Population pharmacokinetics of melphalan in patients with multiple myeloma undergoing high dose therapy

摘要: 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 body size were found to be important determinants clearance. Dose exposure correlate with the development mucositis. WHAT STUDY ADDS • This is largest study on conducted date. It first uniform patient (patients multiple myeloma) which both unbound pharmacokinetics are examined. Factors plasma clearance, fat free mass haematocrit. Haematocrit not previously identified an influential covariate any study. The importance transplant outcome was demonstrated by preliminary pharmacodynamic results showing significant associations melphalan-related toxicity. A association disease response showed promising trends, but will examined more detail longer follow-up whole cohort. AIMS To i) investigate using approach, ii) identify clinical factors that affect disposition iii) evaluate role toxicity response. METHODS Population modelling (using NONMEM) performed concentration–time data from 100 patients (36–73 years) who had received median 192 mg m−2 dose. Model derived estimates (AUC) serious those good (≥90% decrease paraprotein concentrations) compared Mann-Whitney test. RESULTS two compartment model generated mean for (CL) 27.8 128 l h−1, respectively. Estimated haematocrit CL, reducing inter-individual variability CL 34% 27% 42% 30%. Total AUC (range 4.9–24.4 mg l−1 h) 1.0–6.5 mg l−1 h) significantly higher oral mucositis (≥grade 3) long hospital admissions (P < 0.01). Patients responded well (median 3.2 vs. 2.8 mg l−1 h, P 0.05) when assessed diagnosis post-melphalan 21.3 13.4 mg l−1 h, P= 0.06), pre- post-melphalan. CONCLUSIONS Creatinine influence Melphalan related while efficacy shows trends studied further.