This study was prompted by an apparent increase in the number of patients who had been clinically and biochemically stable for months or years, suddenly complaining that their symptoms of flushing, diarrhea, or wheezing were worsening in spite of stable or increasing LAR dosing. These acute changes in clinical symptoms prompted a review of their plasma octreotide levels over time. Previous work has demonstrated that monthly LAR doses of 10 mg/mo led to plasma levels of approximately 1200 pg/mL (levels that approximate the Kd
of octreotide for sst 2), whereas doses of 20, 30, and 60 mg/mo led to plasma levels of approximately 2500, 5000, and 11,000 pg/mL, respectively.1–3
Extrapolating from the previously published data, we would predict that doses of 120 mg of LAR per month would have yielded plasma octreotide values of 20,000 to 22,000 pg/mL. In stark contrast, current dosing of LAR at 30, 60, or 120 mg/mo in patients with carcinoid tumors produces significantly lower plasma levels of 2500, 5000, and 7500 pg/mL, respectively, a decrease over previously reported or expected levels of 50% or more.
Several possibilities exist that may explain why we are currently observing lower octreotide plasma levels in patients receiving chronic LAR therapy than previously described. First, with chronic LAR therapy, there may be the development of antibodies to octreotide. The development of these antibodies might interfere with the accurate measurement of octreotide in plasma. Although these antibodies have never been reported with the LAR formulation, anti-octreotide antibodies have been demonstrated in patients receiving chronic octreotide acetate therapy by subcutaneous administration or by transnasal administration.7
Although these antibodies are present in up to 75% of patients receiving long-term octreotide therapy by subcutaneous administration, we have not seen a time-dependent decrease in plasma levels in patients treated with subcutaneous therapy by multiple daily injection or continuous subcutaneous infusion (data not shown). However, we have switched LAR patients who failed to achieve high (greater than 10,000 pg/mL) plasma octreotide levels to continuous subcutaneous infusion octreotide therapy to determine if this change in the route of administration and the change in the formulation would increase plasma levels and improve control of symptoms. We hypothesized that if antibodies were responsible for the acute lowering of plasma octreotide levels, switching the route of administration would not change plasma levels. For example, a 65-year-old woman with metastatic carcinoid and the carcinoid syndrome had been under excellent symptom control for several years on octreotide LAR at a monthly dose of 30 mg/mo. Her concomitant octreotide plasma level was 4035 pg/mL, a value within our previously reported range of plasma octreotide levels in patients receiving 30 mg/mo of LAR. An increase in flushing and a slight increase in her chromogranin A and pancreastatin values prompted an increase in her octreotide dose to 60 mg of LAR per month. After 3 months of LAR therapy at this dose, her octreotide level dropped to 3837 pg/mL. Her flushing and fatigue continued to increase, and her LAR dose was again increased to 120 mg/mo. After 3 months on this high drug dose, her plasma octreotide level rose to only 5581 pg/mL, a level far less than we would have expected on this LAR dose. Her symptoms continued to increase and her biomarkers also increased significantly. Based on our inability to achieve octreotide values greater than 10,000 pg/mL on this very high (120 mg/mo) dose of LAR, we decided to begin octreotide acetate therapy by continuous subcutaneous administration at a dose of 2 mg/d (60 mg/mo). In spite of her receiving only half of the monthly octreotide dose (as compared with her LAR therapy), her plasma octreotide level rose to 25,436 pg/mL after 1 week of infusional therapy and remained more than 15,000 pg/mL even 3 months after the discontinuation of the LAR preparation. She was asymptomatic after starting the octreotide by continuous subcutaneous infusion and has remained totally asymptomatic on this subcutaneous drug dose.
Second, all of these patients receive LAR as intramuscular injections in the upper outer quadrants of their buttocks. Repeated injections into these sites may be responsible for progressively lower effectiveness of the drug because there is a well-described association between these injections and the development of a granulomatous reaction in the gluteus muscle. Although we believe this to be possible in an occasional patient, we do not believe that the magnitude of the clinical observations presented here are compatible with this possible explanation. Furthermore, patients who only recently started LAR have plasma levels of octreotide consistent with patients on identical chronic dosing and have levels far lower than those seen in the past with identical LAR doses.
Third, there could be changes in the octreotide radio-immunoassay over time. To ensure that changes in plasma octreotide values over time were due to actual differences in plasma levels and not to differences in the octreotide assay values reported over time, several experiments were performed. Plasma samples from patients previously reported were reassayed for this study by Inter Sciences Institute.1
Octreotide plasma levels reported from assays performed 3 years ago were essentially identical to current reassay values (). These data demonstrate the resistance of octreotide to degradation, even when stored in plasma at −80°C for 3 years. In addition, low, intermediate, and high control standards for each octreotide assay done over the last 3 years were plotted against one another. This comparison showed that over time, low, intermediate, and high octreotide standards produced essentially identical octreotide values over time (data not shown). Thus, we believe that the current report of a reduction in plasma octreotide levels in patients given LAR represents true changes in plasma drug levels rather than changes in the assay measurement of plasma octreotide levels (). These significantly decreased plasma drug levels imply that the bioavailability of LAR must have decreased significantly over time. This is supported by the ability to restore desirable levels of octreotide with continuous subcutaneous infusions of octreotide.
Figure 1 This figure demonstrates the stability of the octreotide assay over time. The 2 curves represent plasma octreotide values (sorted in ascending order) for individual samples assayed at the time of the Woltering octreotide study (triangles) and reassayed (more ...)
