Nonpredictable Pharmacokinetic Behavior of High-Dose Cyclophosphamide in Combination with Cisplatin and 1,3-Bis(2-Chloroethyl)-1-Nitrosourea1

Vol. 5, 747–751, April 1999 Clinical Cancer Research 747

Nonpredictable Pharmacokinetic Behavior of High-Dose Cyclophosphamide in Combination with Cisplatin and 1,3-Bis(2-chloroethyl)-1-nitrosourea1

Yago Nieto,2 Xuesheng Xu, Pablo J. Cagnoni, of the drug unpredictable from an initial measurement on Steve Matthes, Elizabeth J. Shpall, day 1. Thus, in this combination, measurement of levels of Scott I. Bearman, James Murphy, and parent CPA, with the objective of real-time therapeutic monitoring of this drug, is not informative. Roy B. Jones University of Colorado Bone Marrow Transplant Program [Y. N., P. J. C., S. M., E. J. S., S. I. B., R. B. J.] and Department of INTRODUCTION Biostatistics [X. X., J. M.], University of Colorado, Denver, Colorado HDC3 with stem cell support attempts to overcome cell 80262 resistance to standard-dose chemotherapy by exploiting the dose-response effects of combinations of antineoplastic drugs. ABSTRACT Considering the high potential for toxicity with HDC, ongoing research is pursuing the application of TDM to HDC. TDM Our objective was to assess whether the total area prospectively adjusts for interindividual variability of concen- under the curve (AUC) of high-dose cyclophosphamide trations achieved after the first dose of a drug to a final target PK (CPA), combined with cisplatin and 1,3-bis(2-chloroethyl)- parameter. This strategy is based on two requirements: (a) the 1-nitrosourea, could be predicted from its AUC on the first knowledge that, for a particular drug, a certain PK parameter is day of treatment. We reviewed the AUC of CPA in 470 associated with either a toxic or a therapeutic pharmacodynamic patients who underwent pharmacokinetic monitoring of the effect; and (b) the demonstration that the drug’s PK behavior is drug. All patients received the same high-dose regimen of consistent and predictable using an initial measurement. CPA, cisplatin, and 1,3-bis(2-chloroethyl)-1-nitrosourea Some successful applications of TDM to HDC include the (STAMP-I) with identical antiemetic support. Subsequently, prospective dose adjustment of busulfan to reduce the incidence patients who experienced a toxic death, relapsed after high- of hepatic venoocclusive disease (1). PK-guided Phase I trials of dose chemotherapy, or remained relapse-free at a minimum busulfan have been proven to be feasible (2). A recent prospec- follow-up of 1 year after high-dose chemotherapy were an- tive randomized trial in childhood acute lymphoblastic leukemia alyzed for a correlation between the total AUC of CPA and compared conventional dosing of methotrexate, teniposide, and both relapse-free survival and toxic death. The AUC of CPA cytarabine, based on the body surface area, with individualized decreased from day 1 to day 2 in most patients. However, its dosing of the three drugs based on a target AUC range (3). The changes from day 2 to day 3 varied significantly. Neither the outcome of patients with B-cell acute lymphoblastic leukemia value of AUC on day 1 nor its decreasing trend from day 2 was significantly improved with TDM compared to conven- to day 3 could predict the AUC on day 3 and the total AUC. tional dosing. Our pharmacodynamic analysis in 335 patients failed to CPA is widely used in HDC for hematological and solid show a correlation between the total AUC of CPA and either malignancies. Its toxic profile at high doses includes cardiac toxic death or relapse-free survival. The significant inter- necrosis, venoocclusive disease of the liver, and hemorrhagic subject variability in the AUC of CPA makes the final AUC cystitis. Ayash et al. (4) retrospectively reported an inverse correlation between the AUC of the parent compound and both cardiotoxicity and tumor response. Their results suggest the potential need for TDM of CPA. Received 9/29/98; revised 12/3/98; accepted 12/7/98. Four hundred seventy patients underwent PK monitoring of The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked high-dose CPA at the University of Colorado Bone Marrow advertisement in accordance with 18 U.S.C. Section 1734 solely to Transplant Program. CPA was delivered in combination with indicate this fact. CDDP and BCNU. We reviewed the PKs of CPA to determine 1 This study was supported by NIH Grant RO-1 CA61532 (to R. B. J.). 2 whether day 1 AUC could be predictive of AUCs on subsequent To whom requests for reprints should be addressed, at University of days and of the total AUC. Colorado Bone Marrow Transplant Program, Box B-190, 4200 East 9th Avenue, Denver, CO 80262. Phone: (303) 372-9000; Fax: (303) 372- 9003; E-mail: [email protected]. 3 The abbreviations used are: HDC, high-dose chemotherapy; TDM, PATIENTS AND METHODS therapeutic drug monitoring; PK, pharmacokinetic; AUC, area under the Patient Population. As of March 1998, PK monitoring curve; CPA, cyclophosphamide; CDDP, cisplatin; BCNU, 1,3-bis(2- of CPA had been performed on 470 patients treated with the chloroethyl)-1-nitrosourea; NHL, non-Hodgkin’s lymphoma; HD, same CPA-containing combination. Diagnoses were breast can- Hodgkin’s disease; PBPC, peripheral blood progenitor cell; CI, contin- ϭ ϭ ϭ uous infusion; AUCd1, AUCd2, and AUCd3, AUC on days 1, 2, and 3, cer (n 406), NHL (n 50), and HD (n 14). All patients had respectively; 4-OHCPA, 4-hydroxycyclophosphamide; AP, aldophos- a Southwest Oncology Group performance status of Ͻ2 and phamide. acceptable pretransplant organ function (creatinine clearance,

