MEPACT Powder for concentrate for dispersion for infusion Ref.[9701] Active ingredients: Mifamurtide

The pharmacokinetics of mifamurtide have been characterised in healthy adult subjects following a 4 mg intravenous infusion and in paediatric and adult patients with osteosarcoma following a 2 mg/m² intravenous infusion.

In 21 healthy adult subjects mifamurtide was cleared rapidly from serum (minutes) with a half-life of 2.05 ± 0.40 hours, resulting in a very low serum concentration of total (liposomal and free) mifamurtide. The mean area under the curve (AUC) was 17.0 ± 4.86 h x nM and C_max (maximum concentration) was 15.7 ± 3.72 nM.

In 28 osteosarcoma patients aged 6 to 39 years serum total (liposomal and free) mifamurtide concentrations declined rapidly with a mean half-life of 2.04 ± 0.456 hours. BSA-normalised clearance and half-life were similar across the age range and consistent with that determined in healthy adult subjects, supporting the recommended dose of 2 mg/m².

In a separate study in 14 patients, mean serum concentration-time curves of total and free mifamurtide that were assessed after the first infusion of mifamurtide and after a last infusion 11 or 12 weeks later, were almost superimposable and the mean AUC values of the free mifamurtide after the first and last infusion were similar. These data indicate that neither total nor free mifamurtide accumulated during the treatment period.

At 6 hours after injection of radiolabelled liposomes containing 1 mg mifamurtide, radioactivity was found in liver, spleen, nasopharynx, thyroid, and, to a lesser extent, in lung. The liposomes were phagocytosed by cells of the reticuloendothelial system. In 2 of 4 patients with lung metastases, radioactivity was associated with lung metastases.

Metabolism of liposomal MTP-PE has not been studied in humans.

After injection of radiolabelled liposomes containing mifamurtide, mean half-life of radiolabelled material was biphasic with an α-phase of about 15 minutes and a terminal half-life of approximately 18 hours.

Special populations

Renal impairment

The pharmacokinetics of a single 4 mg dose of mifamurtide following a 1 hour intravenous infusion were evaluated in adult volunteers with mild (n=9) or moderate (n=8) renal impairment and in age-, sex-, and weight-matched healthy adults with normal renal function (n=16). There was no effect of mild (50 mL/min ≤ creatinine clearance [CLcr] ≤ 80 mL/min) or moderate (30 mL/min ≤ CLcr < 50 mL/min) renal insufficiency on the clearance of total MTP-PE, when compared with that observed in healthy adult subjects with normal renal function (CLcr > 80 mL/min). Additionally, the systemic exposures AUC from zero to infinity (AUC_inf of free (non-liposome associated) MTP-PE in mild or moderate renal insufficiency were similar to those observed in healthy adult subjects with normal renal function.

Hepatic impairment

The pharmacokinetics of a single 4 mg dose of mifamurtide following a 1 hour intravenous infusion were evaluated in adult volunteers with mild (Child-Pugh class A; n=9) or moderate (Child-Pugh class B; n=8) hepatic impairment and in age, sex-, and weight-matched healthy adults with normal hepatic function (n=19). There was no effect of mild hepatic impairment on the systemic exposure (AUC_inf) of total MTP-PE. Moderate hepatic impairment resulted in a small increase in AUC_inf of total MTP-PE, with the geometric least square mean ratio (expressed as ) for moderate hepatic impairment in reference to the matched normal hepatic function group being 119 (90% confidence interval [CI]: 94.1%-151%). Pharmacokinetic variability was higher in the moderate hepatic impairment group (co-efficient of variation in systemic exposure [AUC_inf] was 50% versus <30% in the other hepatic function groups).

Mean half-lives of total and free MTP-PE in mild hepatic impairment were 2.02 hours and 1.99 hours, respectively, and were comparable to those in subjects with normal hepatic function (2.15 hours and 2.26 hours, respectively). Mean half-lives of total and free MTP-PE in moderate hepatic impairment were 3.21 hours and 3.15 hours, respectively. Additionally, the geometric mean plasma AUC_inf of free (non-liposome associated) MTP-PE in mild and moderate hepatic impairment were 47% higher than the corresponding values in the matched normal hepatic function groups. These changes were not considered to be clinically meaningful as the maximum tolerated dose (4-6 mg/m²) of mifamurtide is 2-3 times the recommended dose (2 mg/m²).

In sensitive species (rabbit and dog) the highest daily dose of liposomal mifamurtide that did not cause adverse effects was 0.1 mg/kg, corresponding to 1.2 and 2 mg/m², respectively. The no-adverse-effect level for mifamurtide in animals corresponds roughly to the 2 mg/m² recommend dose for humans.

Data from a six-month dog study of daily intravenous injections of up to 0.5 mg/kg (10 mg/m²) mifamurtide provide an 8- to 19-fold cumulative exposure safety margin for overt toxicity for the intended clinical dose in humans. Major toxic effects associated with these high daily and cumulative doses of mifamurtide were mainly exaggerated pharmacological effects: pyrexia, signs of pronounced inflammatory response manifested as synovitis, bronchopneumonia, pericarditis and inflammatory necrosis of the liver and bone marrow. The following events were also observed: haemorrhage and prolongation of coagulation times, infarcts, morphological changes in the wall of small arteries, oedema and congestion of the central nervous system, minor cardiac effects, and slight hyponatraemia. Mifamurtide was not mutagenic and did not cause teratogenic effects in rats and rabbits. Embryotoxic effects were observed only at maternal toxic levels.

There were no results from general toxicity studies that suggested harmful effects on male or female reproductive organs. Specific studies addressing reproductive function, perinatal toxicity and carcinogenic potential have not been performed.