Nancy G. B. Agrawal

A Study to Determine the Effects of Food and Multiple Dosing on the Pharmacokinetics of Vorinostat Given Orally to Patients with Advanced Cancer

Purpose: This phase I study, conducted in advanced-stage cancer patients, assessed the safety and tolerability of oral vorinostat (suberoylanilide hydroxamic acid), single-dose and multiple-dose pharmacokinetics of vorinostat, and the effect of a high-fat meal on vorinostat pharmacokinetics. Experimental Design: Patients (n = 23) received single doses of 400 mg vorinostat on day 1 (fasted) and day 5 (fed) with 48 hours of pharmacokinetic sampling on both days. Patients received 400 mg vorinostat once daily on days 7 to 28. On day 28, vorinostat was given (fed) with pharmacokinetic sampling for 24 hours after dose. Results: The apparent t1/2 of vorinostat was short (∼1.5 hours). A high-fat meal was associated with a small increase in the extent of absorption and a modest decrease in the rate of absorption. A short lag time was observed before detectable levels of vorinostat were observed in the fed state, and Tmax was delayed. Vorinostat concentrations were qualitatively similar following single-dose and multiple-dose administration; the accumulation ratio based on area under the curve was 1.21. The elimination of vorinostat occurred primarily through metabolism, with <1% of the given dose recovered intact in urine. The most common vorinostat-related adverse experiences were mild to moderate nausea, anorexia, fatigue, increased blood creatinine, and vomiting. Conclusions: Vorinostat concentrations were qualitatively similar after single and multiple doses. A high-fat meal increased the extent and modestly decreased the rate of absorption of vorinostat; this effect is not anticipated to be clinically meaningful. Continued investigation of 400 mg vorinostat given once daily in phase II and III efficacy studies is warranted.

Pharmacodynamic and pharmacokinetic effects of TPA023, a GABAA α2,3 subtype-selective agonist, compared to lorazepam and placebo in healthy volunteers

TPA023, a GABAA α2,3 αsubtype-selective partial agonist, is expected to have comparable anxiolytic efficacy as benzodiazepines with reduced sedating effects. The compound Lacks efficacy at the α1 subtype, which is believed to mediate these effects. This study investigated the effects of 0.5 and 1.5 mg TPA023 and compared them with pLacebo and Lorazepam 2 mg (therapeutic anxioLytic dose). Twelve healthy maLe volunteers participated in this placebo-controlled, double-blind, double-dummy, four-way, cross-over study. Saccadic eye movements and visual analogue scales (VAS) were used to assess the sedative properties of TPA023. The effects on posturaL stability and cognition were assessed using body sway and a standardized battery of neurophysiological memory tests. Lorazepam caused a significant reduction in saccadic peak velocity, the VAS alertness score and impairment of memory and body sway. TPA023 had significant dose dependent effects on saccadic peak velocity (85 deg/sec maximum reduction at the higher dose) that approximated the effects of Lorazepam. In contrast to Lorazepam, TPA023 had no detectabLe effects on saccadic Latency or inaccuracy. Also unlike Lorazepam, TPA023 did not affect VAS alertness, memory or body sway. These results show that the effect profile of TPA023 differs markedly from that of Lorazepam, at doses that were equipotent with regard to effects on saccadic peak veLocity. Contrary to Lorazepam, TPA023 caused no detectabLe memory impairment or postural imbalance. These differences reflect the selectivity of TPA023 for different GABAA receptor subtypes.

