Disposition of temozolomide in a patient with glioblastoma multiforme after gastric bypass surgery.

Temozolomide, used for anaplastic gliomas and glioblastoma multiforme, is an oral drug that is stable under acidic, but labile under neutral and basic conditions. Although the bioavailability of temozolomide is approximately 100%, pathology or anatomical changes of the gastrointestinal tract may adversely affect absorption, and consequently therapeutic response. HPLC-UV was used to evaluate temozolomide plasma pharmacokinetics in a patient with unresponsive glioblastoma multiforme who had previously undergone gastric bypass as part of a weight-loss strategy. Temozolomide plasma pharmacokinetics were comparable to values reported for patients with normal gastrointestinal anatomy. These data imply that progression of disease in this patient was not due to inadequate temozolomide concentrations. Physicians need to become aware of the rapidly increasing population of patients who have had a gastric bypass and require oral therapy, of which our case is representative. The effect of gastric bypass on pharmacokinetics will need to be evaluated on a drug-by-drug basis.

Effect of a proton pump inhibitor on the pharmacokinetics of imatinib.

AIMS: Imatinib mesylate (Gleevec/Glivec), which has revolutionized the treatment of chronic myeloid leukemias (CML) and gastrointestinal stromal tumours (GIST), has been reported to cause gastric upset. Consequently, proton pump inhibitors (PPI) are frequently co-administered with imatinib. Because PPI can elevate gastric pH and delay gastric emptying or antagonize ATP-binding-cassette transporters, they could influence imatinib absorption and pharmacokinetics. We aimed to evaluate whether use of omeprazole has a significant effect on imatinib pharmacokinetics. METHODS: Twelve healthy subjects were enrolled in a two-period, open-label, single-institution, randomized cross-over, fixed-schedule study. In one period, each subject received 400 mg imatinib orally. In the other period, 40 mg omeprazole (Prilosec) was administered orally for 5 days, and on day 5 it was administered 15 min before 400 mg imatinib. Plasma concentrations of imatinib and its active N-desmethyl metabolite CGP74588 were assayed by LC-MS, and data were analyzed non-compartmentally. RESULTS: PPI administration did not significantly affect the imatinib area under the plasma concentration vs time curve (AUC) (34.1 microg ml(-1) h alone vs 33.1 microg ml(-1) h with omeprazole, P= 0.64; 80% power), maximum plasma concentration (C(max)) (2.04 microg ml(-1) alone vs 2.02 microg ml(-1) with omeprazole, P= 0.97), or half-life (13.4 h alone vs 14.1 h with omeprazole, P= 0.13). CONCLUSIONS: Our results indicate that the use of omeprazole does not significantly affect the pharmacokinetics of imatinib, as opposed to, for example, dasatinib where PPI decreased AUC and C(max) two-fold.

Imatinib mesylate pharmacokinetics before and after sleeve gastrectomy in a morbidly obese patient with chronic myeloid leukemia.

Abstract Imatinib is widely used to treat chronic myeloid leukemia and gastrointestinal stromal tumors. The agent, administered orally, has approximately 98% oral bioavailability, achieves maximum plasma concentration approximately 2-4 hours after ingestion, and has a plasma half-life of approximately 18 hours. As maintaining an adequate plasma imatinib concentration is essential to achieving a favorable therapeutic response, it is important to determine whether gastrointestinal surgery, pathologic conditions, or anatomic changes negatively affect imatinib absorption, and thereby result in subtherapeutic plasma imatinib concentrations. We describe a 36-year-old, morbidly obese woman with chronic myeloid leukemia who received treatment with alpha-interferon and cytarabine over 5 years. Her chemotherapy was then switched to imatinib 400 mg/day because she failed to achieve a molecular response with the other two agents. A complete molecular response was achieved with imatinib. Four years later, she underwent a sleeve gastrectomy while receiving imatinib. Imatinib plasma pharmacokinetic values were assessed before and on four occasions during the year after the sleeve gastrectomy. The patient's trough plasma concentration before surgery (1558 ng/ml) was consistent with those found in the literature (>/= 1000 ng/ml), whereas her trough concentrations after surgery were 46-60% lower (629-836 ng/ml) than the preoperative value. Despite this, the patient remained in complete molecular remission for 1 year after surgery. Monitoring plasma imatinib concentrations is recommended in morbidly obese patients with chronic myeloid leukemia or gastrointestinal stromal tumors who undergo gastric procedures. Additional pharmacokinetic studies, however, are needed in these patients.

A high-performance liquid chromatography-mass spectrometry assay for quantitation of the tyrosine kinase inhibitor nilotinib in human plasma and serum.

Nilotinib (AMN-107, Tasigna) is a small-molecule inhibitor of BCR/ABL, approved for chronic myelogenous leukemia. We developed and validated, according to FDA-guidelines, an LC-MS assay for sensitive, accurate and precise quantitation of nilotinib in 0.2 mL human plasma or serum. After acetonitrile protein precipitation, separation is achieved with a hydro-Synergi column and a 0.1% formic acid in methanol/water-gradient. Detection uses electrospray, positive-mode ionization mass spectrometry. Between 5 (LLOQ) and 5000 ng/mL, accuracy (92.1-109.5%), intra-assay precision (2.5-7.8%), and inter-assay precision (0-5.6%)) were within FDA limits. We demonstrated the suitability of this assay by quantitating plasma concentrations of nilotinib in a healthy volunteer after oral administration of 400 mg nilotinib.