Edward T. Hellriegel

Clinical Pharmacokinetic Profile of Modafinil

Modafinil is a unique wake-promoting agent for oral administration. Its pharmacological properties are distinct from those of other CNS agents, and it selectively targets neuronal pathways in the sleep/wake centres of the brain.After single or multiple oral doses, modafinil is readily absorbed, reaching maximum plasma concentrations at 2–4 hours after administration and pharmacokinetic steady state within 2–4 days. Its pharmacokinetics are dose-independent between 200 and 600 mg/day. The elimination half-life is approximately 12–15 hours, which is largely reflective of the pharmacokinetics of the longer-lived l-enantiomer.Modafinil is primarily eliminated via metabolism, mainly in the liver, with subsequent excretion in the urine. Less than 10% of the dose is excreted as unchanged drug. Metabolism is largely via amide hydrolysis, with lesser contributions from cytochrome P450 (CYP)-mediated oxidative pathways. In patients who are renally or hepatically compromised, the elimination processes can be slowed, and in a similar manner (although to a lesser extent), elimination in the elderly may be reduced due to normal effects of aging.Because modafinil is administered concomitantly with other medications, the potential for metabolic drug-drug interactions has been examined both in vitro and in vivo. In vitro, modafinil was observed to produce a reversible inhibition of CYP2C19 in human liver microsomes. It also caused a small, but concentration-dependent, induction of CYP1A2, CYP2B6 and CYP3A4 activities and suppression of CYP2C9 activity in primary cultures of human hepatocytes. Clinical studies have been conducted to examine the potential for interactions with methylphenidate, dexamfetamine, warfarin, ethinylestradiol and triazolam. The only substantive interactions observed were with ethinylestradiol and triazolam, apparently through induction of CYP3A4, primarily in the gastrointestinal system. Overall, the results of the interaction studies suggest that modafinil has potential to affect the pharmacokinetics of drugs that are metabolised by certain CYP enzymes. Compounds that induce or inhibit CYP activity are unlikely to have major effects on the pharmacokinetics of modafinil.In summary, the results show that modafinil is a moderately long-lived drug that is well absorbed and extensively metabolised.

Armodafinil and Modafinil Have Substantially Different Pharmacokinetic Profiles Despite Having the Same Terminal Half-Lives Analysis of Data from Three Randomized, Single-Dose, Pharmacokinetic Studies

AbstractBackground and objective: Armodafinil, a non-amphetamine, wakefulness-promoting medication, is the R- and longer-lasting isomer of racemic modafinil. Armodafinil has been shown to improve wakefulness in patients with excessive sleepiness (ES) associated with treated obstructive sleep apnoea, shift work disorder or narcolepsy. In comparison with modafinil, armodafinil maintains higher plasma concentrations later in the day in healthy subjects. The objective of this analysis was to characterize the pharmacokinetic parameters related to those higher concentrations. Methods: Data from three randomized studies in healthy adult subjects receiving single doses of either armodafinil (50,100,200,250, 300 or 400 mg) or modafinil (400 mg) were pooled, and subsequently dose-normalized to a 200 mg dose for each drug. Non-compartmental pharmacokinetic parameters were assessed. Results: Armodafinil and modafinil both had a mean single-dose terminal elimination half-life of∼13 hours, with similar mean maximum plasma drug concentration (Cmax) and median time to Cmax values. After reaching Cmax, plasma concentrations appeared to decline in a monophasic manner with armodafinil, but in a biphasic manner with modafinil due to the initial rapid elimination of its S-isomer. As a result, mean area under the plasma drug concentration versus time curve (AUC) from time zero to the time of the last measurable concentration (AUClast) and AUC from time zero to infinity (AUC∞) values were 33% and 40% higher, respectively, with armodafinil compared with modafinil on a milligram-to-milligram basis. Conclusions: Despite similar half-lives, plasma concentrations following armodafinil administration are higher late in the day than those following modafinil administration on a milligram-to-milligram basis. The different pharmacokinetic profile of armodafinil may result in improved wakefulness throughout the day in patients with ES compared with modafinil.

