Population pharmacokinetics of liposomal amphotericin B in adults with HIV-associated cryptococcal meningoencephalitis.

BACKGROUND: Single, high-dose liposomal amphotericin B (LAmB; AmBisome, Gilead Sciences) has demonstrated non-inferiority to amphotericin B deoxycholate in combination with other antifungals for averting all-cause mortality from HIV-associated cryptococcal meningitis. There are limited data on the pharmacokinetics (PK) of AmBisome. The aim of this study was to describe population PK of AmBisome and conduct a meta-analysis of the available studies to suggest the optimal dosing for cryptococcal meningoencephalitis. METHODS: Data from a Phase II and Phase III trial of high-dose, short-course AmBisome for cryptococcal meningoencephalitis were combined to develop a population PK model. A search was conducted for trials of AmBisome monotherapy and meta-analysis of clinical outcome data was performed. RESULTS: A two-compartment model with first-order clearance of drug from the central compartment fitted the data best and enabled the extent of inter-individual variability in PK to be quantified. Mean (SD) population PK parameter estimates were: clearance 0.416 (0.363)  L/h; volume of distribution 4.566 (4.518) L; first-order transfer of drug from central to peripheral compartments 2.222 (3.351)  h-1, and from peripheral to central compartment 2.951 (4.070)  h-1. Data for the meta-analysis were insufficient to suggest optimal dosing of AmBisome for cryptococcal meningoencephalitis. CONCLUSIONS: This study provides novel insight into the PK of AmBisome at the population level and the variability therein. Our analysis also serves to highlight the paucity of data available on the pharmacodynamics (PD) of AmBisome and underscores the importance of thorough and detailed PK/PD analysis in the development of novel antifungals, by demonstrating the challenges associated with post hoc PK/PD analysis.

Pulsed low intensity ultrasound enhances mineralisation in preosteoblast cells.

Pulsed low intensity ultrasound has been shown to be highly efficacious in the treatment of nonunion fractures and in the acceleration of fresh fracture healing. MC3T3-E1 subclone 14 cells were cultured for up to 25 days either with or without a daily treatment with low intensity pulsed ultrasound. It was determined that, on day 10 there was a dramatic increase in alkaline phosphatase and MMP-13 mRNA levels detected in ultrasound-treated cultures compared with untreated controls. The activity of alkaline phosphatase was significantly increased at days 6, 8 and 10. On day 10, the amount of mineralisation within cultures, assessed using alizarin red staining, was significantly increased in ultrasound-treated cultures compared with untreated controls. These results suggest that one of the mechanisms that low intensity pulsed ultrasound has on fracture repair is to enhance the process of endochondral ossification where the soft callus is converted to mineralised hard callus.