Iclaprim Human Pharmakonetics14 Feb 2019 19:24
FYI dose rates and how change to fixed dose 80mg May effect AUC levels which are liver related
Human Pharmacokinetics
Iclaprim achieves high concentrations in skin and skin structure and lung compartments. Icalprim also rapidly concentrates in the gastrointestinal tract, adrenal glands, kidneys, and liver, with a high volume of distribution exceeding 4–5 times the total body water volume. Iclaprim has 93% plasma protein binding. Iclaprim and its metabolites are rapidly and extensively excreted in the bile and urinary route. Iclaprim is metabolized by both phase 1 (CYP3A4 and CYP23C19) and phase 2 (CYP2C9 and CYP2D6) enzymes. Most of the phase 1 metabolites are subsequently conjugated to glucuronide metabolites. Less than 2% of unchanged iclaprim was found in urine and feces, confirming extensive metabolism.
Pharmacokinetic parameters of iclaprim from population PK in cSSSI pivotal studies with dosing of 0.8 mg/kg every 12 hours gave similar values to those obtained in phase 1 PK studies (Table 1). The initial phase 1 studies of weight-based doses of iclaprim showed the PK of iclaprim to be linear, with dose-proportional increases in both AUC and Cmax over a wide range of doses [14]. Exposure did not change over time for up to 10 sequential days of dosing, nor was exposure altered in subjects with renal impairment. A 2-fold increase in AUC was observed in subjects with moderate hepatic impairment, suggesting that dose adjustments may be indicated in that population. Iclaprim is not a potent inhibitor of CYP450 enzymes, and drug-drug interaction (DDI) studies showed a less-than-2-fold increase in iclaprim levels in the presence of of the CYP3A4 inhibitor ketoconazole. Therefore, no dose adjustments are indicated when iclaprim is co-administered with inhibitors or substrates of CYP450 enzymes. In addition, unlike trimethoprim-sulfamethoxazole, iclaprim has no effect on renal excretion of potassium and serum potassium concentrations
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