M Sandström 1, MO Karlsson 1, P Ljungman 2, Z Hassan 3, EN Jonsson 1, C Nilsson 3, O Ringden 4, GÖberg 5, A Bekassy 6 and M Hassan 3.

Transcription

1 (21) 28, Nture Publishing Group All rights reserved /1 $15. Phrmcokinetics Popultion phrmcokinetic nlysis resulting in tool for dose individuliztion of busulphn in bone mrrow trnsplnttion recipients M Sndström 1, MO Krlsson 1, P Ljungmn 2, Z Hssn 3, EN Jonsson 1, C Nilsson 3, O Ringden 4, GÖberg 5, A Bekssy 6 nd M Hssn 3 1 Deprtment of Phrmceuticl Biosciences, Division of Phrmcokinetics nd Drug Therpy, Fculty of Phrmcy, Uppsl University, Sweden; 2 Deprtment of Medicine, Division of Hemtology, Huddinge University Hospitl, Stockholm, Sweden; 3 Deprtment of Medicine, Division of Hemtology, Lbortory of Hemtology, KFC Novum, Huddinge University Hospitl, Stockholm, Sweden; 4 Center for Allogeneic Stem Cell Trnsplnttion, Division of Clinicl Immunology, Huddinge University Hospitl, Stockholm, Sweden; 5 Deprtment of Medicine, Division of Hemtology, Uppsl University Hospitl, Uppsl, Sweden; nd 6 Deprtment of Peditrics, Lund University Hospitl, Lund, Sweden Summry: The ims of the present study were (1) to investigte nd quntify the phrmcokinetics, including inter-occsion vribility nd covrite reltionships, of busulphn in BMT ptients nd (2) to develop user-friendly initil dosing nd therpeutic drug monitoring (TDM) strtegy for the tretment of those ptients with busulphn. The phrmcokinetics of busulphn ws studied in 64 dults nd 12 children who received busulphn (1 mg/kg) four times dily for 4 dys. A one-comprtment model with first order bsorption nd lg time ws sufficient in describing the concentrtion-time profile. Orl clernce (CL/F) ws found to be correlted to weight (+1.2%/kg), ALT ( 13%/ ct/l) nd concomitnt phenytoin tretment (+21%). CL/F nd the volume of distribution (V/F) were estimted to 9.23 l/h nd 39.3 l, respectively, in typicl individul. Inter-occsion vribility (9.4%) in CL/F ws estimted to be less thn inter-individul vribility (28%), prerequisite for the vlue of TDM. Byesin CL/F estimtes bsed on three smples were in good ccordnce with those bsed on ll smples. The finl popultion model ws implemented into the progrm Excel. The resulting flexible nd esy to use dosing progrm might be used for both initil nd, requiring only three plsm smples, mintennce dose individuliztion of busulphn therpy. (21) 28, Keywords: busulphn; phrmcokinetics; popultion nlysis; phenytoin; TDM; phrmcokinetic interction Correspondence: M Sndström, Deprtment of Phrmceuticl Biosciences, Division of Phrmcokinetics nd Drug Therpy, Fculty of Phrmcy, Uppsl University, Box 591, S Uppsl, Sweden Received 21 Februry 21; ccepted 17 July 21 Busulphn is n lkylting gent tht, in combintion with cyclophosphmide, is widely used in high doses s prt of the myelobltive conditioning regimen prior to both llogenic nd utologous bone mrrow trnsplnttion. 1 4 As do most cytotoxic drugs, busulphn hs nrrow therpeutic window. Over-dosing hs been shown to increse the risk of developing veno-occlusive disese (VOD), wheres under-dosing my result in engrftment filure or relpse. Although therpeutic window for busulphn is not clerly defined, previous reports indicte tht dily exposure (AUC, re under the concentrtion-time curve) of pproximtely 2 24 mg.h/l in ptients receiving busulphn four times dily for 4 dys, ie totl AUC of 8 96 mg.h/l, prevents therpy filure without being ssocited with n uncceptbly high risk of developing VOD. 5 8 The phrmcokinetics of busulphn hve been extensively investigted in both children nd dults. 