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The influence of interferon-alpha on the pharmacokinetics of cyclophosphamide and its 4-hydroxy metabolite in patients with multiple myeloma.
- Source :
-
European journal of haematology [Eur J Haematol] 1999 Sep; Vol. 63 (3), pp. 163-70. - Publication Year :
- 1999
-
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.
- Subjects :
- Aged
Antineoplastic Agents therapeutic use
Antineoplastic Agents, Alkylating metabolism
Area Under Curve
Cyclophosphamide blood
Cyclophosphamide metabolism
Drug Interactions
Female
Humans
Interferon-alpha therapeutic use
Leukocyte Count drug effects
Male
Middle Aged
Multiple Myeloma drug therapy
Antineoplastic Agents pharmacology
Antineoplastic Agents, Alkylating pharmacokinetics
Cyclophosphamide analogs & derivatives
Cyclophosphamide pharmacokinetics
Interferon-alpha pharmacology
Multiple Myeloma metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0902-4441
- Volume :
- 63
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- European journal of haematology
- Publication Type :
- Academic Journal
- Accession number :
- 10485271
- Full Text :
- https://doi.org/10.1111/j.1600-0609.1999.tb01764.x