Maximum Measured Plasma Concentration Research Articles

Pharmacokinetics of single- and multiple-dose flumatinib in patients with chronic phase chronic myeloid leukemia.

Flumatinib is a novel, oral breakpoint cluster region-abelson (BCR-ABL) tyrosine kinase inhibitor that has demonstrated manageable safety and promising efficacy in patients with newly diagnosed chronic phase (CP) chronic myeloid leukemia (CML). This study evaluated the pharmacokinetic (PK) profiles of flumatinib mesylate tablets at a dose of 400 mg and 600 mg in patients with CML-CP. The study was registered at chictr.org Identifier (ChiCTR2100044700). In this open-label, pharmacokinetic study, eligible patients were administered a single-dose of flumatinib 400 mg or 600 mg on day 1, followed by 2-day washout and 8 consecutive days of once-daily administration. Serial plasma samples were assayed for flumatinib and its metabolites (N-demethylate metabolite M1 and amide-bond hydrolytic metabolite M3). Twenty-nine patients were assigned to flumatinib 400 mg (n=14) or 600 mg (n=15). Serum concentrations of flumatinib reached maximum measured plasma concentration (Cmax) at a median time of 2 hours after each single dose, and then eliminated slowly with a mean apparent terminal disposition half-life (t1/2) from 16.0 to 16.9 hours. Following single- and multiple-dose administration, flumatinib exposure (Cmax, area under the concentration-time curve from 0 to t hours (AUC0-t), area under the concentration-time curve from 0 hours to infinity (AUC0-∞)) increased in an approximately dose-proportional manner. There was approximately 4.1- and 3.4- fold drug accumulation at steady-state after multiple-dose administration at 400 mg and 600 mg, respectively. The drug-related AEs associated with both treatments were primarily low-grade and tolerable events. Analysis of PK parameters indicated that flumatinib exposure increased in an approximately dose-proportional manner. Further research needs to be conducted in a large sample-size study.

Bioequivalence of a hybrid pegylated liposomal doxorubicin hydrochloride injection and Caelyx®: A single-dose, randomized, multicenter, open-label, two-period crossover study in patients with advanced ovarian cancer

ObjectiveTo evaluate the bioequivalence of a hybrid pegylated liposomal doxorubicin (PLD) hydrochloride injection with reference product Caelyx®. MethodsThis multicenter, open-label, balanced, randomized, two-treatment, two-period, two-sequence, single-dose, crossover, bioequivalence study was conducted in female patients aged ≥18 years and ≤75 years with ovarian cancer, whose disease progressed or recurred after platinum-based chemotherapy, and who were scheduled to start PLD therapy. Patients were intravenously infused drugs over 1 h at 50 mg/m2 dose two hours after breakfast on the first day of the chemotherapy cycle in period-I and crossed over to the other arm in period-II (day 29). Pharmacokinetic (PK) analyses were performed using two separate, validated liquid chromatography-mass spectrometry methods for encapsulated and unencapsulated doxorubicin. ResultsBoth the test and reference formulations were well-tolerated and safe. The pharmacokinetic analysis for both encapsulated and unencapsulated doxorubicin was conducted in 50 patients and PK parameters were found to be comparable between test and reference products. The geometric mean ratios (90% confidence interval) of hybrid PLD/Caelyx® were; maximum measured plasma concentration (Cmax): 91.94-97.28%, area under the plasma concentration versus time from time 0 to t (AUC0-t): 95.19-103.67%, AUC from time 0 to ∞ (AUC0-∞): 95.13-103.66% for encapsulated doxorubicin and for unencapsulated doxorubicin Cmax: 92.08-116.46%, AUC0-t: 91.91-108.28%, AUC0-∞: 93.45-110.05%. ConclusionThe PLD formulation was found to be bioequivalent to Caelyx®.

Pharmacokinetic and bioavailability study of lercanidipine hydrochloride fast disintegrating tablets in rabbits by high-performance liquid chromatography

In the present study, fast disintegrating tablets of Lercanidipine Hydrochloride (LFDT) were tested in vivo in the buccal cavity of the rabbits. Various pharmacokinetic parameters were analysed in the study, including maximum measured plasma concentration (Cmax), time of maximum measured plasma concentration (tmax) and area under the plasma concentration vs time curve (AUC). Also, the comparative study of the Lercanidipine Hydrochloride fast disintegrating tablets (LFDT) was performed with the marketed conventional tablets of the drug (LMKT). The technique selected for the bioanalytical analysis of the blood samples of the rabbits for pharmacokinetic data computation was High-Performance Liquid Chromatography. An already well-established and validated method was used to analyse the blood samples of the rabbits. The results revealed that the rate of absorption was improved for fast disintegrating tablets of Lercanidipine Hydrochloride (LFDT) as compared to the marketed conventional tablets of the drug (LMKT). This indicated that drug was rapidly absorbed from the fast disintegrating tablet and attained elevated plasma concentration in a short interval after dosing than the marketed formulation. However, the value of tmax was drastically shorter for LFDT than the LMKT. The average peak plasma concentration also designated a rise in the extent of absorption (AUC). From the present study, it was concluded that the fast disintegrating tablet batch (LFDT) had much more improved pharmacokinetic parameters as compared to its conventional marketed counterpart (LMKT).

