Population pharmacokinetic modeling of cefadroxil renal transport in wild-type andPept2knockout mice

Abstract

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 wildtype and Pept2 knockout mice using the NONMEM approach.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 wildtype and Pept2 knockout mice were well estimated, respectively, as: volume of central compartment V1 (3.43 vs. 4.23 mL), volume of peripheral compartment V2 (5.98 vs. 8.61 mL), inter-compartment clearance Q (0.599 vs. 0.586 mL/min), and linear elimination rate constant K10 (0.111 vs. 0.070 min−1). Moreover, the secretion kinetics (i.e., Vm1 = 17.6 nmoL/min and Km1 = 37.1 μM) and reabsorption kinetics (i.e., Vm2 = 15.0 nmoL/min and Km2 = 27.1 μM) of cefadroxil were quantified in kidney, for the first time, under in vivo conditions.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.

Species Differences in Human and Rodent PEPT2-Mediated Transport of Glycylsarcosine and Cefadroxil in Pichia Pastoris Transformants

“…At the present time, it is uncertain how well the species-dependent differences in substrate affinity for PEPT2 in the yeast transformant model reflect that of PEPT2 in vivo. One might infer a faithful translation of results based on the observation that the in vitro affinity of mPEPT2 for cefadroxil in yeast (K m = 15.6 mM) was very similar to the in vivo affinity of PEPT2 observed in mice (K m = 27.1 mM) during a population pharmacokinetic analysis of cefadroxil renal transport in wild-type and knockout animals (Xie et al, 2016). A species-dependent uptake of PEPT1 substrates in yeast P. pastoris was also observed in vivo when comparing the area under the plasma concentration-time curve and maximum plasma concentration (C max ) of orally administered cefadroxil in wild-type mice, humanized PEPT1 mice, and clinical data obtained from the literature (Hu and Smith, 2016).…”

Physiologically Based Pharmacokinetic Modeling of Cefadroxil in Mouse, Rat, and Human to Predict Concentration–Time Profile at Infected Tissue

“…As shown in Table 3 , there are some discrepancies between predicted K p values in human and observed values in mouse and rat, especially for kidney. Cefadroxil was excreted primarily by the kidney, with over 90% of the administered dose being recovered in the urine intact within 24 h. PEPT2 (SLC15A2) mediates the renal reabsorption of cefadroxil ( Xie et al, 2016 ). The predicted method cannot consider this factor and led to the discrepancy.…”

“…Cefadroxil is a substrate of PEPT2 (SLC15A2), and PEPT2 mediates the renal reabsorption of cefadroxil ( Xie et al, 2016 ). The renal clearances of mouse, rat, and human were 0.52, 3.00, and 141.67 ml/min in this study.…”

Novel Population Pharmacokinetic Approach to Explain the Differences between Cystic Fibrosis Patients and Healthy Volunteers via Protein Binding

“…We considered an alternative model where renal clearance was split into a glomerular filtration and tubular secretion clearance similar to prior analyses [53,54,55,56]. Cefotiam is a low renal extraction ratio drug since its unbound renal clearance of 23.8 L/h is equivalent to approximately 32% of renal blood flow (74 L/h) [57].…”