standard solution, 50 ␮g/ml diphenhydramine, were dispensed into plastic disposable tubes. Solid-phase extraction columns (LC-SI 3-ml Extraction Columns; Supelco Inc., Bellefonte, PA) were preconditioned with 3 ml of the elution solution (85% high-pressure liquid chromatography-grade ethyl acetate and 15% high-pressure liquid chromatography-grade methanol) followed by 3 ml of water. The plasma containing internal standard was then added to the column. The columns were eluted with 1.5 ml of the elution solution. The eluant was centrifuged at 2000 rpm for 5 min, and 0.8 ml of the supernatant was trans- ferred to 1-ml autosampler vials. One ␮l of each vial was injected, with a split ratio of 20:1. A capillary column-equipped gas chromatograph with nitrogen-phosphorus detection was Fig. 1 Treatment schema. Doses are expressed in mg/m2/day. CDDP used. The time/concentration data were analyzed with WIN- was delivered in a 72-h CI. NONLIN Version 1.1 nonlinear regression software (SCI Soft- ware, Cary, NC). The detection limit of this assay was 0.1 ␮g/ml. Its intra- and interrun precision coefficient variation was Ͻ10%. This analysis can be performed overnight with results Ͼ60 ml/min; left ventricular ejection fraction, Ͼ45%; diffusing available the next morning prior to the subsequent CPA dose. capacity of the lung for carbon monoxide and forced expiratory Pharmacodynamic Analysis. A pharmacodynamic volume in 1 s, Ͼ60% of predicted; and bilirubin/aspartate ami- analysis of CPA was performed in patients who experienced a notransferase/alanine aminotransferase, Ͻ2 times the upper nor- toxic death, relapsed after HDC, or remained free of evidence of mal limit). A bone marrow harvest or leukapheresis of granu- recurrence at a minimum follow-up of 1 year. A total of 335 locyte-colony stimulating factor-mobilized PBPCs were patients were evaluated for a potential correlation between the performed prior to admission. total AUC of CPA and the occurrence of toxic death. Median Chemotherapy. The treatment schema is depicted in follow-up for this sample is was 28 months (range, 1–89 Fig. 1. The doses of CPA, CDDP, and BCNU were those previously described by Peters et al. (5) On days Ϫ6, Ϫ5, and months). Ϫ4, CPA was given as a daily 1-h infusion starting between 9 This patient sample was broken down into the following and 11 a.m., at 1875 mg/m2/day (total dose, 5625 mg/m2), and subgroups to ascertain the correlation of CPA AUC with a CDDP was administered as a 72-h CI at 165 mg/m2.OndayϪ3, therapeutic end point (relapse-free survival) within each of ϭ 600 mg/m2 BCNU was infused over 2 h. All doses of chemo- the subgroups: stage II–III breast cancer (n 115); stage IV ϭ therapy were calculated on the actual body weight, unless that breast cancer (n 163), including both patients with no ϭ weight was Ն20% over the ideal body weight, in which case