Abstract P5-09-18: Vitamin D3 supplementation, musculoskeletal (MS) symptoms and aromatase inhibitor (AI) pharmacokinetics from the vitamin D3AI study

Rationale and objectives: Musculoskeletal (MS) symptoms are reported to affect up to 50% of women on AI and may lead to poor medication adherence. Vitamin D 3 supplementation may decrease the MS pain, stiffness and weakness reported by women treated with AIs. We are conducting a controlled clinical trial (D 3 AI study) to assess the efficacy of vitamin D 3 supplements in decreasing these symptoms and to examine the effects of vitamin D 3 on the pharmacokinetics of AIs and on AI medication adherence. Methods: To test the effects of a daily dose of 4000IU D 3 when compared to the usual care of 600IU D 3 over a 7 month study period, 371 post-menopausal women on AIs were screened for MS symptoms using the average of ≥ 1.5 on the musculoskeletal subscale questions of the Breast Cancer Prevention Trial symptoms scale (BCPT-MS). Subjects meeting inclusion criteria who consented to study participation (n = 48) received 600IU D 3 during a 1 month run-in period prior to randomization. Following this run-in period, baseline serum 25(OH)D was assayed by a chemiluminescent immunoassay (Liaison analyzer, DiaSorin). AI adherence diaries were completed during the 1 month run-in and population pharmacokinetics (PK) studies were performed on the first participants enrolled for anastrozole (n = 8) and letrozole (n = 10) at baseline (after 1 month on 600IU D 3 ) and again at 6 months after randomization to either 600IU or 4000IU D 3 . For PK studies, plasma samples were collected pre- AI dose and at 2- and 4 hr post AI dose and analyzed with validated tandem mass spectrometry (LC-MS/MS). PK parameters for each drug were determined by non-linear mixed effects modeling (NONMEM) and one-compartment models with first-order absorption were used to describe the plasma concentration-time data. Results: Thirty percent (n = 112/371) of subjects screened met the inclusion criteria of experiencing MS symptoms (BCPT-MS ≥1.5) and data on the first 48 subjects randomized are presented. BCPT-MS score at screening was 2.48 ± 0.62 (mean±sd). At baseline (following one month run-in period of 600 IU D 3 ) BCPT-MS was 2.41±0.65 (mean±sd). Baseline serum 25(OH)D was 36±11 ng/ml (mean±sd) and AI adherence was 99% during this 30 day run-in period. Inter -individual variability of AI pharmacokinetic properties ((% CV) estimates of apparent AI clearance (CI/F) for anastrozole was 25% and for letrozole, 43.1%. Conclusions: AI-associated MS symptoms did not affect AI adherence in this population during the 30 day run-in period. Daily vitamin D 3 supplements of 600IU for 30 days was adequate to maintain serum 25(OH)D levels of >30 ng/ml. The approximate 3 to 4-fold inter -individual variability in AI drug clearance may have a clinically meaningful impact on prevalence of symptoms, serum estrogen concentrations and treatment efficacy. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-09-18.