Single‐Dose and Steady‐State Pharmacokinetics of Fentanyl Buccal Tablet in Healthy Volunteers

This study evaluated the single‐dose and steady‐state pharmacokinetics of fentanyl buccal tablet 400 μg in healthy adult volunteers. After receiving naltrexone 50 mg to block opioid receptor–mediated effects of fentanyl, subjects received fentanyl buccal tablet 400 μg on day 1, then every 6 hours from day 4 to day 9 (21 doses). Naltrexone 50 mg was administered every 12 hours throughout the study. Plasma fentanyl concentrations were determined for 72 hours after administration of fentanyl buccal tablet 400 μg on day 1 and the last dose of fentanyl buccal tablet 400 μg on day 9. Following single‐ and multiple‐dose administration of fentanyl buccal tablet, the median time to maximum concentration (tmax) was 52.2 and 49.8 minutes, respectively. Peak plasma concentration of fentanyl (Cmax) was 0.88 ng/mL for the single‐dose regimen and 1.77 ng/mL for the multiple‐dose regimen. Steady state was reached within 5 days, consistent with the observed median half‐life of approximately 22 hours following multiple doses. Observed accumulation of fentanyl after multiple doses of fentanyl buccal tablet was slightly greater than would be expected based on the single‐dose data. This was attributed to the redistribution of fentanyl from a deep tissue compartment into the plasma. This study indicates that fentanyl buccal tablet has predictable pharmacokinetics following multiple‐dose administration.

Comparison of Equivalent Doses of Fentanyl Buccal Tablets and Arteriovenous Differences in Fentanyl Pharmacokinetics

BackgroundThe fentanyl buccal tablet (FBT) is designed to enhance the rate and extent of fentanyl absorption through the buccal mucosa.AimTo evaluate the bioequivalence of μg-equivalent doses of FBT administered as single and multiple tablets and assess differences in the arterial and venous pharmacokinetics of FBT in healthy volunteers.MethodsTwenty-seven healthy adults, aged 19–5 years, participated in the randomised, open-label, three-period, crossover study. In the first two periods, FBT was administered as four 100μg tablets simultaneously or one FBT 400μg to assess bioequivalence. Venous blood samples were obtained over a 72-hour period to measure plasma fentanyl concentrations. In the third period, arterial and venous blood samples were obtained simultaneously from before administration of one FBT 400μg through 4 hours after administration to evaluate the impact of arterial versus venous sampling on the pharmacokinetic profile. As subjects were not opioid tolerant, naltrexone was administered to block opioid receptor-mediated effects of fentanyl. Adverse events were recorded throughout.ResultsMaximum plasma concentration (Cmax) and area under the plasma concentration-time curve from time zero to infinity (AUC∞) on average were approximately 12% and 13% higher, respectively, for FBT administered as four 100μg tablets simultaneously compared with one FBT 400μg. Maximum plasma concentrations in the arterial circulation were approximately 60% higher and occurred 15 minutes earlier than those measured from the venous circulation. No serious adverse events were reported during the study.ConclusionDespite small differences in Cmax and AUC∞ (on average 12% and 13%, respectively), FBT administered as four 100μg tablets simultaneously compared with one 400μg tablet did not meet the criteria for bioequivalence. An increased surface area exposure with four tablets compared with one tablet may account for the slightly higher maximum concentrations observed with four 100μg tablets. A substantially higher Cmax was reached earlier in the arterial than in the venous circulation.

Interaction Profile of Armodafinil with Medications Metabolized by Cytochrome P450 Enzymes 1A2, 3A4 and 2C19 in Healthy Subjects