Characterization of Etoricoxib, a Novel, Selective COX‐2 Inhibitor

Etoricoxib is a potent selective COX‐2 inhibitor in man. Ex vivo whole‐blood assays assessed COX‐2 inhibition after oral administration of etoricoxib in single (5–500 mg) and multiple (25–150 mg) once‐daily doses to healthy human subjects. A separate study examined ex vivo gastric mucosal PGE2 synthesis after etoricoxib (120 mg qd), naproxen (500 mg bid), or placebo for 5 days. The effect of etoricoxib 120 mg qd on the COX‐1‐mediated antiplatelet effects of low‐dose aspirin (ASA) was also assessed. The mean (time)–weighted average inhibition (WAI) of lipopolysaccharide (LPS)–stimulated PGE2(COX‐2 assay) versus placebo was dose related after single (range: 3.1%–99.1%) and multiple doses (range: 52.5%–96.7%). PGE2 remained significantly inhibited 24 hours postdose at steady state. Inhibition of LPS‐stimulated PGE2 showed a strong relationship with etoricoxib plasma concentrations; ex vivo, IC50 was almost identical to in vitro. Multiple dosing of etoricoxib (up to 150 mg qd) showed no important effects on serum TXB2, bleeding time, or platelet aggregation (COX‐1‐mediated effects). The nonselective nonsteroidal anti‐inflammatory (NSAID) naproxen significantly inhibited (∼78%) ex vivo prostaglandin synthesis in gastric mucosa; etoricoxib had no effect. Etoricoxib did not interfere with the antiplatelet effects of low‐dose ASA, as assessed by serum TXB2 and platelet aggregation. Etoricoxib was generally well tolerated, even at doses above the clinical dose range. Based on these results, etoricoxib is a potent selective inhibitor of COX‐2 after single and multiple dosing regimens and does not inhibit prostaglandin synthesis in the gastric mucosa, even at doses above the clinical dose range of 60 to 120 mg.

Etoricoxib in acute pain associated with dental surgery: A randomized, double-blind, placebo- and active comparator-controlled dose-ranging study

BACKGROUND Patients experiencing acute pain after surgery, including dental surgery, often require analgesia. Ideally, the chosen analgesic should have a rapid onset and sustained effect. Etoricoxib is a new cyclooxygenase-2-selective inhibitor that has demonstrated analgesic efficacy in the treatment of acute pain with a rapid onset and long-lasting pain relief. OBJECTIVE The goal of this study was to determine the analgesic effect of single oral doses of etoricoxib 60, 120, 180, and 240 mg compared with placebo in the treatment of pain after dental surgery. Ibuprofen was used as an active control. METHODS This was a randomized, double-blind, parallel-group, single-dose, placebo- and active comparator-controlled study performed at a single center. It consisted of 3 visits (prestudy, treatment, and poststudy). Eligible patients were aged > or =16 years with moderate or severe pain after surgical extraction of > or =2 third molars, of which > or =1 was an impacted mandibular molar. Patients were assessed over 24 hours and reported pain intensity and pain relied at 14 predefined time points. Plasma samples for a pharmacokinetic/pharmacodynamic analysis were collected from a subset of patients at baseline and the 14 predefined time points. The end points included total pain relief over 8 hours (TOPAR8, the primary end point), sum of pain intensity difference over 8 hours, patients global evaluation of treatment, median time to onset of pain relief (2-stopwatch method), peak pain relief, and duration of analgesic effect (median time to use of rescue medication). Adverse events were collected up to 14 days postdose. RESULTS Three hundred ninety-eight (63.1% women, 36.9% men; mean age, 21.1 years; 72.1% white, 27.9% other; mean number of third molars removed, 3.5; 65.2% experiencing moderate pain) were randomly allocated to receive etoricoxib 60 mg (n = 75), etoricoxib 120 mg (n = 76), etoricoxib 180 mg (n = 74), etoricoxib 240 mg (n = 76), ibuprofen 400 mg (n = 48), and placebo (n = 49). All active treatments had significantly greater overall analgesic effect (TOPAR8) compared with placebo (P < or 0.001). Patients who received etoricoxib 120 and 180 mg had significantly higher TOPAR8 scores than those who received etoricoxib 60 mg ( P < = 0.001) and ibuprofen (P < 0.05 etoricoxib 120 mg; P < or = 0.001 etoricoxib 180 mg). Least-squares mean TOPAR8 scores for etoricoxib 60, 120, 180, and 240 mg, ibuprofen, and placebo were 16.0, 22.0, 23.5, 20.7, 18.6, and 5.2, respectively. The median time to onset of analgesia was 24 minutes for etoricoxib 120, 180, and 240 mg, and 30 minutes for etoricoxib 60 mg and ibuprofen. There were no significant differences in the onset of analgesia between etoricoxib 120, 180, and 240 mg and ibuprofen. The duration of analgesic effect was >24 hours for etoricoxib 120, 180, and 240 mg, and 12.1 hours for etoricoxib 60 mg. The duration of effect was significantly longer with all 4 etoricoxib doses compared with ibuprofen (10.1 hours; P < 0.05 etoricoxib 60 mg; < or = 0.001etoricoxib 120, 180, and 240 mg) and compared with placebo (2.1 hours; P < = 0.001). In the pharmacokinetic/pharmacodynamic analysis (n approximately 120), there was a linear relationship between plasma etoricoxib concentrations and pain relief scores up to the maximum observed concentration, followed by a decline in plasma concentrations with persistent analgesia. The most common adverse events were postextraction alveolitis and nausea. CONCLUSIONS In this dose-ranging study, etoricoxib 120 mg was determined to be the minimum dose that had maximal efficacy in patients with moderate to severe acute pain associated with dental surgery. Both etoricoxib and ibuprofen were generally well tolerated.

