Abstract | AIMS: 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.
|
Authors | M Hassan, U S Svensson, P Ljungman, B Björkstrand, H Olsson, M Bielenstein, M Abdel-Rehim, C Nilsson, M Johansson, M O Karlsson |
Journal | British journal of clinical pharmacology
(Br J Clin Pharmacol)
Vol. 48
Issue 5
Pg. 669-77
(Nov 1999)
ISSN: 0306-5251 [Print] England |
PMID | 10594468
(Publication Type: Clinical Trial, Journal Article, Research Support, Non-U.S. Gov't)
|
Chemical References |
- Antineoplastic Agents, Alkylating
- 4-hydroxycyclophosphamide
- Cyclophosphamide
|
Topics |
- Adult
- Antineoplastic Agents, Alkylating
(blood, pharmacokinetics)
- Biotransformation
- Breast Neoplasms
(blood, metabolism)
- Cyclophosphamide
(analogs & derivatives, blood, pharmacokinetics)
- Female
- Half-Life
- Humans
- Middle Aged
- Models, Biological
|