Background Intravenous-busulfan (IV-busulfan) combined with therapeutic drug monitoring to guide dosing improves outcomes after allogeneic hematopoietic cell transplantation (allo-HCT). The best method to estimate busulfan exposure and the optimal exposure in children/young adults remains unclear. We therefore evaluated three approaches to estimate IV-Bu exposure (expressed as cumulative-area-under-the-curve; AUC) and associated busulfan-AUC with clinical outcomes in children/young adults undergoing allo-HCT. Methods In this retrospective analysis, patients (0.1–30.4 years) receiving busulfan-based conditioning regimen from 15 centers were included. Cumulative AUC was calculated by numerical integration using non-linear mixed effect modeling (AUCNONMEM), non-compartmental analysis (AUC0-infinity and AUC to the end of the dose interval AUC0-tau) and by individual centers using a variety of approaches (AUCcenter). Main outcome of interest was event-free survival (EFS). Other outcomes of interest were overall survival, graft-failure, relapse, transplantation related mortality (TRM), acute toxicity (veno-occlusive disease (VOD) and/or acute graft versus-host disease (aGvHD), chronic GvHD (cGvHD) and cGVHD-free event-free survival (GEFS). Propensity score adjusted cox proportional hazard models, Weibull models, and Fine-Gray competing risk regressions were used. Results 674 patients were included (41% malignant, 59% non-malignant) Estimated 2-year EFS was 69.7%. The median busulfan AUCNONMEM was 74.4 mg*h/L (CI95% 31.1–104.6 mg*h/L). The median AUCNONMEM correlated poorly with AUCcenter (R2 = 0.254). Patients with optimal IV-busulfan AUC of 78–101 mg*h/L showed 81% EFS at 2 years compared to 66.1% and 49.5% in the low (<78 mg*h/L) and high (>101 mg*h/L) busulfan AUC group respectively (P=0.011). Graft-failure/relapse occurred more frequently in the low AUC group (HR=1.75 P<0.001). Acute toxicity, cGvHD and TRM was significantly higher in the high AUC group (HR 1.69, 2.99 and 1.30), independent of indication. Interpretation These results demonstrate that improved clinical outcomes may be achieved by targeting the busulfan-AUC to 78–101 mg*h/L using a new validated pharmacokinetic-model for all indications.
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• There has been one previous population pharmacokinetic analysis of total melphalan given as a short infusion in 84 adults (mixed diagnoses) and creatinine clearance and body size were found to be important determinants of total melphalan clearance. Dose and exposure to total melphalan were found to correlate with the development of mucositis. WHAT THIS STUDY ADDS• This is the largest population pharmacokinetic study on melphalan conducted to date. It is the first conducted in a uniform patient population (patients with multiple myeloma) and the first in which both total and unbound melphalan pharmacokinetics are examined. Factors found to be important determinants of total and unbound plasma clearance of melphalan were creatinine clearance, fat free mass and haematocrit. Haematocrit has not previously been identified as an influential covariate in any previous study. The importance of total and unbound melphalan exposure on transplant outcome was demonstrated by preliminary pharmacodynamic results showing significant associations with melphalan-related toxicity. A preliminary analysis of the association with disease response showed promising trends, but will be examined in more detail with longer follow-up of the whole cohort. AIMSTo i) investigate the pharmacokinetics of total and unbound plasma melphalan using a population approach, ii) identify clinical factors that affect melphalan disposition and iii) evaluate the role of melphalan exposure in melphalan-related toxicity and disease response. METHODSPopulation pharmacokinetic modelling (using NONMEM) was performed with total and unbound concentration-time data from 100 patients (36-73 years) who had received a median 192 mg m -2 melphalan dose. Model derived estimates of total and unbound melphalan exposure (AUC) in patients with serious melphalan toxicity and those who had a good disease response (Ն90% decrease in paraprotein concentrations) were compared using the Mann-Whitney test. RESULTSA two compartment model generated population mean estimates for total and unbound melphalan clearance (CL) of 27.8 and 128 l h -1 , respectively. Estimated creatinine clearance, fat free mass and haematocrit were important determinants of total and unbound CL, reducing the inter-individual variability in total CL from 34% to 27% and in unbound CL from 42% to 30%. Total AUC (range 4.9-24.4 mg l -1 h) and unbound AUC (range 1.0-6.5 mg l -1 h) were significantly higher in patients who had oral mucositis (Նgrade 3) and long hospital admissions (P < 0.01). Patients who responded well had significantly higher unbound AUC (median 3.2 vs. 2.8 mg l -1 h, P < 0.05) when assessed from diagnosis to post-melphalan and higher total AUC (median 21.3 vs. 13.4 mg l -1 h, P = 0.06), when assessed from pre-to post-melphalan. CONCLUSIONSCreatinine clearance, fat free mass and haematocrit influence total and unbound melphalan plasma clearance. Melphalan exposure is related to melphalan toxicity while the association with efficacy shows promising tren...
