High lapatinib plasma levels in breast cancer patients: risk or benefit?

AIMS AND BACKGROUND: Lapatinib is a tyrosine kinase inhibitor targeting epidermal growth factor receptors 1 (EGFR/HER1) and 2 (HER2) used in the treatment of patients with HER2-positive breast cancer. The aim of the present study was to determine lapatinib plasma levels in breast cancer patients treated with lapatinib plus capecitabine. PATIENTS AND METHODS: We assessed lapatinib plasma levels in blood samples from 21 breast cancer patients treated with lapatinib plus capecitabine using the standard regimen in an expanded access program. Liquid chromatography tandem mass spectrometry was used for measuring lapatinib plasma concentrations. The validated method was applied for measurement of 55 plasma samples. RESULTS: The median lapatinib plasma level was 5.09 µg/mL, with large interindividual differences. Patients of lower weight tended to have higher lapatinib plasma levels (Spearman correlation coefficient R = -0.435, P = 0.055). One patient's lapatinib plasma levels were markedly higher than those of the others, with a median level of 11.25 µg/mL and repeatedly exceeding 7.80 µg/mL. The treatment was terminated after 8 months when hyperbilirubinemia occurred. CONCLUSIONS: The lapatinib plasma levels reported here are twice as high as the clinically effective steady-state geometric mean maximum concentration. We conclude that increased lapatinib body levels occur when patients are in a nonfasting state at the time of drug intake and when lapatinib doses are not adjusted to low body weight or weight loss during treatment. In Europe, dose adjustments are not recommended in the case of hepatic function impairment. Thus, attention should be paid to changes in liver function test results in clinical practice, especially in patients of small stature and weight, given the risk of high plasma concentrations. Prospective lapatinib plasma level assessment in treated patients might be useful to confirm or refute the possible correlation of high lapatinib plasma levels with hepatic and/or other toxicities.

Flow injection analysis vs. ultra high performance liquid chromatography coupled with tandem mass spectrometry for determination of imatinib in human plasma.

BACKGROUND: The aim of this study was to develop, validate and compare flow injection analysis (FIA) and ultra-high-performance liquid chromatography (LC)/tandem mass spectrometry methods for the determination of imatinib in plasma from patients with chronic myeloid leukemia. METHODS: The plasma for analysis by both methods was deproteinated by methanol containing d8-imatinib. The separation was achieved on a 1.7 µm C18 column with a linear gradient (4 mM ammonium formiate and acetonitrile, pH 3.2). FIA was performed at flow rate of 0.03 mL/min (0.1% formic acid in methanol). Multiple reaction monitoring mode on the tandem mass spectrometer (API 4000, AB Sciex) in positive ESI were used for detection. RESULTS: The total analysis times were 3.2 (LC) and 0.75 min (FIA). Both methods were successfully validated and applied to the plasma patients samples. The limits of quantification were 4.1 and 30.8 ng/mL; imprecisions were less than 5.7% and recovery ranged between 93 and 105%, for the LC and FIA, respectively. The methods revealed an agreement with a mean difference of 1.46 ng/mL (SD 28.95 ng/mL). CONCLUSIONS: The high-throughput methods that were developed are suitable for the therapeutic drug monitoring of imatinib in plasma. They can be used in routine clinical practice.

Capillary electrophoresis determination of thiopurine methyl transferase activity in erythrocytes.

Thiopurine S-methyltransferase (TPMT) catalyzes methylation of thiopurine drugs (e.g. 6-mercaptopurine, azathioprine). Decreased activity of TPMT is associated with hematopoietic toxicity after administration of standard doses of the drugs. We developed capillary electrophoretic method for determination of TPMT enzyme activity in erythrocytes. Limit of quantification of the method is 1.5 micromol/L (S/N=6). The recovery of 6-methylmercaptopurine was 87.5-94.8%, imprecision value (as CV, n=10) was 1.68% (within-day) and 2.53% (between-day). Erythrocyte TPMT activities were measured in 60 healthy adult volunteers.