Population pharmacokinetic modeling of cefadroxil renal transport in wild-type and Pept2 knockout mice

Abstract

1. Cefadroxil is a broad-spectrum β-lactam antibiotic that is widely used in the treatment of various infectious diseases. Currently, poor understanding of the drug’s pharmacokinetic profiles and disposition mechanism(s) prevents determining optimal dosage regimens and achieving ideal antibacterial responses in patients. In the present retrospective study, we developed a population pharmacokinetic model of cefadroxil in wild-type and Pept2 knockout mice using the nonlinear mixed effect modeling (NONMEM) approach.

2. Cefadroxil pharmacokinetics were best described by a two-compartment model, with both saturable and nonsaturable elimination processes to/from the central compartment. Through this modeling approach, pharmacokinetic parameters in wild-type and Pept2 knockout mice were well estimated, respectively, as follows: volume of central compartment V₁ (3.43 versus 4.23 mL), volume of peripheral compartment V₂ (5.98 versus 8.61 mL), intercompartment clearance Q (0.599 versus 0.586 mL/min) and linear elimination rate constant K₁₀ (0.111 versus 0.070 min⁻¹). Moreover, the secretion kinetics (i.e. V_m1 = 17.6 nmoL/min and K_m1 = 37.1 µM) and reabsorption kinetics (i.e. V_m2 = 15.0 nmoL/min and K_m2 = 27.1 µM) of cefadroxil were quantified in kidney, for the first time, under in vivo conditions.

3. Our model provides a unique tool to quantitatively predict the dose-dependent nonlinear disposition of cefadroxil, as well as the potential for transporter-mediated drug interactions.

• Disposition
• kidney
• mice
• pharmacokinetics
• transporters

Declaration of interest

The authors declare no competing interest.