Pharmacokinetic characteristics of fentanyl iontophoretic trandermal system over a range of applied current

Figures & data

Table 1. Fentanyl dose absorbed from an iontophoretic transdermal system [2].

Study	Original ITS treatment	Dose absorbed Mean (s.d.)
		100 μA	140 μA	170 μA	200 μA	230 μA
1	Single dose	24.8 (5.2)	35.1 (12.1)	39.5 (10.9)	49.7 (8.8)	53.9 (12.8)
2	Two consecutive doses	48.8 (13.9)	NA	74.3 (12.5)	NA	NA

ITS: Iontophoretic transdermal system; NA: Not applicable; s.d.: Standard deviation.

Table 2. Treatment sequences.

Sequence	Period 1	Period 2	Period 3
1	A	B	C
2	B	A	C
3	A	B	D
4	B	A	D
5	A	B	E
6	B	A	E

Treatment A: Fentanyl citrate (equivalent to 80 mcg fentanyl) administered over 20 min by i.v. infusion every hour through 23.33 h.

Treatment B: Two consecutive fentanyl doses each delivered over10 min by the Modified ITS (170 μA) every hour through 23.33 h.

Treatment C: Two consecutive fentanyl doses, each delivered over10 min by the Modified ITS (140 μA) every hour through 23.33 h.

Treatment D: Two consecutive fentanyl doses, each delivered over10 min by the Modified ITS (200 μA) every hour through 23.33 h.

Treatment E: Two consecutive fentanyl doses, each delivered over 10 min by the Modified ITS (230 μA) every hour through 23.33 h.

ITS: Iontophoretic transdermal system.

Table 3. Summary of subject enrollment and disposition.

	Number (%) of subjects
Number in the safety population	65
Naltrexone treatment failure	0
Naloxone treatment failure	0
Number in the randomized population	52
Number completed	36 (69.2)
Number discontinued	16 (30.8)
Reason for discontinuation
Suspected technical failure of system	11 (21.2)
Other	5 (9.6)

The ‘Other’ reasons for discontinuation were as follows: three subjects withdrew due to a schedule conflict, one subject chose not to continue and one subject dropped due to the missed i.v. dosed.

Concentration data were not available for any of the three treatment periods for 9 subjects; therefore, these subjects were excluded from the PK population and all PK analyses. For both Periods 2 and 3, there were no concentration data available from four subjects and for Period 3, there were no concentration data available from six subjects. Therefore, these subjects were excluded from PK analyses for the respective treatment groups/periods but included in the reported data for the earlier period(s).

i.v.: Intravenous; PK: Pharmacokinetic.

Figure 1. Mean serum fentanyl concentration-time profiles after i.v. infusion or iontophoretic transdermal system treatments. (A) 23 – 48 h. (B) 23 – 25 h.

Figure 2. Comparison of mean (± standard deviation) fentanyl serum concentrations for the modified iontophoretic transdermal system at 170 μA (n = 41) and the i.v. infusion treatment (n = 43).

Table 4. Fentanyl pharmacokinetic parameters after intravenous infusion or modified iontophoretic transdermal system.

Treatment	AUC23 – 25 (hr*ng/ml) Mean (s.d.)	Cmax (ng/ml) Mean (s.d.)	tmax (hr) Median (min, max)	t1/2 (hr) Mean (s.d.)	λZ* hr^-1 Mean (s.d.)	Dose Absorbed^‡ μg Mean (s.d.)
i.v. Fentanyl	2.2 (0.5)	1.5 (0.4)	23.4 (23.0 – 28.0)	13.0 (7.4)	0.06 (0.02)	NA
Modified ITS 140 μA	1.5 (0.4)	0.9 (0.2)	23.2 (23.0 – 28.0)	11.5 (3.1)	0.06 (0.01)	56.0 (14.0)
Modified ITS 170 μA	1.9 (0.5)	1.3 (0.4)	23.0 (23.0 – 26.0)	11.0 (4.4)	0.07 (0.02)	69.9 (13.2)
Modified ITS 200 μA	2.5 (0.5)	1.5 (0.3)	23.0 (23.0 – 23.8)	11.9 (5.9)	0.07 (0.02)	86.5 (16.0)
Modified ITS 230 μA	3.4 (1.3)	2.1 (0.7)	23.0 (23.0 – 24.0)	11.1 (3.1)	0.07 (0.02)	117.8 (21.3)

*Individual values for t_1/2 and λ_z were excluded from descriptive statistics when r² < 0.75. Summaries for t_1/2 and λ_z were excluded for subject data when r² criteria (r² < 0.75) were not met.

^‡Dose Absorbed calculated from the ratio of the AUC_{23 – 25} for the modified ITS to the i.v. infusion treatment multiplied by the i.v. dose of 80 mcg.

λ_z: Terminal elimination rate constant; AUC_{23 – 25}: Area under the concentration versus time curve over the 2-h period from the 23 through 25 h after initiation of the study system; C_max: Maximum concentration; ITS: Iontophoretic transdermal system; i.v.: Intravenous; NA: Not applicable; s.d.: Standard deviation; t_max: Time to maximum concentration.

Figure 3. Box plot comparisons of AUC _{23 – 24} after i.v. infusion or modified iontophoretic transdermal system administration of fentanyl by treatment group. Standard box plot is defined by the interquartile range (IQR) with upper (75%) and lower (25%) quartiles (the box). Whiskers indicate the 1.5 IQR (50% of the difference between the third and fourth quartiles). Outliers (outside of the 1.5 IQR) are designated by markers. The median is represented by a solid line.

Figure 4. Mean dose absorbed (with standard deviations) from two consecutive doses using the modified iontophoretic transdermal system at various applied currents (line is a linear regression fit with r² = 0.96), compared to dose absorbed from the original iontophoretic transdermal system at 170 μA (circle).

Table 5. Statistical comparison of fentanyl dose absorbed from the modified ITS (test, n = 40) and the original ITS (reference, n = 31) [2].

Ref.Geo. Mean (Geo. %CV) [2]	Test Geo. Mean (Geo. %CV)	Ratio % (Test/Ref)	Lower 90% CI	Upper 90% CI	Power
73.78 (15.3)	68.75 (18.9)	93.18	87.13	99.65	0.98

Power was assessed based on 93.18% of geometric mean ratio and its 90% CI within 80% to 125% (or based on a mean difference of 0.152 in the Ln domain).

CV: Coefficient of variation; ITS: Iontophoretic transdermal system.

Sathyan G, Jaskowiak J, Evashenk M, Gupta S. Characterisation of the pharmacokinetics of the fentanyl HCl patient-controlled transdermal system (PCTS): effect of current magnitude and multiple-day dosing and comparison with IV fentanyl administration. Clin Pharmacokinet 2005;44(Suppl 1):7–15

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