The main constraints on the administration of @entity581 are the risks of nephrotoxicity and @entity2167 , which can lead to acute, renal, vestibular, and @entity2167 . In the present study we focused on nephrotoxicity. No reliable predictor of nephrotoxicity has been found to date. We have developed a deterministic model which describes the pharmacokinetic behavior of @entity581 (with a two-compartment model), the kinetics of @entity4028 accumulation in the renal cortex, the effects of @entity581 on renal cells, the resulting effects on renal function by tubuloglomerular feedback, and the resulting effects on serum @entity1011 concentrations. The pharmacokinetic parameter values were estimated by use of the NPEM program. The estimated pharmacodynamic parameter values were obtained after minimization of the least-squares objective function between the measured and the calculated serum @entity1011 concentrations. A simulation program assessed the influences of the dosage regimens on the occurrence of nephrotoxicity. We have also demonstrated the relevancy of modeling of the circadian rhythm of the renal function. We have shown the ability of the model to fit with 49 observed serum @entity1011 concentrations for a group of eight @entity1 treated for @entity884 by comparison with 49 calculated serum @entity1011 concentrations (r(2) = 0.988; P < 0.001). We have found that for the same daily dose, the nephrotoxicity observed with a thrice-daily administration schedule appears more rapidly, induces a greater decrease in renal function, and is more prolonged than those that occur with less frequent administration schedules (for example, once-daily administration). Moreover, for once-daily administration, we have demonstrated that the time of day of administration can influence the incidence of @entity4028 nephrotoxicity. The lowest level of nephrotoxicity was observed when @entity581 were administered at 1:30 p.m. Clinical application of this model might make it possible to adjust @entity4028 dosage regimens by taking into account both the efficacies and @entity137 of the drugs.

XXXX nephrotoxicity: modeling, simulation, and control.

@entity1 :: ('9606', 'Species') :: ['patients'] @entity137 :: ('MESH:D064420', 'Disease') :: ['toxicities'] @entity2167 :: ('MESH:D006311', 'Disease') :: ['auditory toxicities', 'ototoxicity'] @entity581 :: ('MESH:D000617', 'Chemical') :: ['aminoglycosides'] @entity1011 :: ('MESH:D003404', 'Chemical') :: ['creatinine'] @entity4028 :: ('CHEBI:47779', 'Chemical') :: ['aminoglycoside'] @entity884 :: ('MESH:D004696', 'Disease') :: ['endocarditis']
@entity4028 :: (CHEBI:47779,Chemical) :: ['Aminoglycoside']
