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Keywords:

  • melphalan;
  • myeloma;
  • optimal dosing;
  • population pharmacokinetics;
  • transplantation

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.

AIMS To 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.

METHODS Population 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 (≥90% decrease in paraprotein concentrations) were compared using the Mann-Whitney test.

RESULTS A 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 (≥grade 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.

CONCLUSIONS Creatinine 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 trends that will be studied further.