Vol.7 No. 3 (Sup/L) Apti11992
Journal of Pain and Symptom
Management SI 7
Suneel K. Gupta, phII, Mary Southam, PhD, Robert Gale, MS, and Stephen S. Hwang, PbD WA
Corporation,PaloAlto, Calijinnia
Abstract Fentanyl is an opioid traditiom@ adminis&& by in&.&n or ipljectionand more recentb in a rate-controlledtransdennal dosageform. E5is systemis afour-hxyer kminate on a protectiveliner. A backing layerseals andprotects the drug resmoir, the sourcefor continuousdeIivq offattanyl. A membrane control the releaserate offk?any/jom the system.An adhesivelaplerattach the~stem to skin and releases an initial loadingdose offmtanyi. ??ze rate offentanyl deLizqvthroughskin ir determinedby the ~stem and the skin at the apphcationsite. Tie release ratejom the ystem is approximatedby Fick’sjrst law of d&.&n and is controlledby the rate-control&g membrane.A camp&e simulationmodel that combines both in vitro rehme data and the pharmacokineticmodelhas been devekped wrd used to show the in@uence of various
physiologic and systemvariableson serumf.&anyi concen&&ons.JPain Symptom Manage
1992;7:Sl7-S26. &?y Words Fentuny4 phannacokinetics, transderma!,~stemjkctionaii~
The transdermal therapeutic system (‘ITS) for fentanyl, TIX (fkntanyl),is a new dosage form that provides a distinctly different regimen and duration of action than the drug’s traditional IM or IV bolus forms. Because ?ITS (fentanyl) presents physicians with additional opportunities for preventing or treating pain in their cancer patients, it is important to understand the system’s functionality and the pharmacokinetics of fentanyl in this dosage form. In this paper, the functionality and phannacokinetics of TTS (fentanyl)are reported brieflyprior to a discussion of the mathematical models developed to predict the serum fentanyl concentrations following system application. Comparisons are provided of potential changes in serum concentration, given Addressreprint requeststa: Suneel Gupta, PhD, ALZA Corporation,950 Page MillRoad, PO Box 10950, Palo Alto, CA 94303-0802. 0 U.S. Cancer Pain Relier Committee, 1992 Published by Elsetier, New York, New York
changes in physiologic and system parameters that influence drug-release rates and systemic drug absorption horn this transdermal dosage form. The quantitative effect of the system’s rate-controlling membrane on drug delivery to minimize drug input variations is described.
ITS (fentanyl)releases fentanyl continuously for 3 days on application to intact skin. Four systems are available to provide delivery rates ranging from 25 to 100 pg/hr (Table 1); higher rates are achievable by multiple-system application. The system (Figure I) is a four-layer laminate on a protective liner. The backing layer, a clear polyester/ethylene film, is heat sealed around the perimeter of the rate-contiolling membrane. This backing provides a physical barrier to prevent loss of fentanyl and excipients. A drug reservoir of fentanyl base dissolved in ethanol and gelled with
0885-3924/92/35.00
Guptnetal.
S18
W. 7&o. 3 (Sup~l.)April1992
Table 1 ITS (Fentanyl)Systems
Nominal delivery rate WW
Dose TTS TTS TTS ITS
(fcntanyl)-25 (fentanyl)-50 (fcntanyQ75 (fcntanyl)-100
25 50 75 100
m,
transdcrmal therapeutic system.
System area (cm?
Total fentanyl content (mg) 2.5 5 7.5 10
10 20 30 40 ---
hydroxyethyl celluloseis the source for continuous, S-day fentanyl delivery. The rate-controlling membrane, an ethylene-vinyl acetate copolymer film, determines the rate of fentanyl release corn the system to the skin surface. A silicone medical adhesive layer permits free passage of the drug, provides effective attachment to skin, and releases the initial loading dose of drug to skin. In the package, a liner protects the adhesive; it is removed before system application. The composition of all systems is identical per unit area (cm*). During manufacture, fentanyl base is incorporated only into the drug reservoir. After manufacture, fentanyl from this source migrates through tbe rate-controlling membrane until the fentanyl concentration in the adhesive reaches an equilibrium with that in the reservoir. Fentanyl in the adhesive is referred to as the loading dose. After equilibration, total fentanyl content of the system sufficesto maintain saturation in the drug reservoir. When the system is applied to skin, the drug partitions from the adhesive into the adhesive/skin interface and begins to diffuse through skin and into the systemic circulation. Initially, the transport rate of drug into the circulation is low, but it increases to a plateau value as a drug-concentration gradient is established across the skin. The preplateau period is called the transport lag time. As drug concentration in the adhesive declines, additional drug diffusesCorn the reservoir through the rate-controlliig membrane into the adhesive.
Regional variation in skinpermeability to certain drugs or chemicals in vivo in animals and humans is well documented.*-3 Roy and Flynn,+ however, reported that for fentanyl the in vitro permeation rate through different skin sites-thigh, abdomen, upper arm, and chest-showed little variation. When in vitro experiments with TTS (fentanyl) were conducted using hip-skin and chest-skin samples from the same subject, similar transdertnal fluxeswere found, suggesting system control. In the clinical trials evaluating the safety, efficacy, and clinical utility of TTS (fentanyl), systems were applied to skin sites on the chest, back, and t+l+r arm. No one site of application couid be associated with a higher incidence of side effects or lower efficacy. Zh$xrature Drug permeation through skin is an activated process. The effect of temperature on in vitro transdermal fentanyl flux after system application on cadaver skin was estimated with temperature controlled at 32’ and 37%. Over thii range, drug flux approximately doubled. By interpolation, the transdermal flux at 34.5% was essentiallyidentical to the in vivo flux determined in the bioavailability study.5 Given the doubling of release rate in vitro with a 5% change in temperattIre, an in viva study was conducted in 20 volunteers to determine regional skin-temperature differences under occlusion.6 Transdermal placebo systems were used to occlude lo-cm* areas of skin on the thigh, forearm, back, chest, and postauricular areas. A sensitive thermistor was placed between the skin and the placebo to measure temperature. The data showed the thigh to be the coolest (32.3%) and the postauricular area to be the warmest (34.9%). The back and chest were similar in temperature (33.4%
Occlusive
Backing
Drug Reservoir Rate-controlling Membrane Adhesive Kg. 1. Cross-s&on of a transdcrmal therapeuticsystem(not
Protective Peel Strip
to scale).
Sealed
Edges
vol. PNO.3 (suppl.)April 1992
Systm Functionali& of Tkmsdemal Fentanyl
and 34.3”@, respectively). This study indicates that skin temperature
under occlusion
does not difkr
suffkiently from site to site to cause diirent drug-input rates. Intersubject variability was shown to be minimal, with a coefficient of variation (CV) of 2.6% for the chest.
