Web Enhancement B: NONMEM coding related to sufentanil dosing.
Bolus dosing related to thermal expansion during the implant procedure: Presence of a bolus dose was indicated to NONMEM through dosing records. A sufentanil dose of 1 µg was administered in the depot compartment at the time of implant. Magnitude of the dose was estimated by applying a bioavailability factor, F4, to this dose. This bioavailability factor is evaluated only at the exact time of implant. Thus, it quantifies the bolus dose in µg.
Dosing related to the implant: This dosing was indicated to NONMEM in the $PK and $DES blocks of NMTRAN code. A series of linear splines with either four or five knots (cutpoints) was described (web enhancement A). A dummy variable, ITIME, quantifies the time relative to the implant (IMPL). INPUT quantifies the release rate for Chronogesic sufentanil during each time period. Lines 2-4 of the code in Web Enhancement A use linear interpolation to describe release rate as a function of the heights of the spline at the beginning and end of each interval. Lines 5 and 6 of this section of code define release rate of the implant system as zero before placement of the implant and after its removal (EXPL). Thus, except for the bolus described above, data records do not indicate dosing related to the implant.
For analyses using four knots, the first knot is placed at the time of implant and its height (i.e., release rate at the time of the implant) is estimated. Both time of the second knot and its height are estimated; time of this knot is constrained to be between 1 and 60 h after the implant. Time of the third knot and its height are both estimated; time of this knot is constrained to be between 72 and 150 h after the implant. The fourth knot occurs at the time of removal; height of this knot is estimated. For analyses using five knots, the additional knot is interposed between knots 1 and 2 of the four-knot approach; both time and height of this knot are estimated.