Population pharmacokinetics of total and unbound melphalan in patients with multiple myeloma

Background: Melphalan, an alkylating agent, is an active chemotherapeutic agent in the treatment of multiple myeloma. High dose melphalan is used prior to autografting, but additional knowledge about the pharmacokinetics, combined with toxicity and efficacy data is needed to optimise the dose.

Aims: To (1) investigate the pharmacokinetics of total and unbound plasma melphalan using a population approach and (2) identify clinical factors that affect melphalan disposition.

Methods: Population pharmacokinetic modelling (using NONMEM) was performed with total and unbound concentration-time data from 100 patients (36–73years) who had received a median 192mg/m2 melphalan dose. The population pharmacokinetic models for total and unbound melphalan were developed separately.

Results: A two compartment model generated population mean estimates for total and unbound melphalan clearance (CL) of 27.8 and 128L/h, 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%. The population mean estimates for total and unbound Volume of distribution into the central compartment (V1) were 13.1 L and 60.1 L, respectively. Inclusion of fat free mass as a determinant of V1, reduced the intersubject variability in V1 of total melphalan from 60% to 58% and that of unbound melphalan from 57% to 39%. The models were accurate and stable when compared with the results of 1000 bootstrap runs. Visual predictive checks also indicated acceptable model performance.

Conclusions: Creatinine clearance, fat free mass and haematocrit influence total and unbound melphalan plasma clearance, while fat free mass influences total and unbound V1.We are collecting toxicity and efficacy data, and once target exposure estimates associated with optimal outcome are identified, we hope to develop a dosing algorithm for melphalan in myeloma.