Philmore Robertson

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.

Absolute and Relative Bioavailability of Fentanyl Buccal Tablet and Oral Transmucosal Fentanyl Citrate

This study assessed the absolute and relative bioavailabilities and transmucosal and gastrointestinal absorbency of fentanyl buccal tablet (FBT) and oral transmucosal fentanyl citrate (OTFC). In a randomized crossover design, 26 healthy subjects received FBT 400 μg (transmucosal), FBT 800 μg (oral), OTFC 800 μg (transmucosal), and fentanyl 400 μg (intravenous). The transmucosal FBT had the highest absolute bioavailability (0.65) compared with the oral FBT (0.31) or transmucosal OTFC (0.47). More fentanyl was absorbed transmucosally from FBT than OTFC (48% vs 22%). Median tmax values were shorter following the transmucosal FBT (47 minutes) than the oral FBT (90 minutes) or the transmucosal OTFC (91 minutes). Transmucosal administration of FBT compared with dose‐normalized OTFC resulted in higher total systemic fentanyl exposure, higher early systemic exposure, and higher Cmax. The rate and extent of fentanyl absorption were greater following administration of FBT compared to OTFC. An approximately 30% smaller dose of FBT achieved systemic exposures comparable to OTFC.

Phase I trial of orally administered CEP-701, a novel neurotrophin receptor-linked tyrosine kinase inhibitor

Purpose: A phase I clinical trial in patients with advanced carcinomas was conducted using the orally available neurotrophin receptor-linked tyrosine kinase receptor inhibitor, CEP-701. The objectives were to determine the maximum tolerated dose (MTD), dose-limiting toxicities, and pharmacokinetic profile of this orally administered agent. Patients and methods: A total of 30 patients were accrued to receive escalating BID doses of CEP-701 in cycles lasting 28 days. Between 3 and 6 patients were enrolled at each dose level. Once the MTD was determined, nine de novo patients were recruited to receive that level of drug. Pharmacokinetic studies were performed after the first dose, with additional sampling to assess intraindividual variability. Results: The dosages ranged from 5 mg BID to 160 mg BID. While the criteria for MTD were not met at the dose levels administered, DLTs were observed at 80 and 120 mg BID. Treatment related adverse events, especially of the gastrointestinal system, made CEP-701 poorly tolerated at dosages above 40 mg BID. While CEP-701 did not produce an objective tumor response in any patient, 7 of the 30 patients received treatment for 3 months or more, including 3 who were on study with stable disease for more than 6 months. Orally administered CEP-701 was rapidly absorbed, with a mean tmax between 1 and 3 hours. At higher dose levels, serum drug levels showed greater than dose-proportional increases by Day 28 versus Day 1. Conclusion: CEP-701 40 mg BID was well tolerated by patients with advanced malignancy and is the recommended dose level for planned phase II trials. Further study is necessary to determine the clinical efficacy of this novel new chemotherapeutic agent.

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.

Absorption of fentanyl from fentanyl buccal tablet in cancer patients with or without oral mucositis : A pilot study

AbstractBackground and objectives: Patients with cancer, particularly those undergoing chemotherapy or radiotherapy, may develop oral mucositis. This is the first study to investigate the absorption profile of fentanyl buccal tablet (FBT) — an effervescent formulation of fentanyl indicated for the management of breakthrough pain in opioid-tolerant cancer patients — in patients with or without oral mucositis. Methods: In this open-label study, patients with or without oral mucositis self-administered a single 200μg dose of FBT by placing the tablet between the upper gum and cheek above a molar tooth. Venous blood samples for measurement of plasma fentanyl concentrations were collected at regular intervals up to 8 hours following FBT administration. Parameters of interest included maximum plasma concentration (Cmax), time to reach Cmax (tmax), area under the plasma concentration-time curve from time zero to 8 hours (AUC8), and AUC from time zero to the median tmax (AUCtmax′). Adverse events were monitored throughout the study. Oral mucosal examinations and measurements of vital signs were performed at intervals up to 8 hours following FBT administration. Results: Sixteen patients, 8 with and 8 without oral mucositis, received FBT and completed the study. The severity of oral mucositis was mild in the patients exhibiting this condition. Median Cmax values were comparable: 1.14 ng/mL (range 0.26–2.69 ng/mL) in patients with mucositis, and 1.21 ng/mL (range 0.21–2.34 ng/mL) in patients without mucositis. The tmax was not significantly different in the two groups: median tmax was 25.0 min (range 15–45 min) in patients with mucositis and 22.5 min (range 10–121 min) in patients without mucositis. Median AUCtmax′ values were 0.17ng · h/mL (range 0.04–0.52 ng · h/ mL) in patients with mucositis, and 0.20 ng · h/mL (range 0.00–0.65 ng · h/mL) in patients without mucositis. The corresponding AUC8 values were 2.05 ng · h/mL (range 1.16–3.83 ng · h/mL) and 1.55 ng · h/mL (range 0.74–3.07 ng · h/ mL), respectively. FBT was generally well tolerated in this small group. No application site adverse events or changes in oral mucosal assessments were reported. Conclusion: The absorption profile of a single dose of FBT 200μg was similar in patients with or without mild oral mucositis. The compound was generally well tolerated.

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.