Mona Darwish

Comparative kinetics and dynamics of zaleplon, zolpidem, and placebo

This study evaluated the relationship of dose, plasma concentration, and time to the pharmaco‐dynamics of zaleplon and zolpidem, 2 structurally distinct benzodiazepine receptor agonists.

Rapid Disappearance of Zaleplon from Breast Milk after Oral Administration to Lactating Women

Five lactating mothers were administered the therapeutic dose of zaleplon (10 mg) orally in an open‐label, single‐dose, pharmacokinetic study. Plasma and breast milk were sampled through 8 hours after dose administration for subsequent determinations of zaleplon and its major, though inactive, plasma metabolite 5‐oxo‐zaleplon. Zaleplon concentrations peaked in plasma and milk approximately 1 hour after dosing and then disappeared rapidly. The mean terminal half‐life was slightly greater than 1 hour. Milk concentrations “mirrored” plasma concentrations closely with no discernible delay between peak times. The average milk‐to‐plasma (M/P) concentration ratio for zaleplon was approximately 0.50 over the time course. 5‐oxo‐zaleplon was undetectable in all but one milk sample. The maximum exposure of an infant to zaleplon during a feeding at peak milk concentrations was estimated to range from 1.28 μg to 1.66 μg, corresponding to 0.013% to 0.017% of the maternal dose or 0.320 μg/kg to 0.415 μg/kg for a 4 kg infant. The results indicate that zaleplon taken by a nursing mother is transferred through breast milk to her infant in very small quantities that are unlikely to be clinically important.

Single- and Multiple-dose Pharmacokinetics of a Hydrocodone Bitartrate Extended-release Tablet Formulated With Abuse-deterrence Technology in Healthy, Naltrexone-blocked Volunteers

PURPOSE A hydrocodone extended-release (ER) formulation was developed to provide sustained pain relief with twice-daily dosing. Developed using the CIMA abuse-deterrence technology platform (CIMA Labs Inc, Brooklyn Park, Minnesota), this formulation also provides resistance against rapid release of hydrocodone when tablets are comminuted and resistance against dose dumping when tablets are taken with alcohol. Two open-label studies evaluated hydrocodone ER pharmacokinetics (PK) after single- and multiple-dose administration in healthy, naltrexone-blocked subjects. METHODS In the single-dose period of both studies, healthy subjects aged 18 to 45 years of age received hydrocodone ER (study 1, 45 mg; study 2, 90 mg). In the multiple-dose period of study 1, subjects received one 45-mg hydrocodone ER tablet twice daily from the morning of day 1 through the morning of day 6. In the multiple-dose period of study 2, subjects received hydrocodone ER twice daily, titrated to 90 mg over 10 days (days 1 and 2, 45 mg; days 3 and 4, 60 mg; days 5-10, 90 mg). All subjects received naltrexone to block opioid receptors. Blood samples were collected pre-dose and through 72 hours post-dose in the single-dose period and after the final dose in the multiple-dose period. PK measures included maximum observed plasma drug concentration (C(max)), area under the plasma drug concentration by time curve from time 0 to the time of the last measurable drug concentration (AUC(0-t)), time to C(max) (T(max)), observed accumulation ratio (R(obs)), and steady-state plasma concentration (C(ss)). Safety and tolerability were assessed. FINDINGS The PK analyses included 36 subjects from study 1 and 33 from study 2. Plasma hydrocodone PK parameters after single- and multiple-dose administration of hydrocodone ER 45 mg (study 1) were dose-normalized to 90 mg and pooled with data from study 2. As expected, C(max) was higher (125.4 vs 57.2 ng/mL), AUC(0-t) was higher (2561 vs 1095 ng·h/mL), and T(max) occurred earlier (5.0 vs 8.0 hours) with multiple-dose administration. Mean R(obs) after multiple-dose administration of hydrocodone ER was also slightly higher than predicted from single-dose data (2.8 vs 2.4). C(ss) were achieved within 5 days of twice-daily administration of both doses. Mean fluctuation with hydrocodone ER 45 or 90 mg was 36.4% and 33.9%, respectively, and mean swing was 46.9% and 43.5%, respectively. The incidence of adverse events was similar in the single-dose (33%) and multiple-dose (29%) periods in study 1 and slightly higher in the multiple-dose (76%) than in the single-dose (53%) period in study 2. IMPLICATIONS The PK profile of hydrocodone ER was qualitatively similar after single- and multiple-dose administration. The steady-state profile demonstrated sustained exposure with limited swing and fluctuation. Single and multiple doses of hydrocodone ER (45 and 90 mg) were generally well tolerated in healthy subjects receiving naltrexone; however, exposure to naltrexone may have confounded the interpretation of safety findings.