Safety, Tolerability and Pharmacokinetics of Single Ascending and Multiple Oral Doses of Tegoprazan in Healthy Chinese Subjects

Tegoprazan is one of the potassium-competitive acid blockers (P-CABs). It exhibits its anti-secretory effects by competitively and reversibly blocking the availability of K+ of the H+, K+-ATPase. This study was designed to investigate the safety and pharmacokinetics of tegoprazan in healthy Chinese subjects. Thirty-eight healthy Chinese subjects were recruited in this randomized, single-center, double-blind, placebo-controlled study, with a single ascending dose of 50, 100, 200 mg and a multiple dose of 100 mg for 10 days. The plasma concentration of tegoprazan was determined by a validated liquid chromatography tandem mass spectrometry (LC-MS/MS) method. Pharmacokinetics were evaluated via non-compartmental and compartmental model analysis. Safety was assessed by physical examinations, vital signs, clinical laboratory tests, and electrocardiograms. No serious adverse event was observed in this study. After single-dose administration (50, 100 and 200 mg), tegoprazan was rapidly absorbed with a median maximum measure plasma concentration (Tmax) at 0.5h and declined with a terminal (elimination) half-life (t1/2) of 3.87-4.57h. The maximum measured plasma concentration (Cmax) for tegoprazan was 813.80, 1494.60 and 2829.00 ng/mL. Meanwhile, the correspondingarea under the concentration-time curve (AUC)from time zero to infinity (AUC0-inf)was 2761.00, 5980.05 and 11,044.72 ng∙h/mL in 50, 100, 200 mg group, respectively. Dose-dependent increase was observed in the value of Cmax and AUC after administration of tegoprazan 50 to 200 mg. The two-compartment model well described the pharmacokinetic profile of tegoprazan. In the steady state, no accumulation was found after repeated administration at the 100-mg dose level. No experimental differences were found based on gender. Tegoprazan was well tolerated in the dose range of 50-200 mg in single- and 100 mginmultiple-dose studies. Tegoprazan shows dose linearity with oral administration after a single dose of 50 to 200 mg and less drug accumulation after 10 days of continuous administration in 100 mg.

Pharmacokinetics of Coadministered Viloxazine Extended-Release (SPN-812) and Methylphenidate in Healthy Adults.

Background and ObjectivesViloxazine extended-release (viloxazine ER, SPN-812) is a novel non-stimulant with activity at serotonin receptors and the norepinephrine transporter, which is under investigation as a potential treatment for attention-deficit/hyperactivity disorder. Given the potential for viloxazine ER to be coadministered with other pharmacotherapies, this trial investigated the pharmacokinetics and safety of combination viloxazine ER + methylphenidate versus viloxazine ER or methylphenidate alone.MethodsIn this single-center, crossover, open-label trial, healthy adult participants received oral administration of 700 mg viloxazine ER alone, 36 mg methylphenidate alone, and combination viloxazine ER (700 mg) + methylphenidate (36 mg), with blood samples collected over 4 days post-administration. The active drug in viloxazine ER (viloxazine) and methylphenidate was measured using chromatographic tandem mass spectrometry. Safety assessments included adverse events (AEs), vital signs, echocardiograms, and clinical laboratory evaluations.ResultsOf 36 healthy adults who were enrolled, 34 completed the trial. The geometric least squares mean ratios are reported as [combination/single drug (90% confidence intervals)]. For viloxazine ER, maximum measured plasma concentration (Cmax) = 100.98% (96.21–105.99), area under the concentration–time curve from time zero to the last measurable time (AUCt) = 98.62% (96.21–101.08), and area under the concentration–time curve from time zero to infinity (AUC∞) = 98.96% (96.55–101.44). For methylphenidate, Cmax = 103.55% (97.42–110.07), AUCt = 106.67% (101.01–112.64), and AUC∞ = 106.61% (100.99–112.54). All reported AEs were mild in severity.ConclusionsCoadministration of viloxazine ER and methylphenidate did not impact the pharmacokinetics of viloxazine or methylphenidate relative to administration of either drug alone. The combination appeared to be safe and well tolerated.

Bioavailability of Orally Administered Active Lipid Compounds from four Different Greenshell™ Mussel Formats.