Background and objectiveArmodafinil, a wakefulness-promoting agent, is the pure R-enantiomer of racemic modafinil. The objective of this article is to summarize the results of three clinical drug-interaction studies assessing the potential for drug interactions of armodafinil with agents metabolized by cytochrome P450 (CYP) enzymes 1A2, 3A4 and 2C19. Study 1 evaluated the potential for armodafinil to induce the activity of CYPlA2 using oral caffeine as the probe substrate. Study 2 evaluated the potential for armodafinil to induce gastrointestinal and hepatic CYP3A4 activity using intravenous and oral midazolam as the probe substrate. Study 3 evaluated the potential for armodafinil to inhibit the activity of CYP2C19 using oral omeprazole as the probe substrate.MethodsHealthy men and nonpregnant women aged 18–5 years with a body mass index of ≤30 kg/m2 each participated in one of three open-label studies. Studies 1 and 2 were sequential design studies in which caffeine (oral 200 mg) or midazolam (2 mg intravenously followed by 5 mg orally) was administered before initiation of oral armodafinil administration and again after at least 22 days of oral armodafinil administration at 250 mg/day. Study 3 was a two-way crossover study in CYP2C19 extensive metabolizers to whom omeprazole (oral 40 mg) was administered alone or with oral administration of armodafinil 400 mg 2 hours before the omeprazole dose. Pharmacokinetic samples were obtained for caffeine, midazolam and omeprazole for up to 48 hours postdose. The primary pharmacokinetic parameters included the area under the plasma concentration-time curve from time zero to infinity (AUC∞) and the maximum observed drug plasma concentration (Cmax). Safety and tolerability were also assessed.ResultsA total of 77 healthy subjects participated in the three studies (study 1, n = 29; study 2, n = 24; study 3, n = 24). Prolonged armodafinil administration had no effect on the Cmax or the AUC of oral caffeine compared with administration of caffeine alone. However, prolonged administration of armodafinil reduced the AUC of midazolam after intravenous and oral doses by approximately 17% and 32%, respectively, and decreased the Cmax of oral midazolam by approximately 19% compared with administration of midazolam alone. Armodafinil coadministration increased the AUC of oral omeprazole by approximately 38% compared with administration of omeprazole alone. Armodafinil alone or in combination with each of the three probe substrates was well tolerated, with headache and dizziness being the most commonly reported adverse events.ConclusionsArmodafinil did not induce CYP1A2 but was a moderate inducer of CYP3A4 and a moderate inhibitor of CYP2C19 in healthy subjects. Armodafinil was generally well tolerated when administered with caffeine, midazolam or omeprazole. Dosage adjustments may be required for drugs that are substrates of CYP3A4 (e.g. Ciclosporin, triazolam) and CYP2C19 enzymes (e.g. diazepam, phenytoin) when administered with armodafinil.

Effect of modafinil on the pharmacokinetics of ethinyl estradiol and triazolam in healthy volunteers

Modafinil has been reported to produce a concentration‐related induction of CYP3A4/5 activity in vitro in primary cultures of human hepatocytes.

Pharmacokinetic profile of armodafinil in healthy subjects: pooled analysis of data from three randomized studies.

AbstractBackground and objectives: Armodafinil R-modafinil) is the R- and longer-lasting isomer of the racemic compound modafinil, a wakefulness-promoting medication. Armodafinil is eliminated approximately three times more slowly than the S-isomer of racemic modafinil. Published studies have demonstrated the efficacy of armodafinil for treating excessive sleepiness associated with obstructive sleep apnoea, shift work disorder and narcolepsy. The objectives of this study were to describe the pharmacokinetic profile, tolerability and safety of armodafinil in healthy subjects. Methods: Pooled pharmacokinetic data from three separate randomized studies in 119 healthy subjects who received single or multiple (once daily for up to 14 days) oral doses of armodafinil ranging between 50 and 400 mg were analysed. The impact of food on the single-dose pharmacokinetic profile of armodafinil was also assessed in subjects following an overnight fast and after the consumption of a standard fatty meal. Results: Armodafinil was readily absorbed and exhibited linear pharmacokinetics over the 50–400 mg dose range. Peak plasma concentrations were reached around 2 hours after administration in the fasted state. Food had no effect on the overall bioavailability of armodafinil; however, the peak concentration was delayed by approximately 2–4 hours. In the multiple-dose study, dose proportionality was confirmed by linear regression analyses of the log-transformed area under the plasma concentration versus time curve (AUC) and maximum plasma concentration (Cmax) values as a function of dose. After reaching the peak, plasma concentrations of armodafinil declined in a monophasic manner, with a mean elimination half-life of approximately 15 hours. Steady state appeared to be reached within 7 days. At steady state, the systemic exposure to armodafinil was 1.8 times that observed after single-dose administration. Armodafinil was generally well tolerated, the most frequent adverse events being headache, dizziness and nausea. Conclusions: In the present analysis, armodafinil exhibited linear pharmacokinetics over the dose range of 50–400 mg. While food affected the rate but not the extent of absorption, peak plasma concentrations were reached in approximately 2 hours when the drug was taken on an empty stomach. With once-daily dosing, steady state appeared to be reached within 7 days. After reaching peak plasma levels, concentrations of armodafinil declined monophasically, with a mean elimination half-life of around 15 hours. Armodafinil was generally well tolerated.