Abuse Potential with Oral Route of Administration of a Hydrocodone Extended-Release Tablet Formulated with Abuse-Deterrence Technology in Nondependent, Recreational Opioid Users

Objective. To compare the oral abuse potential of hydrocodone extended-release (ER) tablet developed with CIMA® Abuse-Deterrence Technology with that of hydrocodone immediate release (IR). Design. Randomized, double-blind, placebo-controlled, crossover study. Setting and Patients. One study site in the United States; adult nondependent, recreational opioid users. Methods. After confirming their ability to tolerate and discriminate hydrocodone IR 45 mg from placebo, eligible participants were randomized to receive each of the following oral treatments once: finely crushed placebo, hydrocodone IR 45-mg powder, intact hydrocodone ER 45-mg tablet, and finely crushed hydrocodone ER 45-mg tablet. Primary pharmacodynamic measure was “at the moment” drug liking. Secondary measures included overall drug liking, drug effects (e.g., balance, positive, negative, sedative), pupillometry, pharmacokinetics, and safety. Results. Mean maximum effect (Emax) for “at the moment” drug liking was significantly lower for intact (53.9) and finely crushed hydrocodone ER (66.9) vs. hydrocodone IR (85.2; P < 0.001). Drug liking for intact hydrocodone ER was comparable to placebo (Emax: 53.9 vs. 53.2). Secondary measures were consistent with these results, indicating that positive, negative, and sedative drug effects were diminished with intact and crushed hydrocodone ER tablet vs. hydrocodone IR. The 72-hour plasma concentration-time profile for each treatment mimicked its respective “at the moment” drug-liking-over-time profile. Incidence of adverse events was lower with intact hydrocodone ER (53%) vs. hydrocodone IR (79%) and finely crushed hydrocodone ER (73%). Conclusions. The oral abuse potential of hydrocodone ER (intact and finely crushed) was significantly lower than hydrocodone IR in healthy, nondependent, recreational opioid users. Hydrocodone ER was generally well tolerated.

Effects of Renal Impairment and Hepatic Impairment on the Pharmacokinetics of Hydrocodone After Administration of a Hydrocodone Extended‐Release Tablet Formulated With Abuse‐Deterrence Technology

Two open‐label, single‐dose, parallel‐group studies assessed effects of renal and hepatic impairment on the pharmacokinetics of a hydrocodone extended‐release (ER) formulation developed with the CIMA Abuse‐Deterrence Technology platform. Forty‐eight subjects with normal renal function or varying degrees of renal impairment received hydrocodone ER 45 mg (study 1); 16 subjects with normal hepatic function or moderate hepatic impairment received hydrocodone ER 15 mg (study 2). Blood samples were obtained predose and through 144 hours postdose. Mean maximum observed plasma hydrocodone concentration (Cmax) in subjects with normal renal function, mild, moderate, and severe impairment, and end‐stage renal disease was 28.6, 33.4, 42.4, 36.5, and 31.6 ng/mL, and mean area under the plasma hydrocodone concentration‐versus‐time curve from time 0 to infinity (AUC0–∞) was 565, 660, 973, 983, and 638 ng·h/mL, respectively. Incidence of adverse events was 57%, 38%, 44%, 33%, and 56%, respectively. Mean Cmax with normal hepatic function and moderate impairment was 10.1 and 13.0 ng/mL, and mean AUC0–∞ was 155 and 269 ng·h/mL, respectively. Incidence of adverse events was 38% in both groups. Altered systemic exposure in renally or hepatically impaired populations (up to ∼70% higher) should be considered when titrating to an effective dose of hydrocodone ER.

Evaluation of the Potential for Pharmacokinetic Drug–Drug Interaction Between Armodafinil and Carbamazepine in Healthy Adults

PURPOSE Polypharmacy is common in psychiatry practice and can lead to an increased risk of drug interactions. Armodafinil, a wakefulness-promoting agent, has been studied as adjunctive therapy for the treatment of major depressive episodes associated with bipolar I disorder. Armodafinil and the mood stabilizer carbamazepine are both inducers of and substrates for cytochrome P450 (CYP3A4). This study was designed to evaluate the bidirectional carbamazepine-armodafinil pharmacokinetic drug-drug interaction. METHODS This was an open-label, single-center study conducted in healthy adult men. Subjects assigned to group 1 received a dose of carbamazepine (200 mg) alone and a dose after pretreatment with daily dosing of armodafinil (titrated to 250 mg/d). Subjects assigned to group 2 received a dose of armodafinil (250 mg) alone and a dose after pretreatment with carbamazepine BID (titrated to 400 mg/d). Pharmacokinetic parameters for carbamazepine, armodafinil, and their major circulating metabolites were determined when dosed alone and after pretreatment with the other drug. The safety and tolerability of armodafinil and carbamazepine were also assessed throughout the study. FINDINGS Eighty-one subjects enrolled in the study (group 1 = 40; group 2 = 41), of whom 79 (group 1 = 40; group 2 = 39) were evaluable for pharmacokinetic analysis and 80 (group 1 = 40; group 2 = 40) were evaluable for safety analysis. In group 1, pretreatment with armodafinil reduced systemic exposure to carbamazepine by 12% for Cmax and 25% for AUC (based on comparison of geometric means). Similarly, in group 2, pretreatment with carbamazepine reduced systemic exposure to armodafinil by 11% for Cmax and 37% for AUC. Systemic exposure to the metabolites of these agents that are formed via CYP3A4 were increased after pretreatment in each group. There were no new or unexpected adverse events. IMPLICATIONS Systemic exposure to both carbamazepine and armodafinil was reduced after pretreatment with the other drug; systemic exposure to the metabolites of each drug, which are formed via CYP3A4, was increased. These changes were consistent with the induction of CYP3A4. Both drugs were generally safe and well tolerated alone and in combination under the conditions studied. Dose adjustment may be required when initiating or discontinuing armodafinil and carbamazepine cotherapy.