Greenshell™ mussel (GSM, Perna canaliculus) is New Zealand’s most important aquaculture species. They are a good source of long chain-polyunsaturated fatty acids (n-3 LC PUFA). Beyond a traditional food product, GSMs are also sold as mussel powders and oil extract formats in the nutraceutical markets. In this study, a four-sequence, single dose, randomized crossover human trial with eight evaluable healthy male participants was undertaken to determine the bioavailability of the n-3 LC PUFA in four different GSM formats (oil, powder, food ingredient and half-shell unprocessed whole mussel) by measuring area under the curve (AUC) and maximal concentration (CMax). Blood samples were collected at baseline and up to 48 h after initiation of product consumption in each administration period. There were minor differences between the bioavailability of FA (fatty acid) between the different GSM formats. Eicosapentaenoic acid (EPA) peak concentrations and plasma exposures were significantly lower with GSM oil compared to GSM half-shell and GSM powder formats, which resulted in AUC0–48 for the intake of GSM half-shell mussel and GSM powder being significantly higher than that for GSM oil (p = 0.013, f= 4.84). This equated to a 20.6% and 24.3% increase in the amount of EPA present in the plasma after consumption of half-shell mussels and mussel powder respectively compared to GSM oil. GSM oil produced the shortest median time to maximal plasma n-3 LC PUFA concentration of all evaluated products demonstrated by a shorter maximum measured plasma concentration (TMax = 5 h). Docosahexaenoic acid (DHA) and n-3 LC PUFA plasma exposure parameters were statistically comparable across the four GSM products evaluated.

Improved bioavailability of cromolyn sodium using inhaled PA101 delivered via eFlow® nebulizer

ABSTRACT In 1960s, cromolyn sodium (CS) has been introduced as the first non-steroidal anti-inflammatory drug for the treatment of allergic and mast-cell driven diseases. Its applicability has been limited due to a poor bioavailability. Here we present pharmacokinetic data of a novel high concentration formulation of CS (PA101) delivered via a high-efficiency nebulizer (eFlow®) in healthy volunteers (HVs), allergic asthmatics and patients with indolent systemic mastocytosis (ISM). In HVs, PA101 40 mg and 80 mg (30 L) and PA101 40 mg (40 L), IntalTM (via LC® Plus) 20 mg and Nalcrom® (oral suspension) 200 mg showed maximum measured plasma concentration (Cmax) of 156, 236, 88.6, 17.8 and 5.23 ng/mL, respectively, with respective areas under the plasma time-concentration curve (AUC) of 338, 526, 212, 40.6 and 33.3 h·ng/mL. Systemic exposure (AUC) to CS with PA101 40 mg was approximately 8-fold and 11-fold higher compared to IntalTM and Nalcrom® in HVs, respectively. PA101 via eFlow® yielded comparable PK profiles in HVs and patients. Systemic bioavailability of PA101 was approximately 25% compared to approximately 1% for Nalcrom® and approximately 10% for IntalTM, respectively. These data warrant further research on the therapeutic potential of PA101 (via eFlow®) in allergic and mast-cell driven diseases.

A Single Dose, Four-Way, Open-Label Bioavailability Study of Oral Acetaminophen and Ibuprofen Combinations (Maxigesic®) under both Fasting and Fed Conditions

The use of fixed-dose combination pain relief has the potential to enhance analgesic efficacy. The pharmacokinetic properties of oral medication can be altered by many factors, including food, concomitant medications, and drug formulation. During the present study the pharmacokinetic parameters of an acetaminophen and ibuprofen combination was tested in four formulations. Testing was performed in two clinical trials examining either fasting or fed dosing conditions in healthy male participants. Both trials were single center, open-label, randomized, single dose studies with a four-way crossover design to compare an oral suspension product, a sachet product, and two different tablet formulations (FDC500/150 and FDC325/97.5). Each dose contained acetaminophen 975-1000 mg and ibuprofen 292.5-300 mg. A total of 26 participants completed the fasting study, while 28 completed the fed study. The absorption limits of different formulations of acetaminophen and ibuprofen were within the 80-125% bioequivalence range in both fasting and fed conditions as measured by the area under the plasma concentration– time curve from time zero to the time of the last measurable plasma concentration (AUC(0-t)) and the area under the curve from time zero to infinity (AUC(0-∞)). The maximum measured plasma concentration (Cmax) for the two tablet formulations were bioequivalent in fed conditions for both acetaminophen and ibuprofen, while in fasting conditions ibuprofen was also bioequivalent. Food reduced the Cmax and increased the time at which maximum measured plasma concentration occurred (tmax) of both acetaminophen and ibuprofen. This effect was largest in the sachet and oral suspension formulations, likely due to the drug being dissolved prior to administration, conferring more rapid absorption from the gastrointestinal tract. All treatments were well tolerated, with no treatment-emergent adverse events occurring. Overall, differing formulations and fasting conditions can alter the pharmacokinetic parameters Cmax, AUC(0-t), AUC(0-∞) and tmax of acetaminophen and ibuprofen combinations although the overall absorption remains bioequivalent.

