highest dose ws deleted nd the robust trend procedure ws repeted for the reduced rnge of doses with the men squre error term from the nlysis of ll doses. This step-down process ws ccomplished with contrst sttements following one-wy nlysis of vrince nd is similr to the procedure described by Tukey et l. (23). Results with P vlue of <.5 were considered sttisticlly significnt. RESULTS This study ws conducted with 26 helthy mle volunteers rnging from 21 to 3 yers of ge (See Tbles 1 to 3). No demogrphic differences existed between groups. As result of dverse events in three subjects, 23 subjects were included in the phrmcokinetic nlysis. dverse events requiring exclusion from the study were urticri in two subjects (12 mg/kg) nd thrombocytopeni in one subject (3 mg/kg). As result of the dverse event t 3 mg/kg, other subjects in this group were dministered only 1 doses. Plots of the men observed serum concentrtion-time profiles following 3, 12, nd 3 mg/kg re presented in Fig. 1, 2, nd 3, respectively. A plot of the observed nd predicted serum concentrtion-time profiles for representtive subject is presented in Fig. 4. Excellent greement between the TABLE 2. Teicoplnin phrmcokinetic prmeters upon multiple-dose intrvenous dministrtion of 12 mg/kg to helthy volunteers Sub Age Wt Ht VC Vss V CL CLI MRT t1/2 (yr) (kg) (cm) (liters/kg) (liters/kg) (liters/kg) (mi/h/kg) (ml/h/kg) (h) (h) " b Medin Men SD For bbrevitions, see Tble 1, footnote. btheoreticlly, CLR is smller thn or equl to CL; since CL is determined primrily by CLR, norml vribility in dt results in CLR being slightly lrger thn CL.

4 118 SMITHERS ET AL. ANTIMICROB. AGENTS CHEMOTHER. TABLE 3. Teicoplnin phrmcokinetic prmeters upon multiple-dose intrvenous dministrtion of 3 mg/kg to helthy volunteers Sub Age Wt Ht VC vss V CL CLR MRT ti/2 (yr) (kg) (cm) (liters/kg) (liters/kg) (liters/kg) (m/h/lkg) (mih/kg) (h) (h) 1i " Medin Men SD For bbrevitions, see Tble 1, footnote. btheoreticlly, CLR is smller thn or equl to CL; since CL is determined primrily by CLR, norml vribility in dt results in CLR being slightly lrger thn CL. observed nd predicted serum concentrtion-time profiles indictes the dequcy of these nlyses. For ll subjects except subject 13, weight of llc2 ws used. A weight of l/c, which ws used for subject 13, resulted in more rndom residuls. Individul phrmcokinetic prmeters of teicoplnin following multiple-dose intrvenous dministrtion of 3, 12, nd 3 mg/kg re shown in Tbles 1, 2, nd 3, respectively. Sttisticl nlyses indicted no dose-relted differences in teicoplnin totl clernce (P =.2) or renl clernce (P =.64) (Fig. 5 nd 6, respectively). With ll three doses, significnt decrese in the stedy-stte volume of distribution with n increse in the dose ws observed (P =.7) (Fig. 7). As result of decresing volume of distribution with n incresing dose, the terminl disposition hlf-life following 3 mg/kg ws significntly shorter thn tht observed following 3 or 12 mg/kg (P =.4), with no difference between 3 nd 12 mg/kg (P =.3) (Fig. 8). DISCUSSION Teicoplnin is glycopeptide ntibiotic which is ctive ginst erobic nd nerobic grm-positive bcteri (4, 8, 12, 15). Results from previous studies conducted with norml helthy volunteers indicte tht the phrmcokinetics of teicoplnin upon multiple-dose intrvenous dministrtion