6,9 11 In dults the elimintion cpcity of busulphn is correlted to ptient weight (WT), wheres in children body surfce re (BSA) seems to be better indictor. 12 Although corrected for those fctors, wide inter-individul vribility in orl clernce, CL divided by frction bsorbed (CL/F), hs been described by mny uthors. 6,13 Severl explntions for this hve been proposed mong which re differences in ge, genetics, circdin rhythm, disese nd drug drug interctions. 7,14 17 Since there seems to be reltionship between busulphn exposure nd phrmcodynmics it hs been speculted tht the use of busulphn could be optimized using therpeutic drug (concentrtion) monitoring (TDM) tht hs lso been prctised. 8,18,19 In one study, it ws shown tht the incidence of VOD in ptients who initilly experienced n AUC of less thn 5.5 mg.h/l ws reduced from 75% to 18% when TDM-bsed dose djustments were crried out. 18 Severl pproches for routine estimtion of individul busulphn CL/F hve been proposed. 1,12,2 22 However, the proposed methods re either bsed on full profile chrcteriztion or limited smpling lgebric eqution nd hve prcticl nd/or sttisticl disdvntges.

2 658 Popultion phrmcokinetics of busulphn The vlue of TDM in nti-cncer therpy is often limited by intr-individul vribility. Severl uthors hve reported n indiction of inter-occsion vribility in the CL/F of busulphn However, this phenomenon hs to our knowledge not yet been quntified. The ims of the present study were (1) to investigte nd quntify the phrmcokinetics, including inter-occsion vribility nd covrite reltionships, of busulphn in BMT ptients; nd (2) to develop user-friendly initil dosing nd TDM strtegy for the tretment of such ptients with busulphn. Mterils nd methods Ptients A totl of 76 Cucsin ptients (64 dults nd 12 children), receiving their first BMT in Sweden between 1987 nd 1996, were studied. Busulphn ws given orlly four times dily. Seventy-one ptients received 16 doses s prt of their conditioning nd five ptients (CML) received only eight doses combined with totl body irrdition (TBI). The dose dministered ws 1 mg/kg (bsed on ctul weight) with one exception: one child received 2 mg/kg (bsed on ctul weight). In order to prevent seizures cused by busulphn, either phenytoin or clonzepm ws dministered orlly for 5 dys, strting the dy before inititing busulphn therpy. Thirty-six dults nd seven children were treted with phenytoin, 5 mg/kg once dily. The remining group of ptients received clonzepm, dults 2 3 mg nd children mg, twice dily. The study popultion is described in Tble 1. The study ws pproved by the regionl ethicl committee of Krolinsk Institutet nd the locl ethicl committees of Uppsl University hospitl nd Lund University hospitl. Smpling nd busulphn determintion Blood smples were withdrwn from permnently plced centrl venous lines before strting busulphn therpy nd therefter t.25,.5,.75, 1, 1.5, 2, 3, 4, 5 nd 6 h fter the first dose. Smples ssocited with the intermedite doses were drwn immeditely before dose dministrtion. After the lst dose smpling ws mde ccording to the initil smpling scheme nd in ddition blood ws collected t 8, 1, 12, 16, 2 nd 24 h fter given dose. Blood ws collected in heprinized (15 units) glss tubes nd therefter centrifuged t 2 g. The plsm ws stored in 2 C until nlysis. Busulphn ws determined using gschromtogrphy with electron cpture detection s described elsewere. 