Pharmacokinetics and pharmacodynamics of liposomal mifamurtide in adult volunteers with mild or moderate hepatic impairment

Abstract

Aims: To evaluate the pharmacokinetics and pharmacodynamics after a single dose of liposomal mifamurtide (liposomal muramyl tripeptide phospatidyl ethanolamine; MEPACT(®)) in adult subjects with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment in comparison with age-, weight- and sex-matched healthy subjects with normal hepatic function.

Methods: Subjects received a 4 mg dose of liposomal mifamurtide via 1 h intravenous infusion. Blood samples were collected over 72 h for pharmacokinetic and pharmacodynamic assessments (changes in serum interleukin-6, tumour necrosis factor-α and C-reactive protein).

Results: Thirty-seven subjects were enrolled: nine with mild hepatic impairment, eight with moderate hepatic impairment and 20 matched healthy subjects. Geometric least-square mean ratios of total mifamurtide AUCinf for the mild hepatic impairment and moderate hepatic impairment groups vs. matched healthy subjects were 105% (90% confidence interval, 83.6-132%) and 119% (90% confidence interval, 94.1-151%), respectively, which are below the protocol-specified threshold (150%) to require development of dose-modification recommendations. Pharmacodynamic parameters for changes in serum interleukin-6 and tumour necrosis factor-α concentrations were generally similar across hepatic function groups. Mifamurtide-induced increases in serum C-reactive protein were attenuated in the moderate hepatic impairment group, consistent with the liver being the major organ of C-reactive protein synthesis. No grade ≥3 adverse events were seen in subjects administered mifamurtide (4 mg).

Conclusions: These results support the conclusion that mild or moderate hepatic impairment does not produce clinically meaningful effects on the clinical pharmacokinetics or pharmacodynamics of mifamurtide; no dose modifications are needed in these special patient populations based on clinical pharmacological considerations.

Keywords: MEPACT®; hepatic impairment; liposomes; mifamurtide; pharmacodynamics; pharmacokinetics.

Figure 1

Mean plasma concentration–time profiles (A; , mild; , moderate; and , healthy all) and individual (), mean () and geometric mean values () of the area under the plasma concentration–time curve from time 0 to infinity (AUC_inf; B) of total mifamurtide in subjects with mild or moderate hepatic impairment and in matched healthy subjects (‘healthy all’ represents the mean across all subjects in the two matched healthy subject groups)

Figure 2

Mean plasma concentration–time profiles (A; , mild; , moderate; and , healthy all) and individual (), mean () and geometric mean values () of AUC_inf (B) of free (nonliposome-associated) mifamurtide in subjects with mild or moderate hepatic impairment and in matched healthy subjects (‘healthy all’ represents the mean across all subjects in the two matched healthy groups)

Figure 3

Time course of median change from baseline serum interleukin-6 (IL-6; A; , mild; , moderate; and , healthy all) and individual (), mean () and median values () of area under the effect–time curve from time 0 to time of the last point of quantifiable effect (AUEC_last) for change from baseline serum IL-6 (B) by hepatic function group

Figure 4

Time course of median change from baseline serum tumour necrosis factor-α (TNF-α; A; , mild; , moderate; and , healthy all) and individual (), mean () and median values () of AUEC_last for change from baseline serum TNF-α (B) by hepatic function group

Figure 5

Time course of median change from baseline serum C-reactive protein (CRP; A; , mild; , moderate; and , healthy all) and individual (), mean () and median values () of observed maximal effect (E_obs,max) for change from baseline serum CRP (B) by hepatic function group