re liner over the rnge of 3 to 12 mg/kg (11, 14, 21). In the present study, the phrmcokinetics of teicoplnin upon multiple-dose intrvenous dministrtion of 3, 12, nd 3 mg/kg were investigted. Results of the present study indicte tht teicoplnin totl nd renl clernces re independent of dose nd tht totl clernce is determined primrily by renl clernce. At 3 mg/kg, the stedy-stte volume of distribution decreses. According to the model of ie nd Toer (13), decrese in the volume of distribution cn result from n increse in plsm protein binding, decrese in tissue protein binding, or both. Although these fctors re not investigted in this study, previous work indictes tht teicoplnin plsm protein binding is independent of concentrtion over the rnge of 2 to 1 mg/liter nd tht teicoplnin binds primrily to lbumin (2, 1). Since lbumin concentrtions in subjects dministered 3 mg/kg were similr to those in subjects dministered 3 nd 12 mg/kg, it is presumed tht the decrese in the volume of distribution is relted to reduction in tissue protein binding. As result of the decresed volume of distribution with no chnge in clernce, the terminl disposition hlf-life is decresed (9). As determined with MLTIDOSE (2) nd the results obtined in this study, predicted medin (rnge) stedy-stte trough concentrtions in serum following 3, 12, nd 3 mg/kg every 24 h s 3-min constnt-rte intrvenous infusions re 7.2 (5.7 to 8.6), 27.7 (22.3 to 3.8), nd 58.1 (51.7 to 87.8) mg/liter, respectively. Sttisticl nlysis indictes tht stedy-stte concentrtions in serum increse in proportion to dose Cs 1.6 y co r' 1.2 uj Z J 9 LL *2 O.8 6- ul 3 FIG. 6. Tieicoplnin totl clernce (CLR) versus dose (D) upon multiple-dose intrvenous dministrtion of 3, 12, nd 3 mg/kg to norml volunteers. Circles re the observed dt; the line is the predicted reltionship from liner regression [CLR = + (.18 D); r2 =.12; slope, P =.65; intercept, P <.1] cn 12 FIG. 7. Teicoplnin stedy-stte volume of distribution (Vss) versus dose (D) upon multiple-dose intrvenous dministrtion of 3, 12, nd 3 mg/kg to norml volunteers. Circles re the observed dt; the line is the predicted reltionship from liner regression [Vss = (.11 * D); r2 =.48; slope, P =.7; intercept, P <.1]. 3

5 VOL. 36, 1992 PHARMACOKINETICS OF TEICOPLANIN UPON. MULTIPLE DOSING 119 Dose TABLE 4. Comprison of teicoplnin phrmcokinetics upon multiple-dose intrvenous dministrtion of 3, 6, 12, nd 3 mg/kg to helthy volunteers Medin vlue (rnge) for: (mg/kg) Vss (liters/kg) CL (mi/b/kg) CLR (mn/ h/g2 ) 3 b (1.-2.4) 14.8 ( ) 1.4 ( ) 156 (66-48) 3c 1.94 ( ) 11.9 ( ) 12.1 ( ) 143 (62-192) 6d 6 1. (.8-2.3) 12.4 ( ) 11.1 ( ) 138 (68-327) 6e (.9-1.6) 12.2 ( ) 11.1 ( ) 159 ( ) 12e (.9-1.3) 14. ( ) 1.3 ( ) 155 (13-171) 12C 9.77 (.6-1.4) 12. ( ) 11. ( ) 166 (58-231) 3C 4.68 ( ) 13.2 ( ) 12.3 ( ) 96 (77-1) n, number of subjects. For other bbrevitions, see Tble 1, footnote. b Dt re from reference 11. c Dt re from the present study. d Dt re from reference 14. e Dt re from reference 21. Results from multiple-dose studies with similr designs re summried in Tble 4 (11, 14, 21; lso the present study). In the present study, the stedy-stte volumes of distribution ppered to be lower thn those previously' observed. Other thn intersubject vribility, there' is no pprent explntion for these results. When results