LUMINITY Gas and solvent for dispersion for injection/infusion Ref.[27908] Active ingredients: Perflutren

The pharmacokinetic properties of Luminity were evaluated in normal healthy subjects and subjects with chronic obstructive pulmonary disease (COPD) following intravenous administration of a 50 µl/kg dose of the product.

The perflutren component of Luminity was rapidly cleared from the systemic circulation via the lungs. The percentage of the perflutren dose excreted in expired air was approximately 50% of the administered dose due to the small quantities of perflutren given and the inability to quantify low levels of perflutren by gas chromatography. In most subjects after 4-5 minutes, perflutren was undetectable in blood and expired air. Perflutren concentrations in blood were shown to decline in a mono-exponential fashion with a mean half-life of 1.3 minutes in healthy subjects and 1.9 minutes in COPD subjects. The systemic clearance of perflutren was similar in healthy and COPD subjects. Total lung clearance (CLlung) of perflutren was shown to be no different in healthy subjects compared to COPD subjects. CLlung was found to be significantly reduced (51%) in females compared to males (all subjects). These results suggest that overall perflutren systemic elimination is rapid and is not significantly reduced in COPD patients compared to healthy subjects. Doppler ultrasound measurements were performed with Luminity in conjunction with the pharmacokinetic evaluation of perflutren. Doppler signal intensity corresponded well with measured and extrapolated perflutren concentrations in blood. The time to maximum Doppler signal intensity t_max was shown to be similar to the perflutren blood t_max (1.13 versus 1.77 minutes). The observed 99% drop in Doppler signal intensity within 10 minutes (t_1/2 approximately 2 minutes) was in agreement with the decline in measurable blood levels of perflutren.

Fundamental and non-linear imaging techniques (second harmonic, multipulse phase and/or amplitude modulation) using both continuous and triggered acquisition were utilised in clinical studies with Luminity.

The naturally occurring phospholipids in Luminity (see section 6.1) are distributed in the endogenous lipid pools in the body (for example, liver) whereas the synthetic component (MPEG5000) has been shown to be excreted in the urine in preclinical studies. All lipids are metabolised to free fatty acids. The pharmacokinetics and metabolism of MPEG5000 DPPE have not been evaluated in humans.

Pharmacokinetics in special population groups

Elderly

Pharmacokinetics has not been specifically studied in the elderly.

Renal impairment

Pharmacokinetics has not been specifically studied in the renal disease patients.

Hepatic impairment

Pharmacokinetics has not been specifically studied in the hepatic disease patients.

Preclinical data reveal no special hazard for humans based on conventional studies of genotoxicity, fertility, embryo/foetal development, parturition or post-natal development, and local tolerance.

Abnormal respiration, heart rate changes and decreased activity were observed soon after intravenous injection of Luminity at doses ≥0.3 ml/kg in single and repeat-dose toxicity studies in rats and monkeys. Higher doses of the product, typically ≥1 ml/kg, resulted in more severe signs including unresponsiveness and occasionally death. These levels are substantially above the recommended maximal clinical dose. Rats treated with Luminity for 1 month exhibited dose-related, reversible perivascular and peribronchiolar eosinophil infiltration, alveolar macrophage accumulation and increased goblet cell size and number in the lungs. These effects were observed at exposure levels in excess of the maximum human exposure indicating little relevance to clinical use.