so present.
In vitro studies in human liver microsomes indicate that tigecycline does not inhibit metabolism mediated by any of the following 6 cytochrome P450 (CYP) isoforms: 1A2, 2C8, 2C9, 2C19, 2D6, and 3A4 by competitive inhibition. In addition, tigecycline did not show NADPH-dependency in the inhibition of CYP2C9, CYP2C19, CYP2D6 and CYP3A, suggesting the absence of mechanism-based inhibition of these CYP enzymes.
Elimination
The recovery of the total radioactivity in faeces and urine following administration of 14C-tigecycline indicates that 59 % of the dose is eliminated by biliary/faecal excretion, and 33 % is excreted in urine. Overall, the primary route of elimination for tigecycline is biliary excretion of unchanged tigecycline. Glucuronidation and renal excretion of unchanged tigecycline are secondary routes.
The total clearance of tigecycline is 24 L/h after intravenous infusion. Renal clearance is approximately 13 % of total clearance. Tigecycline shows a polyexponential elimination from serum with a mean terminal elimination half-life after multiple doses of 42 hours although high interindividual variability exists.
Special populations
Hepatic Insufficiency
The single-dose pharmacokinetic disposition of tigecycline was not altered in patients with mild hepatic impairment. However, systemic clearance of tigecycline was reduced by 25 % and 55 % and the half-life of tigecycline was prolonged by 23 % and 43 % in patients with moderate or severe hepatic impairment (Child Pugh B and C), respectively (see section 4.2).
Renal Insufficiency
The single dose pharmacokinetic disposition of tigecycline was not altered in patients with renal insufficiency (creatinine clearance <30 ml/min, n=6). In severe renal impairment, AUC was 30 % higher than in subjects with normal renal function (see section 4.2).
Elderly Patients
No overall differences in pharmacokinetics were observed between healthy elderly subjects and younger subjects (see section 4.2).
Paediatric Population
The safety and efficacy of tigecycline in the paediatric population 8 to <18 years of age have not been established.
Tigecycline pharmacokinetics was investigated in two studies. The first study enrolled children aged 8-16 years (n=24) who received single doses of tigecycline (0.5, 1, or 2 mg/kg, with no dose limitation) administered intravenously over 30 minutes. The second study was performed in children aged 8 to 11 years (n=47) who received multiple doses of tigecycline (0.75, 1, or 1.25 mg/kg up to a maximum dose of 50 mg) every 12 hours administered intravenously over 30 minutes. No loading dose was administered in these studies. The pharmacokinetic parameters may be observed in the table below.
Dose Normalized to 1 mg/kg Mean ± SD Tigecycline Cmax and AUC in Children
Age (yr)
N
Cmax (ng/mL)
AUC (ng•h/mL)*
Single dose
8 – 11
8
3881 ± 6637
4034 ± 2874
12 - 16
16
8508 ± 11433
7026 ± 4088
Multiple dose
8 - 11
47
1899 ± 2954
2833 ± 1557
* single dose AUC0-œ, multiple dose AUC0-12h
The target AUC0-12h in adults after the recommended dose of 100 mg loading and 50 mg every 12 hours, was approximately 2500 ng•h/mL
Gender
There were no clinically relevant differences in the clearance of tigecycline between men and women. AUC was estimated to be 2 |