Pharmacokinetics of armodafinil and modafinil after single and multiple doses in patients with excessive sleepiness associated with treated obstructive sleep apnea: A randomized, open-label, crossover study

BACKGROUND Armodafinil (the R-isomer of racemic modafinil) and modafinil are wakefulness-promoting medications for excessive sleepiness associated with treated obstructive sleep apnea (OSA). The R-isomer of racemic modafinil has a half-life of approximately15 hours; the S-isomer has a half-life of 4 to 5 hours. The R-and S-isomers are equipotent, producing equivalent pharmacologic activity at equal concentrations. OBJECTIVE The aim of this work was to compare the pharmacokinetic profiles of armodafinil (R-modafinil) and modafinil (racemic mixture with equal quantities of R- and S-isomers) at equal doses in patients with residual excessive sleepiness associated with continuous positive airway pressure-treated OSA. METHODS This open-label study was conducted at 5 US centers from July 2008 to March 2009. Patients were randomized to 1 of 2 crossover administration sequences, ABCD or BADC, where A was a single armodafinil 200-mg dose, B was a single modafinil 200-mg dose, C was multiple daily modafinil 200-mg doses, and D was multiple daily armodafinil 200-mg doses. During multiple-dose administration, patients received 100 mg once daily for days 1 and 2, and 200 mg once daily for days 3 through 10. The pharmacokinetic parameters of principal interest for assessing the bioequivalence of armodafinil and modafinil were maximum concentration at 7 to 11 hours after dosing and the concentration-versus-time curve for this period. Analysis was performed via achiral high-performance liquid chromatography with ultraviolet detection using blood samples obtained over 72 hours after single-dose administration and over 24 hours after the multiple-dose regimen. For post hoc evaluation of bioequivalence, 90% CI values were also constructed for the geometric mean ratios of armodafinil to modafinil. Tolerability was assessed by the reported adverse events, clinical laboratory testing, vital sign measurements, ECGs, and physical exams. RESULTS The study population was 83.3% male (35/42) and 76.2% white (32/42) with a mean (SD) age of 47.0 (8.30) years and a weight range of 66.3 to 127.4 kg. Plasma drug concentration-versus-time curves suggested comparable terminal half-lives (mean [SD] values were 16.5 [4.44] and 14.4 [3.22] hours for armodafinil and modafinil, respectively) but higher systemic exposure with armodafinil than modafinil (mean [SD] AUC(0-∞) values were 108.8 [31.66] and 66.4 [20.06] microg · h/mL for armodafinil and modafinil, respectively), as indicated by the high geometric mean ratios for the AUC (the AUC(0-∞)) ratio after a single dose was 1.64 [95% CI, 1.60-1.68; P < 0.001], and the AUC(0-τ) ratio after multiple doses was 1.69 [95% CI, 1.65-1.72; P < 0.001]) and, to a lesser extent, the ratio of the maximum plasma drug concentration after multiple doses (C(max) ratio = 1.37 [95% CI, 1.33-1.41; P < 0.001]). In addition, the ratios and associated 90% CIs for Cmax (137 [1.341.40]) and AUC(0-τ) (169 [1.66-1.75]) after multiple-dose administration did not meet the US Food and Drug Administration (FDA) criteria for bioequivalence (ie, ratio of geometric means between 80% and 125%). Reported adverse events were mild to moderate in intensity. The most frequently reported adverse events while receiving armodafinil or modafinil were headache (29% and 2%, respectively), diarrhea (12% and 5%), nausea (10% and 2%), and dizziness (10% and 5%). CONCLUSIONS In this crossover study of patients with treated OSA, overall systemic exposure after armodafinil 200-mg administration was greater than that following modafinil 200-mg administration after both single and multiple doses. The pharmacokinetic profiles of the 2 drugs were notably different and did not meet the FDA criteria for bioequivalence.

Comparison of steady-state plasma concentrations of armodafinil and modafinil late in the day following morning administration: post hoc analysis of two randomized, double-blind, placebo-controlled, multiple-dose studies in healthy male subjects.