cross these studies re combined (Tble 4), the medin phrmcokinetic prmeters include' totl clernce of 12.6 ml/h/kg, renl clernce of 11. mi/h/kg, stedy-stte volume of distribution of 1.Q liter/kg, nd terminl disposition hlf-life of 155 h. Sttisticl nlyses of these results indicte no dose-relted differences for ny phrmcokinetic prmeters over the dose rnge of 3 to 12 mg/kg. In ddition, no dose-relted differences exist for teicoplnin totl nd renl clernces from 3 to 3 mg/kg (P =.96 nd P '=.2, respectively). Howeyer, t 3 mg/kg, significnt decrese in the stedy-stte volume of distribution (P =.2) is observed, nd s consequence, the terminl disposition hlf-life decrese is 'of borderline significnce (P =.7). In conclusion, teicoplnin totl nd renl clernces re independent of dose upon multiple-dose intrvenous dministrtion of 3 to 3 mg/kg to norml mle volunteers. The stedy-stte volume of distribution decreses s the dose increses, resulting in decrese in the terminl disposition hlf-life. However, the decreses in the volume of distribution nd terminl disposition hlf-life re of limited clinicl importnce, since totl clernce, which reltes the verge 25 2 I 15 UL I1 5 I FIG. 8. Teicoplnin terminl disposition hlf-life (1/2) versus dose (D) upon multiple-dose intrvenous dministrtion of 3, 12, nd 3 mg/kg to norml volunteers. Circles re the observed dt; the line is the predicted reltionship from liner regression [t1/2, = (1.722* D); r2 =.32; slope, P =.439; intercept, P <.1]. stedy-stte concentrtion in serum to the dose, shows no dose-relted differences. This is further confirmed on the bsis of the dose-proportionl increse in stedy-stte trough concentrtions in serum. Since the predicted serum concentrtion-time profiles re bsed on results obtined from norml volunteers, dditionl verifiction of these results with ptients (e.g., monitoring of concentrtion in serum) could be useful in identifying subpopultions in which the phrmcokinetics of teicoplnin re significntly ltered (17). ACKNOWLEDGMENTS We re grteful to the following individuls for their constructive review of the mnuscript, their ssistnce in the nlysis of smples, nd/or their help in conducting this study: Frnk J. Blistreri, Hrold Boxenbum, Nicolette L.'Cvllro, Irene L. Dyke, Michel C. Grhm, Gillin Ivers-Red, Gerld D. Myer, Mrci E. Morgn, Richrd A. Okerholm, nd Isrel Rios. REFERENCES 1. Antony, K. K., E. W. Lewis, M. T. Kenny, J. K. Dulworth, M. B. Brckmn, R. Kum, L. Yuh, M. G. Elier, nd G. A. Thompson Phrmcokinetics nd biovilbility of new formultion of teicoplnin following intrvenous nd intrmusculr dministrtion to humns. J. Phrm. Sci. 8: Assndri, A., nd A. Bernreggi Binding of teicoplnin to humn serum lbumin. Eur. J.'Clin. Phrmcol. 33: Boxenbum, H. G., S. Riegelmn, nd' R. M. Elshoff Sttisticl estimtions in phrmcokinetics. J. Phrmcokinet. Bio'phrm. 2: Cynmon, M. H., nd P. H. Grnto Comprison of the in vitro ctivities of teichomycin A2 nd vncomycin ginst stphylococci nd enterococci. Antimicrob. Agents Chemother. 21: Ericksoh, R. C., A. R. Hildebrnd, P. F. Hoffinn, nd C. B. Gibson A sensitive biossy for teicoplnin in the presence or bsence of other ntibiotics. Dign. Microbiol. Infect. Dis. 12: Gibldi, M., nd D. Perrier Phrmcokinetics, 2nd ed. Mrcel Dekker, Inc., New York. 7. Hmpel, F. R., E. M. Ronchetti, P. J. Rousseeuw, nd W. A. Sthel Robust sttistics: the pproch bsed on influence functions, p , John Wiley nd Sons, New York. 8. Jdej, L., V. Finstein, B. LeBlnc, nd G. P. Bodey Comprtive in vitro ctivities of teichomycin nd other ntibiotics ginst JK diphtheroids. Antimicrob. Agents Chemother. 24: Jusko, W. J Guidelines for collection nd nlysis of phrmcokinetic dt, p In W. E. Evns, J. J. Schentg,