It is commonly assumed that the dxug-absorption rate is governed by the partition/diEkion
process through the stratum comeum. This is a simplified view of the more complex physiologic situation. Actually, drug absorption is controlled by both drug permeation through skin and blood flow to skin. Although generally blood flow is ignored in percutaneous absorption models, its significance becomes obvious when one considers a hypothetical situation in which blood flow is completely cut off. In this extreme, blood flow clearly would control systemic drug absorption. Therefore, the importance of blood flow to overall systemic fentanyl absorption was evaluated. Both the sldn permeation and the blood-flowdependent drug removal from the skin site are pseudolirst-order rate processes; specifkally, one may view them as two sequential first-order processes. The pseudo-steady-state drug flux is controlled by an apparent first-order rate constant Pa,,p,which is a function of the drug/skin penneabiity Pskn, and the blood flow Q, as given by the following equation:
1 -=-+P
apP
1 Pskin
h
Altman found that the blood supply to a chest-skin site ranges from 0.0122 to 0.0224 The skin-permeability
mL/min/cm’L.7
constant of fentanyl is calcu-
lated to be 0.75 mL/min/cm2.8
Thus, the blood flow
is 60- to 120-fold greater than that of the fentanylpermeability
constant. For practical purposes, there-
fore, skin permeation
governs
the rate of drug
appearance in the systemic circulation, and blood flow to and from the skin site has very little tiuence on the systemic drug-absorption physiological
l&k 2
Eflfect of~aGous G~~&ions on Ste Pentany &sorption Rates
Normal
Blood Flow
rate under normal
conditions.
Because differences among skin sites in thickness could give rise to variations in skin permeability,
s19
Skin flux increased
200 200
200 400
100 133
system increased
400
400
200
Systemrate increased Bothskinand
400
200
133
JW,steady-state rate kom syste.m;Jti,,, maximal rate ofabsorption by the skin;J,,, net transdermal Lntanyl absorption rate.
the challenge is to minimize the effect of such factors on drug input. One successtklapproach has been to vest control over the rate of drug delivery in the dosage form. Shaw and Theeuwesg reported that, for transdermal systems,
L +k = JLt where J_+ = steady-state release rate from system, Jsldn= maximal rate of fentanyl absorption by skin, adJnet= net transdermal fentanyl absorption rate.
The rate of drug release fkomTTS (fentanyl)and the average rate of drug uptake by the skin are approximately equal (about 4 pg/hr/cm2). This indicates that ‘ITS (fentanyl) is 50% rate controlled. Using the method of Shaw and Theeuwesg and knowing the degree of system control and the coefficient of variation of the inherent skiu permeability to fentanyl, one can calculate the theoretical decrease in the coefficient of variation in drug input after a rate-controlled system is applied to the skin. TIYS (fentanyl) delivers fentanyl through skin at a rate determined partially by the system and partially by skin at the application site; the total resistance is divided equally between the membrane and the skin. The CV of skin-fentanyl transport was 44% for 17 different cadaver skin samples. Thus the rate control in the system reduces the drug-transport variation from 44% to 22%. In addition, the control membrane offers the safety feature of limiting drug input. Table 2 lists net permeation rates resulting fkom a twofold increase in either system-delivery rate or skinpermeation rate or both simultaneously.In conclusion, the 50% system control helps dampen the effects on systemic drug input of changes in both fentanyl release rate and the drug’s skin-permeation rates.
Phamacokinetics of TTS (Rentanyl) The average serum fentanyl clearance
value after IV infusion was 46.7 L/hr (CV 49’) and the h&life wzs 6.1 hr.5 Following successive applications of ITS (fentanyl)- 100, the trough fentanyl concentration in plasma was 1.62 ng/mL, and the peak-occurring after 22 hr of application-was 2.6 ng/mL.l” The apparent fentanyl half-life after removal of TTS (fentanyl) was 17 hr, significantly longer than the half-lie after IV infusion, indicating that drug absorption from the skin continued after system removal. After a 24hr application, the average amount of drug released from a TI’S (fentanyl)-100 patch was 3.4 mg of the original IO-mg content. Total drug absorbed was 2.98 mg (92% of dose delivered).
Mathematical Models of lTS (Ewttanyl) The aim of mathematical modeling is to establish a relationship between the in vitro release rate and the serum fentanyl concentrations and to predict serum fentanyl concentrations under various system and physiologic extremes. Modeling the transdermal absorption process is complex, primarily because the serum drug concentration-time proftie following ITS (fentanyl) application is governed by three kinetic processes: drug release from the dosage form to skin, drug absorption from the skin site into the systemic circulation, and drug disposition in the body. To establish a pharmacokinetic model, serum concentratkn data obtained from the bioavailability study conducted in surgical patients were used for this analysk5 In brief, 8 adults undergoing elective major surgery received a single IV fentanyl infusion (750 lig over 5 min) followed by ‘ITS (fentanyl)-100 ug/hr applied 24 hr later. Frequent blood samples wtre collected over 24 hr after the infusion, then during the 24-hr ITS application, and up to 48 hr after ‘ITS removal. Serum fentanyl concentrations were determined using gas chroma-
C(t)
Vol.7,hh. 3 (&#L) April 1992
Guj~t~ et al.
s20
=
tography with mass spectrophotometry (GWMS). In the development of our models, the in vitro release-rate values were 1005, 184, and 114 ug/hr for the time intervals O-2, 2-12, and 12-24 hr, respectively. To establish a mathematical model for fentanyl absorption, the following assumptions were made with respect to the kinetics of drug release from the dosage form and the kinetics of percutaneous absorption: 1. The in vitro release rate is the in vivo release rate, and subjects can have difIerent in vivo extents of absorption. 2. The percutaneous absorption fust-order process.
is assumed to be a
Another factor that sects the modeling is the codelivery of a permeation enhancer, in thii case ethanol. Therefore, the equation for the absorption process should account for the effect of ethanol. The serum fentanyl profile following IV administration exhibits a triexponential disposition function,” and the three exponential terms account for 0.05%, 1.7%, and 98% of area under the curve (AUC); i.e., the first two exponential terms account for only 2% of the total area. Blood samples were collected every 2 hr following ‘ITS (fentanyl) application; therefore, a one-compartment model without the distribution phase was used as an approximation to simplify the equations. Both clearance and volume of distribution at steady state were obtained from the IV fentanyl data. For transdermal fentanyl, the dispositicn was described by first-order absorption and a onecompartment open model. The transdermal absorption-rate constant (Ka) and the lag time (L) were estimated by fitting Equation 1 (Model 1) to the data.
Model 1 In Equation 1 (below), Ke is the elimination-rate constant, Vss is the volume of distribution at steady state, and clearance (CL) equals VspKe. F is the ratio of amount absorbed to in vitro amount released. Bi is the i* in vitro zero-order release rate
+ Rj F &l
(1 - exp’K~@)(expl++L-T”l>
- VspKe
(Kal - Ke)
(I)
til. 7 No. 3 (Suppi.)April 1992
$wkm Fkutionalityof T’ansdermalFentagyl
starting at time Ti for the duration zi,
or
@=t-L-Ti whent-L-Tiszi 6 =%i whent-L-TiiTi
Ethanol is incorporated in the reservoir to enhance drug solubity in the system and drug flux through shin. Thus, fentanyl flux is a function of the ethanol concentration being delivered. Ethanol skin flux is about 500 times greater than fentanyl flux. During TTS (fentanyl)use, the fentanyl fhtx in the presence of ethanol is 4 ug/hr/cm2, tvke the value obtained without ethanol codelivery. It is reasonable to assume that after system removal horn the skin, ethanol will be lost (absorbed and/or evaporated) much more quicldy than fentanyl, and thus the rate of fentanyl absorption from shin to blood will decrease by 50%. To account for the difference in the skin-fentanyl permeation rate in the presence or absence of ethanol in skin, a second model (Model 2) was established with two absorption-rate constants and the lag time. Equation 1 (Model 1) describes the profile from 0 to 24 hr; Equation 2 describes the profile after system remok. Model
2
In Equation 2, hr is the amount remaining in skin to be absorbed at hour 24 and C24 is the concentration in serum at hour 24. Kal and Ka2 are the absorption-rate constants during TTS application (O-24 hr) and postapplication ( > 24 hr), respectively. F is the ratio of amount of fentanyi absorbed following TTS (fentanyl) 24hr application to the amount of fentanyl released in vitro over a 24hr period. The amount of fentanyl absorbed is calculated as a product of fentanyl clearance and the AI_JC(followingTTS application. CpP(t) = C2,.expW+‘Wl cp3(t) _ h4F K& (expWW-2Wl
- exp-Wt-2Wl)
Vss-(Ke-Ka2) Cpost(t) = CpP(t) + CpJ(t)
(2!