the evidence of disease (n 38) and those with macroscopic ϭ ϭ average between the actual and ideal body weight was used to tumor at the time of transplant (n 125); NHL (n 44); and calculate the body surface area. Unselected marrow or PBPCs HD (n ϭ 13). were infused on days Ϫ1, 0, and ϩ1, whereas CD34-selected Statistical Methods. Using patients as the random vari- PBPCs were infused on day Ϫ1. All patients received granulo- able and time as the fixed factor, we fitted a mixed model to cyte-colony stimulating factor 5–10 ␮g/kg/day i.v. over 30 min test the relationship between the values of the AUC of CPA from day Ϫ1 until neutrophil engraftment. and time (days 1, 2, and 3). The relationships between Supportive Care. On day Ϫ7, i.v. hydration at 250 ml/ AUCd1 and AUCd2 and between AUCd2 and AUCd3 were m2/h, to ensure a urinary output of Ͼ200 ml/h, and continuous studied by fitting simple linear models. A ␹2 test was used to bladder irrigation were initiated and continued through day Ϫ3, test the distribution of proportions of four patterns of AUC after the delivery of BCNU. Prior to chemotherapy, patients changes. These patterns were “decrease” (the AUC consis- were transfused irradiated packed RBCs to a target hematocrit tently decreasing from day 1 to day 3), “up-down” (the AUC of Ն42. No transfusions were given during chemotherapy. All increasing from day 1 to day 2 but then decreasing to day 3), patients received the same antiemetic regimen, consisting of “down-up” (the AUC decreasing from day 1 to 2 but then prochlorperazine (loading dose of 10 mg i.v. followed by 1 increasing from day 2 to 3), and “increase” (the AUC con- mg/m2/h as a CI), diphenhydramine (25 mg every 6 h i.v.), and sistently increasing throughout the 3 treatment days). lorazepam (1 mg/m2 every 4 h i.v.). A standard prophylactic ANOVA and the t test were used to detect differences in the antimicrobial regimen was initiated on day Ϫ2. magnitude of AUCd1 among the four groups as well as Analytical Methods. Blood samples for CPA were ob- differences in the decreasing scale from AUCd1 to AUCd2 tained in 10-ml heparinized collection tubes, stored at 4°C, and between decrease and down-up groups. assayed within 24 h using a modification of the method of The total AUC of CPA was compared in patients with and El-Yazigi and Martin (6). Blood samples were obtained remote without a toxic death using the Kruskal-Wallis test. A two-tailed from the site of CPA infusion at 30, 60, 90, 120, 180, 300, 420, t test was used to evaluate the association of CPA AUC 540, 780, 1020, and 1260 min after the start of each daily with relapse. All statistical calculations were performed using infusion. After the samples were centrifuged at 2000 rpm for 10 the SAS software package Version 6.12 (SAS Institute Inc., min, 1 ml of the supernatant plasma and 1 ml of the internal Cary, NC).