Pharmacokinetics and Bioavailability of a Fixed-Dose Combination of Ibuprofen and Paracetamol after Intravenous and Oral Administration.

Background and ObjectivesPreviously published studies have suggested the lack of a pharmacokinetic interaction between ibuprofen and paracetamol when they are delivered as a fixed-dose oral combination. The aim of this study was to determine the pharmacokinetic profile and safety of a fixed-dose intravenous (IV) combination, containing 3 mg/mL ibuprofen and 10 mg/mL paracetamol, in comparison with its individual components. The study also assessed the relative bioavailability of the same doses of the active ingredients when they were administered as an oral formulation.MethodsA single-dose, open-label, randomized, five-period cross-over sequence pharmacokinetic study was undertaken in 30 healthy volunteers. Serial plasma samples were assayed for both paracetamol and ibuprofen concentrations, using validated liquid chromatography–tandem mass spectrometry methods. Pharmacokinetic parameters were computed using standard non-compartmental analyses. Adverse events were also assessed. The ratios of the maximum measured plasma concentration (Cmax), the area under the plasma concentration–time curve (AUC) from time zero to the time of the last measurable plasma concentration (AUCt) and AUC from time zero to infinity (AUC∞) were analysed for bioequivalence as determined by 90 % confidence intervals.ResultsThe pharmacokinetic parameters of ibuprofen and paracetamol were very similar for the combination and monotherapy IV preparations; the ratios of the Cmax, AUCt and AUC∞ values fell within the 80–125 % acceptable bioequivalence range. Precise dose proportionality for both compounds was also determined for the half dose of the IV formulation in comparison with the full dose. The relative bioavailability of paracetamol (93.78 %) and ibuprofen (96.45 %) confirmed the pharmacokinetic equivalence of the oral and IV formulations of the fixed-dose combination.ConclusionConcomitant administration of 3 mg/mL ibuprofen and 10 mg/mL paracetamol in a fixed-dose IV combination does not alter the pharmacokinetic profiles of either drug. The IV and oral dose forms of such a combination are pharmacokinetically equivalent.

Early pharmacokinetic of ropivacaine without epinephrine after injection into the psoas compartment

Large amounts of local anaesthetics (LA) are used during psoas compartment block (PCB), especially if combined with sciatic nerve block. Data regarding early pharmacokinetics of ropivacaine for PCB are lacking, notably when a vasoconstrictive agent has not been added. PCB was established in 11 patients using 150 mg ropivacaine without epinephrine. Free and total arterial plasma concentrations of ropivacaine were measured at nine time points during the following 30 min. Also total protein, albumin, and α1-acid glycoprotein concentrations were analysed. Ropivacaine plasma concentrations were found in all patients within 30 s after injections. Maximum measured plasma concentrations were measured in all but two patients within the first 10 min. One patient experienced partial intravascular injection. Plasma concentrations showed wide inter-individual variability. Ranges of maximum measured plasma concentrations of total and free ropivacaine were 422-3905 and 5-186 ng ml(-1), respectively. The Pearson correlation between total and free concentrations was 0.96. No obvious relationship between concentrations of different plasma proteins (total protein, albumin, α1-acid glycoprotein) and ropivacaine concentrations was found. Maximal 5% of the measured ropivacaine was unbound. All blocks were successful and no signs of toxicity were observed. Maximum measured plasma concentrations of ropivacaine after PCB must be expected within 10 min. Although plasma concentrations stayed below toxic thresholds, our study demonstrates the risk of this regional anaesthesia technique. The clinical study was not registered because enrolment of study patients occurred in 2006.

Tazarotene Foam versus Tazarotene Gel: A Randomized Relative Bioavailability Study in Acne Vulgaris

Tazarotene, a retinoid pro-drug, is available in gel, cream and foam for the topical treatment of acne vulgaris. This single-centre, randomized, open-label study assessed relative bioavailability of its active metabolite tazarotenic acid after dosing of tazarotene foam or gel. Subjects with moderate-to-severe acne received a mean, once-daily dose of 3.7 g tazarotene foam or gel applied to face, chest, upper back and shoulders. Blood samples were collected pre-dose on multiple days and multiple time points over a 72-h period to measure plasma tazarotenic acid and tazarotene. Mean tazarotenic acid area under the plasma concentration-time curve (AUC) and maximum measured plasma concentration (Cmax) values were significantly higher for gel versus foam. Cmax occurred within 5-6 h after dosing, with an apparent terminal elimination half-life (t½) of 18-22 h. Accumulation was observed upon repeated dosing with steady-state conditions achieved at day 20. Mean tazarotene concentrations were also higher following gel application versus foam. Both foam and gel demonstrated an acceptable safety profile. Tazarotene foam, 0.1 % is an alternative to gel with less systemic exposure.

