No abstract

Transthyretin (ATTR) amyloidosis is a multisystem disease caused by organ deposition of amyloid fibrils derived from the misfolded transthyretin (TTR) protein. The purpose of this article is to provide an overview of current treatment regimens and summarize important considerations for each agent. A literature search was performed with the PubMed database for articles published through October 2020. Search criteria included therapies available on the market and investigational therapies used for ATTR amyloidosis treatment. Both prospective clinical trials and retrospective studies have been included in this review. Available therapies discussed in this review article are tafamidis, diflunisal, patisiran, and inotersen. Tafamidis is FDA approved for treatment of wild-type ATTR (ATTRwt) and hereditary ATTR (ATTRv) cardiomyopathy, and patisiran and inotersen are FDA approved for ATTRv polyneuropathy. Diflunisal does not have an FDA-labeled indication for amyloidosis but has been studied in ATTRv polyneuropathy and ATTRwt cardiomyopathy. Investigational therapies include a TTR stabilizer, AG10; 2 antifibril agents, PRX004 and doxycycline/ tauroursodeoxycholic acid; and 2 gene silencers, vutrisiran and AKCEA-TTR-LRx; and clinical trials are ongoing. ATTR amyloidosis treatment selection is based on subtype and presence of cardiac or neurological manifestations. Additional considerations such as side effects, monitoring, and administration are outlined in this review.

A Phase 1 study of high‐dose “pulse” methotrexate infusions combined with citrovorum factor “rescue” in advanced lung cancer indicated consistent tumor response in eight patients. A dose schedule allowing for repeated treatments, and thus suitable for prolonged management, was developed. Three patients treated accordingly for 8 to 10 months continue to show regression of their original lesions without evidence of new metastases. These observations are consistent with previously proposed concepts for use of citrovorum “rescue” after administration of high‐dose “pulses” of folic acid antagonists.

Objectives To compare a Bayesian clinical decision support (CDS) dose-optimizing software program with clinician judgement in individualizing vancomycin dosing regimens to achieve vancomycin pharmacokinetic (PK)/pharmacodynamic (PD) targets in a paediatric population. Methods A retrospective review combined with a model-based simulation of vancomycin dosing was performed on children aged 1 year to 18 years at the University of California, San Francisco Benioff Children’s Hospital Mission Bay. Dosing regimens recommended by the clinical pharmacists, ‘clinician-guided’, were compared with alternative ‘CDS-guided’ dosing regimens. The primary outcome was the percentage of occasions predicted to achieve steady-state trough levels within the target range of 10–15 mg/L, with a secondary outcome of predicted attainment of AUC24 ≥400 mg·h/L. Statistical comparison between approaches was performed using a standard t-test. Results A total of n = 144 patient occasions were included. CDS-guided regimens were predicted to achieve vancomycin steady-state troughs in the target range on 70.8% (102/144) of occasions, as compared with 37.5% (54/144) in the clinician-guided arm (P < 0.0001). An AUC24 of ≥400 mg·h/L was achieved on 93% (112/121) of occasions in the CDS-guided arm versus 72% (87/121) of occasions in the clinician-guided arm (P < 0.0001). Conclusions In a simulated analysis, the use of a Bayesian CDS tool was better than clinician judgement in recommending vancomycin dosing regimens in which PK/PD targets would be attained in children.