Using seconds-resolved pharmacokinetic datasets to assess pharmacokinetic models encompassing time-varying physiology.
Br J Clin Pharmacol
; 89(9): 2798-2812, 2023 09.
Article
in En
| MEDLINE
| ID: mdl-37186478
ABSTRACT
AIM:
Pharmacokinetics have historically been assessed using drug concentration data obtained via blood draws and bench-top analysis. The cumbersome nature of these typically constrains studies to at most a dozen concentration measurements per dosing event. This, in turn, limits our statistical power in the detection of hours-scale, time-varying physiological processes. Given the recent advent of in vivo electrochemical aptamer-based (EAB) sensors, however, we can now obtain hundreds of concentration measurements per administration. Our aim in this paper was to assess the ability of these time-dense datasets to describe time-varying pharmacokinetic models with good statistical significance.METHODS:
We used seconds-resolved measurements of plasma tobramycin concentrations in rats to statistically compare traditional one- and two-compartmental pharmacokinetic models to new models in which the proportional relationship between a drug's plasma concentration and its elimination rate varies in response to changing kidney function.RESULTS:
We found that a modified one-compartment model in which the proportionality between the plasma concentration of tobramycin and its elimination rate falls reciprocally with time either meets or is preferred over the standard two-compartment pharmacokinetic model for half of the datasets characterized. When we reduced the impact of the drug's rapid distribution phase on the model, this one-compartment, time-varying model was statistically preferred over the standard one-compartment model for 80% of our datasets.CONCLUSIONS:
Our results highlight both the impact that simple physiological changes (such as varying kidney function) can have on drug pharmacokinetics and the ability of high-time resolution EAB sensor measurements to identify such impacts.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Tobramycin
/
Models, Biological
Type of study:
Prognostic_studies
Limits:
Animals
Language:
En
Journal:
Br J Clin Pharmacol
Year:
2023
Document type:
Article
Affiliation country:
Estados Unidos