Comparison of oral absorption models for pregabalin: usefulness of transit compartment model

Abstract

Pregabalin is an anticonvulsant used for the treatment of neuropathic pain and partial seizure in adults. The aim of this study was to develop a population pharmacokinetic (PK) model to describe the absorption characteristics of pregabalin given fasted or after meals. Data from five healthy subject PK studies (n=88) of single- or multiple-dose pregabalin (150 mg) were used. Pregabalin was administered twice daily, without meals or 30 min after a meal (regular or high-fat diet) in the morning and 30 min or 4 h after a meal (regular diet) in the evening. Serial plasma samples were collected up to 24 h after the last dose for PK analysis. Because the peak concentrations were not properly modeled by a conventional first-order absorption model, Erlang frequency distribution, Weibull-type absorption, and transit compartment models were tested on a two-compartment linear PK model using a nonlinear mixed-effects method (NONMEM; version 7.3). The transit compartment model best described the absorption characteristics of pregabalin regardless of meal status. We conclude that the absorption model should be carefully chosen based on the principle of model development and validation and not by following a conventional first-order absorption model for its popularity and simplicity, especially when the PK dataset includes densely sampled absorption-phase data.

Population Pharmacokinetic/Pharmacodynamic Analysis of Nociceptive Pain Models Following an Oral Pregabalin Dose Administration to Healthy Subjects

“…Our developed structural PK model corresponds with previously published models in terms of model structure and rapid absorption of pregabalin after a lag time . The research performed by Hong et al . investigated different structural oral absorption models for pregabalin in which they reported that a first‐order absorption process did not suffice.…”

“…Additional sampling in the absorption phase, between 0 and 1 hour after dosing, could improve the characterization of the absorption phase of pregabalin, which would allow for a better comparison with previous analyses. The use of GFR in healthy subjects as a covariate on CL was also suggested by Hong et al 27 However, this could not be confirmed in this study, which may be explained by our inclusion of the allometric relationship of weight on CL, as there is multicollinearity between body weight and the Cockroft-Gault derived GFR, or the low sample size used in this study. The inclusion of allometric scaling on the V d and CL of pregabalin gave a significant drop in OFV.…”

“…25,26 The research performed by Hong et al 27 investigated different structural oral absorption models for pregabalin in which they reported that a first-order absorption process did not suffice. However, in our developed PK model, the implementation of multiple transit compartments, which was suggested by Hong et al, 27 to fit the absorption phase did not prove to be superior over a first-order absorption with lag time. Additional sampling in the absorption phase, between 0 and 1 hour after dosing, could improve the characterization of the absorption phase of pregabalin, which would allow for a better comparison with previous analyses.…”

“…Our developed structural PK model corresponds with previously published models in terms of model structure and www.psp-journal.com rapid absorption of pregabalin after a lag time. 25,26 The research performed by Hong et al 27 investigated different structural oral absorption models for pregabalin in which they reported that a first-order absorption process did not suffice. However, in our developed PK model, the implementation of multiple transit compartments, which was suggested by Hong et al, 27 to fit the absorption phase did not prove to be superior over a first-order absorption with lag time.…”

Pregabalin in the Management of Painful Diabetic Neuropathy: A Narrative Review

“…Pregabalin’s bioavailability is over 90% and is dose independent [ 37 ]. Food does not affect pregabalin’s overall exposure; however, it can reduce the rate of absorption with the content of the food having little effect on this [ 38 , 39 ]. Maximal serum concentrations appear 0.7–1.3 h post-dose [ 39 ] with the serum half-life ranging from 4.6 to 6.8 h [ 39 ].…”