The Effect of Increasing Zoledronic Acid Dose and Infusion Rate on Pharmacokinetics, Pharmacodynamics, and Renal Function in Patients with Multiple Myeloma.
Bibliographic record
Abstract
Abstract 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 Cmax 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 Cmax (± 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 AUC0–6h (± SD) was 403 (± 135), 877 (± 177), and 1,233 (± 259) after Infusions 1, 3, and 5, respectively. Mean modeled AUC0–24h (± 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 Cmax 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.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.003 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".