A mechanism-based pharmacokinetic-enzyme model for cyclophosphamide autoinduction in breast cancer patients. Export

@article{citeulike:5659552, 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 stem cell 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 model with 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 l h-1 (90\% C.I. 0.92-2.58) and 1.14 l 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 the pharmacokinetics 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.}, author = {Hassan, M. and Svensson, U. S. and Ljungman, P. and Bj\"{o}rkstrand, B. and Olsson, H. and Bielenstein, M. and Abdel-Rehim, M. and Nilsson, C. and Johansson, M. and Karlsson, M. O.}, citeulike-article-id = {5659552}, citeulike-linkout-0 = {http://view.ncbi.nlm.nih.gov/pubmed/10594468}, citeulike-linkout-1 = {http://www.hubmed.org/display.cgi?uids=10594468}, issn = {0306-5251}, journal = {British journal of clinical pharmacology}, keywords = {cyclophosphamide, interindividual, pharmacokinetics, variability}, month = {November}, number = {5}, pages = {669--677}, posted-at = {2009-08-27 20:18:25}, priority = {2}, title = {A mechanism-based pharmacokinetic-enzyme model for cyclophosphamide autoinduction in breast cancer patients.}, url = {http://view.ncbi.nlm.nih.gov/pubmed/10594468}, volume = {48}, year = {1999} }

TY - JOUR ID - citeulike:5659552 L3 - citeulike-article-id:5659552 N2 - 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 stem cell 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 model with 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 l h-1 (90% C.I. 0.92-2.58) and 1.14 l 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 the pharmacokinetics 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. IS - 5 JF - British journal of clinical pharmacology SN - 0306-5251 EP - 677 TI - A mechanism-based pharmacokinetic-enzyme model for cyclophosphamide autoinduction in breast cancer patients. VL - 48 SP - 669 KW - cyclophosphamide KW - interindividual KW - pharmacokinetics KW - variability AU - Hassan, M AU - Svensson, US AU - Ljungman, P AU - Björkstrand, B AU - Olsson, H AU - Bielenstein, M AU - Abdel-Rehim, M AU - Nilsson, C AU - Johansson, M AU - Karlsson, MO PY - 1999/11// UR - http://view.ncbi.nlm.nih.gov/pubmed/10594468 ER -