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

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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- 5 5 5 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 ,2 and phamide. acceptable pretransplant organ function (creatinine clearance, Downloaded from clincancerres.aacrjournals.org on September 29, 2021. © 1999 American Association for Cancer Research. 748 Nonpredictable Pharmacokinetics of High-Dose CPA standard solution, 50 mg/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) fol- lowed 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 ml 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 mg/ml. Its intra- and interrun precision coefficient variation was ,10%. This analysis can be performed overnight with results .60 ml/min; left ventricular ejection fraction, .45%; 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, .60% of predicted; and bilirubin/aspartate ami- analysis of CPA was performed in patients who experienced a notransferase/alanine aminotransferase, ,2 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 26, 25, and months). 24, 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.Onday23, therapeutic end point (relapse-free survival) within each of 5 600 mg/m2 BCNU was infused over 2 h. All doses of chemo- the subgroups: stage II–III breast cancer (n 115); stage IV 5 therapy were calculated on the actual body weight, unless that breast cancer (n 163), including both patients with no 5 weight was $20% over the ideal body weight, in which case the evidence of disease (n 38) and those with macroscopic 5 5 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 5 13). were infused on days 21, 0, and 11, whereas CD34-selected Statistical Methods. Using patients as the random vari- PBPCs were infused on day 21. All patients received granulo- able and time as the fixed factor, we fitted a mixed model to cyte-colony stimulating factor 5–10 mg/kg/day i.v. over 30 min test the relationship between the values of the AUC of CPA from day 21 until neutrophil engraftment. and time (days 1, 2, and 3). The relationships between Supportive Care. On day 27, i.v. hydration at 250 ml/ AUCd1 and AUCd2 and between AUCd2 and AUCd3 were m2/h, to ensure a urinary output of .200 ml/h, and continuous studied by fitting simple linear models. A x2 test was used to bladder irrigation were initiated and continued through day 23, test the distribution of proportions of four patterns of AUC after the delivery of BCNU.
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