Assessment of the Abuse Potential of the Orexin Receptor Antagonist, Suvorexant, Compared With Zolpidem in a Randomized Crossover Study.

Suvorexant is a dual orexin receptor antagonist approved in the United States and Japan for the treatment of insomnia at a maximum dose of 20 mg. This randomized double-blind crossover study evaluated the abuse potential of suvorexant in 36 healthy recreational polydrug users with a history of sedative and psychedelic drug use. Single doses of suvorexant (40, 80, and 150 mg: 2-7.5 × maximum dose), zolpidem (15 and 30 mg: 1.5-3 × maximum dose), and placebo were administered, with a 10-day washout between treatments. Subjective and objective measures, including visual analog scales (VASs), Addiction Research Center Inventory, and cognitive/psychomotor tests, were evaluated for 24-hour postdose. Suvorexant had significantly greater peak effects on "drug liking" VAS (primary endpoint) than placebo. Although effects of suvorexant on abuse potential measures were generally similar to zolpidem, they remained constant across doses, whereas zolpidem often had greater effects at higher doses. Suvorexant (all doses) had significantly fewer effects than zolpidem 30 mg on secondary measures, such as "high" VAS, Bowdle VAS, and Addiction Research Center Inventory morphine-benzedrine group. The overall incidence of abuse-related adverse events, such as euphoric mood and hallucination, was numerically lower with suvorexant than zolpidem. In agreement with its classification as a schedule IV drug, suvorexant demonstrated abuse potential, compared with placebo. The abuse potential was similar to zolpidem using certain measures, but with a reduced incidence of abuse-related adverse events. Although this suggests that the overall abuse liability of suvorexant may be lower than zolpidem, the actual abuse rates will be assessed with the postmarketing experience.

Estimating time to steady state using the effective rate of drug accumulation.

Unless all of a drug is eliminated during each dosing interval, the plasma concentrations within a dosing interval will increase until the time course of change in plasma concentrations becomes invariant from one dosing interval to the next, resulting in steady state. A simple method for estimating drug concentration time to steady state based on multiple dose area under the plasma concentration-time curve and effective rate of drug accumulation is presented. Several point estimates and confidence intervals for time to 90% of steady state are compared, and a recommendation is made on how to summarize and present the results.

Evaluation of methods for estimating time to steady state with examples from phase 1 studies.

An overview is provided of the methodologies used in determining the time to steady state for Phase 1 multiple dose studies. These methods include NOSTASOT (no-statistical-significance-of-trend), Helmert contrasts, spline (quadratic) regression, effective half life for accumulation, nonlinear mixed effects modeling, and Bayesian approach using Markov Chain Monte Carlo (MCMC) methods. For each methodology we describe its advantages and disadvantages. The first two methods do not require any distributional assumptions for the pharmacokinetic (PK) parameters and are limited to average assessment of steady state. Also spline regression which provides both average and individual assessment of time to steady state does not require any distributional assumptions for the PK parameters. On the other hand, nonlinear mixed effects modeling and Bayesian hierarchical modeling which allow for the estimation of both population and subject-specific estimates of time to steady state do require distributional assumptions on PK parameters. The current investigation presents eight case studies for which the time to steady state was assessed using the above mentioned methodologies. The time to steady state estimates obtained from nonlinear mixed effects modeling, Bayesian hierarchal approach, effective half life, and spline regression were generally similar.

Pharmacokinetics of famotidine in infants.

BACKGROUND: Although famotidine pharmacokinetics are similar in adults and children older than 1 year of age, they differ in neonates owing to developmental immaturity in renal function. Little is currently known about the pharmacokinetics of famotidine in infants aged between 1 month and 1 year, a period when renal function is maturing. OBJECTIVE: To characterise the pharmacokinetics of famotidine in infants. DESIGN: This was a two-part multicentre study with both single dose (Part I, open-label) and multiple dose (Part II, randomised) arms. PATIENTS: Thirty-six infants (20 females and 16 males) who required treatment with famotidine and who had an indwelling arterial or venous catheter for reasons unrelated to the study. METHODS: Infants in Part I were administered a single dose of famotidine 0.5 mg/kg; the dose was intravenous or oral according to the judgement of the attending physician. Infants receiving 0.5 mg/kg intravenously were divided into two groups by age, and pharmacokinetic parameters in infants 0-3 months and >3 to 12 months of age were compared. Infants in Part II were randomised to one of the following treatments: 0.25 mg/kg/dose intravenously or 0.5 mg/kg/dose orally on day 1 and subsequent days, or 0.25 mg/kg/dose intravenously or 0.5 mg/kg/dose orally on day 1 followed by doses of either 0.5 mg/kg/dose intravenously or 1 mg/kg/dose orally on subsequent days. From day 2 onwards, age-adjusted dose administration regimens (once daily in infants <3 months of age and every 12 hours in infants >3 months of age) were used; the total number of famotidine doses ranged from 3 to 11 and the total number of days of dose administration ranged from two to eight. RESULTS: In infants <3 months of age, plasma and renal clearance of famotidine were decreased compared with infants >3 months of age. Pharmacokinetic parameters for the older infants (i.e. those >3 months) were similar to those previously reported for children and adults. Approximate dose-proportionality, no accumulation on multiple dosing and an estimated bioavailability similar to adult values were also observed. CONCLUSION: A short course of famotidine therapy in infants appears generally well tolerated, and the characteristics of famotidine pharmacokinetics during the first year of life are explained to a great degree by the development of renal function, the primary route of elimination for this drug.