Single- and Multiple-Dose Pharmacokinetics of Etoricoxib, a Selective Inhibitor of Cyclooxygenase-2, in Man

The single‐ and multiple‐dose pharmacokinetics of etoricoxib, a selective inhibitor of cyclooxygenase‐2, were examined in two clinical studies. Single‐dose pharmacokinetics—including dose proportionality, absolute bioavailability of the highest dose‐strength (120‐mg) tablet, and the effect of a high‐fat meal on the bioavailability of that tablet—were investigated in a two‐part, open, balanced crossover study in two panels of healthy subjects (12 per panel). Steady‐state pharmacokinetics were investigated in an open‐label study in which 24 healthy subjects were administered 120‐mg single and multiple (once daily for 10 days) oral doses of etoricoxib tablets. The pharmacokinetics of etoricoxib were found to be consistent with linearity through doses at least twofold greater than the highest anticipated clinical dose of 120 mg. Etoricoxib administered as a tablet was rapidly and completely absorbed and available; the absolute bioavailability was estimated to be 100%. A high‐fat meal decreased the rate of absorption without affecting the extent of absorption of etoricoxib; therefore, etoricoxib can be dosed irrespective of food. Steady‐state pharmacokinetics of etoricoxib, achieved following 7 days of once‐daily dosing, were found to be reasonably predicted from single doses. The accumulation ratio averaged 2.1, and the corresponding accumulation t1/2 averaged 22 hours, supporting once‐daily dosing. Etoricoxib was generally well tolerated.

Dose proportionality of oral etoricoxib, a highly selective cyclooxygenase-2 inhibitor, in healthy volunteers.

To assess dose proportionality of etoricoxib across the anticipated clinical dose range, a single panel of 12 healthy subjects was administered single oral doses of etoricoxib of 5,10, 20, 40, and 120 mg in an open, two‐part, five‐period crossover study. Plasma samples were collected after each dose and analyzed for etoricoxib concentrations. The pharmacokinetics of etoricoxib appear to be linear over the entire dose range examined, from 5 to 120 mg. Etoricoxib was found to be well tolerated across the 5 to 120 mg dose range.

Multiple-Dose Pharmacokinetics, Pharmacodynamics, and Safety of Taranabant, a Novel Selective Cannabinoid-1 Receptor Inverse Agonist, in Healthy Male Volunteers

Taranabant is a cannabinoid‐1 receptor inverse agonist for the treatment of obesity. This study evaluated the safety, pharmacokinetics, and pharmacodynamics of taranabant (5, 7.5, 10, or 25 mg once daily for 14 days) in 60 healthy male subjects. Taranabant was rapidly absorbed, with a median tmax of 1.0 to 2.0 hours and a t1/2 of approximately 74 to 104 hours. Moderate accumulation was observed in Cmax (1.18‐ to 1.40‐fold) and AUC0–24 h (1.5‐ to 1.8‐fold) over 14 days for the 5‐, 7.5‐, and 10‐mg doses, with an accumulation half‐life ranging from 15 to 21 hours. Steady state was reached after 13 days. After multiple‐dose administration, plasma AUC0–24 h and Cmax of taranabant increased dose proportionally (5–10 mg) and increased somewhat less than dose proportionally for 25 mg. Taranabant was generally well tolerated up to doses of 10 mg and exhibited multiple‐dose pharmacokinetics consistent with once‐daily dosing.

