J.-L. Steimer, B. Fotteler, R. Gieschke, H.Wiltshire, N. Buss
F. Hoffmann-La Roche Ltd., Basel, Switzerland & Welwyn, UK
This abstract (ll) is the follow-up report of the abstract (1) presented at PAGE 1997 “Mixed-effects modeling of the Dose-AUC relationship of saquinavir single dose in healthy subjects”
In a retrospective meta-analysis of dose-AUC data with mixed-effects modeling, the dependency of AUC (and therefore bioavailability) of saquinavir (SQV) on dose and cofactors was investigated. In Abstract I we reported results on a data set consisting of 726 (dose-AUC) observations from 277 healthy subjects. We herein report modeling progress based on 1534 dose-AUC data of SQV in 401 healthy volunteers (HV) and 161 HIV-positive patients (PT) enrolled in 23 clinical studies. SQV had been given mostly orally (in 22 studies, 550 subjects) but also intravenously (4 studies, 29 subjects), in doses ranging from 6 to 72 mg iv and from 75 to 1800 mg po as single dose, b.i.d. or t.i.d. dosing. Coadministration of the protease inhibitor ritonavir (RTV) was investigated in three studies (155 subjects). The primary goals of the mixed- effects model-building were to integrate the findings on multiple factors influencing exposure and bioavailability of SQV, and to predict typical values (e.g. mean) and variability (e.g. CV%) of AUC as well as derived variables (e.g. systemic (bio)availability), at tested and un-tested dosing conditions. The integrated mathematical Dose-AUC model that was developed for the first-pass loss and the disposition clearance of SQV in healthy volunteers was expanded to account for additional features of SQV pharmacokinetics such as: a) accumulation of SQV between first dose and week 1-2 of repeated dosing; b) larger exposure in patients than in healthy subjects; c) in case of multiple dosing with both SQV and RTV, time-variant decrease in exposure of SQV. Due to the complexity of both the data set and the model, NONMEM Version 5 (beta) had to be used. The “mixture model” feature available in this version revealed helpful in order to account for heterogeneity in gut wall metabolism between two (sub- )populations. As a result from the modeling work a) the accumulation could be explained by self-inhibition of SQV under multiple dosing conditions; b) increased exposure in patients could be ascribed to a difference in gut wall functionality or a difference in liver enzymatic capacity or to both; however the current database still lacks the power to discriminate between these rival assumptions; c) time-variant decrease in SQV exposure with RTV could be explained by enzyme induction due to RTV.
Based on the current Model 10J5, preliminary computer simulations were carried out in order to predict exposure (AUC) to SQV in various situations including: fasted/fed state in patients; co-administration of ritonavir or nelfinavir in patients; different grades of liver impairment. Each simulation covered a number of different administration or pathophysiological conditions: the “food” simulation covered 144, the “ritonavir” simulation 280, the “liver function” simulation 240 and the “nelfinavir” simulation 144. For instance, the “food” simulation suggested that the 1200 mg soft gelatin capsule (SGC) even when given fasted to patients produced higher exposure than the 600 mg hard gelatin capsule given after food. This modeling forecast was later supported in an experimental study with SGC in healthy volunteers.
The mathematical model in combination with simulation was and can further be used to guide SQV dose selection, under a broad variety of administration conditions which could never all be assessed in studies in man. However, the predictive ability of these simulations should not be overemphasized, as in the “extrapolation” mode (beyond the range of studied conditions) the degree of uncertainty remains large.
Acknowledgment: The authors thank all investigators for making their data available to them, especially: Dr. Fran Brown, Roche; Dr. Ann Hsu, Abbott (SQV+RTV study); Drs. St. Kraehenbuehi and K. Fattinger, University Hospital Zuerich (iv & po study, including grapefruit juice).
Reference: PAGE 7 (1998) Abstr 680 [www.page-meeting.org/?abstract=680]
Poster: oral presentation