AbstractBackground and objective: Armodafinil, the R- and longer-lasting isomer of modafinil, may maintain higher plasma drug concentrations compared with racemic modafinil because of stereospecific differences in elimination of its isomers. This analysis set out to compare the steady-state pharmacokinetic profiles of armodafinil and modafinil on a milligram-to-milligram basis following once-daily administration. Methods: A post hoc analysis of two multiple-dose pharmacokinetic studies in healthy male subjects aged 18–50 years was conducted to compare dose-normalized (200 mg/day) plasma drug concentration and pharmacokinetic data for subjects in each study who completed 7 days of once-daily (morning) administration of armodafinil (n = 34) or modafinil (n = 18). Results: Dose-normalized plasma concentrations of armodafinil on day 7 were higher than those of modafinil, with the greatest differences being observed later in the day. Across the 24-hour dose interval, plasma drug concentration fluctuation and swing were 28% and 42% less, respectively, with armodafinil than with modafinil. In addition, average late-day (3pm to 7pm after an 8am dosing) plasma drug concentrations and partial values for the area under the plasma concentration versus time curve for 7–11 hours after dosing were both 44% higher with armodafinil. Conclusions: At steady state, armodafinil produces consistently higher plasma drug concentrations late in the day than modafinil when compared on a milligram- to-milligram basis. The distinct pharmacokinetic profile of armodafinil compared with that of the racemate may result in fundamentally different durations of action. These differences between the two medications cannot be made equivalent by increasing the dose of the racemate without introducing potential safety concerns.

Single-dose pharmacokinetics of once-daily cyclobenzaprine extended release 30 mg versus cyclobenzaprine immediate release 10 mg three times daily in healthy young adults : a randomized, open-label, two-period crossover, single-centre study.

AbstractBackground and objective: Cyclobenzaprine immediate release (CIR) has shown efficacy in the treatment of muscle spasm associated with acute, painful musculoskeletal conditions. An extended-release formulation of cyclobenzaprine (CER) has been developed to provide effective muscle spasm relief with once-daily dosing. The objective of this study was to compare the pharmacokinetics of CER and CIR. Methods: This was a single-centre study of 18 healthy young adults (aged 18–45 years). Healthy volunteers were assigned to receive either a single dose of CER 30 mg or three doses of CIR 10 mg on days 1 and 15 (separated by a 14-day washout) in an open-label, two-period crossover study. Pharmacokinetic parameters were monitored through 168 hours after the last dose in each dose period; adverse events (AEs) were monitored during the study through 3 weeks after the last dose of study drug. Cyclobenzaprine was administered as a single oral 30 mg dose of CER or three 10 mg oral doses of CIR given every 8 hours over 24 hours. Statistical tests were conducted against a two-sided alternative hypothesis at a 0.05 level of significance with equivalence limits of 80% and 125%. Measures included area under the plasma cyclobenzaprine concentration versus time curve (AUC) to 168 hours and infinity, maximum plasma cyclobenzaprine concentration (Cmax), and time to observed Cmax (tmax). Results: Eighteen subjects were randomized and 17 completed both periods of the study. CER exhibited a consistent concentration-time profile with a single peak, in contrast to the pharmacokinetic profile for CIR, which displayed multiple peaks and troughs over the 24-hour period. The pharmacokinetic profile of CER 30 mg was characterized by an absorption phase with a median tmax of approximately 6 hours, compared with the initial peak of CIR (following the first dose) of about 4 hours. Mean plasma concentrations at 4 hours were comparable (12.1 ng/mL for CER; 12.4 ng/mL for CIR). Systemic cyclobenzaprine exposure (AUC and Cmax) was similar across both formulations. The Cmax for CER 30 mg was 19.2 ng/mL (median tmax = 6 hours) and for CIR (following the third dose) was 18.1 ng/mL (median tmax =12 hours). All AEs were mild in intensity; the most common AE was somnolence. Conclusion: The pharmacokinetic profile of once-daily CER reflected the mode of administration, providing a controlled release of cyclobenzaprine with sustained plasma concentrations, in contrast to the fluctuating profile of CIR. CER 30 mg once daily and CIR 10 mg three times daily resulted in comparable systemic exposures.