26 Phrmcokinetic nlysis Determintion of the best phrmcokinetic model describing the concentrtion-time profile of busulfn ws mde by mixed effects modelling, using the centered FOCE method within the progrm NONMEM version VI. 27 The model ws built in steps. First, the bsic phrmcokinetic model ws developed nd then inter-occsion vribility (IOV) nd significnt covrites were dded. IOV ws introduced into the model s previously proposed. 28 Due to limittions in NONMEM in hndling IOV, concentrtions following nine of the intermedite occsions from ech ptient hd to be excluded from the dt set, nd dt from the first nd sixteenth dose were used together with trough concentrtions from five evenly smpled occsions. However, to minimize the risk of msking vribility cused by circdin rhythm phrmcokinetic informtion from ll qurtiles of the dy ws kept in the finl dt set. Additive, proportionl nd combined dditive-proportionl residul error models were evluted. The influence of the covrites ge, sex, BSA, WT, serum sprtte trnsminse (AST) nd serum lnine trnsminse (ALT), serum bilirubin (BILI) nd concomitnt phenytoin (PHE) tretment on CL/F nd V/F were investigted. Since there were no dt concerning PHE phrmcokinetics, only being on or off tretment ws considered. The covrites were introduced into the bsic model, in terms of liner reltionships, nd finlly the significnce (P.1) of ech ws tested by excluding them one t time. All evluted reltionships between the phrmcokinetic prmeters nd the continuous covrites were centered round the medin. The model building process ws guided by grphicl evlution within the progrm Xpose, version 3., 29 s well s the objective function vlue produced by NONMEM which is goodness of fit sttistic. For hierrchil models, drop in the objective vlue by more thn 3.84, 6.63 nd 1.83 denotes n improved fit tp.5,.1 nd.1, respectively, for one-prmeter difference. NONMEM lso produces individul prmeter estimtes, which re Tble 1 Popultion description Dose mg/dose BSA m 2 Age yr WT kg AST ct/l ALT ct/l BILI mol/l All ptients verge (s.d.) 61.6 (2.6) 1.67 (.42) 31.9 (15.1) 61.7 (21.4).54 (.33).66 (.56) 7.2 (3.3) (n = 74) rnge medin Children verge (s.d.) 22.9 (9.65).82 (.27) 5.6 (3.5) 21.2 (9.8).73 (.57).46 (.26) 4. (1.35) (n = 12) rnge medin Adults verge (s.d.) 69. (11.9) 1.83 (.18) 36.9 (1.4) 69.5 (12.2).5 (.26).7 (.6) 7.9 (3.2) (n = 62) rnge medin

3 obtined s empiricl Byes estimtes. Individul predicted concentrtions re bsed on those estimtes. Sprse smpling strtegy Since rich smpling is not only risk for the ptient but lso time- nd money-consuming, sprse smpling strtegy ws evluted. The time points 2, 4 nd 5 h fter the dministrtion of the initil dose, which were considered to cover the mjor prt of the concentrtion-time profile, were chosen. Therefter the individul prmeter estimtes were predicted s empiricl Byes estimtes in NONMEM, using the observtions t those time points, together with the finl popultion model. Model vlidtion The finl model ws vlidted s follows. One tenth of the individuls in the full dt set were rndomly omitted in sequence, resulting in 1 reduced dt sets, ech consisting of nine tenths of the full dt set. The prmeters in the finl model were then re-estimted bsed on ech reduced dt set, resulting in 1 new models. Ech of these models ws used to predict the prmeters of the individuls omitted either bsed on no observed concentrtions or bsed on smples withdrwn t 2, 4 nd 5 h fter the first dose. Simultions The expected consequences in terms of AUC following the four different dosing strtegies () nd (b) trditionl dosing, (c) dosing ccording to the finl popultion model nd (d) dosing s per the three-smple dptive control, were simulted for the individuls in the study popultion. The doses used in the simultion were hence () 1 mg/kg (bsed on ctul weight), (b) 37.5 mg/m 2, (c) trget AUC (AUC trget ) times the individul verge CL/F predicted by the finl popultion model only (CL/F pop,v ) nd (d) AUC trget times the individul course-verge orl clernce estimtes predicted from only three observtions, nd the finl popultion model (CL/F i,v,sprse ). AUC trget ws in the simultions set to 5.5 mg.h/l, which is bsed on erlier findings. 