AU models were fitted using the nonlinearregression, extended, least-square method. The estimated disposition parameters after fitting IV data are listed in Table 3 and were used as constants while fitting TTS (fentanyl) data. From
S2I
Model 1, the mean absorption-rate constant obtamed from fitting the individualserum concenuations was 0.0896 hr-’ (Table 4). This value corresponds to a half-lifeof8 hr, much shorter than the terminal haNWe of 17 hr observed after TTS (fentanyl)removal. During the nonlinear-regression analysis of he data in Model 2, the slope of the log of serum concentrations measured following TTS removal was used for the Ka2 as constant. Figure 2 displays the mean of the observed and predicted fentanyl concentration-tune data obtained using Model 2. Following ITS application, the mean absorption rate constant during application (Kal) was 0.0782 hr-’ and the mean terminal slope value was 0.0402 hr-I. The ratio of these two rate constants was 1.95 and is similar to the ratio of steady-state fentanyl flux through skin with and without ethanol in the reservoir. Thus, Model 2 seems to be a reasonable mathematical pharmacokinetic model to simUlate the serum fentanyl concentrations.
A complete simulation model combining both in vitro release and pharmacokinetic models also has been developed using computer software cahed STELLA (High Perhormance Systems, NH). Several factors were considered in developing the complete model. Drug-transport processes through shin are best approximated by either the first or the second law of diffi.tsion.”The main drug characteristics that intluence the transfer rate are the partition co&cient and the diffusioncoefficient in the stratum corneum. Other influential factors are the thicknesses of various skin layers, the &ion coefficients through these layers, and the composition of the layers. For most drugs, the ratio of diffusion coefficients through stratum corneum and epi&& is about 1: 1000, and the stratum corneum is perceived as the rate-controlling membrane. In this model, the process of skin absorption was assumed to foilow Fick’s first law of diffusion: dQ= dt
DKpC hr
(3)
where dQ/dt is the rate of skinpenetration, D is the effective diffusion coefficient of drug in stratum corneum, Kp is the partition coefficient of drug between s&r and vehicle, C is the concentration of drug h vehicle, and hr is the effective diffusionpath length.
Vol.7 X0.3 (SupP) A/nil 1992
Guptaet al.
s22
Table3 Pharmacokinetic Parameters Estimated Following Fitting a Triexponential Function to Fentanyl Serum Concentration Data Obtained With a 5-Min IV Infusion Parameter Al A2 A3 Kl (min-‘) K2 (min-‘) K3 (mir-‘) K31 (min-‘) K21 (mill-‘) KlO @in-‘) K12 (min-‘) K13 (min-‘)
vc6)
vss (L) CL (LIhr) MRT (hr)
1
3
2
4
5
Subjectno. 6
7
8
Mean
SD
CV
17.01 23.04 51.40 26.05 42.48 32.66 28.08 16.15 7.74 6.87 61.12 46.75 34.48 46.79 149.62 26.82 37.10 28.35 16.08 20.78 126.23 209.11 59.62 157.82 147.25 155.62 222.01 85.30 224.21 92.80 0.2301 0.4808 0.7742 0.3056 0.5151 0.2934 1.0360 0.2777 0.4544 0.5613 0.0286 0.0131 0.0074 0.0098 0.0126 0.0281 0.0130 0.0845 0.045 1 0.0386 0.0010 0.0013 0.0005 0.0008 0.0008 0.0016 0.0016 0.0027 0.0013 0.0032 0.0045 F.0053 0.0010 0.0018 0.0026 0.0057 0.0076 0.0088 0.0045 0.0136 0.0268 0.0339 0.0378 0.0219 0.0764 0.0772 0.0610 0.2380 0.1144 0.0771 0.0379 0.0523 0.0881 0.0553 0.0563 0.0259 0.0353 0.0885 0.0235 0.0699 0.3545 0.5607 0.1307 0.3039 0.2017 0.4160 0.5385 0.1044 0.2053 0.1210 0.0697 0.0469 0.0963 0.1085 0.1023 0.0746 0.1344 0.0539 0.0587 0.2455 35.27 731.0 74.72 9.78
15.52 330.4 82.48 4.01
22.98 268.8 32.44 8.29
10.52 198.1 44.19 4.48
18.40 285.4 41.84 6.82
6.92 377.2 21.73 17.36
8.09 549.6 42.78 12.84
9.19 446.7 30.51 14.64
15.86 398.4 46.33 9.78
10.28 185.4 22.85 5.156
65.26 99.89 37.77 56.96 102.1 63.85 78.8 101.1 45.95 66.36 68.01 64.80 46.54 49.32 52.74
SD, standard deviation; CV, coefficient of variation; V, volume oI’ccntral compartment; Vss, volume of distribution at steady state; CL, clcarancc ( = Vss x Kc); MRT, mean residence time; A, exponent; K, coellicient.
It is not easy to estimate the variables such as D, Kp, and hr for an individual subject in a clinical study, but for a given formulation and subject, the variables D, Kp, and hr are constant, and Equation 3 can be simplified to a first-order process: Jskc s
_SL= dt
(4)
where Jsk is the skin-drug flux when skin is in contact with a saturated drug solution with concentrations of S and JS,/S equals D Kp/hr, which can be estimated using data from in vitro steadystate skin flux experiments, and C is the concentra-
tion of drug in vehicle. Upon application, the drug from the adhesive diffuses onto skin and subsequently into the body, while drug is released simultaneously from the reservoir to the adhesive layer at a rate controlled by the rate-controlling membrane (maximum, 100-130 pg/hr). This results in an initial decline in fentanyl concentration in the adhesive layer and in the transfer rate from the adhesive to skin until an equilibrium is reached. At steady state, transfer rates from reservoir to adhesive and adhesive to skin are the same. Steady-state release rate from the reservoir to the adhesive layer is 100 ug/hr.
