Measuring Gleevec Levels in Blood

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This could be helpful in tailoring a patient's Gleevec dose.

Widmer et al (2006) suggest that measuring blood levels of alpha-1 acid

glycoprotein (which binds imatinib) can allow one to deduce the amount

of

unbound imatinib in blood...

Earlier papers have suggested fancier methods that are not widely

available.

1: Br J Clin Pharmacol. 2006 Jul;62(1):97-112.

Population pharmacokinetics of imatinib and the role of alpha-acid

glycoprotein.

Widmer N, Decosterd LA, Csajka C, Leyvraz S, Duchosal MA, Rosselet A,

Rochat

B,

Eap CB, Henry H, Biollaz J, Buclin T.

Division of ClinicAl Pharmacology, University Hospital, Lausanne,

Switzerland.

AIMS: The aims of this observational study were to assess the

variability in imatinib pharmacokinetics and to explore the relationship

between its disposition and various biological covariates, especially

plasma alpha1-acid glycoprotein concentrations. METHODS: A population

pharmacokinetic analysis

was

performed using NONMEM based on 321 plasma samples from 59 patients with

either

chronic myeloid leukaemia or gastrointestinal stromal tumours. The

influence

of

covariates on oral clearance and volume of distribution was examined.

Furthermore, the in vivo intracellular pharmacokinetics of imatinib was

explored

in five patients. RESULTS: A one-compartment model with first-order

absorption

appropriately described the data, giving a mean (+/-SEM) oral clearance

of

14.3

l h-1 (+/-1.0) and a volume of distribution of 347 l (+/-62). Oral

clearance

was

influenced by body weight, age, sex and disease diagnosis. A large

proportion of

the interindividual variability (36% of clearance and 63% of volume of

distribution) remained unexplained by these demographic covariates.

Plasma alpha1-acid glycoprotein concentrations had a marked influence on

total

imatinib

concentrations. Moreover, we observed an intra/extracellular ratio of 8,

suggesting substantial uptake of the drug into the target cells.

CONCLUSION: Because of the high pharmacokinetic variability of imatinib

and the reported relationships between its plasma concentration and

efficacy and toxicity,

the

usefulness of therapeutic drug monitoring as an aid to optimizing

therapy

should

be further investigated. Ideally, such an approach should take account

of

either

circulating alpha1-acid glycoprotein concentrations or free imatinib

concentrations.

PMID: 16842382 [PubMed - in process]

2: J Chromatogr B Analyt Technol Biomed Life Sci. 2004 Apr

25;803(2):285-92.

Determination of imatinib (Gleevec) in human plasma by solid-phase

extraction-liquid chromatography-ultraviolet absorbance detection.

Widmer N, Beguin A, Rochat B, Buclin T, Kovacsovics T, Duchosal MA,

Leyvraz

S,

Rosselet A, Biollaz J, Decosterd LA.

Division de Pharmacologie Clinique, Laboratoire BH 18-218, Departement

de Medecine, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne

CHUV, Switzerland.

A sensitive HPLC method has been developed for the assay of imatinib in

human

plasma, by off-line solid-phase extraction followed by HPLC coupled with

UV-Diode Array Detection. Plasma (750 microl), with clozapine added as

internal

standard, is diluted 3 + 1 with water and subjected to a solid-phase

extraction

on a C18 cartridge. After matrix components elimination with 2000 microl

of water (in two aliquots of 1000 microl), imatinib is eluted with 3 x

500

microl

MeOH. The resulting eluate is evaporated under nitrogen at room

temperature

and

is reconstituted in 180 microl 50% methanol. A 50 microl volume is

injected

onto

a Nucleosil 100-5 microm C18 AB column. Imatinib is analyzed using a

gradient

elution program with solvent mixture constituted of methanol and water

containing both 0.05% ammonium acetate. Imatinib is detected by UV at

261

nm.

The calibration curves are linear between 0.1 and 10 microg/ml. The

limit of quantification and detection are 0.05 and 0.01 microg/ml,

respectively. The

mean

absolute recovery of imatinib is 96%. The method is precise with mean

inter-day

CVs within 1.1-2.4%, and accurate (range of inter-day deviations -0.6 to

+0.7%).

The method has been validated and is currently being applied in a

clinical

study

assessing the imatinib plasma concentration variability in a population

of chronic myeloid leukemia- and gastro-intestinal stromal

tumor-patients.

PMID: 15063337 [PubMed - indexed for MEDLINE]