The Effect of Increasing Zoledronic Acid Dose and Infusion Rate on Pharmacokinetics, Pharmacodynamics, and Renal Function in Patients with Multiple Myeloma.
Notice bibliographique
Résumé
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.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,001 | 0,003 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,001 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».