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Titolo:
A mechanism-based pharmacokinetic-enzyme model for cyclophosphamide autoinduction in breast cancer patients
Autore:
Hassan, M; Svensson, USH; Ljungman, P; Bjorkstrand, B; Olsson, H; Bielenstein, M; Abdel-Rehim, M; Nilsson, C; Johansson, M; Karlsson, MO;
Indirizzi:
Huddinge Univ Hosp, KFC, Hematol Lab, S-14186 Huddinge, Sweden Huddinge Univ Hosp Huddinge Sweden S-14186 Lab, S-14186 Huddinge, Sweden Huddinge Univ Hosp, Div Clin Pharmacol, Dept Med Lab Sci & Technol, S-14186 Huddinge, Sweden Huddinge Univ Hosp Huddinge Sweden S-14186 nol, S-14186 Huddinge, Sweden Karolinska Pharm, Uppsala, Sweden Karolinska Pharm Uppsala SwedenKarolinska Pharm, Uppsala, Sweden Uppsala Univ, Dept Pharm, Div Biopharmaceut & Pharmacokinet, Uppsala, Sweden Uppsala Univ Uppsala Sweden pharmaceut & Pharmacokinet, Uppsala, Sweden Apoteksbolaget Cent Lab, Stockholm, Sweden Apoteksbolaget Cent Lab Stockholm Sweden et Cent Lab, Stockholm, Sweden Uppsala Univ, Uppsala, Sweden Uppsala Univ Uppsala SwedenUppsala Univ, Uppsala, Sweden
Titolo Testata:
BRITISH JOURNAL OF CLINICAL PHARMACOLOGY
fascicolo: 5, volume: 48, anno: 1999,
pagine: 669 - 677
SICI:
0306-5251(199911)48:5<669:AMPMFC>2.0.ZU;2-V
Fonte:
ISI
Lingua:
ENG
Soggetto:
HIGH-DOSE CYCLOPHOSPHAMIDE; BONE-MARROW TRANSPLANTATION; HUMAN LIVER-MICROSOMES; PLASMA HALF-LIFE; CLINICAL PHARMACOKINETICS; IFOSFAMIDE ACTIVATION; PHOSPHORAMIDE MUSTARD; WARFARIN-FLUCONAZOLE; MESSENGER-RNA; IN-VITRO;
Keywords:
4-hydroxycyclophosphamide; autoinduction; breast cancer; cyclophosphamide; enzyme induction model; pharmacokinetics;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Clinical Medicine
Life Sciences
Citazioni:
52
Recensione:
Indirizzi per estratti:
Indirizzo: Hassan, M Huddinge Univ Hosp, KFC, Hematol Lab, S-14186 Huddinge, Sweden Huddinge Univ Hosp Huddinge Sweden S-14186 86 Huddinge, Sweden
Citazione:
M. Hassan et al., "A mechanism-based pharmacokinetic-enzyme model for cyclophosphamide autoinduction in breast cancer patients", BR J CL PH, 48(5), 1999, pp. 669-677

Abstract

Aims This study investigated the pharmacokinetics of cyclophosphamide (CP)and its main metabolite 4-hydroxycyclophosphamide (4-OH-CP) in patients with breast cancer undergoing high dose chemotherapy prior to autologous stemcell transplantation. An enzyme turn-over model was also developed to study the time course of cyclophosphamide induction. Methods Fourteen patients received a combination of CP (6 g m(-2)), thiotepum (500 mg m(-2)) and carboplatin (800 mg m(-2)) as a 96 h infusion. Plasma concentrations of CP and 4-OH-CP were determined with h.p.l.c. and a pharmacokinetic and enzyme turn-over model applied to data using NONMEM. Results CP plasma concentrations were described by a two-compartment modelwith a noninducible and an inducible pathway, the latter forming 4-OH-CP. In the final enzyme model, CP affects the amount of enzymes by increasing the enzyme production rate. CP concentrations decreased during the infusion with no subsequent change in 4-OH-CP concentrations. CP inducible and noninducible clearance were estimated to 1.76 1 h(-1) (90% C.I. 0.92-2.58) and 1.14 1 h(-1) (0.31-1.85), respectively. The induction resulted in an approximately doubled CP clearance through the inducible pathway at the end of treatment. The model predicted the enzyme turn-over half-life to be 24 h. Conclusions The presented mechanism-based enzyme induction model where thepharmacokinetics of the inducer and the enzyme pool counterbalance each other successfully described CP autoinduction. It is reasonable to believe that CP affects its own elimination by increasing the enzyme production rate and thereby increasing the amount of enzyme by which CP is eliminated.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 05/07/20 alle ore 00:40:00