ealthy adult subjects with normal renal function with trends towards lower AUC and Cmax in adolescents. In the younger age groups (26 years and 711 years), total clearance was higher compared with that in adolescents, resulting in a lower level of exposure (AUC and Cmax) and elimination half-life. Efficacy was not assessed in this study.
A separate study was conducted to eva luate the pharmacokinetics of daptomycin after a single 8 mg/kg or 10 mg/kg dose of Cubicin as either a 1 or 2 hour infusion in paediatric subjects aged 2 to 6 years, inclusive, with proven or suspected Gram-positive infection who were receiving standard antibiotic therapy.
The mean exposure (AUC0-) was approximately 429 and 550 μg*hr/ml after the administration of 8 and 10 mg/kg single doses, respectively, similar to the exposure seen in adults at the 4 mg/kg dose at steady state (495 μg*hr/ml). The pharmacokinetics of daptomycin appears to be linear in the dose range studied. The half life, clearance and volume of distribution were similar at both dose levels.
Obesity
Relative to non-obese subjects daptomycin systemic exposure measured by AUC was about 28% higher in moderately obese subjects (Body Mass Index of 2540 kg/m2) and 42% higher in extremely obese subjects (Body Mass Index of > 40 kg/m2). However, no dose adjustment is considered to be necessary based on obesity alone.
Gender
No clinically significant gender-related differences in daptomycin pharmacokinetics have been observed.
Renal impairment
Following administration of a single 4 mg/kg or 6 mg/kg dose of daptomycin to subjects with various degrees of renal impairment, total daptomycin clearance (CL) decreased and systemic exposure (AUC) increased as renal function (creatinine clearance) decreased.
Based on pharmacokinetic data and modelling, the daptomycin AUC during the first day after administration of a 6 mg/kg dose to patients on HD or CAPD was 2-fold higher than that observed in patients with normal renal function who received the same dose. On the second day after administration of a 6 mg/kg dose to HD and CAPD patients the daptomcyin AUC was approximately 1.3-fold higher than that observed after a second 6 mg/kg dose in patients with normal renal function. On this basis, it is recommended that patients on HD or CAPD receive daptomycin once every 48 hours at the dose recommended for the type of infection being treated (see section 4.2).
Hepatic impairment
The pharmacokinetics of daptomycin is not altered in subjects with moderate hepatic impairment (ChildPugh B classification of hepatic impairment) compared with healthy volunteers matched for gender, age and weight following a single 4 mg/kg dose. No dosage adjustment is necessary when administering daptomycin in patients with moderate hepatic impairment. The pharmacokinetics of daptomycin in patients with severe hepatic impairment (ChildPugh C classification) have not been eva luated.
5.3 Preclinical safety data
In studies of clinically-relevant duration (1428 days), daptomycin administration was associated with minimal to mild degenerative/regenerative changes in skeletal muscle in the rat and dog. Microscopic changes in skeletal muscle were minimal (approximately 0.05% of myofibres affected) and at the higher doses were accompanied by elevations in CPK. No fibrosis or rhabdomyolysis was observed. Depending on the study duration, all muscle effects, including microscopic changes, were fully re
