Endocrine Abstracts

Background: TE is indicated for the treatment of carcinoid syndrome diarrhea in patients with metastatic neuroendocrine tumors.

Objective: To evaluate the effects of a proton pump inhibitor (OMP) and H2 antagonist (FAM) on the PK of TE and its active metabolite LP-778902 via an open-label study of OMP (40 mg orally QD × 4 days) or FAM (40 mg orally BID × 4 days) with a single 250 mg oral dose of TE. Eligible subjects: healthy, nonsmoking, aged ≥18-≤65 years/BMI ≥18.0-≤32.0 kg/m². Parallel cohorts of 16 subjects each received 250 mg TE on Day 1 followed by a 72-hour washout. On Day 4–6 subjects received either OMP (n=16) or FAM alone (n=16). On Day 7 subjects received 250 mg TE and OMP or FAM. Fasting and meals were controlled. PK blood samples were collected on Day 1 and 7. Safety assessments were conducted at Screening and throughout the study.

Analysis: PK parameters included maximum observed concentration (C_max), time of maximum concentration (T_max), area under the plasma concentration-time curve extrapolated to infinity (AUC_inf), and AUC from first dose until the last quantifiable concentration (AUC_t). A lack of DDI was declared if the 90% confidence intervals (CIs) for the ratios of geometric least square means fell within the accepted range of 0.8 – 1.25 for AUC_t, AUC_inf, and C_max.

Results: For TE alone, mean AUC_t, AUC_inf, and C_max were 3.4, 2.8, 1.7 and 2.2, 2.1, and 1.2 times higher when TE was co-administered with OMP or FAM, respectively. Median T_max for TE was delayed by 1.3 hours and 0.5 hours, respectively. Boundaries of the 90% CIs were not within the 0.8–1.25 interval, indicating a DDI with OMP and FAM on TE exposure. However, no-significant difference in exposure (AUC_t, AUC_inf) to LP-778902 was observed and there was a <7% decrease in C_max, following coadministration of TE with either OMP or FAM. There were no clinically significant findings in any safety assessments. One subject who received FAM experienced mild pruritis that was considered unlikely related to either study drug and resolved by the end of the study.

Conclusion: Single oral doses of 250 mg TE administered alone or with either OMP or FAM were safe and well tolerated. Coadministration with either OMP or FAM alters the exposure of TE but has no marked effect on exposure to the active, more potent metabolite, LP-778902, and therefore, is unlikely to be clinically significant.