5,7,18 The simulted AUCs (AUC pred ) were clculted s dose divided by individul course verge orl clernce estimtes predicted from ll vilble smples nd the finl popultion model (CL/F i,v,ll ). Popultion phrmcokinetics of busulphn Results The dt The rw dt re presented in Figure 1. Due to dosing history incompleteness, dt from three of the individuls hd to be excluded from the dt set. The finl dt set consisted of totl of 1884 concentrtions (1144 courses) from 62 dults nd 12 children (Tble 1). Missing informtion bout ALT from 1 of the ptients in the finl dt set ws substituted with the medin vlue.55 mol/l. Phrmcokinetic nlysis A one-comprtment model with first order bsorption nd lg-time (Tlg) ws found to be sufficient in describing the vilble concentrtion-time dt. Inter-individul vribility (IIV) ws estimted on ll prmeters lthough on Tlg it ws only needed in ssocition with the first dose. IOV hd significnt influence on the prmeters CL/F, V/F nd k. The prmeter estimtes for the finl popultion model re given in Tble 2, wheres the individul prmeter estimtes re summrized in Tble 3. Model predicted concentrtions re pprent in Figure 2, b. A strong correltion estimted to.92 (SE rel 19%) ws found between CL/F nd V/F. A weker correltion,.62 (SE rel 6%), ws found between the IOV terms of CL/F nd V/F. The prmeter CL/F ws found to be significntly correlted with WT, ALT nd PHE, wheres WT ws the only covrite tht influenced V/F of busulphn. CL/F nd V/F both incresed with incresing WT. CL/F decresed with incresing ALT nd ws found to be higher in the ptients who were on PHE. The influence of PHE on CL/F ws lredy seen t the initil busulphn dose nd ws found to further increse (linerly) during the whole course. The finl popultion model predicts 21% higher course-verge CL/F in ptients on PHE, compred to those off PHE. Inclusion of the covrites sex, ge, BSA, AST nd BILI did not result in ny further improvement. A run bsed on dt from only the 64 ptients from whom ALT ws known resulted in prmeter estimtes tht differed only mrginlly from the estimtes in the finl model. The prmeter estimtes from the 1 different models tht re bsed on the reduced dt sets show only smll vritions. The coefficent of vrition (CV) of the prmeters mimicked the stndrd errors of the corresponding prmeter estimtes in the finl popultion model. 659 Tool for initil dosing nd dose djustments The gol ws to construct user-friendly id tht cn be used to optimize initil dosing for reching trget AUC, give good estimte of the individul verge CL/F nd, finlly, clculte the individulized mintennce dose tht results in n AUC ner the trget. Furthermore, since scheme with fixed smpling time points is not only inconvenient, but lso increses the risk of smpling time errors, flexible instrument is desirble. Therefore TDM templte ws developed, implementing the finl popultion model nd the Byesin fitting lgorithm, using the Excel progrm. Busulphn concentrtion ( m g/l) Figure Time fter initil dose (h) Observed busulphn concentrtions vs time.

