Pharmacokinetics and Toxicity of Oral (-)-(S)-Bromofosfamide in Lung Cancer Patients

Abstract

Summary The pharmacokinetics and toxicity of (-)-(S)-bromofosfamide ((2S)-(2-chloroethyl-amino)-3-(2-bromoethyl)-1,3,2-oxaza-phosphorinae 2-oxide, CAS 146452-37-1, CBM-11) were determined in ten patients with non-small cell lung cancer following an oral dose of 1.38 g/m2 B.S.A. (Body Surface Area). The drug was given as a powder in gelatine capsules to fasting patients. Plasma samples were collected during the first 24 h after administration. All samples, after extraction with chloroform, were assayed by a reverse phase HPLC method using UV detection at 200 nm. Orally administered (-)-(S)-bromofosfamide showed relatively fast absorption kinetics. Peak concentration of 47 ?g/ml was observed after 1 h. The average half-life was about 5 h. Toxicities associated with oral (-)-(S)-bromofosf-amide therapy consisted of symptoms regarding the central nervous system, gastrointestinal tract and urinary tract. Neurotoxic symptoms were the most common clinically significant side effects and probably dose limiting.

Preactivated Oxazaphosphorines Designed for Isophosphoramide Mustard Delivery as Bulk Form or Nanoassemblies: Synthesis and Proof of Concept

“…The different fractions containing the compound of interest were pooled and concentrated under reduced pressure to yield a yellow to brown oily residue corresponding to the compound of interest 9c (90 mg, yield 28%). 1 4.75 (dt, 1H, J = 20.9 Hz and J = 3.2 Hz, H 4 ), 5.12 (tt, 1H, J = 1.2 Hz and J = 6.8 Hz, CH C(CH 3 ) 2 ), 5.39 (td, 1H, J = 1.2 Hz and J = 6.6 Hz, OCH 2 CH C(CH 3 )). 13 4.2.5.…”

“…To circumvent the toxicity related to the release of chloroacetaldehyde, pharmacomodulation of IFO has been investigated. Synthesis of analogues by engraftment of methyl groups on the side chains (to avoid chloroacetaldehyde release) or replacement of the chlorine atoms by bromine was described. Agents that do not require in vivo biotransformation for activation including isophosphoramide mustard , and glufosfamide , have also been proposed, some of them reaching phase I clinical trial such as mafosfamide or phase III for palifosfamide.…”