Analytical method validation for biomarkers as a drug development tool: points to consider.

Biomarkers are an important drug developmental tool. Assessment of quantitative analytical methods of biomarkers is not included in any regulatory documents in Japan. Use of biomarkers in clinical evaluations and supporting the post-marketing evaluation of drug efficacy and/or adverse reactions requires assessment and full validation of analytical methods for these biomarkers. The Biomarker Analytical Method Validation Study Group is a research group in Japan comprising industry and regulatory experts. Group members discussed and prepared this 'points to consider document' covering measurements of endogenous metabolites/peptides/proteins by ligand binding assays and chromatographic methods with or without mass spectrometry. We hope this document contributes to the global harmonization of biomarker assay validation.

Effects of peritoneal dialysis on pharmacotherapy: a deductive pharmacokinetic-model approach to predict drug concentration profiles in plasma and peritoneal fluid.

The aim of this study was to present a deductive compartment pharmacokinetic (PK) model to predict the concentration profiles of drugs in plasma and peritoneal fluid in peritoneal dialysis (PD) rats. PK parameters of model drugs in normal and experimentally induced acute renal failure (ARF) rats not undergoing PD were obtained inductively in a common regression manner with a two-compartment model. In PD normal and ARF rats, PK parameters relating to the transfer of drugs to the peritoneal dialysate and the progress of renal failure were deductively modified to simulate the drug concentration-time profiles in plasma and in the peritoneal fluid in PD rats. The deductively introduced modifiers were the volume of distribution in the peripheral compartment, plasma protein binding, and solvent movement factor to the peritoneal fluid. Predicted profiles of tolbutamide, propranolol and cefazolin in PD normal and ARF rats were compared with the corresponding observed data. This minimal deductive approach yielded satisfactory accuracy in the prediction of both the plasma and peritoneal fluid concentrations of tolbutamide and propranolol.

Comparative study of increased plasma quinidine concentration in rats with glycerol- and cisplatin-induced acute renal failure.

A comparative study of altered plasma concentration of quinidine in rats with glycerol- and cisplatin-induced acute renal failure (ARF) was conducted with quinidine used as a positively charged and liver-metabolized therapeutic compound. Although apparent total body clearance of quinidine decreased to 68 and 48% of the normal value in glycerol- and cisplatin-induced ARF rats, respectively, its distribution decreased only in glycerol-induced ARF rats. The plasma unbound fraction of quinidine decreased in glycerol-induced ARF rats, which was not observed in cisplatin-induced ARF rats. The plasma level of alpha(1)-acid glycoprotein (AGP) increased in glycerol-induced ARF, but not in cisplatin-induced ARF rats. It is therefore conceivable that the plasma concentration of positively charged and liver-metabolized compounds generally increases due to hepatic elimination suppressed as renal function decreases, but the pharmacokinetic impact of suppressed hepatic elimination is occasionally difficult to observe in some ARF model rats since it may be blurred by the influence of increased plasma AGP level.

Peritoneal dialysis alters tolbutamide pharmacokinetics in rats with experimental acute renal failure.

The plasma concentration profile of the antidiabetic agent tolbutamide was investigated in glycerol-induced acute renal failure (ARF) rats receiving or not receiving peritoneal dialysis (PD) to assess the impact of performing dialysis on tolbutamide pharmacokinetics. It was revealed that the plasma concentration of tolbutamide was decreased by 23.4% by performing PD in ARF rats, while it was not changed by PD in normal rats. The decrease in the plasma concentration of tolbutamide was nearly proportional to the increase in its volume of distribution. To clarify the mechanisms responsible for the decreased tolbutamide concentration caused by PD, the plasma protein binding of tolbutamide was examined in normal and ARF rats. The plasma unbound fraction of tolbutamide was higher in ARF rats than in normal rats, and the dissociation constants were 3.5+/-0.7 and 5.5+/-0.2 microg in normal and ARF rats, respectively. These results indicated that the unbound fraction of tolbutamide was increased in ARF rats because of its protein binding being suppressed. It is therefore likely that since a measurable amount of tolbutamide can distribute in peritoneal dialysate in ARF rats, but not in normal rats, the plasma concentration of tolbutamide was decreased by performing PD only in ARF rats. These findings suggest that diabetes medication with tolbutamide should be carefully performed in patients receiving dialysis treatment.