A Study Investigating the Absorption and Pharmacokinetics of a Newly Developed Paracetamol/Caffeine Formulation Containing Sodium Bicarbonate in Healthy Volunteers

Aims: To assess pharmacokinetic (PK) bioequivalence between a newly developed formulation, rapid-relese paracetamol plus sodium bicarbonate and caffeine (RAPC), containing 500 mg paracetamol + 65 mg caffeine + 325 mg sodium bicarbonate), and the currently marketed Panadol® Extra product in both the fasted and semi-fed states. Study Design: A single center, randomized, open label, four-way crossover, PK study. Place and Duration of Study: MDS Pharma Services (Now Celerion), 2420, W. Baseline Road, Tempe, AZ 85283, between July 17, 2009 to August 10, 2009. Methodology: We included 30 healthy volunteers (20 males, 10 females; age range 18-55 years). The characterized PK parameters included total and partial area under the concentration time curve (AUC0-30min, AUC0-60min, AUC0-t/AUC0-∞), time to reach peak drug plasma concentration/therapeutic level (Tmax/Tc≥4ug/ml), and maximum measured plasma concentration (Cmax). The safety of the study treatments was also assessed. Results: In both fasted and semi-fed states, the exposure to paracetamol and caffeine for new RAPC formulation was bioequivalent to Panadol® Extra for AUC0-10 hrs, AUC0-∞ and Cmax with 90% confidence intervals (CIs), all being within the range 0.80 to 1.25, except for a higher paracetamol Cmax for RAPC in fasted state. RAPC exhibited significantly greater early absorption for both paracetamol (≥1.8-fold greater) and caffeine (≥1.3-fold greater) as determined by AUC0-30min and AUC0-60min, as well as significantly faster Tmax for both paracetamol (about 30 minutes faster) and caffeine (≥15 minutes faster) compared to currently marketed Panadol® Extra in both fasted and semi-fed states. The time to reach the therapeutic paracetamol plasma concentration (Tc≥4µg/ml) was about 12 and 33 minutes faster in fasted and semi-fed states respectively. The new formulation was safe and well tolerated. Conclusion: The newly developed RAPC formulation was found to be bioequivalent to Panadol® Extra caplets, and showed significantly faster absorption in both fasted and semi-fed states.

A Phase 1, randomized, open-label crossover study to evaluate the safety and pharmacokinetics of 400 mg albaconazole administered to healthy participants as a tablet formulation versus a capsule formulation

BackgroundAlbaconazole is a novel triazole being developed for the oral treatment of fungal diseases. Once-weekly oral dosing with 400 mg albaconazole for 24 or 36 weeks resulted in high rates of clinical and mycological resolution for distal subungual onychomycosis, as well as a favorable safety and tolerability profile.PurposeTo compare four 100-mg albaconazole capsules to one 400-mg albaconazole tablet for bioavailability, bioequivalence, tolerability, and safety.Patients and methodsForty participants were enrolled in this Phase I, open-label, two-sequence crossover study. Twenty participants were exposed to a single 400-mg tablet dose of albaconazole before being crossed over to a single dose of four 100-mg albaconazole capsules. The second group of 20 participants received the study products in reverse order. Blood samples were taken over 15 days post-dose to assess the plasma concentrations and pharmacokinetic parameters of albaconazole and its primary metabolite, 6-hydroxyalbaconazole. Safety was assessed throughout the study.ResultsThe area under the curve (AUC) and maximum measured plasma concentration (Cmax) of the albaconazole tablet were approximately 10% and 22% lower, respectively, than for the albaconazole capsules. Statistical significance was reached for the Cmax but not for the AUC measurements (AUC0-t and AUC0-inf). Because the 90% confidence intervals based on the differences between the tablet and capsule were outside the 80%–125% range for both the Cmax and AUC, we concluded that the formulations were not bioequivalent with respect to the rate or extent of absorption. Both formulations were safe and well-tolerated in this study. All adverse events (AEs) were generally mild and were mainly gastrointestinal- or nervous system-related (eg, dizziness, headache). No electrocardiogram findings were reported as an AE, and no serious AEs or deaths were reported.ConclusionThe AUC and Cmax of albaconazole after a single 400-mg oral dose administered as a tablet formulation were lower than those of a capsule formulation. Albaconazole tablets and capsules cannot, therefore, be considered bioequivalent.