Table 1 Values of CPA AUC (␮g/ml/minϪ1) on the 3 treatment Table 3 AUC values (␮g/ml/minϪ1) on day 1 for the four days (n ϭ 470) different patterns Day Pattern of No. of AUC change observations Mean AUCd1 SD 123 Decrease 312 37,000 15,300 Mean 36,000 25,900 23,400 Down-up 145 35,200 13,900 SE 655 540 500 Increase 1 34,900 Up-down 12 31,500 12,300

Table 2 Patterns of AUC change Pattern of No. of Table 4 Decreasing scale of AUC (␮g/ml/minϪ1) from day 1 to day AUC change observations % 2 for the four different patterns Decrease 312 66.38 Pattern of No. of Mean net difference Down-up 145 30.85 AUC change observations (AUCd1 Ϫ AUCd2) SD Increase 1 0.21 Up-down 12 2.55 Decrease 312 11,900 7,200 Down-up 145 12,700 6,500

RESULTS day 2 to day 3. For each individual patient, neither the value of Overall, the values of CPA AUC tended to decrease over AUCd1 nor the decreasing trend from AUCd1 to AUCd2 could the three days of treatment, as shown in Table 1. The mixed predict the direction of the subsequent change in the last treat- model demonstrates that the mean value of AUC decrease is ment day. ␮ Ϫ1 6,300 g.min.ml per day, when considering the patient pop- In addition, we did not find a correlation in our series ulation as a whole. When the group of patients was studied at the between the total AUC of CPA with either a toxic (treatment- subject level, four different patterns of changes in the AUC related death) or a therapeutic end point (relapse-free survival). values became apparent (Table 2). A consistently decreased In contrast, Ayash et al. (4), showed a significant inverse asso- AUC value over time (decrease pattern) was seen in 66.5% of ciation between the AUC of CPA and both end points using a the subjects. Of these, 30.6% demonstrated a decrease in the different high-dose regimen of CPA, thiotepa, and carboplatin AUC from day 1 to day 2 but an increase from day 2 to day 3 (STAMP-V). (down-up); 0.2% and 2.6% of the patients had increase and CPA is an inactive prodrug that undergoes a complex ␹2 up-down patterns, respectively. The test showed that the metabolic process, which is summarized in Fig. 2 (7). It is ϭ proportions of the four patterns were not uniform (P 0.001). hydroxylated by the cytochrome P450 system to its active The data were analyzed in an attempt to identify a phar- metabolite 4-OHCPA, which equilibrates with its acyclic tau- macological reason for the four different patterns. The value of tomer AP. 4-OHCPA and AP enter the cell, where AP under- the AUCd1 was compared among the four groups (Table 3). The goes ␤-elimination of acrolein to form phosphoramide mustard, ANOVA test showed no significant difference of AUCd1 the ultimate bialkylating moiety. Hepatic or erythrocyte alde- ϭ among the four patterns (P 0.4). The decreasing trend in the hyde dehydrogenase isoenzymes, particularly aldehyde dehy- Ϫ AUC in the first 2 treatment days, i.e., AUCd1 AUCd2, was drogenase-1, can oxidize AP to inactive metabolites that are compared between the decrease and down-up groups (Table 4). excreted in the urine. In addition, CPA can also be excreted Ϫ The t test did not show a significant difference in AUCd1 unchanged in the urine or undergo P450-mediated side-chain ϭ AUCd2 between both groups (P 0.24). oxidation to inactive compounds. Pharmacodynamic Analysis. The association between Measurement of the parent compound for pharmacody- the occurrence of toxic death and the total CPA AUC did not namic analysis has important limitations. The P450-mediated ϭ reach statistical significance (P 0.18) in the sample of 335 hydroxylation of CPA is subject to interactions with other drugs, patients analyzed. such as busulfan (8), phenytoin (8), CDDP (9), ondansetron In addition, the AUC of CPA did not correlate with relapse (10), or dexamethasone (11). High-dose CPA demonstrates non- ϭ in any of the groups evaluated: stage II–III breast cancer (P linear elimination kinetics, in both a concentration- (12) and ϭ 0.36), all stage IV breast cancer patients (P 0.45), stage IV time-dependent (13) fashion. A 7-fold intersubject difference in ϭ breast cancer patients with no evidence of disease (P 0.74), exposure to 4-OHCPA was observed after CPA/total body irra- stage IV patients breast cancer with macroscopic lesions at diation, in which CPA is given first (8). Chen et al. (13) ϭ ϭ ϭ transplant (P 0.18), NHL (P 0.15), and HD (P 0.84). described nonlinear clearance and altered hepatic metaboliza- tion of CPA combined with thiotepa. These authors noticed a

DISCUSSION large range in Km in the P450-mediated oxidation of CPA for Our retrospective analysis of the AUC of CPA shows that, patients receiving single-agent CPA (14). although AUC generally decreased from day 1 to day 2 and Because the population in this study was homogeneous in exhibited an overall reduction throughout the 3 treatment days, terms of concomitant antineoplastic drugs, hydration, concur- there were significant variations in the changes of the AUC from rent antiemetics, and pretreatment hematocrit and liver function

