Clinical value of monitoring plasma octreotide levels during chronic octreotide long-acting repeatable therapy in carcinoid patients.

Octreotide is one of the most commonly used medications in the treatment of symptomatic neuroendocrine tumors (NETS). Traditionally, the vast majority of NETS patients receiving this medication have prompt and effective relief of their symptoms. We have previously shown that plasma octreotide levels correlate with both patient weight and the monthly dose of medication administered.1 In that study, trough plasma octreotide values were reported to be approximately 1250, 2500, 5000, and 11,000 pg/mL for long-acting repeatable (LAR) doses of 10, 20, 30, and 60 mg/mo, respectively.1 Octreotide acetate (Sandostatin; Novartis Pharmaceutical Company, East Hanover, NJ) is an octapeptide congener of native somatostatin that is widely used for the control of the symptoms associated with functionally active NETS.1–3 Octreotide acetate controls symptoms by inhibiting the secretion of peptides and amines associated with these functional tumors. Octreotide binds preferentially to sst 2, one of a family of somatostatin receptors (sst 1–sst 5).3 Octreotide acetate binds to the sst 2 receptor with an affinity (Kd, 50% receptor saturation) of approximately 1 nM (≅1000 pg/mL). Nearly complete saturation of the sst 2 receptor should occur, with circulating drug levels approximately 10 times higher than the Kd (1 nM, or ≅10,000 pg/mL).4–6 Subsequent inhibition of G-protein–associated signal transduction pathways block secretory vesicle exocytosis and the release of the target peptide or amine, thus effectively controlling symptoms. Clinically, the LAR form of octreotide is widely used for long-term symptom control, and the aqueous form of octreotide is commonly used (40%–70% of patients) as “rescue” medication for the acute control of symptoms.1–3 Long-acting repeatable octreotide is currently available in 3 doses: 10, 20, and 30 mg. These doses are most commonly administered once a month; however, patients receiving a dose of more than 30 mg/mo often have more frequent administration of 30-mg dose rather than multiple injections at the same time. Dosing this medication is at the discretion of the physician; however, the recommended starting dose of this drug is 20 mg/mo.1–3 Few, if any, physicians currently choose an alternative starting dose of LAR based on the patient's weight, height, body surface area, or body mass index. In the registration trials for this drug, up to 40% of patients required rescue medication several times a week, independent of the monthly LAR dose (10, 20, or 30 mg/mo) used for long-term symptom control.3 This implies that circulating drug levels produced by these doses of this medication are inadequate to completely saturate sst 2, and thus, the drug levels are not adequate to maximally suppress symptoms or tumor growth.4–6 Recently, Anthony et al7 showed that in current clinical practice, 20% to 40% of patients received LAR doses higher than the maximal dose (30 mg/mo) approved by the Food and Drug Administration to adequately control symptoms or to suppress tumor progression. Recently, we have made several clinical and biochemical observations that led us to hypothesize that there may be an acute loss of bioactivity (decrease in drug release over time) with the current drug formulation of octreotide LAR (Sandostatin LAR). First, we observed a loss of effective symptom control in patients who have used octreotide acetate LAR at a constant dose for prolonged periods of time. In previous studies, approximately 40% of patients needed rescue medication for poorly controlled symptoms. It was our clinical impression that the number of patients requiring rescue and the number of rescue episodes per week increased significantly during the time frame of this study.3 Second, we have observed that patients who are currently using LAR have significantly lower trough plasma levels of octreotide than those previously published in the Novartis LAR drug registration trial or in our previously published plasma octreotide level study.1,2 Third, we have observed that patients who are given LAR at progressively higher doses (60–120 mg/mo) commonly fail to achieve plasma drug levels that will saturate the sst 2 receptors (approximately 10 nM or ≈10,000 pg/mL). To confirm these observations, patients in our clinical practices who used chronic octreotide LAR therapy had their charts reviewed for their LAR doses (mg/mo) and their plasma octreotide levels (pg/mL). All plasma octreotide levels were measured by a single laboratory (Inter Science Institute, Inglewood, Calif). Finally, we compared current plasma octreotide levels produced by a LAR dose to previously reported plasma levels for that LAR dose and investigated the use of octreotide administered by continuous subcutaneous infusion as a means to restore plasma octreotide levels to those expected for a given octreotide dose (mg/mo).1,3