Steady-state bioavailability of prescription omega-3 on a low-fat diet is significantly improved with a free fatty acid formulation compared with an ethyl ester formulation: the ECLIPSE II study

The systemic bioavailability of free fatty acid (FFA) forms of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) compared with ethyl ester (EE) forms is dependent on the presence of intestinal lipases and is highest during consumption of high-fat meals. Given that patients with cardiovascular disease are advised to reduce dietary fat intake, potentially lowering the bioavailability and therapeutic benefit, the hypothesis that FFA forms provide for higher bioavailability compared with EE forms under low-fat diet conditions was tested where the pharmacokinetics of the FFA form (Epanova™) were compared with those of an ethyl ester form (Lovaza®) following repeat dosing. Fifty-two healthy male and female subjects were equally allocated to one of two open-label, parallel-group cohorts. Following a Therapeutic Lifestyle Changes diet for a minimum of 7 days, blood samples were drawn for endogenous values for EPA and DHA over a 24-hour period. Subjects were then administered 4 × 1 g capsules of either Epanova (OM3 FFA) or Lovaza (OM3 EE) once daily for 14 days, following which serial blood samples were drawn over a 24-hour period to characterize the bioavailability of EPA and DHA from the respective formulations. In addition, changes from baseline in lipid profile were explored. Systemic bioavailability, as measured by area under the curve from time zero to 24 hours (AUC0-τ) and the maximum measured plasma concentrations during the 0–24 hour dosing interval (Cmax,ss) of unadjusted total plasma EPA + DHA were approximately 3-fold and 3.9-fold higher, respectively, for Epanova relative to Lovaza. Following baseline adjustment, the magnitude of difference in bioavailability was approximately 5.8-fold and 6.5-fold higher in AUC0-τ and Cmax, respectively, for Epanova relative to Lovaza. Serum triglycerides were reduced by a significantly greater extent (P = 0.013) for Epanova relative to Lovaza (21% versus 8%). The bioavailability of the FFA forms of EPA and DHA in Epanova are significantly greater than the bioavailability from the EE forms present in Lovaza under low-fat dietary conditions normally recommended for patients with cardiovascular disease. This increased bioavailability may lead to improved triglyceride-lowering in patients with hypertriglyceridemia.

A Phase I Study Evaluating the Pharmacokinetic Profile of a Novel, Proprietary, Nano-formulated, Lower-Dose Oral Indomethacin

Background: Safety and tolerability concerns associated with nonsteroidal anti–inflammatory drugs (NSAIDs) have prompted the development of lower–dose formulations. This phase 1 clinical study characterizes the pharmacokinetic (PK) profile of an investigational, proprietary, nano–formulated, lower–dose oral indomethacin (nano–formulated indomethacin) compared with standard oral indomethacin in healthy subjects. Methods: Forty healthy subjects were enrolled in a single–dose, randomized, 5-period, 5-treatment crossover study. Subjects received nano–formulated indomethacin 20 mg (fasted), or nano–formulated indomethacin 40 mg or standard indomethacin 50 mg (fed and fasted). Pharmacokinetic parameters, including maximum measured plasma concentration (Cmax), time to maximum measured concentration (Tmax), elimination half–life (T1/2), and area under the concentration–time (AUC) curve, along with safety and tolerability, were assessed. Results: There was a more rapid mean (± standard deviation) Tmax for nano–formulated indomethacin 20 mg (1.11 ± 0.55 h) and 40 mg (1.25 ± 0.60 h) compared with indomethacin 50 mg (1.97 ± 0.81 h) under fasting conditions, demonstrating faster absorption for the nano–formulated indomethacin. The T1/2 was similar for nano–formulated indomethacin 40 mg and indomethacin 50 mg. The Cmax for nano–formulated indomethacin 40 mg was higher compared with indomethacin 50 mg in fasted subjects (3115 ± 900 ng/mL vs 2759 ± 936 ng/mL, respectively), and slightly lower in fed subjects (1360 ± 424 ng/mL vs 1408 ± 469 ng/mL, respectively). There was a 26% reduction in drug exposure (AUC0-∞) when subjects received nano–formulated indomethacin 40 mg compared with indomethacin 50 mg under fasting conditions (6861 ± 1585 h*ng/mL vs 9306 ± 2234 h*ng/mL, respectively). Safety and tolerability were comparable between formulations. Conclusion: The nano–formulated, lower–dose indomethacin had an improved PK profile compared with indomethacin. Under the advisory issued by worldwide regulatory agencies regarding use of lowest effective doses, these data may support use of lower–dose NSAID formulations that improve safety/tolerability while maintaining pain relief similar to standard NSAID formulations.

