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CC-90001 selectively inhibits c-Jun N-terminal kinase (JNK), a stress-activated protein implicated in fibrosis. In 3 phase 1 trials evaluating CC-90001 pharmacokinetics, pharmacodynamics, and safety, healthy adults (N = 184) received oral CC-90001 in a single dose (10-720 mg) or multiple doses (30-480 mg once daily for 7-18 days) or placebo. CC-90001 was rapidly absorbed (median time to maximum concentration, 1-4 hours) and eliminated with a mean terminal elimination half-life of 12-28 hours. Steady state was reached on day 5, with a mean accumulation ratio of 1.5- to 2-fold following daily dosing. Exposure was similar in fed versus fasted participants and in Japanese versus non-Japanese participants. CC-90001 demonstrated dose- and exposure-dependent inhibition of JNK as determined by histopathological analysis of c-Jun phosphorylation in ultraviolet-irradiated skin. The most common treatment-emergent adverse events were nausea and headache; all were mild or moderate in intensity. Based on exposure-response analysis using high-quality electrocardiogram data, no clinically relevant QT prolongation liability for CC-90001 was observed. Overall, single- and multiple-dose CC-90001 were generally safe and well tolerated at the tested doses and demonstrated JNK pathway engagement. These results support further clinical evaluation of CC-90001.

As a first-in-class, selective, potent inhibitor of the isocitrate dehydrogenase-2 (IDH2) mutant protein, enasidenib was approved by the US Food and Drug Administration in 2017 for the treatment of adult patients with relapsed or refractory acute myeloid leukemia with an isocitrate dehydrogenase-2 mutation. An in vitro study showed that enasidenib at clinically relevant concentrations has effects on multiple drug metabolic enzymes and transporters, including inhibition of P-glycoprotein, breast cancer resistance protein, organic anion transporter (OAT) P1B1, and OATP1B3 transporters. Therefore, a drug-drug interaction study was conducted to assess the impact of enasidenib at steady state on the pharmacokinetics of several probe compounds in patients with relapsed or refractory acute myeloid leukemia or myelodysplastic syndrome, including the probes herein described in this article, digoxin and rosuvastatin. Results from 8 patients (all Asian) with a mean age of 67.1 years showed that following coadministration of enasidenib (100 mg, 28-day once-daily schedule) for 28 days (at steady state), digoxin's (0.25 mg) area under the plasma concentration-time curve from time 0 to 30 days was 1.2-fold (90% confidence interval, 0.9-1.6), compared with digoxin alone. Following coadministration of enasidenib (100 mg, 28-day once-daily schedule) for 28 days (at steady state), rosuvastatin's (10 mg) area under the plasma concentration-time curve from time 0 to infinity was 3.4-fold (90% confidence interval, 2.6-4.5) compared with rosuvastatin alone. These results should serve as the basis for dose recommendations for drugs that are substrates of P-glycoprotein, breast cancer resistance protein, OATP1B1, and OATP1B3 transporters, when used concomitantly with enasidenib.

Introduction The purpose of this study was to evaluate the absolute bioavailability (BA) of AG-221 following a single oral dose of 100 mg AG-221 and an intravenous (IV) dose of ~ 100 μg AG-221 containing approximately 300 nCi of [14C]-AG-221. Methods This was a phase 1, open-label study. Six subjects who met all of the inclusion criteria and none of the exclusion criteria were enrolled in the study. After an overnight fast of at least 10 h, the subjects received an oral dose (coated tablet) of 100 mg of AG-221 at 0 h on dosing day. Four hours after the oral dose, the subjects received 100 μg AG-221 containing ~ 300 nCi of [14C]-AG-221 administered as an IV bolus. Blood samples were collected and analyzed for plasma concentrations of AG-221 and [14C]-AG-221 using a validated liquid chromatography with tandem mass spectrometry (LC–MS/MS) system and high-performance liquid chromatography (HPLC) fractionation followed by accelerator mass spectrometry analysis (AMS), respectively. Safety was evaluated throughout the study. Results The absolute BA after a 100-mg oral dose of AG-221 was measured as 57.2%. While the total clearance was 1.37 L/h, ~ 1/60 of the liver blood flow in a typical 70-kg human subject, the first-pass extraction was estimated to be less than 2%, assuming that the total clearance was entirely due to liver metabolism. Thus, the fraction of the AG-221 dose absorbed was at least 50%. AG-221 was safe and well tolerated when given under fasted conditions in a single 100-mg dose as a coated tablet with a microtracer [14C]-AG-221 solution, as few drug-related treatment-emergent adverse events (TEAEs) were reported. No clinically significant changes or findings were noted in the clinical laboratory evaluations, vital sign measurements, and electrocardiograms (ECGs) performed during this study. Conclusions In healthy subjects under fasting conditions, the absolute BA following oral administration of a 100-mg AG-221 tablet was 57.2%. AG-221 was safe and well tolerated in healthy male subjects when administered as a single 100-mg film-coated tablet plus 100 µg [14C]-AG-221 given intravenously. Trial Registration ClinicalTrials.gov identifier, NCT02443168. Funding Celgene Corporation.