4 66 Tble 2 Finl popultion model estimtes Popultion phrmcokinetics of busulphn Prmeter Estimte IIV % IOV % Covrite effects c WT ALT on PHE %/kg %/ ct/l initil, % time dep, %/h Phrmcokinetic CL/F (l/h) b 9.23 (4.2) 28 (17) 9.4 (43) 1.24 (9.) 12.7 (27) 13.3 (58) 1.43 (19) prmeters V/F (l) b 39.3 (2.5) 3 (22) 16 (43) 1.37 (9.8) k (h 1 ) 1.68 (3.) 99 (36) 76 (19) Tlg initil (h).218 (1.3) 22 (36) Tlg ss (h).218 (1.3) Residul error dditive ( g/l) 28.1 (33) proportionl (%) 23 (5.4) Vlues within brckets represent reltive stndrd errors in % of the estimtes. b The vlues presented for CL/F nd V/F represent estimtes for the typicl individul in the popultion, ie n 61.8 kg individul off phenytoin mediction hving n ALT of.55 ct/l. c Positive vlues denote n increse, wheres negtive vlues denote decrese on the typicl phrmcokinetic prmeters. Tble 3 Individul prmeter estimtes CL/F i,v,ll V/F i k i Tlg i t 1/2 h 1 h h l/h ml/min/kg l l/kg All ptients verge (s.d.) 1.29 (3.86) 3.6 (1.31) 4.1 (16.5).69 (.23) 2.46 (3.8).22 (.3) 2.68 (.42) (n = 74) rnge Children verge (s.d.) 5.55 (1.7) 4.98 (2.6) 18.4 (6.2).96 (.35) 4.99 (6.52).19 (.3) 2.3 (.36) (n = 12) rnge Adults verge (s.d.) (3.43) 2.69 (.64) 44.3 (14.4).64 (.16) 1.97 (2.85).23 (.2) 2.75 (.39) (n = 62) rnge CL/F i,v,ll = individul model predicted course-verge orl clernce bsed on ll smples; V/Fi = individul model predicted volume of distribution corrected for biovilbility; k i = individul model predicted bsorption rte constnt; Tlg i = lg time; t 1/2 = hlf-life. 35 b 35 Observed concentrtion ( m g/l) Observed concentrtion ( m g/l) Figure Model predicted concentrtion ( mg/l) (, b) Model predicted vs observed busulphn concentrtion. Individul model predicted concentrtion ( mg/l) Ech vlidtion model ws used to predict the prmeters of the individuls omitted. The correltion between the predicted course-verge CL/F without ny phrmcokinetic informtion (smples) from the ptients (CL/F pop,v,vl ), nd the CL/F i,v,ll is pprent in Figure 3. The individul CL/F estimtes t the first dose, predicted from the vlidtion model nd only three smples withdrwn 2, 4 nd 5 h fter the initil dose (CL/F i,init,sprse,vl ) were estimted to

5 Popultion phrmcokinetics of busulphn b c CL/Fi,v,ll (l/h) CL/Fi, ll (l/h)init CL/Fi,v,ll (l/h) CL/Fpop,v,vl (l/h) CL/Fi,init,sprse,vl (l/h) CL/Fi,v,sprse,vl (l/h) Figure 3 ( c) Individul CL/F estimtes predicted from ll vilble smples vs the corresponding estimtes predicted from either or three smples withdrwn t 2, 4 nd 5 h fter the first dose. () Course-verge CL/F estimted from ll vilble smples nd the finl popultion model (CL/F i,v,ll ) vs the corresponding estimte predicted by the respective vlidtion model only (CL/F pop,v,vl ), (b) initil (CL/F i,init,ll, CL/F i,init,sprse,vl ) nd (c) courseverge (CL/F i,v,ll, CL/F i,v,sprse,vl ) CL/F estimted by the finl popultion model nd ll smples vs the corresponding estimtes predicted by the respective vlidtion model nd three smples. Empty nd filled dimonds represent dt from ptients on nd off phenytoin tretment, respectively. 1.1 ± 3.39 l/h, compred to 1.2 ± 3.59 l/h, the estimte predicted from ll vilble smples nd the finl popultion model (CL/F i,init,ll ). The corresponding course-verge estimtes, CL/F i,v,sprse,vl nd CL/F i,v,ll were predicted to 1.4 ± 3.36 l/h nd 1.5 ± 3.67 l/h, respectively (Figure 3b, c). The correltions between the initil CL/F predicted from the finl popultion model nd three smples (CL/F i,init,sprse ) nd CL/F i,init,ll nd lso between CL/F i,v,sprse nd CL/F i,v,ll were mrginlly better nd re not shown. In order to investigte the consequences of different dosing strtegies, the AUCs for the individuls in the present study were clculted bsed on different dosing strtegies. In Tble 4 the predicted exposures re summrized. Using the dose djustment strtegy bsed on three smples in the simultions resulted in decresed CV nd rnge for both children nd dults. The finl TDM templte is displyed in Figure 4. As cn be seen from the Figure, n initil dose is suggested when trget AUC nd the ptients WT, ALT nd PHE sttus hs been filled in by the user. The suggested dose is clculted from the finl popultion