Pharmacokinetic variability of everolimus and impact of concomitant antiseizure medications in patients with tuberous sclerosis complex: A retrospective study of therapeutic drug monitoring data in Denmark and Norway.

The mTOR-inhibitor everolimus is a precision drug with antiepileptogenic properties approved for treatment of epilepsy in persons with tuberous sclerosis complex (TSC) in combination with other antiseizure medications (ASMs). However, the pharmacokinetic variability of everolimus is scarcely described, and the available information on pharmacokinetic interactions is scarce. The purpose of this study was to investigate pharmacokinetic variability of everolimus in patients with TSC, and the impact of age, sex and comedication. In this retrospective observational study we used anonymized data from medical records of patients with TSC using everolimus in Norway and Denmark, 2012 to 2020. Long-term therapeutic drug monitoring (TDM) identified inter-patient and intra-patient variability. The study included 59 patients, (36 females (61%)), median age 22 (range 3-59 years). Polytherapy was used in 50 patients (85%). The most frequently used ASMs were lamotrigine (n = 21), valproate (n = 17), and levetiracetam (n = 13). Blood concentrations of everolimus were measured in all patients. Pharmacokinetic variability of everolimus between patients was extensive, as demonstrated by a 24-fold variability from minimum-maximum concentration/dose (C/D)-ratios. The coefficient of variation (CV) for intra-patient (n = 59) and inter-patient variability (n = 47, ≥3 measurements) was 40% and 43%, respectively. The C/D-ratio of everolimus was 50% lower in 13 patients (22%) using enzyme-inducing ASMs compared to the 30 patients who did not (0.7 vs 1.4 ng/mL mg, P < .05). Age and sex were not significantly associated with changes in C/D-ratios of everolimus. Long-term TDM identified extensive variability in concentrations over time for everolimus both within and between patients, where comedication with enzyme-inducing ASMs was an important contributing factor. The findings suggest a need for TDM in patients with TSC treated with everolimus.

Glucose sensor-augmented continuous subcutaneous insulin infusion in patients with diabetic gastroparesis: An open-label pilot prospective study.

Erratic blood glucose levels can be a cause and consequence of delayed gastric emptying in patients with diabetes. It is unknown if better glycemic control increases risks of hypoglycemia or improves hemoglobin A1c levels and gastrointestinal symptoms in diabetic gastroparesis. This study investigated the safety and potential efficacy of continuous subcutaneous insulin infusion (CSII) and continuous glucose monitoring (CGM) in poorly controlled diabetes with gastroparesis. Forty-five type 1 or 2 patients with diabetes and gastroparesis and hemoglobin A1c >8% from the NIDDK Gastroparesis Consortium enrolled in a 24 week open-label pilot prospective study of CSII plus CGM. The primary safety outcome was combined numbers of mild, moderate, and severe hypoglycemic events at screening and 24 weeks treatment. Secondary outcomes included glycemic excursions on CGM, hemoglobin A1c, gastroparesis symptoms, quality-of-life, and liquid meal tolerance. Combined mild, moderate, and severe hypoglycemic events occurred similarly during the screening/run-in (1.9/week) versus treatment (2.2/week) phases with a relative risk of 1.18 (95% CI 0.85-1.64, P = 0.33). CGM time in hypoglycemia (<70 mg/dL) decreased from 3.9% to 1.8% (P<0.0001), time in euglycemia (70-180 mg/dL) increased from 44.0% to 52.0% (P = 0.02), time in severe hyperglycemia (>300 mg/dL) decreased from 14.2% to 7.0% (P = 0.005), and hemoglobin A1c decreased from 9.4±1.4% to 8.3±1.3% (P = 0.001) on CSII plus CGM. Symptom scores decreased from 29.3±7.1 to 21.9±10.2 with lower nausea/vomiting, fullness/early satiety, and bloating/distention scores (P≤0.001). Quality-of-life scores improved from 2.4±1.1 to 3.1±1.1 (P<0.0001) and volumes of liquid nutrient meals tolerated increased from 420±258 to 487±312 mL (P = 0.05) at 24 weeks. In conclusion, CSII plus CGM appeared to be safe with minimal risks of hypoglycemic events and associated improvements in glycemic control, gastroparesis symptoms, quality-of-life, and meal tolerance in patients with poorly controlled diabetes and gastroparesis. This study supports the safety, feasibility, and potential benefits of improving glycemic control in diabetic gastroparesis.

