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Population pharmacokinetics of cyclophosphamide and its metabolites in hematopoietic stem-cell transplantation patients

A.A. Yao(a), J.T. Slattery(b,c), G.B. McDonald(c), and P. Vicini(a)

(a)Resource Facility for Population Kinetics, University of Washington, Seattle WA; (b)The Department of Pharmaceutics, University of Washington, Seattle WA; (c)Fred Hutchinson Cancer Research Center, Seattle WA

Background: Cyclophosphamide (CY) is an alkylating agent frequently used in the treatment of malignancy and in preparative regimens for hematopoietic stem-cell transplantation. CY is a prodrug that is oxidized to 4-hydroxycyclophosphamide (HCY) at therapeutic concentrations. This is a reaction primarily catalyzed by CYP2C9 and CYP3A4 in human liver(1). HCY is the major active circulating metabolite that enters cells and decomposes to phosphoramide mustard and acrolein. Alternatively, HCY is detoxified to carboxyethylphosphoramide mustard (CEPM) by aldehyde dehydrogenase 1 (ALDH1A1). The formation of CEPM from HCY is the most important metabolic detoxifying pathway of HCY(2,3). CY is also oxidized to deschloroetyl cyclophosphamide, although this reaction accounts for little of CY disposition in humans.

Objectives: [1] To develop an integrated mechanism-based population pharmacokinetic model for CY and its activated metabolites, namely HCY, and CEPM in hematopoietic stem-cell transplant patients. [2] To identify the mechanisms of the effects of the enzymatic autoinduction on CY metabolism and the decrease in human ALDH1A1 activity after CY administration. Methods: Patients 147 patients scheduled to receive unrelated donor bone marrow transplants were studied under a protocol approved by the Institutional Review Board of the Fred Hutchinson Cancer Research Center (Seattle, WA). Patients received 1-hour intravenous infusions of 60 mg/kg cyclophosphamide daily for 2 days, followed by 12-14.4 Gy total body irradiation. Blood samples were obtained just before CY infusion was given, at 0.5, and 1 hour after the beginning of the infusion, and at 1, 3, 6, 8, and 24 hours after the end of the infusion on both day 1 and 2 of treatment. Plasma concentrations of CY, HCY, and CEPM were determined as described previously(1). Data analysis The population pharmacokinetic analysis was conducted with the NONMEM(4) software, version V (Globomax, MD) and the first-order method. Interindividual variability of parameters was modeled using an exponential error model. An integrated model for the pharmacokinetics of CY, HCY, and CEPM was developed which included autoinduction(5) of CY oxidation to HCY and inhibition of ALDH1A1 activity after CY administration.

Results and Discussion: Preliminary results indicated that the elimination of CY was best described by a non-inducible route and an inducible route leading to HCY formation. The inducible clearance was mediated by a hypothetical increase in enzyme concentration. The volume of distribution, non-inducible and initial inducible clearances of CY were: (estimate ▒ S.E.) 0.70 ▒ 0.01 l/kg, 0.0051 ▒ 0.0007 l/hr/kg, and 0.030 ▒ 0.001 l/hr/kg, respectively. The enzyme followed a zero-order formation, with an Emax-type decrease of the first-order rate constant describing elimination of CY with CY concentration: the induction half-life of the enzyme and the first-order rate constant of HCY elimination were estimated to be 9.18 hr, and 178 ▒ 16 hr-1, respectively. The inhibition of CEPM formation by HCY was described by the amount of ALDH1A1 enzyme. The hypothetical enzyme concentration followed a zero-order formation, and its elimination was proportional to the product of ALDH1A1 and HCY concentrations: the formation and elimination constants of CEPM were estimated as 2.18 ▒ 0.09 hr-1, and 0.94 ▒ 0.03 hr-1, respectively. The random effects for the non-inducible, inducible clearances of CY, elimination rate of HCY and zero-order formation rate constant of enzyme were (CV%): 84%, 38%, 28%, and 57%, respectively. Residual unknown variabilities were estimated using additive models for CY and CEPM, and a combination of proportional and additive errors for HCY. The estimated residual variabilities were: 59.7 mM (CY), 44.4% and 2.33 mM (HCY) and 1.85 mM (CEPM). This integrated model enabled the assessment of the complex pharmacokinetics of CY and may help to optimize the dose ranges in order to achieve engraftment without causing undesired effects.

(1) S. Ren, T.F. Kalhorn, G. B. McDonald, C. Anasetti, F. R. Appelbaum, and J.T. Slattery. (1998) Pharmacokinetics of cyclophosphamide and its metabolites in bone marrow transplantation patients. Clin. Pharmacol. Ther. 64: 289-301.
(2) S. Ren, T. F. Kalhorn and J. T. Slattery. (1999) Inhibition of human aldehyde dehydrogenase 1 by the 4-hydroxycyclophosphamide degradation product acrolein. Drug Met. Dispos. 27(1): 133-7.
(3) S. Ren, and J. T. Slattery. (1999) Inhibition of carboxyethylphosphoramide mustard formation from 4-hydroxycyclophosphamide by carmustine. AAPS PharmSci. 1(3): article 14.
(4) S. Beal, and L. Sheiner. NONMEM Users Guide. University of California, San Francisco, 1992.
(5) T. Kerbusch, A.D.R. Huitema, J. Ouwerkerk, H. J. Keizer, R. A. A. Math˘t, J. H. M. Schellens, and J. H. Beijnen. (2000) Evaluation of the autoinduction of ifosfamide metabolism by a population pharmacokinetic approaching using NONMEM. Br. J. Clin. Pharmacol. 49: 555-61.