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

Abstract

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...

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“…However wide variability in melphalan exposure due to pharmacokinetic differences has been reported. In a pharmacokinetic study of high dose melphalan in 100 patients, higher mucositis rates and improved disease response were seen in patients with higher exposure to melphalan, as measured by increased area under the curve of both total and unbound melphalan (Nath et al, 2010).…”

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“…The fact that it was possible to recover more than 60% of the dose in three (of nine) patients in one study suggests that renal excretion is likely to be the major elimination pathway for melphalan. 12 Population PK analyses have also identified renal function as a significant determinant of melphalan clearance, 14,15 with renal clearance estimated to be approximately 40%. 15 …”

“…There are also a number of PK studies on melphalan that have related high melphalan exposure with either increased toxicity, 6,14,15,24 improved efficacy 25 or no obvious discernable effect; [26][27][28] these studies are summarised in Table 2. Kühne et al 15 studied 84 adults with mixed diagnoses (but mainly myeloma) at melphalan doses ranging from 10 to 200 mg/m 2 .…”

“…In our study of 100 myeloma patients, all treated at high doses, melphalan AUC was significantly higher in patients with ⩾ grade 3 oral mucositis and those with long hospital admissions. 14 Many of the PK studies summarised in Table 2 report wide variability in melphalan clearance. Up to a sixfold variation in the AUC results was noted in patients receiving the same mg/m 2 dose.…”

“…Up to a sixfold variation in the AUC results was noted in patients receiving the same mg/m 2 dose. 14,15,25,26,29 Renal function affects melphalan clearance, 14,12,29 and PK interactions have been reported with carboplatin 30,31 and furosemide, 32 both drugs that are eliminated by renal excretion. In patients with severe renal insufficiency (creatinine clearance o 40 ml/min), haemodialysis ensures that melphalan clearance is similar to those with normal renal function.…”