Hypothetically, there may have been an unanticipated change in the drug formulation or its preparation that has been introduced into the LAR manufacturing process. Traditionally, the polymer for this drug encapsulates the octreotide into microspheres. The range of the size of the microspheres is carefully controlled; however, within the range of the microsphere's acceptable diameter, there could be a significant change in size distribution. This could alter the rate of drug release. Alternatively, the thickness of the microsphere's polymer coating could change, significantly altering the drug release characteristics of the LAR preparations.
Based on our tracking of plasma octreotide levels over time in both individual patients and in groups of patients receiving LAR at a given dose per month, it seems that the bioavailability of octreotide LAR has dramatically decreased over time. This may explain the perceived increase in subcutaneous octreotide rescue medication usage that prompted this study. In the drug registration trial for octreotide LAR in carcinoids, approximately 40% of patients used rescue medication on a frequent basis and 70% of patients in the study used rescue at some point during the study.3
Early in our clinical experience with octreotide level measurement, we noticed that patients who had increasing symptoms also had significant decreases in their octreotide plasma levels. Approximately one half of the plasma octreotide levels previously achieved at monthly LAR doses of 30 or 60 mg of LAR per month are now present in our patient population. Even higher monthly doses of LAR (120 mg/mo) show even greater differences between measured and expected octreotide levels. Traditionally, LAR was reported to be 61% bioavailable (drug information insert, Novartis); however, that number no longer seems to be accurate and the bioavailability seems to be in the range of 25% to 30%. To determine if this conclusion was reasonable, we compared the plasma octreotide levels of patients receiving LAR at a dose of 30 mg/mo in the 2 historic studies to the plasma levels seen in patients receiving aqueous octreotide by continuous subcutaneous infusion (n = 15). The mean plasma octreotide level was 5819 ± 3105 pg/mL for patients receiving 30 mg/mo of octreotide by continuous subcutaneous infusion (normalized data). This value is higher than those reported in the Rubin or Woltering studies, no doubt due to the greater bioavailability of subcutaneously administered octreotide.1,3
When we compared the plasma octreotide levels of the patients receiving subcutaneous infusions of octreotide to our more recent retrospective LAR trial values (January 2007–July 2007) or the prospective LAR trial, the decreased plasma octreotide values produced by the current LAR formulation are even more dramatic ().
Comparison of Plasma Octreotide Levels Achieved by 30-mg/mo Doses of Octreotide LAR and by Continuous Subcutaneous Infusion
Clearly, the simplest approach to increasing circulating plasma octreotide levels is to increase the monthly dose of LAR. However, there are several potential reasons not to do this. Toxicity at doses higher than previously reported might be significant, and the expense of extremely high-dose LAR therapy might be cost prohibitive. In our clinical experience, the use of doses of LAR higher than those recommended by the Food and Drug Administration (30 mg/mo) seems to be extremely well tolerated. We have not been able to demonstrate any significant toxicity even when LAR doses of up to 240 mg/mo have been used for longer than 6 months. However, the economic impact of long-term high-dose LAR therapy is substantial.
The data from this study were reviewed to look for individual patient (as compared with group) changes in plasma octreotide levels over time. In patients receiving stable (3 months or longer) LAR doses of 30 mg/mo, 9 of 26 patients had decreases in plasma octreotide levels over time. The mean decrease in drug level was 2165 pg/mL from the first to the last plasma octreotide measurement. In contrast, 7 of 13 patients on stable 60-mg/mo doses of LAR had decreases in plasma octreotide levels over time. The mean decrease in plasma octreotide levels in the 60-mg/mo group was 2495 pg/mL from the first to the last plasma measurement. Finally, 1 of 5 patients on stable 120-mg/mo LAR dose had decreases measured over time. The decrease in plasma octreotide levels in this patient was 2971 pg/mL.
These changes are potentially time dependent. If a patient was on LAR at a dose of 30 mg/mo at the beginning of the study (November 2004) and remained on this dose over time, one might suspect that a drop in plasma octreotide level would be more likely than in a patient who was put on LAR 30 mg/mo during the last 4 months of this study. Unfortunately, fewer octreotide measurements were performed in the early part of the study when the octreotide assay was first offered on a commercial basis. Plasma octreotide levels seemed to fall in late 2005 to early 2006, and those patients who entered the study after that time would be exposed to the conditions that favored lower (but relatively stable during the last 6 months of the study) plasma drug levels.
In conclusion, we have observed that in current studies of octreotide LAR therapy produce plasma octreotide values significantly lower than previously reported.1,3
In addition, the octreotide plasma values have decreased by approximately 29% per year during the last several years. We suggest that patients with progressive symptoms, rising biomarkers or progressive growth of tumors on radiographs should have their octreotide values measured. Patients in whom plasma octreotide levels are less than 10,000 pg/mL should have their LAR dose adjusted, based on serial plasma octreotide determinations. If octreotide levels of 10,000 to 15,000 pg/mL cannot be achieved over time with higher LAR doses, clinicians should consider switching these patients to intermittent dose or continuous subcutaneous infusion octreotide therapy. Clinicians should also be cognizant of the costs associated with high-dose LAR therapy. Subcutaneous octreotide therapy may be a cost-effective alternative in this patient population. Alternatively, lanreotide, a somatostatin receptor subtype 2–preferring somatostatin analog has recently been approved for use in the United States for the treatment of acromegaly. It may be possible to use this medication for the control of symptoms of NETS as out of indication therapy.