Phase I Pharmacologic and Pharmacodynamic Study of the Gamma Secretase (Notch) Inhibitor MK-0752 in Adult Patients With Advanced Solid Tumors

Aberrant Notch signaling has been implicated in the pathogenesis of many human cancers. MK-0752 is a potent, oral inhibitor of γ-secretase, an enzyme required for Notch pathway activation. Safety, maximum-tolerated dose, pharmacokinetics (PKs), pharmacodynamics, and preliminary antitumor efficacy were assessed in a phase I study of MK-0752. MK-0752 was administered in three different schedules to patients with advanced solid tumors. Hair follicles were collected at higher dose levels to assess a gene signature of Notch inhibition. Of 103 patients who received MK-0752, 21 patients received a continuous once-daily dosing at 450 and 600 mg; 17 were dosed on an intermittent schedule of 3 of 7 days at 450 and 600 mg; and 65 were dosed once per week at 600, 900, 1,200, 1,500, 1,800, 2,400, 3,200, and 4,200 mg. The most common drug-related toxicities were diarrhea, nausea, vomiting, and fatigue. PKs (area under the concentration-time curve and maximum measured plasma concentration) increased in a less than dose proportional manner, with a half-life of approximately 15 hours. Significant inhibition of Notch signaling was observed with the 1,800- to 4,200-mg weekly dose levels, confirming target engagement at those doses. One objective complete response and an additional 10 patients with stable disease longer than 4 months were observed among patients with high-grade gliomas. MK-0752 toxicity was schedule dependent. Weekly dosing was generally well tolerated and resulted in strong modulation of a Notch gene signature. Clinical benefit was observed, and rational combination trials are currently ongoing to maximize clinical benefit with this novel agent.

The Pharmacokinetic Parameters of a Single Dose of a Novel Nano–formulated, Lower-Dose Oral Diclofenac

Introduction: There is a clinical need for new nonsteroidal anti–inflammatory drugs (NSAIDs) and/or new formulations that, at minimum, retain the established efficacy of standard NSAIDs while minimizing their associated adverse events. This phase 1 clinical trial characterizes the pharmacokinetic (PK) profile of an investigational, proprietary, nano–formulated, lower–dose oral diclofenac (nano–formulated diclofenac) compared with oral diclofenac in healthy subjects. Methods: A single–center, single–dose, randomized, open–label, 5–period, 5–treatment, 10–sequence crossover study was completed in 30 healthy subjects. Subjects received either nano–formulated diclofenac 18 mg or 35 mg or diclofenac 50 mg in fed and fasting states. The maximum measured plasma concentration (Cmax), time to maximum measured concentration (Tmax), terminal elimination half–life (T1/2), and area under the concentration time curve (AUC), along with safety and tolerability, were assessed. Results: Mean (± standard deviation) Tmax for nano–formulated diclofenac 18 (0.62 ± 0.35 h) and 35 mg (0.59 ± 0.20 h) demonstrated faster absorption than diclofenac 50 mg (0.80 ± 0.50 h). The T1/2 was similar between nano–formulated diclofenac 35 mg and diclofenac 50 mg (1.85 ± 0.45 h vs 1.92 ± 0.38 h, respectively). The Cmax for nano–formulated diclofenac 35 mg and diclofenac 50 mg was comparable in fasted subjects (1347 ± 764 ng/mL vs 1316 ± 577 ng/mL, respectively), but lower in fed subjects (524 ± 222 ng/mL vs 951 ± 391 ng/mL, respectively). As anticipated, there was a 19% reduction in drug exposure (AUC0–∞) when subjects received nano–formulated diclofenac 35 mg compared with diclofenac 50 mg under fasting conditions (1225 ± 322 h*ng/mL vs 1511 ± 389 h*ng/mL, respectively). Safety and tolerability were comparable between nano–formulated diclofenac and diclofenac. Conclusion: The novel nano–formulated, lower–dose diclofenac demonstrated lower systemic exposure, comparable Cmax, and faster absorption compared with diclofenac. In light of the advisory issued by worldwide regulatory agencies regarding use of lowest effective doses, these data may permit use of lower NSAID doses that improve safety and tolerability while, at minimum, relieving pain similar to standard formulations.

First-in-Man Clinical Trial of the Oral Pan-AKT Inhibitor MK-2206 in Patients With Advanced Solid Tumors

