Stephen S. Hwang

System functionality and physicochemical model of fentanyl transdermal system

Fentanyl is an opioid traditionally administered by infusion or injection and more recently in a rate-controlled transdermal dosage form. This system is a four-layer laminate on a protective liner. A backing layer seals and protects the drug reservoir, the source for continuous delivery of fentanyl. A membrane controls the release rate of fentanyl from the system. An adhesive layer attaches the system to skin and releases an initial loading dose of fentanyl. The rate of fentanyl delivery through skin is determined by the system and the skin at the application site. The release rate from the system is approximated by Ficks first law of diffusion and is controlled by the rate-controlling membrane. A complete simulation model that combines both in vitro release data and the pharmacokinetic model has been developed and used to show the influence of various physiologic and system variables on serum fentanyl concentrations.

Testosterone Pharmacokinetics after Application of an Investigational Transdermal System in Hypogonadal Men

This open‐label, randomized, placebo lead‐in, three‐treatment crossover study in 19 hypogonadal men (27–82 years of age) evaluated dose proportionality of serum testosterone concentrations with application of one or two investigational transdermal testosterone systems for application to the arm or torso. Testosterone in vivo kinetics profiles were determined using DeMonS, a recently developed numerical deconvolution method that estimates drug absorption at different time intervals and/or drug disposition model parameters. After application of the investigational transdermal systems, the mean serum testosterone, dihydrotestosterone, estradiol, and free testosterone concentrations were elevated to normal levels. Treatment allowed approximation of the normal circadian pattern of endogenous testosterone secretion, and the increase in serum testosterone concentrations was proportional to the surface area of systems applied. The investigational transdermal system provided effective testosterone replacement therapy as judged by pharmacokinetic parameters.

Effects of Application Site and Subject Demographics on the Pharmacokinetics of Fentanyl HCl Patient-Controlled Transdermal System (PCTS)

AbstractIntroduction: The fentanyl HCl patient-controlled transdermal system (PCTS) is a self-contained, preprogrammed, needle-free system currently in development for acute pain management in a medically supervised setting. The objectives of these studies were to evaluate skin application sites for the fentanyl HCl PCTS and to evaluate the effect of patient demographics on its pharmacokinetics. Methods: The first study was a randomised, open-label, single-centre, 3-treatment, crossover study in which the fentanyl HCl PCTS was applied to the upper outer arm, lower inner arm or chest of healthy volunteers. Fentanyl 25μg was then delivered via this system twice during the first 20 minutes of every hour for 24 hours. The pharmacokinetics of fentanyl were determined and analysed for each application site using ANOVA. The second study was a nonrandomised, nonblind, multicentre, sequential treatment study. Healthy volunteers received fentanyl HCl 40μg via the PCTS three times during the first 30 minutes of each hour for 3 hours. After a 5- to 10-day washout period, fentanyl HCl 120μg was administered intravenously during the first 30 minutes of each hour for 3 hours as a reference treatment. Pharmacokinetic parameters were determined for the fentanyl HCl PCTS, and results were analysed using ANOVA. Safety and tolerability were evaluated in both studies. Results: Application of the system to the upper outer arm or chest resulted in similar maximum serum concentrations (Cmax; 1.193 and 1.176 μg/L, respectively) and areas under the serum concentration-time curve (AUC24–25; 1.033 and 1.015 μg · h/L). However, both Cmax and AUC24-25 were less when the system was applied to the lower inner arm (0.859 μg/L and 0.757 μg · h/L). Subject age, bodyweight, sex and ethnicity had no significant effect on pharmacokinetic parameters. No serious adverse events were reported in either study during or after administration of the fentanyl HCl PCTS. Conclusion: Fentanyl HCl is comparably absorbed from the PCTS when it is applied to the upper outer arm or chest. The pharmacokinetics of fentanyl HCl delivered by the PCTS are unaffected by sex, age, race or weight.

Pharmacokinetics of sublingual sufentanil tablets and efficacy and safety in the management of postoperative pain.

Background and Objectives A sublingual sufentanil tablet is being developed as a potential alternative to intravenous (IV) opioids for the management of postoperative pain. The objective of these studies was to evaluate the pharmacokinetics, efficacy, and safety of sublingual sufentanil tablets for postoperative pain management. Methods The pharmacokinetics of sublingual sufentanil 10 and 80 µg were compared with IV sufentanil in 12 subjects in a phase 1 study. The safety and efficacy of sublingual sufentanil (5–15 µg) were evaluated in double-blind, randomized, placebo-controlled phase 2 studies in patients undergoing knee replacement surgery (n = 101) or open abdominal (ABD) surgery (n = 94). The primary efficacy measurement was the summed pain intensity difference compared with baseline over 12 hours (SPID-12). Results Sublingual sufentanil pharmacokinetics were dose proportional following single doses of 10 and 80 µg. Plasma half-time (time from peak plasma concentration to 50% of peak concentration) was 80 to 90 minutes for sublingual sufentanil compared with 15 minutes or less for IV sufentanil. In the phase 2 studies, greater SPID-12 scores (ie, lower pain intensity) compared with placebo were observed for sublingual sufentanil 15 µg in the knee replacement study (P < 0.05) and for 10 and 15 µg in the ABD study (P < 0.01). All doses of sublingual sufentanil were well tolerated, and the incidence of adverse events was similar between the sublingual sufentanil and placebo groups. Conclusions Sufentanil formulated as a sublingual solid dosage form provides a duration of action that allows effective analgesia for postoperative patients in a medically supervised setting.