Merck’s perspective on the implementation of dried blood spot technology in clinical drug development – why, when and how

This paper communicates Mercks thoughts on why, when and how to use dried blood spot (DBS) technology in a clinical setting, and provides a strategic approach, emphasizing the necessary steps, for successful clinical implementation of this microsampling technique. PK consideration based on relevant in vitro data, that is, blood-to-plasma ratio, hematocrit, plasma unbound fraction and/or blood cell partition, is suggested to be part of the decision tree on when to choose DBS as a surrogate matrix for PK analysis. A quick feasibility assessment addressing analytical challenges, including sensitivity, hematocrit impact and storage stability, needs to be evaluated before initiating DBS studies. Special attention should be paid to the clinical sample collection procedures to ensure data quality. Bridging studies are required to establish the correlation between plasma and DBS data to ensure that pooling of data from the various clinical studies can be used in population PK or PK/PD assessment. Seeking regulatory feedback and guidance on a case-by-case basis is recommended.

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamic Properties of Taranabant, a Novel Selective Cannabinoid‐1 Receptor Inverse Agonist, for the Treatment of Obesity: Results From a Double‐Blind, Placebo‐Controlled, Single Oral Dose Study in Healthy Volunteers

Taranabant is a novel cannabinoid CB‐1 receptor (CB1R) inverse agonist in clinical development for the treatment of obesity. This double‐blind, randomized, placebo‐controlled, single oral dose study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of taranabant (0.5–600 mg) in 24 healthy male volunteers. Single‐dose AUC0‐∞ and Cmax values for taranabant increased approximately linearly ith dose up to 200 mg, with slightly less than dose‐proportional increases in AUC0‐∞ and Cmax values for doses >200 mg. Plasma taranabant had a biphasic disposition, with a median tmax of 1 to 2.5 hours and a terminal elimination tl/2 of 38 to 69 hours. Coadministration of taranabant with a high‐fat meal led to a 14% increase in Cmax and a 74% increase in AUC0‐∞, Clinical adverse experiences ssociated with single doses of taranabant were generally mild and transient. Of the 198 clinical adverse experiences reported, the most common drug‐related ones were nausea (36), headache (22), drowsiness (14), abdominal discomfort/abdominal pain/stomachache (14), hiccups (9), dizziness (8), decreased appetite (7), increased bowel movement (7), mood change (6), tiredness (4), vomiting (4), and sweating increased (4). Taranabant has pharmacokinetic characteristics suitable for a once‐daily dosing regimen.

Clinical pharmacology profile of vorinostat, a histone deacetylase inhibitor

PurposeVorinostat is a histone deacetylase inhibitor that has demonstrated preclinical activity in numerous cancer models. Clinical activity has been demonstrated in patients with a variety of malignancies. Vorinostat is presently indicated for the treatment of patients with advanced cutaneous T cell lymphoma (CTCL). Clinical investigation is ongoing for therapy of other solid tumors and hematological malignancies either as monotherapy or in combination with other chemotherapeutic agents. This review summarizes the pharmacokinetic properties of vorinostat.MethodsMonotherapy pharmacokinetic data across a number of pharmacokinetic studies were reviewed, and data are presented. In addition, literature review was performed to obtain published Phase I and II pharmacokinetic combination therapy data to identify and characterize potential drug interactions with vorinostat. Pharmacokinetic data in special populations were also reviewed.ResultsThe clinical pharmacology profile of vorinostat is favorable, exhibiting dose-proportional pharmacokinetics and modest food effect. There appear to be no major differences in the pharmacokinetics of vorinostat in special populations, including varying demographics and hepatic dysfunction. Combination therapy pharmacokinetic data indicate that vorinostat has a low propensity for drug interactions.ConclusionsVorinostat’s favorable clinical pharmacology and drug interaction profile aid in the ease of administration of vorinostat for the treatment of advanced CTCL and will be beneficial in continued assessment for other oncologic indications. Although a number of studies have been conducted to elucidate the detailed pharmacokinetic profile of vorinostat, more rigorous assessment of vorinostat pharmacokinetics, including clinical drug interaction studies, will be informative.