The Effect of Increasing Zoledronic Acid Dose and Infusion Rate on Pharmacokinetics, Pharmacodynamics, and Renal Function in Patients with Multiple Myeloma.

Background: Zoledronic acid is a new-generation bisphosphonate with demonstrated efficacy and safety in the treatment of bone lesions in patients with multiple myeloma and solid tumors using a monthly regimen of 4 mg infused over 15 minutes. This phase I open-label study investigated the pharmacokinetics (PK), pharmacodynamics (PD), and safety of a monthly regimen of zoledronic acid, at doses of 4, 8, and 12 mg, using an infusion rates model predicted to yield a C_max similar to that for 4 mg infused over 15 minutes.

Methods: Patients received a total of 6 doses of zoledronic acid administered every 28 days: 4 mg via 15-minute infusion on day 1, 8 mg via 60-minute infusion on days 29 and 57, 12 mg via 120-minute infusion on days 85 and 113, and 4 mg via 15-minute infusion on day 141. Assessments of PK, PD (bone and tumor marker levels), and safety (biochemistry, hematology, and renal function) were completed after each dose.

Results: A total of 10 patients (6 male, 4 female) with multiple myeloma were enrolled and 7 completed the 6-month study (1 patient withdrew consent, 2 patients had abnormal lab values). Median age was 57.5 years (range, 42 to 75 years). ECOG performance status was 0 or 1 in 9 patients and 2 in 1 patient. Eight of 10 patients had received prior antineoplastic therapy and all patients had received prior radiation and surgery. Zoledronic acid was generally well tolerated; the most commonly reported adverse events involved the known acute-phase reactions, namely fatigue (60%), myalgia (50%), and arthralgia/nausea/bone pain (40% each), associated with IV bisphosphonates. Transient serum creatinine elevations from baseline were observed in 3 patients and resulted in either dose delay/decrease (n = 1) or discontinuation after Infusion 5 (n = 2). A single serious adverse event was reported in 1 patient (secondary malignancy to the left lung). Clinically significant (grade 3/4) nonrenal-related adverse events occurred in 5 patients. No patient discontinued due to clinically significant adverse events nor died while on study. Mean C_max (± SD) was 329 (± 84) mg/L after the first 4-mg dose (Infusion 1), 407 (± 99) mg/L after the second 8-mg dose (Infusion 3), and 411 (± 75) mg/L after the second 12-mg dose (Infusion 5). These values were nearly identical to the model-extrapolated values. Mean observed AUC_0–6h (± SD) was 403 (± 135), 877 (± 177), and 1,233 (± 259) after Infusions 1, 3, and 5, respectively. Mean modeled AUC_0–24h (± SD) was 603 (± 189), 1,489 (± 451), and 1,662 (± 325) for the same infusion schedule. Decreases from baseline were observed in serum markers of bone metabolism (CTX, NTX, and osteocalcin) after zoledronic acid treatment. There were no relevant changes from baseline in serum interleukin-6, quantitative immunoglobulins, C-reactive protein, or albumin.

Conclusions: Zoledronic acid was safe and well tolerated when infused at doses of 8 and 12 mg over 60 and 120 minutes, respectively, and the model-predicted C_max of zoledronic acid was achieved in patients with multiple myeloma at all doses and infusion rates tested. This study provides a rationale for investigating doses ≥ 4 mg infused over > 15 minutes in a broader clinical trial. Updated analyses will be presented.