Antibody-directed enzyme prodrug therapy: pharmacokinetics and plasma levels of prodrug and drug in a phase I clinical trial |
| |
| Authors: | Janet Martin Stephen M Stribbling Grace K Poon Richard H J Begent Mark Napier Surinder K Sharma C J Springer |
| |
| Institution: | (1) CRC Centre for Cancer Therapeutics, Institute of Cancer Research, CRC Laboratory, 15 Cotswold Road, Sutton, Surrey SM2 5NG, UK Tel.: 0181 643 8901 ext. 4214 Fax: 0181 770 7899, GB;(2) CRC Clinical Research Laboratories, Royal Free Hospital School of Medicine, Department of Clinical Oncology, Rowland Hill Street, London NW3 2PF, UK, GB |
| |
| Abstract: | Antibody-directed enzyme prodrug therapy (ADEPT) was administered to ten patients in a phase I clinical trial. The aim was
to measure plasma levels of the prodrug 4-(2-chloroethyl)(2-mesyloxyethyl) amino] benzoyl-l-glutamic acid (CMDA) and the bifunctional alkylating drug (CJS11) released from it by the action of tumour-localised carboxypeptidase
G2 (CPG2) enzyme. New techniques were developed to extract the prodrug and drug from plasma by solid-phase adsorbtion and
elution and to measure CPG2 activity in plasma and tissue. All extracts were analysed by high-performance liquid chromatography
(HPLC) and liquid chromatography-mass spectrometry (LC-MS). CPG2 activity was found in metastatic tumour biopsies but not
in normal tissue, indicating that localisation had been successful. The clearing agent SB43-gal, given at 46.5 mg/m2, achieved the aim of clearing non-tumour-localised enzyme in the circulation, indicating that conversion of prodrug to drug
could take place only at the site of localised conjugate. Plasma prodrug did not always remain above its required threshold
of 3 μM for the “therapeutic window” of 120 min after dosing, but the presence of residual prodrug after the first administration
of each day indicated that this could be achieved during the remaining four doses over the following 8 h. Despite considerable
inter-patient prodrug plasma concentration variability, the elimination half-life of the prodrug was remarkably reproducible
at 18 ± 8 min. Rapid appearance of the drug in plasma indicated that successful conversion from the prodrug had taken place,
but also undesirable leakback from the site of localisation into the bloodstream. However, drug plasma levels fell rapidly
by at least 50% at between 10 and 60 min with a half-life of 36 ± 14 min. Analysis of the plasma extracts by LC/MS indicated
that this technique might be used to confirm qualitatively the presence of prodrug, drug and their metabolites.
Received: 21 July 1996 / Accepted: 20 January 1997 |
| |
| Keywords: | ADEPT Prodrug Carboxypeptidase G2 |
| 本文献已被 SpringerLink 等数据库收录！ |
|