Effects of aprepitant on cytochrome P450 3A4 activity using midazolam as a probe.

BACKGROUND: Aprepitant is a neurokinin(1) receptor antagonist that enhances prevention of chemotherapy-induced nausea and vomiting when added to conventional therapy with a corticosteroid and a 5-hydroxytryptamine(3) (5-HT(3)) antagonist. Because aprepitant may be used with a variety of chemotherapeutic agents and ancillary support drugs, which may be substrates of cytochrome P450 (CYP) 3A4, assessment of the potential of this drug to inhibit CYP3A4 activity in vivo is important. The effect of aprepitant on in vivo CYP3A4 activity in humans with oral midazolam used as a sensitive probe of CYP3A4 activity was evaluated in this study. METHODS: In this open-label, randomized, single-period study, 16 healthy male subjects were enrolled. Subjects received one of two oral aprepitant regimens for 5 days (8 subjects per regimen): (1) 125 mg aprepitant on day 1 and then 80 mg/d on days 2 to 5 or (2) 40 mg aprepitant on day 1 and then 25 mg/d on days 2 to 5. All subjects also received a single oral dose of midazolam, 2 mg, at prestudy (3 to 7 days before aprepitant treatment) and on days 1 and 5 (1 hour after aprepitant administration). RESULTS: Coadministration of midazolam and 125/80 mg aprepitant increased the midazolam area under the plasma concentration-time curve by 2.3-fold on day 1 (P <.01) and by 3.3-fold on day 5 (P <.01), as compared with midazolam alone (prestudy). The 125/80-mg regimen of aprepitant also increased the midazolam maximum observed concentration by 1.5-fold on day 1 (P <.05) and by 1.9-fold on day 5 (P <.01). The midazolam half-life values increased from 1.7 hours (prestudy) to 3.3 hours on both day 1 and day 5. Coadministration of 40/25 mg aprepitant and midazolam did not result in significant changes in the midazolam area under the plasma concentration-time curve, maximum observed concentration, and half-life at either day 1 or day 5. CONCLUSIONS: The 5-day 125/80-mg regimen of aprepitant produced moderate inhibition of CYP3A4 activity in humans, as measured with the use of midazolam as a probe drug.

Effects of the neurokinin1 receptor antagonist aprepitant on the pharmacokinetics of dexamethasone and methylprednisolone.

BACKGROUND: Aprepitant is a neurokinin(1) receptor antagonist that, in combination with a corticosteroid and a 5-hydroxytryptamine(3) receptor antagonist, has been shown to be very effective in the prevention of chemotherapy-induced nausea and vomiting. At doses used for the management of chemotherapy-induced nausea and vomiting, aprepitant is a moderate inhibitor of cytochrome P4503A4 and may be used in conjunction with corticosteroids such as dexamethasone and methylprednisolone, which are substrates of cytochrome P4503A4. The effects of aprepitant on the these 2 corticosteroids were evaluated. METHODS: Study 1 was an open-label, randomized, incomplete-block, 3-period crossover study with 20 subjects. Treatment A consisted of a standard oral dexamethasone regimen for chemotherapy-induced nausea and vomiting (20 mg dexamethasone on day 1, 8 mg dexamethasone on days 2 to 5). Treatment B was used to examine the effects of oral aprepitant (125 mg aprepitant on day 1, 80 mg aprepitant on days 2 to 5) on the standard dexamethasone regimen. Treatment C was used to examine the effects of aprepitant on a modified dexamethasone regimen (12 mg dexamethasone on day 1, 4 mg dexamethasone on days 2 to 5). All subjects also received 32 mg ondansetron intravenously on day 1 only. Study 2 was a double-blind, randomized, placebo-controlled, 2-period crossover study with 10 subjects. Subjects in one group received a regimen consisting of 125 mg methylprednisolone intravenously on day 1 and 40 mg methylprednisolone orally on days 2 to 3. Subjects in the other group received oral aprepitant (125 mg aprepitant on day 1, 80 mg aprepitant on days 2 to 3) in addition to the methylprednisolone regimen. RESULTS: In study 1, the area under the concentration-time curve from 0 to 24 hours (AUC(0-24)) of oral dexamethasone on days 1 and 5 after the standard dexamethasone plus ondansetron regimen (treatment A) was increased 2.2-fold (P <.010) with coadministration of aprepitant (treatment B). Coadministration of aprepitant with the modified dexamethasone plus ondansetron regimen (treatment C) resulted in an AUC0-24 for dexamethasone similar to that observed after the standard dexamethasone plus ondansetron regimen (treatment A). In study 2, aprepitant increased the AUC0-24 of intravenous methylprednisolone 1.3-fold on day 1 (P <.010) and increased the AUC0-24 of oral methylprednisolone 2.5-fold on day 3 (P <.010). CONCLUSIONS: Coadministration of aprepitant with dexamethasone or methylprednisolone resulted in increased plasma concentrations of the corticosteroids. These findings suggest that the dose of these corticosteroids should be adjusted when given with aprepitant.