Table4 Transdennal Absorption-Rate Constants (Ktil and KA2), Lag Time, and Residual Sum of Squares (RSS) Estimated by Fitting Both Model 1 and Model 2 to Fentanyl Serum Concentrations for TTS (Fentanyl) Model 2
Model 1 Subject no. I 2 3 4 5 6 7 8 Mean SEM CV
$j
;;
Rss
(PI’)
0.16878 0.06267 0.08199 0.07806 0.05760 0.04453 0.08520 0.13835
2.2 0.8 1.0 1.2 2.5 1.2 3.6 3.0
0.5213 0.5567 1.1492 3.4953 3.8892 3.4908 0.7129 0.5303
0.0966 0.0605 0.0775 0.0928 0.0536 0.0634 0.0891 0.0903
0.08964 0.01502 47.4
1.9 0.4 53.7
1.7932 0.5427
0.0782 0.0059 21.4
=g (hr)
Rss
0.0528 0.037 1 0.0426 0.0410 0.0366 0.0317 0.0420 0.0382
0.10 0.43 0.14 2.70 1.14 0.75 1.45 0.10
0.7823 0.3998 0.6852 3.0802 3.7646 2.3725 0.6193 1.1427
0.0402 0.0022 15.4
0.85 0.32 105.9
1.6059 0.4549
2)
m% tmwkmsl hcmpeuk system; %M, standard error orthe mean; CV, cocffiient ofvariation.
Vol.7 No. 3 (SuppE.) April 1992
Systi Funclionaidyof Transdmnal Fentanyl
2.5
523
r
Fig. 2. Mean predicted and observed serum concentrations of fentany! using a one-compartment model with two absoqtion-rate constants. 0
24
48 Time
Skin is a partial barrier to fentanyl absorption. After system application, the steady-state skin flux of fentanyl is about 100 pg/hr for ‘ITS (fentanyl)100 and is a function of the concentration in the adhesive layer (see Equation 4). Once the drug has permeated through skin, it diffuses into the body, as approximated by a &t-order process and as a function of the presence of ethanol. After TTS (fentanyl) is removed from the skin, the rate of drug absorption declines by about 50%; therefore, the absorption-rate constant from skin to body is presented as a fimction of duration of application. The plasma concentration is calculated from a mean volume of distribution at steady state (Vss) of 398 L. The plasma elimination-rate constant value is 0.1022 hr-‘. The developed physicochemical model was validated by comparing the simulated amount with data from in vitro experiments and finally with the
72
(h)
serum fentanyl concentration profiles achieved in clinical trials. As the fentanyl clearance may vary widely between patients, this model should only be used to predict the relative changes in the variables used in the model. The physicochemical model can be used for predicting relative changes in serum fentanyl concentrations by changing various rate-determining variables such as skin thickness, clearance, and release rate fkom the system.
Variability Due to Mmbrane Z47dm.s Displayed in Figure 3 is the effect of changes in thickness of the rate-controlling membrane. The three serum fentanyl concentration-time profiles shown for TTS (fentanyl) would result if the thickness were at the mean and at the extreme ends of the product component specifications.
Fig. 3. Effect of rate-controlling membrane thickness on concentrations of fentanyl in serumduring72-hr wearing of the transdermai therapeutic system (TTS), TTS (fentanyl)-100. 0
36
108
72 Time
(h)
144
Vol.7 X0.3 (Suppl Agril1992
Guptaet al.
S24
6
F’ig. 4. Effect of skin thickness on serum concentrationsof fentanyl during 72-hr wearing of the transdennal therapeutic system (TX), TTS (fentanyl)-100. 36
72 Time (h)
Average skin thickness on the body (except for certain areas such as palms and soles) is 40 p and ranges between 20 and 80 p, as a function of age, gender, and race. Figure 4 displays the predicted effect of the change in skin thickness alone assuming all other variables remain the same. Clearly, for thinner skin (20 p), serum fentanyl concentrations can increase by 1.5 times; if the system is applied on broken skin, serum fentanyl concentrations can reach five times normal values. A system applied to thicker skin causes the lower and flatter serum fentanyl profile shown.
Vatiability Due toBody Tm~mature As the difhuion process depends on the activa-
tion energy, increasing the temperature will increase the fentanyl permeation rate. The net change will depend on the relative degree of system and skin control. Figure 5 depicts the influence of change in body temperature, assuming the didfusion rate from the system remains unchanged. Increasing the temperature by 3’C is expected to increase C, by 25%.
E$ecct$ Variabilityin Clearance Figure 6 depicts the effect of variability in fentanyl clearance values on serum fentanyl concentrations. The best estimate of the inherent variabiity in fentanyl e&nitration comes from IV infusion data; the CV, by these data, was estimated to be 49%. The magnitude of thii value would lead
Fig. 5. EtIect of body temperature on serum concentrations of feutanyl during 72-br wearing of the transdern& thttapeutic system (ITS), TTS (fentanyl)-100 at 37” or 40%. 0
36
72 Time (h)
vol. 7&o. 3 (Suppl.)April 1992
$Gem
Anctionali~
of T7andmmal
Fenfanyl
s2.5
Law Clearance
d Fig. 6. E&t of clearance on serum concentrations of fentanyl during 72-hr wearing of the nansdermal therapeutic system (TTS), TTS (fentanylj-100. 36
72 Time (h)
one to expect a correspondingly large variation in serum fentanyi concentration-time proties. The variabiity due to the system thus appears minimal compared with the inherent biologic variability due to clearance.
The skin permeability of sites selected for TTS (fentanyl) application, the back and chest, is similar. Because skin temperatures at sites recommended for application of TTS (fentanyl), e.g., upper torso, are similar, the drug-absorption
rates from these
sites will be similar. The intersubject variabiity
in drug-absorption
rate is probably only minimaUy affected by skin-site temperature,
because the temperature
is consistent
among subjects (CV = 2.6o/o). Blood
flow
application
to
and
fkom
the
has little influence
skin sire of
on the rate
of
systemic drug absorption under normal physiologic conditions. The rate-controlled TTS
delivery of fentanyl from the
reduces the variation in skin-drug transport
rate by 50%.
In TIfS
conclusion, (fentauyl)
performance
the serum fentanyl profile for is a net
result
of the system
and drug absorption and elimination.
Thus, variability in ITS
(fentanyl) AUC is the sum
of the variability of each process involved, at least in theory. The CV for the total AUC, 44%
however, was
for TTS (fentanyl). This value is lower than
the 49% CV observed following IV infusion in the same group of subjects. It appears, therefore, that the variability in the TI’S (fentanyl) serum concentrations mainly reflects the variability of fentanyl clearance.
1. Feldman RJ, MAibach HI. Regional variation in percutaneous penetration of ‘*C co&sol in man. J Invest Dermatol 1967;48:181-183. 2. Maibach HI, Feldman RJ, Milby TH, Serat WF. Regional variations in percutaneous penetration in man: pesticides.Arch Euviron Health 197 1;23:208-2 Il. 3. Bartek h$J, LaBudde JA, Maibach HI. Skin penneability iu vivo: comparison in rat, rabbit, pig and man. J Iuvest Dermatol1972;5&114-123. 4. Roy SD, Flynn GL. Transdermal delivery of narcotic a&gcsics: pH, anatomical, and subject iufluences on cutaneous permeability of fentauyl and sufentaniL Pharm Res 1990;7:842-847. 5. VamelJR, Shafer SL, Hwaug SS, Coen PA, Stanski DR Absorption characteristics of transdermaliy admkxistered fentauyL Anaesthesiology 1989;70:928-934. 6. Buckles R, hrberbaum M. The use of insulation to d&e local skin temperature. ALZA Corporation 1972 (data on file). 7. Akman PL, Dittmer DS, eds. Biology data book, 2nd ed. Bethesda, MD: FASEB, 1974;3: 1709. 8. Shaw JE, Chandrasekaran SK. Tmnsdermal therapeutic systems. In: Prescott LF, Nio WS, eds. Drug absorption, proceedings of the international conference on drug absorption, Edinbqh, September 1979. &xlgowlah, Australia: ADIS Press, 1979:186-193.
