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

Abstract

Aims: To evaluate the pharmacokinetics and pharmacodynamics following a single dose of liposomal mifamurtide (L-MTP-PE, MEPACT(®)) in adult subjects with mild (calculated creatinine clearance [CLcr ] of 50-80 ml min(-1)) or moderate (CLcr 30-50 ml min(-1)) renal impairment in comparison with age-, weight- and gender-matched healthy subjects with normal renal function (CLcr >80 ml min(-1)).

Methods: Subjects received a 4 mg dose of liposomal mifamurtide via 1 h intravenous infusion. Blood samples were collected over 72 h for analysis of plasma pharmacokinetics of total and non-liposome-associated (free) mifamurtide and assessment of pharmacodynamics (changes in serum interleukin-6 [IL-6], tumour necrosis factor-α [TNF-α], C-reactive protein [CRP]).

Results: Thirty-three subjects were enrolled: nine with mild renal impairment, eight with moderate renal impairment and 16 healthy subjects. Geometric mean (%CV) AUCinf for total mifamurtide was 89.5 (58.1), 94.8 (27.8), 85.1 (29.0), 95.4 (18.1) nM h in the mild renal impairment, mild-matched healthy subject, moderate renal impairment and moderate-matched healthy subject groups, respectively. Mifamurtide clearance was not correlated with CLcr, estimated glomerular filtration rate or iohexol clearance (all r(2) < 0.01). AUCinf of free mifamurtide was similar across the renal function groups. There were no readily apparent differences in serum pharmacodynamic effect parameters (baseline-adjusted AUEClast for IL-6 and TNF-α and Emax for CRP) between the renal function groups. No subjects reported grade ≥3 or serious adverse events.

Conclusions: Mild or moderate renal impairment does not alter the clinical pharmacokinetics or pharmacodynamics of mifamurtide. No dose modifications appear necessary for these patients based on clinical pharmacologic considerations.

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

Figure 1

Total mifamurtide concentrations by renal function group. (A) Mean plasma concentration–time profiles in subjects with () mild or () moderate renal impairment and () healthy all (normal renal function); and (B) (○) individual, () mean and () geometric mean values of AUC_inf by renal function group. (‘healthy all’ = all subjects in the two healthy matched subject groups with normal renal function)

Figure 2

Scatter plots and regression analyses of mifamurtide clearance (CL) vs. the baseline renal function measurements of CL_cr (A), eGFR (B) and CL_iohexol (C). , individual; , regression; , 95% CI

Figure 3

Free (non-liposome-associated) mifamurtide concentrations by renal function group. (A) Mean plasma concentration–time profiles in subjects with () mild or () moderate renal impairment and () healthy all (normal renal function); and (B) (○) individual, () mean and () geometric mean values of AUC_inf by renal function group. (‘healthy all’ = all subjects in the two healthy matched subject groups)

Figure 4

Change from baseline in serum IL-6 by renal function group. (A) Time course of median change in subjects with () mild or () moderate renal impairment, and () healthy all (normal renal function); and (B) (○) individual, () mean and () median values of AUEC_last by renal function group. (‘healthy all’ = all subjects in the two healthy matched subject groups)

Figure 5

Change from baseline in serum TNF-α by renal function group. (A) Time course of median change in subjects with () mild or () moderate renal impairment and () healthy all (normal renal function); and (B) (○) individual, () mean and () median values of AUEC_last by renal function group. (‘healthy all’ = all subjects in the two healthy matched subject groups)

Figure 6

Change from baseline in serum CRP by renal function group. (A) Time course of median change in subjects with () mild or () moderate renal impairment and () healthy all (normal renal function); and (B) (○) individual, () mean and () median values of E_max by renal function group. (‘healthy all’ = all subjects in the two healthy matched subject groups)