Predicting the Development of Orbitopathy in Graves Thyroidopathy Patients: The Potential Role of TSI Testing.

OBJECTIVE: To determine whether thyroid-stimulating immunoglobulin (TSI) testing can predict the risk of development of Graves orbitopathy in newly diagnosed Graves thyroidopathy patients. DESIGN: Retrospective cohort, from 2008 to 2013. SETTING: The Thyroid Referral Center at California Pacific Medical Center. PARTICIPANTS: A retrospective cohort of newly diagnosed Graves thyroidopathy patients from the California Pacific Medical Center Thyroid Referral Center. Patients were included if they had TSIs drawn at or near the time of diagnosis of Graves thyroidopathy. Patients were excluded from the study if they had a long-standing diagnosis of Graves thyroidopathy, orbitopathy at time of diagnosis, no TSIs drawn, or follow up of less than 6 months. MAIN OUTCOME MEASURES: Patients were followed for the development of orbitopathy as determined by their endocrinologists. Results were adjusted for family history, smoking status, age, radioiodine ablation treatment, and race. RESULTS: Thirty-three patients met inclusion criteria out of a screened population of 506 patients. Eight out of 33 patients (24%) developed orbitopathy. The mean time from diagnosis of Graves' thyroidopathy to development of orbitopathy was 11.6 months (median: 7.5 months, range: 1 to 20 months). The mean initial TSI value was 421.3 in those that developed orbitopathy compared to 245.9 in those who had at least 6 months of documented follow-up and did not develop orbitopathy (p = 0.04). Those in the top tercile of initial TSI values were 14 times as likely to develop orbitopathy (relative risk (RR) = 14.0, p = 0.02; multivariate adjusted RR = 13.08, p = 0.03). Family history, smoking status, age, radioiodine ablation, thyroid-stimulating hormone, and race were not statistically significant predictors. CONCLUSIONS: TSI level greater than 400 at time of presentation of Graves thyroidopathy may be a useful predictor of risk for development of orbitopathy. This information will help to identify patients likely to benefit from early referral to an ophthalmologist for possible preemptive therapy to prevent the development of orbitopathy. Prospective cohort studies are needed to definitively establish the metrics for TSI as a predictor of orbitopathy.

The dynamics of post-operative plasma ACTH values following transsphenoidal surgery for Cushing's disease.

Rapid assessment of adrenal function is critical following transsphenoidal surgery (TSS) for Cushing's disease (CD) in order to determine surgical efficacy. We hypothesize that there may be a role for ACTH measurement as a rapid indicator of adrenal function. Following surgery for CD, glucocorticoids were withheld and paired plasma ACTH and serum cortisol levels were measured every 6 h. Post-operative hypocortisolemia was defined as serum cortisol <2 mcg/dl or a serum cortisol <5 mcg/dl with the onset of symptoms of adrenal insufficiency within 72 h. We studied 12 subjects, all female, mean age 44.6 years (range 25-55), including 13 surgeries: nine subjects attained hypocortisolemia. Plasma ACTH levels decreased more in subjects with hypocortisolemia (0.9 pg/ml/hr, P = 0.0028) versus those with persistent disease (0 0.2 pg/ml/hr, P = 0.26) within the first 48 h after surgery. In contrast to subjects with persistent disease, all subjects with hypocortisolemia achieved a plasma ACTH <20 pg/ml by 19 h (range 1-19 h). Four of the nine subjects with hypocortisolemia achieved plasma ACTH <20 pg/ml by 13 h and the remaining five subjects by 19 h. Hypocortisolemia occurred between 3-36 h following achievement of a plasma ACTH <20 pg/ml. In CD, a reduction in postoperative plasma ACTH levels differentiates subjects with surgical remission versus subjects with persistent disease. The utility of plasma ACTH measurements in the postoperative management of CD remains to be determined.