title: The influence of interferon-alpha on the pharmacokinetics of cyclophosphamide and its 4-hydroxy metabolite in patients with multiple myeloma.
abstract: The pharmacokinetics of cyclophosphamide (CP) and its cytotoxic metabolite 4-hydroxycyclophosphamide (4-OHCP) have been studied in multiple myeloma patients treated with the CIB (CP, interferon-alpha (IFN-alpha) and betamethasone) regimen. In the present investigation we aimed to determine whether exposure to CP and its cytotoxic metabolite 4-OHCP is influenced by the concomitant administration of IFN-alpha. Ten patients with previously untreated multiple myeloma entered the study. Each patient received two courses of CIB in randomized order. Interferon was administered either 2 h before the CP infusion in one course or 24 h after the CP infusion in the other course. A cyclophosphamide dose of 750-900 mg/m2 was given as a 2 h constant infusion. Interferon-alpha (10-15 x 10(6) IE) was given subcutaneously. All patients received betamethasone 24 h after CP or later. The elimination of CP was described by monoexponential decay. The administration of IFN-alpha before CP caused a decrease in CP clearance to 63% (P=0.004), a 137% longer half-life (P = 0.004) and a 137% higher peak plasma concentration (P = 0.006) compared to the results obtained when IFN-alpha was administered 24 h after CP. The formation of 4-OHCP was also affected by the administration of IFN-alpha prior to CP, 45% less exposure to 4-OHCP expressed as AUC (P = 0.002) and a 61% lower peak plasma concentration (P = 0.002) compared with that observed when IFN-alpha was administered 24 h after CP. The administration of IFN-alpha after CP resulted in a greater (45%, P = 0.02) decrease in leukocyte count compared with results when IFN-alpha was given before CP. This study demonstrates that the administration of IFN-alpha prior to CP significantly impairs pharmacokinetics of CP and 4-OHCP. When IFN-alpha was administered after CP, a higher exposure to the cytotoxic metabolite 4-OHCP was observed and reflected by a significant decrease in leukocyte count compared to that when IFN-alpha was given before CP. In conclusion, the time of administration of IFN-alpha in relation to concomitant chemotherapy (CP) has to be considered to obtain a higher efficacy of IFN-alpha/alkylating agent combining regimens for induction in multiple myeloma and related disorders.
authors.affiliation: Karolinska Pharmacy, Stockholm, Sweden. hassan@algonet.se
authors.forename: M
authors.initials: M
authors.lastname: Hassan
authors.forename: C
authors.initials: C
authors.lastname: Nilsson
authors.forename: H
authors.initials: H
authors.lastname: Olsson
authors.forename: J
authors.initials: J
authors.lastname: Lundin
authors.forename: A
authors.initials: A
authors.lastname: Osterborg
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D018906:Antineoplastic Agents, Alkylating / Q000378:metabolism / Q000493:pharmacokinetics*; D019540:Area Under Curve; D003520:Cyclophosphamide / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D004347:Drug Interactions; D005260:Female; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology* / Q000627:therapeutic use; D007958:Leukocyte Count / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D018906:Antineoplastic Agents, Alkylating; D016898:Interferon-alpha; C012358:4-hydroxycyclophosphamide; D003520:Cyclophosphamide