S26
9. ShawJE, Tbceuwes F. Transdcrmal dosage forms. In: Prescott LF, Nimmo WS, 4s. Rate control in drug therapy. Edinburgh: Churchii Livingstone, 1985:65-70. 10. Portenoy RK, Southam MA, Gupta SK, et al. Transdermal fentanyl for cancer pain: repeated dose
vol.
Gup ef al.
pharmacokinetics. cation).
7 No. 3 (SupP) April 1992
Anesthesiology
(submitted
for pubh-
11. Hadgraft J. Mathematical models of skin absorption, In: Scott RC, Guy RH, Hadgraft J, eds. Prediction of percutaneous penetration: methods, measurements, modelhng. London: IRC Technical Services, 1990:252-262.
Journal of Pain and Symptom
Management SI 7
Suneel K. Gupta, phII, Mary Southam, PhD, Robert Gale, MS, and Stephen S. Hwang, PbD WA
Corporation,PaloAlto, Calijinnia
Abstract Fentanyl is an opioid traditiom@ adminis&& by in&.&n or ipljectionand more recentb in a rate-controlledtransdennal dosageform. E5is systemis afour-hxyer kminate on a protectiveliner. A backing layerseals andprotects the drug resmoir, the sourcefor continuousdeIivq offattanyl. A membrane control the releaserate offk?any/jom the system.An adhesivelaplerattach the~stem to skin and releases an initial loadingdose offmtanyi. ??ze rate offentanyl deLizqvthroughskin ir determinedby the ~stem and the skin at the apphcationsite. Tie release ratejom the ystem is approximatedby Fick’sjrst law of d&.&n and is controlledby the rate-control&g membrane.A camp&e simulationmodel that combines both in vitro rehme data and the pharmacokineticmodelhas been devekped wrd used to show the in@uence of various
physiologic and systemvariableson serumf.&anyi concen&&ons.JPain Symptom Manage
1992;7:Sl7-S26. &?y Words Fentuny4 phannacokinetics, transderma!,~stemjkctionaii~
The transdermal therapeutic system (‘ITS) for fentanyl, TIX (fkntanyl),is a new dosage form that provides a distinctly different regimen and duration of action than the drug’s traditional IM or IV bolus forms. Because ?ITS (fentanyl) presents physicians with additional opportunities for preventing or treating pain in their cancer patients, it is important to understand the system’s functionality and the pharmacokinetics of fentanyl in this dosage form. In this paper, the functionality and phannacokinetics of TTS (fentanyl)are reported brieflyprior to a discussion of the mathematical models developed to predict the serum fentanyl concentrations following system application. Comparisons are provided of potential changes in serum concentration, given Addressreprint requeststa: Suneel Gupta, PhD, ALZA Corporation,950 Page MillRoad, PO Box 10950, Palo Alto, CA 94303-0802. 0 U.S. Cancer Pain Relier Committee, 1992 Published by Elsetier, New York, New York
changes in physiologic and system parameters that influence drug-release rates and systemic drug absorption horn this transdermal dosage form. The quantitative effect of the system’s rate-controlling membrane on drug delivery to minimize drug input variations is described.
ITS (fentanyl)releases fentanyl continuously for 3 days on application to intact skin. Four systems are available to provide delivery rates ranging from 25 to 100 pg/hr (Table 1); higher rates are achievable by multiple-system application. The system (Figure I) is a four-layer laminate on a protective liner. The backing layer, a clear polyester/ethylene film, is heat sealed around the perimeter of the rate-contiolling membrane. This backing provides a physical barrier to prevent loss of fentanyl and excipients. A drug reservoir of fentanyl base dissolved in ethanol and gelled with
0885-3924/92/35.00
Guptnetal.
S18
W. 7&o. 3 (Sup~l.)April1992
Table 1 ITS (Fentanyl)Systems
Nominal delivery rate WW
Dose TTS TTS TTS ITS
(fcntanyl)-25 (fentanyl)-50 (fcntanyQ75 (fcntanyl)-100
25 50 75 100
m,
transdcrmal therapeutic system.
System area (cm?
Total fentanyl content (mg) 2.5 5 7.5 10
10 20 30 40 ---
hydroxyethyl celluloseis the source for continuous, S-day fentanyl delivery. The rate-controlling membrane, an ethylene-vinyl acetate copolymer film, determines the rate of fentanyl release corn the system to the skin surface. A silicone medical adhesive layer permits free passage of the drug, provides effective attachment to skin, and releases the initial loading dose of drug to skin. In the package, a liner protects the adhesive; it is removed before system application. The composition of all systems is identical per unit area (cm*). During manufacture, fentanyl base is incorporated only into the drug reservoir. After manufacture, fentanyl from this source migrates through tbe rate-controlling membrane until the fentanyl concentration in the adhesive reaches an equilibrium with that in the reservoir. Fentanyl in the adhesive is referred to as the loading dose. After equilibration, total fentanyl content of the system sufficesto maintain saturation in the drug reservoir. When the system is applied to skin, the drug partitions from the adhesive into the adhesive/skin interface and begins to diffuse through skin and into the systemic circulation. Initially, the transport rate of drug into the circulation is low, but it increases to a plateau value as a drug-concentration gradient is established across the skin. The preplateau period is called the transport lag time. As drug concentration in the adhesive declines, additional drug diffusesCorn the reservoir through the rate-controlliig membrane into the adhesive.
Regional variation in skinpermeability to certain drugs or chemicals in vivo in animals and humans is well documented.*-3 Roy and Flynn,+ however, reported that for fentanyl the in vitro permeation rate through different skin sites-thigh, abdomen, upper arm, and chest-showed little variation. When in vitro experiments with TTS (fentanyl) were conducted using hip-skin and chest-skin samples from the same subject, similar transdertnal fluxeswere found, suggesting system control. In the clinical trials evaluating the safety, efficacy, and clinical utility of TTS (fentanyl), systems were applied to skin sites on the chest, back, and t+l+r arm. No one site of application couid be associated with a higher incidence of side effects or lower efficacy. Zh$xrature Drug permeation through skin is an activated process. The effect of temperature on in vitro transdermal fentanyl flux after system application on cadaver skin was estimated with temperature controlled at 32’ and 37%. Over thii range, drug flux approximately doubled. By interpolation, the transdermal flux at 34.5% was essentiallyidentical to the in vivo flux determined in the bioavailability study.5 Given the doubling of release rate in vitro with a 5% change in temperattIre, an in viva study was conducted in 20 volunteers to determine regional skin-temperature differences under occlusion.6 Transdermal placebo systems were used to occlude lo-cm* areas of skin on the thigh, forearm, back, chest, and postauricular areas. A sensitive thermistor was placed between the skin and the placebo to measure temperature. The data showed the thigh to be the coolest (32.3%) and the postauricular area to be the warmest (34.9%). The back and chest were similar in temperature (33.4%
Occlusive
Backing
Drug Reservoir Rate-controlling Membrane Adhesive Kg. 1. Cross-s&on of a transdcrmal therapeuticsystem(not
Protective Peel Strip
to scale).