6 12 SMITHERS ET AL. nd W. J. Jusko (ed.), Applied phrmcokinetics: principles of therpeutic drug monitoring, 2nd ed. Applied Therpeutics, Inc., Spokne, Wsh. 1. Khor, S. P., M. Myersohn, nd G. A. Thompson Teicoplnin (TCP) plsm protein binding by ultrfiltrtion (UF) nd equilibrium dilysis (ED). Phrm. Res. 7:S Mrion Merrell Dow, Inc Dt on file. Teicoplnin phrmcokinetics in norml helthy volunteers upon multiple dose dministrtion of 3 mg/kg. Project report DR Mrion Merrell Dow, Inc., Cincinnti. 12. Neu, H. C., nd P. Lbthvikul In vitro ctivity of teichomycin compred with those of other ntibiotics. Antimicrob. Agents Chemother. 24: ie, S., nd T. N. Toer Effect of ltered plsm protein binding on pprent volume of distribution. J. Phrm. Sci. 68: Outmn, W. R., C. H. Nightingle, K. R. Sweeney, nd R. Quintilini Teicoplnin phrmcokinetics in helthy volunteers fter dministrtion of intrvenous loding nd mintennce doses. Antimicrob. Agents Chemother. 34: Plln, R., M. Berti, B. Goldstein, E. Mpelli, E. Rndisi, R. Scotti, nd V. Arioli Teichomycin: in vitro nd in vivo evlution in comprison with other ntibiotics. J. Antimicrob. Chemother. 11: Rowlnd, M Clinicl phrmcokinetics of teicoplnin. Clin. Phrmcokinet. 18: Rybk, M. J., S. A. Lerner, D. P. Levine, L. M. Albrecht, P. L. McNeil, G. A. Thompson, M. T. Kenny, nd L. Yuh Teicoplnin phrmcokinetics in intrvenous drug busers being treted for bcteril endocrditis. Antimicrob. Agents Chemother. 35: ANTIMICROB. AGENTS CHEMOTHER. 18. Somm, S., nd L. Gstldo Mechnism of ction of teichomycin A2, new ntibiotic, p In P. Periti nd G. G. Grssi (ed.), Current chemotherpy nd immunotherpy. Proceedings of the 12th ICC, vol. 1. Americn Society for Microbiology, Wshington, D.C. 19. Sttisticl Consultnts, Inc PCNONLIN nd NONLIN84: softwre for the sttisticl nlysis of nonliner models. Am. Stt. 4: Thompson, G. A., nd R. C. Shumker MLTIDOSE: multiple-dose simultion progrm for liner systems chrcteried by exponentil functions. Drug. Metb. Rev. 21: Thompson, G. A., J. A. Smithers, M. T. Kenny, J. K. Dulworth, H. K. Kulml, L. Yuh, E. W. Lewis, nd K. K. Antony. Phrmcokinetics of teicoplnin upon multiple dose intrvenous dministrtion of 6 nd 12 mg/kg to norml helthy mle volunteers. Biophrm. Drug Dispos., in press. 22. Trin, G. L., nd M. Bonti Phrmcokinetics of teicoplnin in mn fter intrvenous dministrtion. J. Phrmcokinet. Biophrm. 12: Tukey, J. W., J. L. Ciminer, nd J. F. Heyse Testing the sttisticl certinty of response to incresing doses of drug. Biometrics 41: Verbist, L., B. Tjndrmg, B. Hendrickx, A. Vn Hecken, P. Vn Melle, R. Verbesselt, J. Verhegen, nd P. J. De Schepper In vitro ctivity nd humn phrmcokinetics of teicoplnin. Antimicrob. Agents Chemother. 26: Wgner, J. G Liner phrmcokinetic equtions llowing direct clcultion of mny needed phrmcokinetic prmeters from the coefficient nd exponents of polyexponentil equtions which hve been fitted to the dt. J. Phrmcokinet. Biophrm. 4: