The influence of interferon-α on the pharmacokinetics of cyclophosphamide and its 4-hydroxy metabolite in patients with multiple myeloma

• Published in: European journal of haematology 1999-09, Vol.63 (3), p.163-170
• Main Authors: Hassan, Moustapha, Nilsson, Christina, Olsson, Hanna, Lundin, Jeanette, Österborg, Anders
• Format: Article
• Language: English
• Subjects: 4-hydroxycyclophosphamide; Aged; Antineoplastic agents; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Antineoplastic Agents, Alkylating - metabolism; Antineoplastic Agents, Alkylating - pharmacokinetics; Area Under Curve; Biological and medical sciences; Combined treatments (chemotherapy of immunotherapy associated with an other treatment); cyclophosphamide; Cyclophosphamide - analogs & derivatives; Cyclophosphamide - blood; Cyclophosphamide - metabolism; Cyclophosphamide - pharmacokinetics; Drug Interactions; Female; Humans; Interferon-alpha - pharmacology; Interferon-alpha - therapeutic use; interferon-α; Leukocyte Count - drug effects; Male; Medical sciences; Medicin och hälsovetenskap; Middle Aged; multiple myeloma; Multiple Myeloma - drug therapy; Multiple Myeloma - metabolism; pharmacokinetics; Pharmacology. Drug treatments
• ISSN: 0902-4441; 1600-0609
• DOI: 10.1111/j.1600-0609.1999.tb01764.x

:  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‐α (IFN‐α) 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‐α. 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‐α (10–15 times 106 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‐α 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‐α was administered 24 h after CP. The formation of 4‐OHCP was also affected by the administration of IFN‐α 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‐α was administered 24 h after CP. The administration of IFN‐α after CP resulted in a greater (45%, P = 0.02) decrease in leukocyte count compared with results when IFN‐α was given before CP. This study demonstrates that the administration of IFN‐α prior to CP significantly impairs pharmacokinetics of CP and 4‐OHCP. When IFN‐α 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‐α was given before CP. In conclusion, the time of administration of IFN‐α in relation to concomitant chemotherapy (CP) has to be considered to obtain a higher efficacy of IFN‐α/alkylating agent combining regimens for induction in multiple myeloma and related disorders.