Effects of Food on the Relative Bioavailability of Lapatinib in Cancer Patients

Abstract

A B S T R A C T PurposeThis study was conducted to characterize the effect of food on the relative bioavailability of lapatinib. Patients and MethodsA single 1,500-mg, oral dose of lapatinib was administered to 27 patients with advanced solid tumors on each of three occasions that were 1 week apart, in random order: after an overnight fast, with a low-fat breakfast, and with a high-fat breakfast. ResultsThe low-fat breakfast produced mean increases in lapatinib area under the concentration-time curve (AUC) of 167% (2.67-fold) and maximum concentration (C max ) of 142% (2.42-fold). The high-fat breakfast produced mean increases in lapatinib AUC of 325% (4.25-fold) and C max of 203% (3.03-fold) compared with the fasted state. Increased bioavailability in the fed state did not significantly decrease relative variability. Therefore, absolute variability in systemic exposure was increased. ConclusionThese large increases in lapatinib bioavailability and absolute variability support the recommendation for dosing in the fasted state to achieve consistent therapeutic exposure. Prescribers and patients should consider the potential consequences of toxicity or diminished efficacy that might result from dosing without regard to variations in diet.

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“…A daily dose of 1,250 mg causes steady state levels of Cmax 2.43 mcg/ml (1.57 to 3.77 mcg/ml) and the area under the curve (AUC) 36.2 mcg.hr/ml (23.4 to 56 mcg.hr/ml). With multiple daily dosing, a steady state was achieved within 6 to 7 days 6,17,18, [52][53][54] . When taken with food, lapatinib absorption is increased 52,53 .…”

“…When taken with food, lapatinib absorption is increased 52,53 . In the case of high-fat food (characterized as 50% of fat and 1,000 calories) AUC values were approximately 4-fold higher (Cmax approximately 3-fold higher) 17,18, [52][53][54] . Lapatinib plasma levels were also higher when lapatinib was combined with capecitabine compared to lapatinib alone but the difference did not reach statistical significance 38 .…”

“…The tumor phenotype, predictor status, drug dose as well as other factors may play a role here. Lapatinib has been proven to be more absorbed by a high-fat diet 52,54 . The following steps of lapatinib body passage depend on liver metabolism and cytochrome inducers/inhibitors.…”

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“…So, although, for example, lapatinib's AUC in the fed state is 425% of that in the fasting state, this increase is after administration with a high-fat meal. With a low-fat meal, AUC increases by 267%, about half of that with a high-fat meal (6). If patients took the drug with meals of differing content or at different times relative to a meal, the benefit and risk of the treatment is uncertain (7).…”

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“…A vizsgálatban a betegek három hétig heti egyszer éhgyomorra és alacsony, illetve magas zsírtartalmú reggelivel is beszedték az 1500 mg dózist [59]. Eredményeik szerint, az alacsony zsír-tartalmú reggeli hatására 2,67-szorosára (167%) nőtt a lapatinib esetében az AUC, és 2,42-szorosára (142%) a maximumkoncentráció (C max ).…”