Sealed
Edges
vol. PNO.3 (suppl.)April 1992
Systm Functionali& of Tkmsdemal Fentanyl
and 34.3”@, respectively). This study indicates that skin temperature
under occlusion
does not difkr
suffkiently from site to site to cause diirent drug-input rates. Intersubject variability was shown to be minimal, with a coefficient of variation (CV) of 2.6% for the chest.
It is commonly assumed that the dxug-absorption rate is governed by the partition/diEkion
process through the stratum comeum. This is a simplified view of the more complex physiologic situation. Actually, drug absorption is controlled by both drug permeation through skin and blood flow to skin. Although generally blood flow is ignored in percutaneous absorption models, its significance becomes obvious when one considers a hypothetical situation in which blood flow is completely cut off. In this extreme, blood flow clearly would control systemic drug absorption. Therefore, the importance of blood flow to overall systemic fentanyl absorption was evaluated. Both the sldn permeation and the blood-flowdependent drug removal from the skin site are pseudolirst-order rate processes; specifkally, one may view them as two sequential first-order processes. The pseudo-steady-state drug flux is controlled by an apparent first-order rate constant Pa,,p,which is a function of the drug/skin penneabiity Pskn, and the blood flow Q, as given by the following equation:
1 -=-+P
apP
1 Pskin
h
Altman found that the blood supply to a chest-skin site ranges from 0.0122 to 0.0224 The skin-permeability
mL/min/cm’L.7
constant of fentanyl is calcu-
lated to be 0.75 mL/min/cm2.8
Thus, the blood flow
is 60- to 120-fold greater than that of the fentanylpermeability
constant. For practical purposes, there-
fore, skin permeation
governs
the rate of drug
appearance in the systemic circulation, and blood flow to and from the skin site has very little tiuence on the systemic drug-absorption physiological
l&k 2
Eflfect of~aGous G~~&ions on Ste Pentany &sorption Rates
Normal
Blood Flow
rate under normal
conditions.
Because differences among skin sites in thickness could give rise to variations in skin permeability,
s19
Skin flux increased
200 200
200 400
100 133
system increased
400
400
200
Systemrate increased Bothskinand
400
200
133
JW,steady-state rate kom syste.m;Jti,,, maximal rate ofabsorption by the skin;J,,, net transdermal Lntanyl absorption rate.
the challenge is to minimize the effect of such factors on drug input. One successtklapproach has been to vest control over the rate of drug delivery in the dosage form. Shaw and Theeuwesg reported that, for transdermal systems,
L +k = JLt where J_+ = steady-state release rate from system, Jsldn= maximal rate of fentanyl absorption by skin, adJnet= net transdermal fentanyl absorption rate.
The rate of drug release fkomTTS (fentanyl)and the average rate of drug uptake by the skin are approximately equal (about 4 pg/hr/cm2). This indicates that ‘ITS (fentanyl) is 50% rate controlled. Using the method of Shaw and Theeuwesg and knowing the degree of system control and the coefficient of variation of the inherent skiu permeability to fentanyl, one can calculate the theoretical decrease in the coefficient of variation in drug input after a rate-controlled system is applied to the skin. TIYS (fentanyl) delivers fentanyl through skin at a rate determined partially by the system and partially by skin at the application site; the total resistance is divided equally between the membrane and the skin. The CV of skin-fentanyl transport was 44% for 17 different cadaver skin samples. Thus the rate control in the system reduces the drug-transport variation from 44% to 22%. In addition, the control membrane offers the safety feature of limiting drug input. Table 2 lists net permeation rates resulting fkom a twofold increase in either system-delivery rate or skinpermeation rate or both simultaneously.In conclusion, the 50% system control helps dampen the effects on systemic drug input of changes in both fentanyl release rate and the drug’s skin-permeation rates.
Phamacokinetics of TTS (Rentanyl) The average serum fentanyl clearance
value after IV infusion was 46.7 L/hr (CV 49’) and the h&life wzs 6.1 hr.5 Following successive applications of ITS (fentanyl)- 100, the trough fentanyl concentration in plasma was 1.62 ng/mL, and the peak-occurring after 22 hr of application-was 2.6 ng/mL.l” The apparent fentanyl half-life after removal of TTS (fentanyl) was 17 hr, significantly longer than the half-lie after IV infusion, indicating that drug absorption from the skin continued after system removal. After a 24hr application, the average amount of drug released from a TI’S (fentanyl)-100 patch was 3.4 mg of the original IO-mg content. Total drug absorbed was 2.98 mg (92% of dose delivered).
Mathematical Models of lTS (Ewttanyl) The aim of mathematical modeling is to establish a relationship between the in vitro release rate and the serum fentanyl concentrations and to predict serum fentanyl concentrations under various system and physiologic extremes. Modeling the transdermal absorption process is complex, primarily because the serum drug concentration-time proftie following ITS (fentanyl) application is governed by three kinetic processes: drug release from the dosage form to skin, drug absorption from the skin site into the systemic circulation, and drug disposition in the body. To establish a pharmacokinetic model, serum concentratkn data obtained from the bioavailability study conducted in surgical patients were used for this analysk5 In brief, 8 adults undergoing elective major surgery received a single IV fentanyl infusion (750 lig over 5 min) followed by ‘ITS (fentanyl)-100 ug/hr applied 24 hr later. Frequent blood samples wtre collected over 24 hr after the infusion, then during the 24-hr ITS application, and up to 48 hr after ‘ITS removal. Serum fentanyl concentrations were determined using gas chroma-
C(t)
Vol.7,hh. 3 (&#L) April 1992
Guj~t~ et al.
s20
=
tography with mass spectrophotometry (GWMS). In the development of our models, the in vitro release-rate values were 1005, 184, and 114 ug/hr for the time intervals O-2, 2-12, and 12-24 hr, respectively. To establish a mathematical model for fentanyl absorption, the following assumptions were made with respect to the kinetics of drug release from the dosage form and the kinetics of percutaneous absorption: 1. The in vitro release rate is the in vivo release rate, and subjects can have difIerent in vivo extents of absorption. 2. The percutaneous absorption fust-order process.
is assumed to be a
Another factor that sects the modeling is the codelivery of a permeation enhancer, in thii case ethanol. Therefore, the equation for the absorption process should account for the effect of ethanol. The serum fentanyl profile following IV administration exhibits a triexponential disposition function,” and the three exponential terms account for 0.05%, 1.7%, and 98% of area under the curve (AUC); i.e., the first two exponential terms account for only 2% of the total area. Blood samples were collected every 2 hr following ‘ITS (fentanyl) application; therefore, a one-compartment model without the distribution phase was used as an approximation to simplify the equations. Both clearance and volume of distribution at steady state were obtained from the IV fentanyl data. For transdermal fentanyl, the dispositicn was described by first-order absorption and a onecompartment open model. The transdermal absorption-rate constant (Ka) and the lag time (L) were estimated by fitting Equation 1 (Model 1) to the data.