model, predicted by the course-verge CL/F (CL/F pop,v, which in turn is clculted by the finl popultion model nd the ptients WT, ALT nd PHE sttus) times the trget AUC. When the initil dose hs been dministered nd three blood smples hve been collected nd nlyzed, the ctul dose given together with the busulphn levels cn be emtered. By then clicking the estimte button, the individul verge CL/F will be estimted nd the individulized mintennce dose will be clculted. Discussion Since the outcome nd toxicity following busulphn therpy hve been repetedly shown to correlte with exposure to busulphn, studies hve been designed to detect fctors tht re relted to the elimintion cpcity of the drug. 7,14 17 In order to estimte individul orl clernce nd if necessry djust the dose, severl limited smpling methods hve been suggested. 8,18,19 In spite of the fct tht different fctors relted to busulphn elimintion cpcity hve been identified nd tht some investigtors hve pointed out tht it might be importnt to chieve the trget exposure t the beginning of the therpy, 8 initil dosings hve to dte been bsed on WT or BSA only. The popultion model obtined in the present study tkes severl fctors into considertion. Furthermore, by implementing it into Excel it cn esily be used for initil dose clcultion nd therpeutic drug monitoring. There re severl investigtions on the phrmcokinetics Tble 4 Predicted course-verge AUC in mg.h/l from different simulted dosing strtegies to the studied popultion of ptients Initil dosing strtegies Dose djustment 1 mg/kg 37.5 mg/m 2 AUC trget * CL/F pop,v AUC trget * CL/F i,v,sprse All ptients verge (CV%) 6.17 (33) 6.48 (29) 5.67 (26) 5.61 (17) rnge Children verge (CV%) 4. (49) 5.86 (38) 5.34 (26) 5.46 (13) rnge Adults verge (CV%) 6.59 (26) 6.6 (27) 5.73 (26) 5.63 (17) rnge CL/F pop,v = model predicted course-verge orl clernce; CL/F i,v,sprse = individul three smple bsed predicted course-verge orl clernce.

6 Popultion phrmcokinetics of busulphn 662 Figure 4 Lyout nd description of the templte for busulphn dose individuliztion.

7 of busulphn. The verge individul estimtes of orl clernce in dults nd in children, 2.7 ml/min/kg nd 4.98 ml/min/kg, obtined in the present study re in good ccordnce with those found in previous studies, ie ml/min/kg nd 3. 1 ml/min/kg. 6,12 14,24,3,31 Also, the verge estimte of individul V/F, k nd Tlg in dults nd children obtined in the present study re comprble with estimtes previously reported. 6,12,31 A high correltion between CL/F nd V/F ws found in the present study. A similr result ws obtined by us in popultion nlysis on busulphn dt from children. 1 Since busulphn is low extrction drug over the liver nd in ddition only 1% is bound to plsm proteins 31 the high correltion between CL/F nd V/F might mirror vribility in biovilbility. This conclusion is supported by previous study in which bsorption ws found to vry in both children (22 12%) nd dults (47 13%). 32 The finl popultion model in the present study predicts 13% higher initil CL/F nd 28% higher CL/F t the sixteenth dose in ptients who re receiving phenytoin in prllel with the busulphn tretment, compred to those who re not. These results re comprble to the findings by Hssn et l in study on 17 dult ptients. 33 Busulphn is minly eliminted by the liver. 17,3 It is therefore not surprising tht inclusion of ALT s n influencing fctor on orl clernce becme significnt in the present nlysis. A comprble finding ws reported by Hssn et l, 14 from study where one ptient with elevted liver trnsminses showed extremely high busulphn concentrtions. BSA hs been suggested to be better predictor of busulphn elimintion cpcity thn WT in children nd therefore tht strtegy, ie 37.5 mg/m 2 four times dily during 4 dys, hs been used ltely in this group of ptients. 