AKT signaling is frequently deregulated in human cancers. MK-2206 is a potent, oral allosteric inhibitor of all AKT isoforms with antitumor activity in preclinical models. A phase I study of MK-2206 was conducted to investigate its safety, maximum-tolerated dose (MTD), pharmacokinetics (PKs), pharmacodynamics (PDs), and preliminary antitumor efficacy. Patients with advanced solid tumors received MK-2206 on alternate days. Paired tumor biopsies were mandated at the MTD for biomarker studies. PD studies incorporated tumor and hair follicle analyses, and putative predictive biomarker studies included tumor somatic mutation analyses and immunohistochemistry for phosphatase and tensin homolog (PTEN) loss. Thirty-three patients received MK-2206 at 30, 60, 75, or 90 mg on alternate days. Dose-limiting toxicities included skin rash and stomatitis, establishing the MTD at 60 mg. Drug-related toxicities included skin rash (51.5%), nausea (36.4%), pruritus (24.2%), hyperglycemia (21.2%), and diarrhea (21.2%). PKs (area under the concentration-time curve from 0 to 48 hours and maximum measured plasma concentration) were dose proportional. Phosphorylated serine 473 AKT declined in all tumor biopsies assessed (P = .015), and phosphorylated threonine 246 proline-rich AKT substrate 40 was suppressed in hair follicles at 6 hours (P = .008), on days 7 (P = .028) and 15 (P = .025) with MK-2206; reversible hyperglycemia and increases in insulin c-peptide were also observed, confirming target modulation. A patient with pancreatic adenocarcinoma (PTEN loss; KRAS G12D mutation) treated at 60 mg on alternate days experienced a decrease of approximately 60% in cancer antigen 19-9 levels and 23% shrinkage in tumor measurements. Two patients with pancreatic neuroendocrine tumors had minor tumor responses. MK-2206 was well tolerated, with evidence of AKT signaling blockade. Rational combination trials are ongoing to maximize clinical benefit with this therapeutic strategy.

A Randomized, Open-Label, Crossover Study Evaluating the Effect of Food on the Relative Bioavailability of Linagliptin in Healthy Subjects

Objective The objective of this study was to determine the relative bioavailability of the dipeptidyl-peptidase-4 (DPP-4) inhibitor linagliptin when administered with and without food, in accordance with regulatory requirements to support dosing recommendations for patients. Methods This was a randomized, open-label, crossover study involving 32 healthy white male and female subjects. All subjects received a single dose of 5 mg linagliptin after an overnight fast of at least 10 hours, or immediately after ingestion of a high-fat, high-calorie breakfast. These treatments were separated by a period of 5 weeks. Plasma samples for pharmacokinetic analysis were collected before dosing and at prespecified time points after dosing. The concentration of linagliptin in these samples was analyzed by high-performance liquid chromatography coupled to tandem mass spectrometry. Relative bioavailability was assessed by the total area under the curve between 0 and 72 hours (AUC 0–72) and maximum measured plasma concentration (C max) of linagliptin. Tolerability was also assessed. Results In 32 subjects (mean age, 34.8 years; weight, 74.3 kg; male, 53%; white race, 100%), intake of a high-fat meal resulted in comparable bioavailability with regard to AUC 0–72 (geometric mean ratio [GMR] between the fed and fasted group means was 103.5%; 90% CI, 98.1%–109.2%). Individuals' responses to food ranged from a maximum increase in exposure of 38% to a decrease of 32% relative to the fasted state. The concurrent intake of food increased the time to reach maximum plasma concentration (T max) by approximately 2 hours and reduced C max by about 15% (GMR 84.7%; 90% CI, 75.9%–94.6%). Since adequate drug exposure for inhibition of DPP-4 was still given for the entire 24-hour dosing interval, this result was considered to be of no clinical relevance. Linagliptin was well tolerated during the study. Conclusions Intake of a high-fat meal reduced the rate of linagliptin absorption but had no influence on the extent of absorption; this finding suggests that food has no relevant influence on the efficacy of linagliptin.

Coadministration With Lopinavir and Ritonavir Decreases Exposure to BILR 355, a Nonnucleoside Reverse Transcriptase Inhibitor, in Healthy Volunteers

The objective of this investigation was to evaluate the pharmacokinetic interaction of lopinavir/ritonavir (LPV/r) with BILR 355. In group A, 26 healthy participants were administered LPV/r (400mg/100mg) twice daily for 14 days, followed by coadministration of BILR 355, 150 mg twice daily for an additional 7 days. Pharmacokinetic assessments were performed on days 14 and 21. In group B, 8 healthy participants were given BILR 355/ritonavir (BILR 355/r, 150 mg/100mg) twice daily for 7 days. The pharmacokinetic data from group B (BILR 355/r-alone group) were also pooled with group B subjects from 3 similar phase I drug-drug interaction trials performed in parallel to this study. Coadministration with LPV/r resulted in a 51% decrease in steady-state area under plasma concentration-time curve from 0 to 12 hours (AUC(0-12,ss)) and steady-state maximum measured plasma concentration over a dosing interval (C(max,ss)) and a 50% decrease in steady-state plasma concentration 12 hours post last dosing (C(12,ss)) for BILR 355. Exposure to LPV was not changed after coadministration. BILR 355/r was well tolerated in this study. There was no evidence of increased risk of lopinavir or ritonavir toxicity upon coadministration with BILR 355.