Model 1 In Equation 1 (below), Ke is the elimination-rate constant, Vss is the volume of distribution at steady state, and clearance (CL) equals VspKe. F is the ratio of amount absorbed to in vitro amount released. Bi is the i* in vitro zero-order release rate
+ Rj F &l
(1 - exp’K~@)(expl++L-T”l>
- VspKe
(Kal - Ke)
(I)
til. 7 No. 3 (Suppi.)April 1992
$wkm Fkutionalityof T’ansdermalFentagyl
starting at time Ti for the duration zi,
or
@=t-L-Ti whent-L-Tiszi 6 =%i whent-L-TiiTi
Ethanol is incorporated in the reservoir to enhance drug solubity in the system and drug flux through shin. Thus, fentanyl flux is a function of the ethanol concentration being delivered. Ethanol skin flux is about 500 times greater than fentanyl flux. During TTS (fentanyl)use, the fentanyl fhtx in the presence of ethanol is 4 ug/hr/cm2, tvke the value obtained without ethanol codelivery. It is reasonable to assume that after system removal horn the skin, ethanol will be lost (absorbed and/or evaporated) much more quicldy than fentanyl, and thus the rate of fentanyl absorption from shin to blood will decrease by 50%. To account for the difference in the skin-fentanyl permeation rate in the presence or absence of ethanol in skin, a second model (Model 2) was established with two absorption-rate constants and the lag time. Equation 1 (Model 1) describes the profile from 0 to 24 hr; Equation 2 describes the profile after system remok. Model
2
In Equation 2, hr is the amount remaining in skin to be absorbed at hour 24 and C24 is the concentration in serum at hour 24. Kal and Ka2 are the absorption-rate constants during TTS application (O-24 hr) and postapplication ( > 24 hr), respectively. F is the ratio of amount of fentanyi absorbed following TTS (fentanyl) 24hr application to the amount of fentanyl released in vitro over a 24hr period. The amount of fentanyl absorbed is calculated as a product of fentanyl clearance and the AI_JC(followingTTS application. CpP(t) = C2,.expW+‘Wl cp3(t) _ h4F K& (expWW-2Wl
- exp-Wt-2Wl)
Vss-(Ke-Ka2) Cpost(t) = CpP(t) + CpJ(t)
(2!
AU models were fitted using the nonlinearregression, extended, least-square method. The estimated disposition parameters after fitting IV data are listed in Table 3 and were used as constants while fitting TTS (fentanyl) data. From
S2I
Model 1, the mean absorption-rate constant obtamed from fitting the individualserum concenuations was 0.0896 hr-’ (Table 4). This value corresponds to a half-lifeof8 hr, much shorter than the terminal haNWe of 17 hr observed after TTS (fentanyl)removal. During the nonlinear-regression analysis of he data in Model 2, the slope of the log of serum concentrations measured following TTS removal was used for the Ka2 as constant. Figure 2 displays the mean of the observed and predicted fentanyl concentration-tune data obtained using Model 2. Following ITS application, the mean absorption rate constant during application (Kal) was 0.0782 hr-’ and the mean terminal slope value was 0.0402 hr-I. The ratio of these two rate constants was 1.95 and is similar to the ratio of steady-state fentanyl flux through skin with and without ethanol in the reservoir. Thus, Model 2 seems to be a reasonable mathematical pharmacokinetic model to simUlate the serum fentanyl concentrations.
A complete simulation model combining both in vitro release and pharmacokinetic models also has been developed using computer software cahed STELLA (High Perhormance Systems, NH). Several factors were considered in developing the complete model. Drug-transport processes through shin are best approximated by either the first or the second law of diffi.tsion.”The main drug characteristics that intluence the transfer rate are the partition co&cient and the diffusioncoefficient in the stratum corneum. Other influential factors are the thicknesses of various skin layers, the &ion coefficients through these layers, and the composition of the layers. For most drugs, the ratio of diffusion coefficients through stratum corneum and epi&& is about 1: 1000, and the stratum corneum is perceived as the rate-controlling membrane. In this model, the process of skin absorption was assumed to foilow Fick’s first law of diffusion: dQ= dt
DKpC hr
(3)
where dQ/dt is the rate of skinpenetration, D is the effective diffusion coefficient of drug in stratum corneum, Kp is the partition coefficient of drug between s&r and vehicle, C is the concentration of drug h vehicle, and hr is the effective diffusionpath length.
Vol.7 X0.3 (SupP) A/nil 1992
Guptaet al.
s22
Table3 Pharmacokinetic Parameters Estimated Following Fitting a Triexponential Function to Fentanyl Serum Concentration Data Obtained With a 5-Min IV Infusion Parameter Al A2 A3 Kl (min-‘) K2 (min-‘) K3 (mir-‘) K31 (min-‘) K21 (mill-‘) KlO @in-‘) K12 (min-‘) K13 (min-‘)
vc6)
vss (L) CL (LIhr) MRT (hr)
1
3
2
4
5
Subjectno. 6
7
8
Mean
SD
CV
17.01 23.04 51.40 26.05 42.48 32.66 28.08 16.15 7.74 6.87 61.12 46.75 34.48 46.79 149.62 26.82 37.10 28.35 16.08 20.78 126.23 209.11 59.62 157.82 147.25 155.62 222.01 85.30 224.21 92.80 0.2301 0.4808 0.7742 0.3056 0.5151 0.2934 1.0360 0.2777 0.4544 0.5613 0.0286 0.0131 0.0074 0.0098 0.0126 0.0281 0.0130 0.0845 0.045 1 0.0386 0.0010 0.0013 0.0005 0.0008 0.0008 0.0016 0.0016 0.0027 0.0013 0.0032 0.0045 F.0053 0.0010 0.0018 0.0026 0.0057 0.0076 0.0088 0.0045 0.0136 0.0268 0.0339 0.0378 0.0219 0.0764 0.0772 0.0610 0.2380 0.1144 0.0771 0.0379 0.0523 0.0881 0.0553 0.0563 0.0259 0.0353 0.0885 0.0235 0.0699 0.3545 0.5607 0.1307 0.3039 0.2017 0.4160 0.5385 0.1044 0.2053 0.1210 0.0697 0.0469 0.0963 0.1085 0.1023 0.0746 0.1344 0.0539 0.0587 0.2455 35.27 731.0 74.72 9.78
15.52 330.4 82.48 4.01
22.98 268.8 32.44 8.29
10.52 198.1 44.19 4.48
18.40 285.4 41.84 6.82
6.92 377.2 21.73 17.36
8.09 549.6 42.78 12.84
9.19 446.7 30.51 14.64
15.86 398.4 46.33 9.78
10.28 185.4 22.85 5.156
65.26 99.89 37.77 56.96 102.1 63.85 78.8 101.1 45.95 66.36 68.01 64.80 46.54 49.32 52.74
SD, standard deviation; CV, coefficient of variation; V, volume oI’ccntral compartment; Vss, volume of distribution at steady state; CL, clcarancc ( = Vss x Kc); MRT, mean residence time; A, exponent; K, coellicient.
