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

Christa E. Nath, Peter J. Shaw, Judith Trotman, Lihua Zeng, Stephen B. Duffull, Gareth Hegarty, Andrew J. McLachlan, Howard Gurney, Ian Kerridge, Yiu Lam Kwan, Peter Presgrave, Campbell Tiley, Douglas Joshua, John Earl

Research output: Contribution to journalArticleResearchpeer-review

Abstract

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.

LanguageEnglish
Pages484-497
Number of pages14
JournalBritish Journal of Clinical Pharmacology
Volume69
Issue number5
DOIs
Publication statusPublished - May 2010
Externally publishedYes

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Melphalan
Multiple Myeloma
Pharmacokinetics
Population
Area Under Curve
Therapeutics
Hematocrit
Creatinine
Fats
Paraproteins
Stomatitis

Cite this

Nath, Christa E. ; Shaw, Peter J. ; Trotman, Judith ; Zeng, Lihua ; Duffull, Stephen B. ; Hegarty, Gareth ; McLachlan, Andrew J. ; Gurney, Howard ; Kerridge, Ian ; Kwan, Yiu Lam ; Presgrave, Peter ; Tiley, Campbell ; Joshua, Douglas ; Earl, John. / Population pharmacokinetics of melphalan in patients with multiple myeloma undergoing high dose therapy. In: British Journal of Clinical Pharmacology. 2010 ; Vol. 69, No. 5. pp. 484-497.
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abstract = "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.",
author = "Nath, {Christa E.} and Shaw, {Peter J.} and Judith Trotman and Lihua Zeng and Duffull, {Stephen B.} and Gareth Hegarty and McLachlan, {Andrew J.} and Howard Gurney and Ian Kerridge and Kwan, {Yiu Lam} and Peter Presgrave and Campbell Tiley and Douglas Joshua and John Earl",
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Nath, CE, Shaw, PJ, Trotman, J, Zeng, L, Duffull, SB, Hegarty, G, McLachlan, AJ, Gurney, H, Kerridge, I, Kwan, YL, Presgrave, P, Tiley, C, Joshua, D & Earl, J 2010, 'Population pharmacokinetics of melphalan in patients with multiple myeloma undergoing high dose therapy', British Journal of Clinical Pharmacology, vol. 69, no. 5, pp. 484-497. https://doi.org/10.1111/j.1365-2125.2010.03638.x

Population pharmacokinetics of melphalan in patients with multiple myeloma undergoing high dose therapy. / Nath, Christa E.; Shaw, Peter J.; Trotman, Judith; Zeng, Lihua; Duffull, Stephen B.; Hegarty, Gareth; McLachlan, Andrew J.; Gurney, Howard; Kerridge, Ian; Kwan, Yiu Lam; Presgrave, Peter; Tiley, Campbell; Joshua, Douglas; Earl, John.

In: British Journal of Clinical Pharmacology, Vol. 69, No. 5, 05.2010, p. 484-497.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Population pharmacokinetics of melphalan in patients with multiple myeloma undergoing high dose therapy

AU - Nath, Christa E.

AU - Shaw, Peter J.

AU - Trotman, Judith

AU - Zeng, Lihua

AU - Duffull, Stephen B.

AU - Hegarty, Gareth

AU - McLachlan, Andrew J.

AU - Gurney, Howard

AU - Kerridge, Ian

AU - Kwan, Yiu Lam

AU - Presgrave, Peter

AU - Tiley, Campbell

AU - Joshua, Douglas

AU - Earl, John

PY - 2010/5

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N2 - 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.

AB - 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.

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