Indirect Evaluation of Bone Saturation with Zoledronic Acid After Long-Term Dosing
Abstract
BACKGROUND: Zoledronic acid (ZA), a potent bisphosphonate used for treatment of bone metastasis, has high bone affinity. This post hoc analysis evaluated the effects of long-term treatment and reduction in dosing frequency of ZA on bone saturation.
MATERIALS AND METHODS: Pharmacokinetic data from three independent studies, OPTIMIZE-2 (patients receiving ≥9 doses of bisphosphonates) and two phase I studies, CZOL4460503 and CZOL4460506 (patients who were bisphosphonate naïve/bisphosphonate free for ≥1 year after previous dosing), were pooled. Serial urine and plasma samples were used as surrogate markers to determine ZA plasma area under the curve (AUC) over 6 hours (AUC0-6h) and dose excreted in urine over 6 hours (urine0-6h). Potential relationships between the number of years for which patients had been treated previously at time of study entry and AUC0-6h or urine0-6h were analyzed graphically.
RESULTS: Creatinine clearances for patients were similar across the three studies and at all time points analyzed. The levels of AUC0-6h ZA in plasma at week 0 in every (q) 4 and q12 weekly arms of OPTIMIZE-2 were 0.366 h × mg/L and 0.397 h × mg/L compared with 0.345 h × mg/L and 0.356 h × mg/L in CZOL4460503 and CZOL4460506, respectively. In OPTIMIZE-2, the AUC0-6h ZA plasma levels were the same (0.428 h × mg/L) at week 36 in both q4 and q12 arms. The levels of ZA urine0-6h at week 36 in OPTIMIZE-2 (q4 and q12 week arms), CZOL4460503, and CZOL4460506 were 36.6%, 30.8%, 26.5%, and…
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