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

• Published in: European journal of clinical pharmacology Vol. 68; no. 10; pp. 1347 - 1355
• Main Authors: Venkatakrishnan, Karthik, Kramer, William G., Synold, Timothy W., Goodman, Daniel B., Sides, Evin, Oliva, Cristina
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01.10.2012; Springer; Springer Nature B.V
• Subjects: Acetylmuramyl-Alanyl-Isoglutamine - administration & dosage; Acetylmuramyl-Alanyl-Isoglutamine - adverse effects; Acetylmuramyl-Alanyl-Isoglutamine - analogs & derivatives; Acetylmuramyl-Alanyl-Isoglutamine - pharmacokinetics; Adult; Area Under Curve; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Bone cancer; C-Reactive Protein - metabolism; Clinical Trial; Clinical trials; Drugs; Electrocardiography - methods; Female; Heart - drug effects; Heart - physiology; Humans; Interleukin-6 - blood; Interleukin-6 - metabolism; Liposomes - administration & dosage; Male; Medical sciences; Middle Aged; Pharmacology; Pharmacology. Drug treatments; Pharmacology/Toxicology; Phosphatidylethanolamines - administration & dosage; Phosphatidylethanolamines - adverse effects; Phosphatidylethanolamines - pharmacokinetics; Prospective Studies; Tumor Necrosis Factor-alpha - blood; Tumor Necrosis Factor-alpha - metabolism; Young Adult; Immunomodulator; ECG; L-MTP-PE; QTc; Mifamurtide; Pharmacokinetics; Antineoplastic agent; Human; QT interval; Pharmacokinetic pharmacodynamic relationship; Healthy subject; Liposome; Electrodiagnosis; Electrocardiography
• ISSN: 0031-6970; 1432-1041; 1432-1041
• DOI: 10.1007/s00228-012-1262-1

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.