Transdermal Testosterone Administration in Hypogonadal Men: Comparison of Pharmacokinetics at Different Sites of Application and at the First and Fifth Days of Application

In this study of 13 hypogonadal men (25–69 years of age), three open‐label, randomized treatments were administered to determine the pharmacokinetics of serum testosterone after application of an investigational testosterone transdermal system to the upper buttocks, upper arm, and back. Testosterone in vivo input kinetics profiles were estimated by DeMonS, a recently developed numerical deconvolution method for estimating drug absorption at different time intervals and/or drug disposition model parameters, and compared on the first and fifth days of system application. Area under the concentration‐time curve from 0 to 27 hours (AUC0–27) values for testosterone after one‐day applications to the upper buttocks, upper arm, and back were 9,560 ng · hr/dL, 8,651 ng · hr/dL, and 8,988 ng · hr/dL, respectively. Maximum observed concentration (Cmax) values were 482 ng/dL, 462 ng/dL, and 499 ng/dL, respectively. Serum testosterone concentrations were equivalent to each other, and Cmax values fell within the normal range. No drug accumulation was seen with repeated dosing over 5 days.

In Vitro and In Vivo Evaluation of a Once-Daily Controlled-Release Pseudoephedrine Product

The functionality of a once‐daily, osmotic dosage form—gastrointestinal therapeutic system (pseudoephedrine HCl) or GITS (PeHCl)—was studied in vitro and in vivo. The in vitro release profiles were close to identical from pH 1 to 7.5 and between USP apparatus 2 and 7, independent of paddle speeds from 50 to 200 rpm; GITS also released drug at the normal rate in aqueous media after incubation in bile salts or fatty media. Both strengths of GITS (PeHCl)—240 and 120 mg—were then compared with a commercially available pseudoephedrine solution given every 6 hours and a timed‐release 12‐hour pseudoephedrine capsule given every 12 hours in a randomized 4‐way crossover study in 24 healthy men. All four formulations were equivalent in total drug absorbed. Both GITS treatments had AUCinf values equivalent to those of PeHCl solution and capsules, and Cmax values equivalent to PeHCl capsules. Cmax for GITS and capsule treatments were each significantly lower than for solution, but the differences were small (14–17%). A one‐to‐one correlation was shown between rate of absorption and in vitro release profiles for the GITS products, indicating that drug release from GITS controls absorption. Insensitivity to conditions of in vivo release accounts for the close in vitro/in vivo correlation of release rates. In a second randomized crossover trial (12 men), the effect of a high‐fat breakfast on GITS performance was evaluated. Mean pseudoephedrine concentrations in plasma were close to identical with or without the breakfast, and the treatments were bioequivalent. The validity of the in vitro/in vivo correlation was confirmed in a bioequivalence study in which GITS with similar in vitro release rate profiles, but manufactured under different conditions (batch size, quantitative core composition, manufacturing equipment, and manufacturing site), were shown to be bioequivalent.

Comparison of Plasma Nicotine Concentrations After Application of Nicoderm (Nicotine Transdermal System) to Different Skin Sites

Drug absorption through the skin can vary according to the application site. The nicotine transdermal system, Nicoderm (Alza Corp., Palo Alto, CA) contains a rate‐controlling membrane designed to regulate delivery of nicotine to the skin and thus limit variability in nicotine plasma levels. Plasma nicotine concentrations were compared after application of NTS 14 mg/day to three different skin sites (upper back, upper outer arm, upper chest) in a randomized, crossover study involving 12 healthy male smokers. Plasma nicotine proxies from ail three sites were similar: nicotine concentrations increased rapidly within 2 to 4 hours, reached broad peaks of approximately 11 to 14 ng/mL, and then remained relatively constant between 8 and 24 hours after application. The mean nicotine maximum peak plasma concentration values for nicotine transdermal system application to the arm, back, and chest were equivalent (13.8, 14.6, and 13.2 ng/mL, respectively). The mean time to reach peak concentration (tmax) (3 to 6 hours), and area under the curve (168, 186, and 183 ng · h/mL) values for the arm, back, and chest, respectively, were not significantly different. Thus, bioequivalent plasma nicotine concentrations were achieved irrespective of the application site on the upper body.

