Population Pharmacokinetic Model of Iohexol in Dogs to Estimate Glomerular Filtration Rate and Optimize Sampling Time

Abstract

Monitoring iohexol plasma clearance is considered a useful, reliable, and sensitive tool to establish glomerular filtration rate (GFR) and early stages of kidney disease in both humans and veterinary medicine. The assessment of GFR based on iohexol plasma clearance needs repeated blood sampling over hours, which is not easily attainable in a clinical setting. The study aimed to build a population pharmacokinetic (Pop PK) model to estimate iohexol plasma clearance in a population of dogs and based on this model, to indicate the best sampling times that enable a precise clearance estimation using a low number of samples. A Pop PK model was developed based on 5 iohexol plasma samples taken from 5 to 180 minutes (min) after an intravenous iohexol nominal dose of 64.7 mg/kg from 49 client-owned dogs of different breeds, sexes, ages, body weights, and clinical conditions (healthy or presenting chronic kidney disease CKD). The design of the best sampling times could contain either 1 or 2 or 3 sampling times. These were discretized with a step of 30 min between 30 and 180 min. A two-compartment Pop PK model best fitted the data; creatinine and kidney status were the covariates included in the model to explain a part of clearance variability. When 1 sample was available, 90 or 120 min were the best sampling times to assess clearance for healthy dogs with a low creatinine value. Whereas for dogs with CKD and medium creatinine value, the best sampling time was 150 or 180 min, for CKD dogs with a high creatinine value, it was 180 min. If 2 or 3 samples were available, several sampling times were possible. The method to define the best sampling times could be used with other Pop PK models as long as it is representative of the patient population and once the model is built, the use of individualized sampling times for each patient allows to precisely estimate the GFR.

“De-Shrinking” EBEs: The Solution for Bayesian Therapeutic Drug Monitoring

“…In this work, the method of Combes et al [ 18 ] poorly predicted EBE shrinkage. We consider that this is mainly due to the assumed asymptotic framework.…”

“…The first model used relates to the pharmacokinetics of iohexol in dogs [ 18 ]. This molecule allows establishment of the glomerular filtration rate (GFR).…”

“…The dose chosen to perform the simulation is equal to 1600 mg. This corresponds to the average dose that was used to build the PPK model in the study by Baklouti et al [ 18 ]. Similarly, we performed the simulations with sick dogs with a plasma creatinine level of 2.25 mg/dL that roughly corresponds to the average concentration reported in diseased animals [ 18 ].…”

“…We tested this methodology when a single sample is available at 180 min, corresponding to the best sampling time as identified in the study by Baklouti et al [ 18 ].…”

Comparação entre as depurações de creatinina endógena de quatro horas, vinte e quatro horas e creatinina exógena em cães sadios

“…Outro fator de atenção é que a alimentação baseada em carne fresca também tende a alterar a precisão (Haller, et al, 1998;Miyamoto, 1998;Sargent, Elliot & Jepson, 2021). Ainda, a TFG pode ser utilizada para monitorar o curso da doença renal e modificar dosagens de fármacos que sejam potencialmente nefrotóxicos ou tenham eliminação renal (Grauer, 2019;Baklouti et al 2021) A TFG pode ser calculada usando-se a depuração da creatinina endógena ou exógena. No Brasil, existem dois métodos endógenos descritos na literatura: o duplo de 20 minutos e o de 24 horas (Carneiro, 2002) e ambos possuem vantagens e desvantagens.…”