It is not easy to estimate the variables such as D, Kp, and hr for an individual subject in a clinical study, but for a given formulation and subject, the variables D, Kp, and hr are constant, and Equation 3 can be simplified to a first-order process: Jskc s
_SL= dt
(4)
where Jsk is the skin-drug flux when skin is in contact with a saturated drug solution with concentrations of S and JS,/S equals D Kp/hr, which can be estimated using data from in vitro steadystate skin flux experiments, and C is the concentra-
tion of drug in vehicle. Upon application, the drug from the adhesive diffuses onto skin and subsequently into the body, while drug is released simultaneously from the reservoir to the adhesive layer at a rate controlled by the rate-controlling membrane (maximum, 100-130 pg/hr). This results in an initial decline in fentanyl concentration in the adhesive layer and in the transfer rate from the adhesive to skin until an equilibrium is reached. At steady state, transfer rates from reservoir to adhesive and adhesive to skin are the same. Steady-state release rate from the reservoir to the adhesive layer is 100 ug/hr.
Table4 Transdennal Absorption-Rate Constants (Ktil and KA2), Lag Time, and Residual Sum of Squares (RSS) Estimated by Fitting Both Model 1 and Model 2 to Fentanyl Serum Concentrations for TTS (Fentanyl) Model 2
Model 1 Subject no. I 2 3 4 5 6 7 8 Mean SEM CV
$j
;;
Rss
(PI’)
0.16878 0.06267 0.08199 0.07806 0.05760 0.04453 0.08520 0.13835
2.2 0.8 1.0 1.2 2.5 1.2 3.6 3.0
0.5213 0.5567 1.1492 3.4953 3.8892 3.4908 0.7129 0.5303
0.0966 0.0605 0.0775 0.0928 0.0536 0.0634 0.0891 0.0903
0.08964 0.01502 47.4
1.9 0.4 53.7
1.7932 0.5427
0.0782 0.0059 21.4
=g (hr)
Rss
0.0528 0.037 1 0.0426 0.0410 0.0366 0.0317 0.0420 0.0382
0.10 0.43 0.14 2.70 1.14 0.75 1.45 0.10
0.7823 0.3998 0.6852 3.0802 3.7646 2.3725 0.6193 1.1427
0.0402 0.0022 15.4
0.85 0.32 105.9
1.6059 0.4549
2)
m% tmwkmsl hcmpeuk system; %M, standard error orthe mean; CV, cocffiient ofvariation.
Vol.7 No. 3 (SuppE.) April 1992
Systi Funclionaidyof Transdmnal Fentanyl
2.5
523
r
Fig. 2. Mean predicted and observed serum concentrations of fentany! using a one-compartment model with two absoqtion-rate constants. 0
24
48 Time
Skin is a partial barrier to fentanyl absorption. After system application, the steady-state skin flux of fentanyl is about 100 pg/hr for ‘ITS (fentanyl)100 and is a function of the concentration in the adhesive layer (see Equation 4). Once the drug has permeated through skin, it diffuses into the body, as approximated by a &t-order process and as a function of the presence of ethanol. After TTS (fentanyl) is removed from the skin, the rate of drug absorption declines by about 50%; therefore, the absorption-rate constant from skin to body is presented as a fimction of duration of application. The plasma concentration is calculated from a mean volume of distribution at steady state (Vss) of 398 L. The plasma elimination-rate constant value is 0.1022 hr-‘. The developed physicochemical model was validated by comparing the simulated amount with data from in vitro experiments and finally with the
72
(h)
serum fentanyl concentration profiles achieved in clinical trials. As the fentanyl clearance may vary widely between patients, this model should only be used to predict the relative changes in the variables used in the model. The physicochemical model can be used for predicting relative changes in serum fentanyl concentrations by changing various rate-determining variables such as skin thickness, clearance, and release rate fkom the system.
Variability Due to Mmbrane Z47dm.s Displayed in Figure 3 is the effect of changes in thickness of the rate-controlling membrane. The three serum fentanyl concentration-time profiles shown for TTS (fentanyl) would result if the thickness were at the mean and at the extreme ends of the product component specifications.
Fig. 3. Effect of rate-controlling membrane thickness on concentrations of fentanyl in serumduring72-hr wearing of the transdermai therapeutic system (TTS), TTS (fentanyl)-100. 0
36
108
72 Time
(h)
144
Vol.7 X0.3 (Suppl Agril1992
Guptaet al.
S24
6
F’ig. 4. Effect of skin thickness on serum concentrationsof fentanyl during 72-hr wearing of the transdennal therapeutic system (TX), TTS (fentanyl)-100. 36
72 Time (h)
Average skin thickness on the body (except for certain areas such as palms and soles) is 40 p and ranges between 20 and 80 p, as a function of age, gender, and race. Figure 4 displays the predicted effect of the change in skin thickness alone assuming all other variables remain the same. Clearly, for thinner skin (20 p), serum fentanyl concentrations can increase by 1.5 times; if the system is applied on broken skin, serum fentanyl concentrations can reach five times normal values. A system applied to thicker skin causes the lower and flatter serum fentanyl profile shown.
Vatiability Due toBody Tm~mature As the difhuion process depends on the activa-
tion energy, increasing the temperature will increase the fentanyl permeation rate. The net change will depend on the relative degree of system and skin control. Figure 5 depicts the influence of change in body temperature, assuming the didfusion rate from the system remains unchanged. Increasing the temperature by 3’C is expected to increase C, by 25%.
E$ecct$ Variabilityin Clearance Figure 6 depicts the effect of variability in fentanyl clearance values on serum fentanyl concentrations. The best estimate of the inherent variabiity in fentanyl e&nitration comes from IV infusion data; the CV, by these data, was estimated to be 49%. The magnitude of thii value would lead
Fig. 5. EtIect of body temperature on serum concentrations of feutanyl during 72-br wearing of the transdern& thttapeutic system (ITS), TTS (fentanyl)-100 at 37” or 40%. 0
36
72 Time (h)
vol. 7&o. 3 (Suppl.)April 1992
$Gem
Anctionali~
of T7andmmal
Fenfanyl
s2.5
Law Clearance
d Fig. 6. E&t of clearance on serum concentrations of fentanyl during 72-hr wearing of the nansdermal therapeutic system (TTS), TTS (fentanylj-100. 36
72 Time (h)
one to expect a correspondingly large variation in serum fentanyi concentration-time proties. The variabiity due to the system thus appears minimal compared with the inherent biologic variability due to clearance.
The skin permeability of sites selected for TTS (fentanyl) application, the back and chest, is similar. Because skin temperatures at sites recommended for application of TTS (fentanyl), e.g., upper torso, are similar, the drug-absorption
rates from these
sites will be similar. The intersubject variabiity
in drug-absorption
rate is probably only minimaUy affected by skin-site temperature,
because the temperature
is consistent
among subjects (CV = 2.6o/o). Blood
flow
application
to
and
fkom
the
has little influence
skin sire of
on the rate
of
systemic drug absorption under normal physiologic conditions. The rate-controlled TTS
delivery of fentanyl from the
reduces the variation in skin-drug transport
rate by 50%.
In TIfS
conclusion, (fentauyl)
performance
the serum fentanyl profile for is a net
result
of the system
and drug absorption and elimination.
Thus, variability in ITS
(fentanyl) AUC is the sum
of the variability of each process involved, at least in theory. The CV for the total AUC, 44%
however, was
for TTS (fentanyl). This value is lower than
the 49% CV observed following IV infusion in the same group of subjects. It appears, therefore, that the variability in the TI’S (fentanyl) serum concentrations mainly reflects the variability of fentanyl clearance.
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