Effect of misspecification of the absorption process on subsequent parameter estimation in population analysis

Abstract

A prospective simulation study has been carried out to evaluate the effect of potential misspecification of the absorption rate constant (ka) in population pharmacokinetic analysis when few to no concentration-time data were available in the absorption phase and estimation of ka was not possible. Data were simulated for 100 subjects using a one-compartment model at steady state with first-order input. Data were generated over a range of ka values: ka was misspecified in the NONMEM analysis by factors of 0.25, 0.5, 1, 2, 3, and 4. In general, clearance (CL) was typically estimated with a small, constant underprediction, regardless of the range of misspecification of ka or whether data were present in the absorption phase. The same was not true for volume of distribution (V), values were biased and sensitive to the degree of misspecification, but only when the data contained even a little information about absorption. If studies are to be designed in which information absorption is either not required or is of no therapeutic use, then blood samples could be concentrated in the postabsorption phase and the absorption input fixed according to the best a priori information available.

Population Pharmacokinetic Modeling of the Association between 63396C→T Pregnane X Receptor Polymorphism and Unboosted Atazanavir Clearance

“…This could explain the lack of interindividual variability for the K a . This factor may also affect the determination of interindividual variability for volume of distribution (V) (44). The PK parameter results in this study showed a slightly increased CL/F compared to data obtained with boosted ATV presented in previous studies, which is expected due to the absence of the boosting agent.…”

Population Pharmacokinetic Analysis of Daikenchuto, a Traditional Japanese Medicine (Kampo) in Japanese and US Health Volunteers

“…This was because the t max was observed in many subjects at the first sampling point, which occurred at an early time point of 15 minutes. Wade et al (1993) reported that when no data are present in the absorption phase, the misspecification of the rate of drug absorption or the model used to describe drug absorption has little consequence on the estimation of the remaining population parameters. On the other hand, the goodness-of-fit plot of the model for 10S indicated that the predicted plasma concentrations overestimated the observed plasma concentrations at the highest predicted plasma concentration (i.e., the first sampling point), based on participants who were actually observed during the absorption phase.…”

Influence of CYP2B6 516G>T polymorphism and interoccasion variability (IOV) on the population pharmacokinetics of efavirenz in HIV-infected South African children

“…Other considerations for fixing the k a value were that a large number of the study population described by Kappelhoff and co-workers were black adult South Africans [38]. Both Cabrera and co-workers and Wade and co-workers reported that the estimation of CL/F is not affected by the k a value [30,49]. Interoccasion variability (IOV) was taken into account as proposed by Karlsson et al [50] for the random effects modelling.…”