Comparison of the Nicotine Pharmacokinetics of Nicoderm (Nicotine Transdermal System) and Half‐Hourly Cigarette Smoking

Nicoderm, a nicotine transdermal system (NTS), provides a continuous, transdermal delivery of nicotine and is used as an aid to smoking cessation. In contrast, cigarette smoking yields nicotine concentrations in plasma that rise and fall with each cigarette. The primary objective of this study was to compare nicotine pharmacokinetics after treatment of subjects with either the NTS or controlled smoking. Fourteen healthy adult male smokers, who smoked at least 30 cigarettes per day, were entered into a randomized crossover design trial that compared the NTS, 21 mg/day applied for 24 hours, with half‐hourly smoking during the day. Subjects abstained from smoking for 2 days, and were treated for 5 days with either the NTS (daily) or controlled smoking (30 cigarettes at half‐hourly intervals on days 1 and 5; ad libitum smoking on days 2–4). Blood samples were obtained frequently on days 1 and 5 for analysis of nicotine and cotinine. Pharmacokinetic comparisons showed that nicotine Cmax, area under the curve (AUC)inf, and Cavg for the NTS were lower than corresponding values for controlled smoking; Cmax and Cavg values were approximately half those of smoking. Cmax and Cavg values for cotinine were similarly lower for the NTS compared to controlled smoking. For both treatments, plasma nicotine concentrations were higher on day 5 compared to day 1. Thus, the NTS provides concentrations of nicotine that are lower than smoking.

Pharmacokinetic Properties of Single- and Repeated-dose Sufentanil Sublingual Tablets in Healthy Volunteers

PURPOSE Sufentanil is a μ-opioid agonist with a high therapeutic index in preclinical studies and no active metabolites, and it is highly lipophilic, thereby enabling a transmucosal route of administration. Rapid distribution from the plasma after IV sufentanil administration results in a short duration of action requiring excessive repeated dosing if used for postoperative analgesia. The sufentanil sublingual tablet system (SSTS) is a handheld, preprogrammed, patient-controlled analgesia system designed to allow patients to self-administer sufentanil 15-μg tablets under their tongue with a 20-minute lockout. The pharmacokinetic (PK) characteristics of sufentanil, administered by different routes of delivery and after single and repeated sublingual (SL) administration, were examined in 2 studies. METHODS A randomized, open-label, crossover study in healthy subjects evaluated the PK profile of sufentanil 15 μg administered by different routes: IV, SL, buccal (BU), and PO. A second open-label, crossover study in healthy subjects evaluated the PK parameters after single and repeated doses (full SSTS drug cartridge of 40 consecutive SL doses administered every 20 minutes) of a sufentanil 15-μg SL tablet. Doses were self-administered using the SSTS. FINDINGS In the route of administration study (n = 25), mean Cmax values were highest with IV administration, and bioavailability values were: SL, 59%; BU, 78%; and PO, 9%. The absorption across the oral mucosa was associated with a median plasma half-time (time from Cmax to 50% of Cmax) that was 25-fold longer (2.5 hours) with SL versus IV administration (0.1 hours). In the single- and repeated-dose study (n = 38), mean AUC0-∞ was 125.5 h · pg/mL, and Cmax was 35.0 pg/mL, with a median Tmax of 0.8 hours after the administration of a single sufentanil SL tablet. With 40 consecutive doses, Cmax was 8-fold higher compared with that of a single dose, and steady state was achieved after the 13th dose. Median plasma half-time after the 40th dose was not statistically longer than that after a single dose (2.7 vs 2.2 hours, respectively), and the median Tmax was 0.3 hours after the last repeated dose. IMPLICATIONS These study results support the viability of the SSTS for use in patient-controlled analgesia. The wide range of mean drug concentrations achieved after repeated dosing at 20-minute intervals compared with those with a single dose suggests the flexibility of patient-controlled dosing to meet individual analgesic requirements. The prolonged plasma half-time with SL administration is expected to provide a more appropriate duration of analgesia compared with that of IV administration, and the PK properties of repeated-dose administration support a 20-minute lockout interval.

Effect of dosing time on the total intestinal transit time of non-disintegrating systems.

The total gastrointestinal transit time of nondisintegrating tablets may be affected by dosing time; available literature on this topic is inconclusive. OROS systems are nondisintegrating osmotically driven tablets that release drug over a period of time during their transit through the gastrointestinal tract and are excreted intact in the feces. Total transit times following morning administration of OROS systems pooled from various studies (n = 1,163 systems) showed a distribution with peak frequencies clustering around 24 and 48 h and following night administration (n = 80 systems) was found to cluster around 12 and 36 h. The total transit time distribution appears to be different following morning and night administration. However, on reanalyzing the data considering clock time when the tablet was collected rather than time post-administration, most of the difference between the distribution patterns disappeared. This suggested that total transit times after morning or night administration may be related to the bowel movement habits of the study population. Therefore, OROS systems total transit time were compared to the intrinsic bowel movement pattern of the general population reported in the literature and indeed a good correlation was seen between the two. The total transit time appears to be determined by two factors: the defecation frequency and the probability of its inclusion in the defecation event which is related to its location in the GI tract. A tablet is more likely to be excreted if it is further down in the GI tract. The total transit time data for OROS systems suggest that with the morning dosing the tablet is more likely to be excreted in the bowel movement the next morning. With the night time dosing the tablet may not be far enough in the colon to be excreted in the next morning bowel movement and therefore, it is more likely to be excreted the following morning.