Fentanyl HCl Patient-Controlled Iontophoretic Transdermal System for Pain: Pharmacology

 

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Pharmacology

The IONSYS PCITS contains the analgesic fentanyl HCl in its reservoir. Fentanyl is a synthetic narcotic agonist formulated by Janssen Pharmaceutica during the 1950s in response to the need for an opiate with improved efficacy and fewer adverse effects than morphine and meperidine.[21-23] Clinical researchers sought an alternative product that could be administered intramuscularly or intravenously in the postoperative setting.

The empirical formula of parenteral fentanyl hydrochloride is C22H28N2O•HCl and is known as propanamide, N-phenyl-N-[1-(2 phenylethyl)-4-piperidinyl] monohydrochloride by the IUPAC nomenclature system.[24] The primary indications for use of fentanyl are analgesia and sedation.

The mechanism of action of fentanyl is best described by its agonist interaction with the opioid µ-receptor. These sites of interaction are primarily distributed throughout the central nervous system via the brain, spinal cord, and other tissues. As a lipophilic compound, the central nervous system penetrability of fentanyl is 100 times greater than that of morphine.[19] Fentanyl also possesses less of an emetogenic potential and weaker allergenic (histamine mediated) activity compared with that of morphine or meperidine.

A 3 compartment model may be used to describe the pharmacokinetics of fentanyl.[25,26] The distribution time of 6 minutes, redistribution time of 60 minutes, and terminal elimination half-life of 16 hours are characteristic parameters.[24] As the ionization of fentanyl increases, the plasma protein binding capacity (80-86%) also increases.[27] Manipulations in pH determine distribution of the drug between the central nervous system and plasma compartments. Fentanyl accumulates in adipose tissue and skeletal muscle and is then discharged slowly into the bloodstream. Intravenous administration permits increased concentrations in highly perfused tissues such as the kidneys, lungs, spleen, heart, and brain.

The primary metabolism of fentanyl occurs in the liver via the CYP3A4 isoenzyme with high first-pass clearance.[28] Hepatic N-dealkylation converts fentanyl to norfentanyl, its primary metabolite. This metabolite and other metabolites have minimal pharmacologic activity and are excreted in the urine and bile. Approximately 75% of an intravenous dose is released in the urine as metabolites with less than 10% unchanged drug. Fecal matter may contain 9% of the drug as metabolites. Hemodialysis with high-flux membranes or high-efficiency membranes does not remove a significant portion of fentanyl.[29,30] This is not unexpected, since fentanyl possesses high protein binding, low water solubility, and a large volume of distribution.

Intravenous administration of fentanyl results in nearly immediate onset of drug effects. The time to drug onset varies according to the route of administration: intramuscular, 7-8 minutes; oral transmucosal, 5-15 minutes; and passive transdermal, 12-24 hours.[31] The analgesic duration of action is 30-60 minutes after a single 100 µg intravenous dose, 1-2 hours after intramuscular administration, and 72 hours following transdermal application.

 
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References

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Table 1. Summation of Pharmacokinetic Results of Fentanyl HCl PCITS[39],a

Parameter Dosing Interval
Fentanyl PCITS
25 µg (study I)		 2 sequential doses/h for 23.33 h 6 sequential doses every 3 h for 22 h 72 continuous doses over 12 h  
pts. (n) 25 25 25
Cmax (µg/L) 0.86 (0.30) 0.97 (0.23) 1.32 (0.31)
tmax (h) 23.11 (1.69) 22.04 (0.19) 10.56 (1.44)
t1/2 (h)     15.3 (12.0)
AUCn b (µg·h/L) 0.598 0.584 0.502
Fentanyl PCITS
40 µg (study II)		 2 sequential doses/h for 23.33 h 6 sequential doses every 3 h for 10 h 80 continuous doses over 13.33 h  
pts. (n) 23 23 23
Cmax (µg/L) 1.30 (0.30) 0.91 (0.39) 1.94 (0.43)
tmax (h) 22.74 (1.46) 10.07 (0.69) 12.11 (1.24)
t1/2 (h) 16.1 (5.5) 15.1 (7.4) 22.00 (10.0)
AUCn b (µg·h/L) 0.57 0.43 0.51
Fentanyl PCITS
40 µg (study III)		 6 continuous doses over 1 h 18 continuous doses over 3 h 36 continuous doses over 6 h 80 continuous doses over 13.33 h
pts. (n) 20 20 20 20
Cmax (µg/L) 0.27 (0.18) 0.72 (0.20) 1.08 (0.48) 2.00 (1.24)
tmax (h) 1.86 (1.79) 3.45 (0.33) 6.12 (0.68) 13.00 (1.93)
t1/2 (h) 19.2 (6.0) 10.5 (2.5) 10.4 (4.6) 20.5 (7.2)
AUCn b (µg·h/L) 0.23 0.32 0.36 0.5

 

AUCn = area under the serum concentration-time curve; Cmax = peak serum concentration; PCITS = patient-controlled iontophoretic transdermal system; t1/2 = half-life; tmax = time to Cmax
a Mean (SD)
b AUCn represents the AUC for a single dose and is calculated by dividing the AUC (either AUC or AUC during last dosing interval, depending on the study) by the number of doses administered

 

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Authors and Disclosures

Stacey Mayes, PharmD MS, Emergency Department Clinical Pharmacist, Baptist Medical Center Downtown and Wolfson Children's Hospital, Jacksonville, FL

Marcus Ferrone, PharmD BCNSP, Director, Drug Products Services Laboratory; Assistant Professor of Clinical Pharmacy, Department of Clinical Pharmacy, University of California, San Francisco, CA

 

 
 
 
 
 
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