Patients with renal impairment are more likely to have a high plasma linezolid concentration. In addition, a high plasma linezolid concentration and renal impairment significantly affected the development of linezolid-induced thrombocytopenia. Further studies are required to evaluate whether therapeutic drug monitoring-guided dosage adjustment of linezolid decreases the adverse effects while maintaining treatment efficacy in patients with renal dysfunction.
This method is applicable to (i) prioritize clinical trials for investigating drug interactions during the course of drug development and (ii) predict the clinical significance of unknown drug interactions. If a drug-interaction study is carefully designed using appropriate standard drugs, significant interactions involving CYP3A4 will not be missed. In addition, the extent of CYP3A4-mediated interactions between many other drugs can be predicted using the current method.
Induction of cytochrome P450 3A4 (CYP3A4) expression is often implicated in clinically relevant drug-drug interactions (DDI), as metabolism catalyzed by this enzyme is the dominant route of elimination for many drugs. Although several DDI models have been proposed, none have comprehensively considered the effects of enzyme transcription/translation dynamics on induction-based DDI. Rifampicin is a well-known CYP3A4 inducer, and is commonly used as a positive control for evaluating the CYP3A4 induction potential of test compounds. Herein, we report the compilation of in vitro induction data for CYP3A4 by rifampicin in human hepatocytes, and the transcription/translation model developed for this enzyme using an extended least squares method that can account for inherent inter-individual variability. We also developed physiologically based pharmacokinetic (PBPK) models for the CYP3A4 inducer and CYP3A4 substrates. Finally, we demonstrated that rifampicin-induced DDI can be predicted with reasonable accuracy, and that a static model can be used to simulate DDI once the blood concentration of the inducer reaches a steady state following repeated dosing. This dynamic PBPK-based DDI model was implemented on a new multi-hierarchical physiology simulation platform named PhysioDesigner.
It is suggested that the bioavailability of CYP3A4 substrates might be low due to first-pass metabolism in the small intestine, and it is possible that P-glycoprotein (P-gp) may influence first-pass metabolism in a co-operative manner. We have collected information of the pharmacokinetics of CYP3A4 substrates to evaluate the fraction absorbed (Fa), intestinal availability (Fg) and hepatic availability (Fh) and have investigated the intestinal first-pass metabolism and the effect of P-gp on this. The pharmacokinetic data involved ten compounds metabolized by CYP3A4 in humans, with and without an inhibitor or inducer. FaFg, which is the product of Fa and Fg, and Fh were calculated using three liver blood flow rates (17.1, 21.4, 25.5 mL/min/kg) in consideration of variations in the liver flow rate. Co-administration with an inhibitor of CYP3A4 and treatment of an inducer of CYP3A4 caused an increase and decrease in the FaFg of CYP3A4 substrates, regardless of the liver blood flow, indicating that CYP3A4 substrates exhibit a first-pass effect in their metabolism. This holds true regardless of whether the compounds are P-gp substrates or not. No relationship was observed between FaFg and Fh, regardless of the hepatic blood flow rate and the P-gp substrates. The FaFg of both P-gp and non P-gp substrates decreased as the hepatic intrinsic clearance increased. FaFg was markedly reduced when the hepatic intrinsic clearance was more than 100 mL/min/kg. This in vivo intrinsic clearance corresponds to an in vitro intrinsic clearance of 78 muL/min/mg human hepatic microsomal protein, equivalent to a half-life of 8.9 min for the substrate in a commonly used metabolic stability test with human microsomes (1 mgMs protein/mL). This phenomenon was not observed in substrates of CYP isoforms other than CYP3A4. In conclusion, it is suggested that CYP3A4 substrates which have a hepatic intrinsic clearance of 100 mL/min/kg exhibit a low bioavailability due to intestinal first-pass metabolism, regardless of whether they are substrates of P-gp or not.
By using the method reported in the present study, the susceptibilities of a substrate drug of CYP3A4 to inductive DDIs can be predicted quantitatively. It was indicated that coadministration of rifampicin, phenytoin and carbamazepine may reduce plasma AUCs to less than half for a broad range of CYP3A4 substrate drugs, with CRCYP3A4 values greater than 0.13, 0.21 and 0.33, respectively.
The aim of the study was to quantitatively predict the clearance of three antibiotics, amikacin, vancomycin, and teicoplanin, during continuous hemodiafiltration (CHDF) and to propose their optimal dosage in patients receiving CHDF. For this goal, in vitro CHDF experiments with a polyacrylonitrile (PAN) membrane were first performed using these antibiotics, and then the clearances were compared with in vivo CHDF situations determined in 16 critically ill patients. The in vitro CHDF clearances were described as the product of the outflow rate of a drain (Q outflow ) and the drug unbound fraction in artificial plasma, indicating that drug adsorption to the PAN membrane has minor effect on drug clearance in our settings. The observed in vivo clearances also agreed very well with the predicted values, with a product of Q outflow and plasma unbound fraction, when residual creatinine clearance (CL CR ) was taken into account (within a range of 0.67-to 1.5-fold for 15 of 16 patients). Based on these results, a nomogram of the optimized dosages of amikacin, vancomycin, and teicoplanin was proposed, and it was evident that Q outflow and residual CL CR are major determinants of the dosage and dosing interval for these antibiotics. Although the applicability needs to be confirmed with another type of membrane or higher Q outflow , our nomogram can help determine the dosage setting in critically ill patients receiving CHDF.
The plasma concentration of repaglinide is reported to increase greatly when given after repeated oral administration of itraconazole and gemfibrozil. The present study analyzed this interaction based on a physiologically based pharmacokinetic (PBPK) model incorporating inhibition of the hepatic uptake transporter and metabolic enzymes involved in repaglinide disposition. Firstly, the plasma concentration profiles of inhibitors (itraconazole, gemfibrozil, and gemfibrozil glucuronide) were reproduced by a PBPK model to obtain their pharmacokinetic parameters. The plasma concentration profiles of repaglinide were then analyzed by a PBPK model, together with those of the inhibitors, assuming a competitive inhibition of CYP3A4 by itraconazole, mechanism-based inhibition of CYP2C8 by gemfibrozil glucuronide, and inhibition of organic anion transporting polypeptide (OATP) 1B1 by gemfibrozil and its glucuronide. The plasma concentration profiles of repaglinide were well reproduced by the PBPK model based on the above assumptions, and the optimized values for the inhibition constants (0.0676 nM for itraconazole against CYP3A4; 14.2 mM for gemfibrozil against OATP1B1; and 5.48 mM for gemfibrozil glucuronide against OATP1B1) and the fraction of repaglinide metabolized by CYP2C8 (0.801) were consistent with the reported values. The validity of the obtained parameters was further confirmed by sensitivity analyses and by reproducing the repaglinide concentration increase produced by concomitant gemfibrozil administration at various timings/doses. The present findings suggested that the reported concentration increase of repaglinide, suggestive of synergistic effects of the coadministered inhibitors, can be quantitatively explained by the simultaneous inhibition of the multiple clearance pathways of repaglinide.
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