Pharmacokinetics and pharmacodynamics of liposomal mifamurtide in adult volunteers with mild or moderate renal impairment. (June 2014)

• Record Type: Journal Article
• Authors: Venkatakrishnan, Karthik; Liu, Yi; Noe, Dennis; Mertz, Jaime; Bargfrede, Michael; Marbury, Thomas; Farbakhsh, Kambiz; Oliva, Cristina; Milton, Ashley
• Is Part Of: British journal of clinical pharmacology. Volume 77:Number 6(2014:Jun.)
• Page Start: 986
• Page End: 997
• Publication Date: 2014-06
• Subjects: Pharmacology -- Periodicals; Drugs -- Periodicals; 615.1
• DOI: 10.1111/bcp.12260
• Languages: English
• ISSNs: 0306-5251

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="bcp12260-sec-0001" sec-type="section"> <title>Aims</title> <p>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 [CL<sub>cr</sub>] of 50–80 ml min<sup>−1</sup>) or moderate (CL<sub>cr</sub> 30–50 ml min<sup>−1</sup>) renal impairment in comparison with age‐, weight‐ and gender‐matched healthy subjects with normal renal function (CL<sub>cr</sub> >80 ml min<sup>−1</sup>).</p> </sec> <sec id="bcp12260-sec-0002" sec-type="section"> <title>Methods</title> <p>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]).</p> </sec> <sec id="bcp12260-sec-0003" sec-type="section"> <title>Results</title> <p>Thirty‐three subjects were enrolled: nine with mild renal impairment, eight with moderate renal impairment and 16 healthy subjects. Geometric mean (%CV) AUC<sub>inf</sub> for total mifamurtide was 89.5 (58.1), 94.8 (27.8), 85.1 (29.0), 95.4 (18.1) n<sc>m</sc> 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 CL<sub>cr</sub>, estimated glomerular filtration rate or iohexol clearance (all <italic>r</italic><sup>2</sup> < 0.01). AUC<sub>inf</sub> of free mifamurtide was similar across the renal function groups. There were no readily apparent differences in serum pharmacodynamic effect parameters (baseline‐adjusted AUEC<sub>last</sub> for IL‐6 and TNF‐α and E<sub>max</sub> for CRP) between the renal function groups. No subjects reported grade ≥3 or serious adverse events.</p> </sec> <sec id="bcp12260-sec-0004" sec-type="section"> <title>Conclusions</title> <p>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.</p> </sec> </abstract>