WHAT IS ALREADY KNOWN ABOUT THIS PROJECT? • Mycophenolate mofetil (MMF) is an immunosuppressant drug used for the treatment and prevention of graft vs. host disease in blood or marrow transplantation and acute graft rejection in solid organ transplantation. • Mycophenolic acid (MPA) pharmacokinetics have not been thoroughly studied in paediatric blood or marrow transplant recipients and guidance for optimal dosing of mycophenolic acid in children is lacking. • Mycophenolic acid exhibits considerable inter‐ and intra‐patient pharmacokinetic variability in adults and paediatric transplant recipients. • The AUC of mycophenolic acid over a 12 h dose interval at steady‐state is generally agreed to be the most reliable metric associated with the risk of acute rejection. • Population pharmacokinetic analysis can utilize concentration information from both intensive sampling and sparse sampling to provide pharmacokinetic parameter estimates, estimates of inter‐ individual and intra‐individual variability in these parameters and allows patient characteristics explaining inter‐individual variability to be quantified. WHAT THIS STUDY ADDS • This study is one of the first investigations in which a population pharmacokinetic modelling approach was applied to assess the pharmacokinetics of both intravenous and oral MMF in children and young people undergoing blood or marrow and solid organ transplantation. • Bodyweight and concomitant ciclosporin were found to influence MPA pharmacokinetics. • This study evaluated current dosing strategies and found that they may be suboptimal for children weighing less than 10 kg. AIMS To characterize the population pharmacokinetics of mycophenolic acid (MPA) and evaluate dose regimens using a simulation approach and accepted therapeutic drug monitoring targets in children and young people undergoing blood or marrow, kidney and liver transplantation. METHODS MPA concentration–time data were collected using an age specific sampling protocol over 12 h. Some patients provided randomly timed but accurately recorded blood samples. Total and unbound MPA were measured by HPLC. NONMEM was employed to analyze MPA pharmacokinetic data. Simulations (n= 1000) were conducted to assess the suitability of the MPA dose regimens to maintain total MPA AUC(0,12 h) within the range 30 and 60 mg l−1 h associated with optimal outcome. RESULTS A two‐compartment pharmacokinetic model with first‐order elimination best described MPA concentration–time data. Population mean estimates of MPA clearance, inter‐compartmental clearance, volumes of distribution in the central and peripheral compartments, absorption rate constant and bioavailability were 6.42 l h−1, 3.74 l h−1, 7.24 l, 16.8 l, 0.39 h−1 and 0.48, respectively. Inclusion of bodyweight and concomitant ciclosporin reduced the inter‐individual variability in CL from 54.3% to 31.6%. Children with a bodyweight of 10 kg receiving standard MPA dose regimens achieve an MPA AUC below the target range suggesting they may be at a greater risk of acute rejection. CONCL...
The application of liposomes as drug carriers, which was originally proposed by Gregoriadis in 1981 (10), offers a potential means of manipulating drug pharmacokinetics (PKs) to improve antimicrobial efficacy and reduce toxicity. Amphotericin B (AMB) deoxycholate (Fungizone, D-AmB) has been the "gold standard" therapy for invasive fungal infection for decades due to its broad spectrum of antifungal activity. However, clinical treatment with D-AmB is limited by drug-related nephrotoxicity (7). The encapsulation of AmB in liposomes (AmBisome, L-AmB), which are composed of hydrogenated soy phosphatidylcholine, cholesterol, and distearoylphosphatidylglycerol in a molar ratio of 0.4:2:1:0.8 (7), has been found in preclinical studies to be as effective or, in some cases, more effective but less nephrotoxic than D-AmB in the treatment of a broad spectrum of medically important fungal pathogens, including Candida, Aspergillus, and Cryptococcus species (8, 17, 23). The results of two multicenter, randomized clinical trials in patients with persistent fever and neutropenia (21, 25) and in patients with invasive fungal infections (16) demonstrated the equivalent efficacy and superior safety of L-AmB relative to D-AmB. The reduced toxicity of the liposomal formulation allows for the administration of much higher doses of AmB than those that can be safely administered when given as conventional AmB, leading to the expanding therapeutic potential of L-AmB in comparison with D-AmB.Children with malignant diseases who experience prolonged periods of myelosuppression due to cytotoxic chemotherapy or hematopoietic stem cell transplant are highly susceptible to invasive fungal infections (11). The uses of indwelling vascular catheters and broad-spectrum antibiotics further increase the risk of immunosuppressed children developing invasive fungal infections. The broad-spectrum antifungal activity and improved therapeutic properties of L-AmB may provide an important therapeutic advance in the treatment and prophylaxis of invasive fungal infections in pediatric oncology patients. However, there remains debate about the appropriate dosing regimens in children. No single study has prospectively investigated the pharmacokinetics of L-AmB that might guide rational design of dosing regimens in this special population.The clinical pharmacokinetics of L-AmB have been investigated in healthy adult volunteers after a single intravenous dose (5) and in adult patients after multiple doses (26). All of the studies utilized a traditional pharmacokinetic data analysis approach. However, in the clinical setting where pediatric patients or those with severe illness are studied, only limited numbers of samples can be obtained due to ethical, logistical, and medical considerations. Therefore, the population approach was employed in the present study as it provides not only a solution for combining concentration information from both intensive and sparse sampling but also the valuable knowledge of the population distribution of pharmacokinetic
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.