A pharmacokinetic, pharmacodynamic, and electrocardiographic study of liposomal mifamurtide (L-MTP-PE) in healthy adult volunteers

Purpose This study evaluated the pharmacokinetics (PK), pharmacodynamics (PD), safety/tolerability, and cardiac safety of liposomal muramyl tripeptide phosphatidyl-ethanolamine [mifamurtide (L-MTP-PE)] in healthy adults. Methods L-MTP-PE 4 mg was administered intravenously over 30 min. Study participants were monitored from 24 h preinfusion until 72 h postinfusion. Blood samples were drawn over 0–72 h postdose to determine serum MTP-PE, interleukin (IL)-6, tumor necrosis factor (TNF)-α, and C-reactive protein (CRP) concentrations. Electrocardiograpic (ECG) data were collected via continuous Holter monitoring beginning 24 h predose through 24 h postdose. Changes from time-matched pretreatment baseline QTc and associated two-sided 90 % confidence intervals were calculated. Results Twenty-one participants received L-MTP-PE. Total serum MTP-PE declined rapidly with a terminal half-life of 2.05 ± 0.40 h. PK variability was low, with <30 % coefficient of variation in systemic exposure. Serum concentrations of IL-6, TNF-α, and CRP increased following L-MTP-PE infusion. Maximum observed increases in IL-6 and TNF-α occurred at 4 and 2 h, respectively, returning toward baseline by 8 h postdose. L-MTP-PE was generally well tolerated, with no adverse events greater than grade 3. Headache, chills, tachycardia, nausea, and pyrexia were the most frequent adverse events. L-MTP-PE infusion resulted in an increased heart rate without readily apparent QTc prolongation. Conclusions MTP-PE PK following L-MTP-PE administration were characterized by a short serum half-life and low variability. Increases in IL-6, TNF-α, and CRP and the safety profile were consistent with the immunomodulatory mechanism of action. No clinically significant effect of L-MTP-PE on cardiovascular repolarization was observed based on analysis of ECG QTc intervals..

Medienart:	E-Artikel

Erscheinungsjahr:	2012
Erschienen:	2012

Enthalten in:	Zur Gesamtaufnahme - volume:68
Enthalten in:	European journal of clinical pharmacology - 68(2012), 10 vom: 30. März, Seite 1347-1355

Sprache:	Englisch

Beteiligte Personen:	Venkatakrishnan, Karthik [VerfasserIn] Kramer, William G. [VerfasserIn] Synold, Timothy W. [VerfasserIn] Goodman, Daniel B. [VerfasserIn] Sides, Evin [VerfasserIn] Oliva, Cristina [VerfasserIn]

Links:	Volltext [lizenzpflichtig]

Themen:	ECG Immunomodulator L-MTP-PE Mifamurtide Pharmacokinetics QTc

Anmerkungen:	© Springer-Verlag 2012

doi:	10.1007/s00228-012-1262-1

funding:
Förderinstitution / Projekttitel:

PPN (Katalog-ID):	SPR002578980