Fig. 2 Metabolism of CPA.

tests and because these variables remained homogeneous rapid sample analysis with results available the next morning throughout the 3 treatment days, the intrapatient variability of prior to the subsequent CPA dose, and accurate and reliable CPA AUC seems attributable to less correctable factors. The assays for the determination of 4-OHCPA or AP have only disposition of high-dose CPA by the P450 enzymes is a satu- recently been developed. Anderson et al. (19) described a rable process (12). On the other hand, CPA autoinduces its own method that includes immediate derivatization of the metabo- P-450 metabolism (15–18). Chen et al. (13) observed that au- lites to form a stable oxime. This assay involves gas chroma- toinduction is time dependent, occurring at an average of 29 h tography/mass spectrometry technology and requires a specific after the start of the CPA infusion. Thus, nonpredictable varia- deuterium-labeled internal standard (20). Slattery et al. (8) de- tions in the balance between enzyme saturation and autoinduc- veloped an assay to quantify 4-OHCPA based on the bedside tion, which did not become apparent until after the second day formation of a stable derivative. of treatment, may explain the intrapatient differences in the An important limitation to the monitoring of the active AUC of CPA throughout the days of treatment we observed. metabolites may be the variability in the relative contribution of Studies on the correlation between the AUC of CPA and activating and inactivating reactions to their disposition. Busse 4-OHCPA/AP show contradictory data. Slattery et al. (8) have et al. (21) showed a reduction in the activation of CPA and an shown an inverse correlation between the AUC of CPA and that increase in the inactivation of 4-OHCPA/AP and CPA at high of 4-OHCPA, which is consistent with the clinical observations doses of the drug, compared to conventional doses given to the from Ayash et al. (4) In contrast, Chen et al. (14) found a same patients. These intrapatient changes showed, in turn, wide positive correlation between both AUCs. In addition, these interindividual variability. Thus, the varying shift in the meta- authors found no correlation between these two AUCs when bolic pathways of 4-OHCPA toward inactivating reactions sug- CPA was given concurrently with thiotepa. Therefore, it has gests that the measurement of plasma levels of 4-OHCPA, like been argued that it should be the active metabolites that are the quantitation of the parent drug, may not reflect the intracel- monitored in first place. Study of the actual exposure to these lular levels of phosphoramide mustard, ultimate responsible for reactive and extremely unstable intermediates has been limited the alkylating effects of CPA. In addition, Dockham et al. (22) in the past by analytic methodology. Real-time TDM requires showed a 3-fold interindividual variation in the erythrocyte

fraction of aldehyde dehydrogenase-1, an enzyme that seems to 10. Cagnoni, P. J., Matthes, S., Dufton, C., Shpall, E. J., Bearman, S. I., play an important role in the detoxification of 4-OHCPA. Thus, Purdy, M. H., Day, T., and Jones, R. B. Ondansetron significantly variations in the hematocrit may also change drug disposition. reduces the area under the curve (AUC) of cyclophosphamide (CPA) In conclusion, our study shows that, with the CPA, CDDP, and cisplatin (cDDP). Proc. Am. Soc. Clin. Oncol., 14: 462, 1995. and BCNU regimen, unpredictable intrapatient variations in the 11. Yule, S. M., Boddy, A. V., Cole, M., Price, L., Wyllie, R., Tasso, M. J., Pearson, A. D., and Idle, J. R. Cyclophosphamide pharmacoki- AUC of CPA occur. This strongly suggests that prospective netics in children. Br. J. Clin. Pharmacol., 41: 13–19, 1996. TDM of CPA based on the measurement of the parent com- 12. Grochow, L. B., and Colvin, O. M. Clinical pharmacokinetics of pound is not feasible. 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Downloaded from clincancerres.aacrjournals.org on September 29, 2021. © 1999 American Association for Cancer Research. Nonpredictable Pharmacokinetic Behavior of High-Dose Cyclophosphamide in Combination with Cisplatin and 1,3-Bis(2-chloroethyl)-1-nitrosourea

Yago Nieto, Xuesheng Xu, Pablo J. Cagnoni, et al.

Clin Cancer Res 1999;5:747-751.

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