Effects of low-fat and high-fat meals on steady-state pharmacokinetics of lapatinib in patients with advanced solid tumours.

AIM: To quantify the effect of food on the systemic exposure of lapatinib at steady state when administered 1 h before and after meals, and to observe the safety and tolerability of lapatinib under these conditions in patients with advanced solid tumours. METHODS: This was a three-treatment, randomised, three-sequence cross-over study. Lapatinib was administered 1 h after a low- [B] or a high-fat [C] meal and systemic exposure was compared with that obtained following administration 1 h before a low-fat meal [A]. RESULTS: In total, 25 patients were included, of whom 12 were evaluable for the pharmacokinetic analysis. Both low-fat and high-fat meals affected lapatinib exposure. Lapatinib AUC0-24 increased following lapatinib administration 1 h after a low-fat meal by 1.80-fold (90 % CI: 1.37-2.37) and after a high-fat meal by 2.61-fold (90 % CI: 1.98-3.43). Lapatinib Cmax increased following lapatinib administration 1 h after a low-fat meal by 1.90-fold (90 % CI: 1.49-2.43) and after a high-fat meal by 2.66-fold (90 % CI: 2.08-3.41). The most commonly occurring treatment-related toxicity was diarrhoea (8/25, 32 % CTCAE grade 1 and 2/25, 8 % grade 2) and one treatment-related grade ≥ 3 event occurred (fatigue grade 3, 4 %). CONCLUSIONS: Both low-fat and high-fat food consumed 1 h before lapatinib administration increased lapatinib systemic exposure compared with lapatinib administration 1 h before a low-fat meal. In order to administer lapatinib in a fasted state, it is advised to administer the drug 1 h before a meal.

Clinical pharmacokinetics, platelet response, and safety of eltrombopag at supratherapeutic doses of up to 200 mg once daily in healthy volunteers.

This was a double-blind, placebo-controlled, randomized, parallel, dose-escalation study to assess the pharmacokinetics, platelet response, safety, and tolerability of supratherapeutic doses of eltrombopag (100 mg, 150 mg, and 200 mg once daily) administered for 5 days to 33 healthy adult volunteers. Plasma eltrombopag concentrations accumulated between days 1 and 5, with average increases of 66% to 81% for area under the plasma concentration-time curve from time zero to the end of the 24-hour dosing interval (AUC(0-τ)) and 32% to 45% for maximum observed plasma concentration (C(max)) across doses. After 5 days of dosing, AUC(0-τ) was dose-proportional and C(max) was less than dose-proportional over eltrombopag 100 to 200 mg with slope estimates (90% confidence intervals) of 0.92 (0.45-1.39) and 0.76 (0.29-1.22), respectively. Platelet counts peaked at day 14, and maximum change from baseline platelet count increased dose-dependently, with mean platelet count increases of 14, 67, 107, and 150 Gi/L for placebo and eltrombopag 100 mg, 150 mg, and 200 mg, respectively. There was no notable difference in day 14 mean platelet aggregation between eltrombopag (59 to 74%) and placebo (67%), although this was not tested statistically. There was no notable difference in adverse event frequency across eltrombopag doses. Eltrombopag pharmacokinetics and platelet response were dose-dependent, and doses up to 200 mg/d were well tolerated, with safety profiles similar to placebo.

Eltrombopag does not affect cardiac repolarization: results from a definitive QTc study in healthy subjects.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Some non-anti-arrhythmic drugs delay cardiac repolarization, which can be measured as an increase in the QT interval. Delays in cardiac repolarization create an electrophysiological environment that favours the development of cardiac arrhythmias, which may lead to torsade de pointes, which can be fatal. As part of the clinical development of eltrombopag, a thorough QT(c) study was conducted to evaluate the effects of eltrombopag on cardiac repolarization at both therapeutic and supratherapeutic doses and to characterize the relationship between plasma eltrombopag concentrations and change in QT(c). WHAT THIS STUDY ADDS: This study found no clinically significant QT prolongation for eltrombopag when administered as 50 mg or 150 mg every day for 5 days. There were no safety or tolerability signals of clinical concern. A small incidence of ventricular premature beats was observed, but this was consistent with previously reported incidences in healthy volunteers without apparent heart disease. AIM: To evaluate the effect of eltrombopag on cardiac repolarization and to characterize the relationship between plasma eltrombopag concentrations and change in QT(c). METHODS: This was a double-blind, placebo- and active-controlled, randomized, balanced four-period, crossover study in healthy men and women. Subjects were randomized to receive eltrombopag 50 mg and 150 mg, moxifloxacin 400 mg (positive control) and placebo in one of four sequences. RESULTS: Eighty-seven subjects entered the study and 48 completed. There was no prolongation of QT(c) (Fridericia) following eltrombopag treatment, as the upper limit of the 90% confidence interval (CI) for the time-matched change from baseline in QT(c)F between drug and placebo (ddQT(c)F) did not exceed 10 ms for eltrombopag at either dose. Maximum observed mean treatment difference was 2.29 ms (90% CI 0.34, 4.24) for eltrombopag 150 mg at 1 h post-dose and 11.64 ms (90% CI 9.64, 13.64) for moxifloxacin 400 mg at 4 h. Eltrombopag C(max) and AUC(0,24 h) increased in a dose proportional manner between 50 mg and 150 mg after 5 days' dosing. Proportions of subjects with adverse events were similar across treatments (52-66% of subjects). Most withdrawals (26/39 subjects) were due to elevated platelets. Three subjects were withdrawn for ventricular premature beats (one following each active treatment) reported as related to the study drug. CONCLUSIONS: No clinically significant QT(c) prolongation was observed for eltrombopag at therapeutic and supratherapeutic doses.

A Phase II, open-label study evaluating pazopanib in patients with recurrent ovarian cancer.

OBJECTIVE: The progression-free and median survival of patients with advanced ovarian cancer has not appreciably improved over the last decade. Novel targeted therapies, particularly antiangiogenic agents, may potentially improve clinical outcomes in patients with ovarian cancer. This phase II, open-label study evaluated oral pazopanib monotherapy in patients with low-volume recurrent ovarian cancer. METHODS: Patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal carcinoma with complete CA-125 response to initial platinum-based chemotherapy and subsequent elevation of CA-125 to ≥ 42 U/mL (> 2 × ULN) were treated with pazopanib 800 mg once daily until PD or unacceptable toxicity. This Green-Dahlberg study required 2 CA-125 responses in stage I (20 patients) to proceed to stage II (15 patients). The primary endpoint was CA-125 response (≥ 50% decrease from baseline, confirmed ≥ 21 days after initial evaluation). RESULTS: Eleven of 36 patients (31%) had a CA-125 response to pazopanib, with median time to response of 29 days and median response duration of 113 days. Overall response rate was 18% in patients with measurable disease at baseline. The most common adverse events leading to discontinuation of study drug were grade 3 ALT (8%) and AST (8%) elevation. Only 1 grade 4 toxicity (peripheral edema) was reported. CONCLUSIONS: Pazopanib monotherapy was relatively well tolerated, with toxicity similar to other small-molecule, oral angiogenesis inhibitors, and demonstrated promising single-agent activity in patients with recurrent ovarian cancer. Further studies evaluating the potential role of pazopanib in patients with ovarian cancer are ongoing.