12,15 Recently, study in 279 norml, obese nd under-weight dult nd dolescent ptients showed tht CL/F in tht popultion correlted better with BSA thn WT. 16 In the present study the correltion between CL/F nd BSA did not keep its significnce fter inclusion of WT s slopeintercept reltionship with CL/F. Thus, the reltive merits of BSA nd weight pper to differ depending on the popultion studied. Also, the difficulty in estblishing which of two highly correlted covrites is the better should not be underestimted. The simultions in the present study show in ccordnce with previous reports tht dosing bsed on BSA in children is preferrble over dosing bsed on WT. However, using the popultion model obtined s dosing tool, would hve resulted in further improvement both in terms of CV nd rnge in the study popultion. The trditionl dosing would hve resulted in s precise distribution of AUCs in the popultion of dults studied s would the initil dosing bsed on the finl popultion model. However, the ltter strtegy resulted in nrrower rnge of AUC pred. Hence, lthough initil dosing bsed on either WT or BSA is scled in order to meet AUC trget, those strtegies would hve resulted in extreme AUCs in few individuls in the study popultion. If previously reported indictions on the importnce of reching the trget AUC in ssocition with the first dose remins true, 8 the proposed initil dosing strtegy might hve n dvntge compred to trditionl strtegies. Popultion phrmcokinetics of busulphn The good greement between CL/F i,v,sprse,vl nd CL/F i,v,ll in the present study indictes tht the busulphn concentrtions t the chosen smpling times 2, 4 nd 5 h fter giving doses, together with the popultion model, well predict the individul CL/F estimtes for the 69 evluble ptients. At lest one of the three smples ws missing from seven of the ptients nd those ptients were hence not evluted in this respect. In previous studies where TDM of busulphn hs been crried out, the individul CL/F hve been ssessed using either the trpezoidl methods tht require rich smpling or limited smpling multiliner regression methods. 8,18,19 Since they require few smples nd re esy to use, the limited smpling methods re ttrctive in the clinicl routine. However, they re ssocited with severl drwbcks. A constnt shpe of concentrtion-time profile is ssumed, which is probbly not the cse if the high IIV nd IOV in V nd k found in this nd other studies is true. 6,1,11,31,32 Furthermore, on the wrd, smpling for phrmcokinetic nlysis is not lwys the highest priority. Hence, it is not relistic to believe tht smpling is tking plce exctly t the time-points required by the ctul limited smpling model nd consequently the individul estimtes of the CL/F will be ssocited with some unknown error. Byesin forecsting, which is the method used in the TDM tool suggested in the present report, llows smpling to be crried out off the trget smpling time points s long s the true collection times re noted nd used in the dt nlysis. In ddition, it tkes the vribility terms from the underlying popultion model, including residul vribility (which includes nlysis error nd smpling error ssocited with the dt) nd IIV, into ccount. 34 Consequently, the pproch suggested does not ssume unchngeble shpe of the concentrtion-time profile nd hndles uncertinty better. One condition tht must be fulfilled in order to crry out meningful TDM is tht IOV be lower thn IIV for the phrmcodynmiclly significnt phrmcokinetic prmeter(s). Since there seems to be correltion between AUC nd response/toxicity, the importnt prmeter when considering TDM of busulphn is CL/F. Our results show tht the IOV in tht prmeter is 9.4% compred to IIV of 28%. The low grde of IOV is supported by the results found by other uthors. 7,12,35 In summry, we hve developed popultion model, representtive for both children nd dults, tht tkes liver function, weight nd phenytoin tretment into considertion. The model, including the vribilities in ll prmeters, hs been implemented into user-friendly Excel mcro tht my be used to optimize the initil nd, by Byesin forecsting using three smples, the mintennce dosing of busulphn in BMT ptients. In ddition this study shows tht the interoccsion-vribility in orl clernce of busulphn is less thn the interindividul vribility, which is prerequisite for the vlue of TDM. Acknowledgements This study ws supported by the Swedish Children Cncer Society (grnt 1999/33) nd Swedish Cncer Society (grnts 4147-B99 2XBB nd 334-B97 6XAA). 663

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