Time-varying compartmental models capture hours-scale variation in the
elimination kinetics of vancomycin
Abstract
Background and Purpose: Pharmacokinetics have traditionally been
assessed using concentration measurements from methods with low temporal
resolution, such as blood draws, leading to profiles being estimated
from sparse or blended data. Recent advances in in vivo sensors,
however, now enable the collection of hundreds of observations over a
few-hours for each individual drug administration. Previous analyses of
such data for the antibiotic tobramycin have identified significant
(several-fold), hours-scale changes in the efficiency with which this
renally cleared drug is eliminated. Here we apply similar analyses to
study the pharmacokinetics of another renally cleared drug, the
antibiotic vancomycin. Experimental Approach: We estimate vancomycin
pharmacokinetic profiles using previously collected time-dense plasma
concentration measurements within six anesthetized rats. Specifically,
we fit standard one- and two-compartment models, as well as time-varying
one-compartment models (in which the proportionality relating
concentration to elimination rate is time-varying), to these data to
investigate if the time-varying models are statistically preferred for
describing individual-level vancomycin pharmacokinetics, over standard
one- and two-compartment models. Key Results: One-compartment models
incorporating time-varying elimination proportionalities are
statistically preferred over standard one- and two- compartment models
for 5 of our 6 vancomycin time courses. When the initial impact of the
distribution phase is removed from these data, a reciprocally
time-varying one-compartment model is preferred over the standard-one
compartment model in 4 of 5 considered datasets. Conclusion and
Implications: These results provide further animal-model evidence that
the pharmacokinetics of renally cleared drugs can vary significantly
over timescales as short as a few hours.