Pomalidomide is an immunomodulatory drug and the dosage of 4 mg per day taken orally on days 1‐21 of repeated 28‐day cycles has been approved in the European Union and United States to treat patients with relapsed/refractory multiple myeloma. Because pomalidomide is extensively metabolized prior to excretion, a total of 32 subjects (8 healthy subjects in group 1; 8 subjects with severe hepatic impairment in group 2; 8 subjects with moderate hepatic impairment in group 3; and 8 subjects with mild hepatic impairment in group 4) were enrolled in a multicenter, open‐label, single‐dose study to assess the impact of hepatic impairment on pomalidomide exposure. Following administration of a single oral dose of 4‐mg pomalidomide, the geometric mean ratios of pomalidomide total plasma exposures (AUC) were 171.5%, 157.5%, and 151.2% and the geometric mean ratios of pomalidomide plasma peak exposures (Cmax) were 75.8%, 94.8%, and 94.2% for subjects with severe, moderate, or mild hepatic impairment, respectively, versus healthy subjects. Pomalidomide administered as a single oral 4‐mg dose was safe and well tolerated by healthy subjects and subjects with severe, moderate, or mild hepatic impairment. Based on the pharmacokinetic results from this study, the pomalidomide prescribing information approved by the US Food and Drug Administration recommends for patients with mild or moderate hepatic impairment (Child‐Pugh classes A or B), a 3‐mg starting daily dose (25% dose reduction) and for patients with severe hepatic impairment (Child‐Pugh class C), a 2‐mg starting daily dose (50% dose reduction).

This phenomenological research examines the situation of Badjao Street Children specifically about their daily routines in the street and the culture related reason for going back in the street despite the decent life which the government has planned in their newly built homes. The study utilizes the qualitative phenomenological research and used interview guide questions and observation checklist. The findings were analyzed using ngColaizzi’s method. The results of findings show that the age of most Badjao street children ranges from 10 to 12 years old, male and are grade 3 students. Regarding their routines, they attend school, help their family by assisting in the household and by taking care of their siblings. They also go on streets to beg and ask for help, especially those who do not go to school. The routines of these children, especially begging may be attributed to the poverty which their families are experiencing when they transfer to Cabanatuan City. They are used to the works of the sea and are not used to jobs which they can do on the land. They resulted in begging since they do not know other ways of finding money to spend on their foods and other daily expenses. This research recommends intervention programs like livelihood training, values formations, and education.

Yan Li,1 Liangang Liu,2 Lian Huang,3 Xiaomin Wang,4 Matthew Hoffmann,4 Josephine Reyes,1 Maria Palmisano,1 Simon Zhou1 1Translational Development and Clinical Pharmacology, 2Biometrics and Data Operations, 3Pharmaceutical Science Drug Product Development, 4Non-Clinical Development, Celgene Corporation, Summit, NJ, USA Objective: The aim of this study was to evaluate the bioavailability of a pomalidomide oral liquid suspension relative to the commercial capsule formulation and to assess the food effect on the pomalidomide oral liquid suspension when administered as a single 4mg dose. Methods: This was an open-label, randomized, three-period, two-sequence crossover study in healthy subjects consisting of a screening phase, a baseline assessment phase, a treatment phase with three periods, and a follow-up phone call phase. Blood samples for pharmacokinetics (PK) assessment were collected up to 48h postdose during each treatment period. Safety was evaluated throughout the study. Results: Pomalidomide exposures were comparable in healthy subjects administered with a single oral 4mg dose as the reference capsule or as the test liquid suspension formulations, demonstrated as the 90% confidence intervals of the geometric mean ratios for area under the plasma concentration–time curve calculated from time 0 to the last measurable concentration at time t (AUC0–t), area under the plasma concentration–time curve from time 0 to infinity (AUC0–∞), and peak (maximum) plasma drug concentration (Cmax) were completely contained within the bioequivalence range of 80–125%. Administration of the pomalidomide liquid suspension with a high fat meal resulted in a 3.0h delay in pomalidomide time to Cmax (tmax) and an ~ 34.5% reduction in Cmax. However, the AUCs were comparable after dose administration with and without food. Conclusion: A single oral dose of 4mg of liquid suspension was bioequivalent to a single oral dose of 4mg of capsule formulation. There was no clinically relevant impact of food on pomalidomide liquid suspension. Single oral doses of 4mg pomalidomide were safe and well tolerated when administered as a liquid suspension under fed and fasted conditions or as a capsule under fasted conditions. Keywords: pomalidomide, liquid suspension, bioavailability, bioequivalence, food effect

Yan Li,1 Xiaomin Wang,2 Liangang Liu,3 Josephine Reyes,1 Maria Palmisano,1 Simon Zhou1 1Translational Development and Clinical Pharmacology, Celgene Corporation, Summit, NJ, USA; 2Non-Clinical Development, Celgene Corporation, Summit, NJ, USA; 3Biometrics and Data Operations, Celgene Corporation, Summit, NJ, USA Objective: To assess whether pomalidomide can distribute into human semen and its duration in human semen. Method: A phase 1, randomized, double-blind, placebo-controlled study (CC-4047-CP-006) was conducted to evaluate the safety, tolerability, and pharmacokinetics of pomalidomide (CC-4047) following multiple daily doses in healthy male subjects. Semen samples were collected on Day −1 and 4 hours after dosing on Day 4 to quantify the pomalidomide concentrations in ejaculate after multiple oral doses of pomalidomide. Result: Our study showed that pomalidomide was present in male subjects’ semen samples, and the average amount of pomalidomide in a single ejaculate 4 hours after dosing was less than 0.0022% of the daily 2 mg dose. There was a good correlation between the semen concentrations and the plasma concentrations, suggesting that the plasma concentration may be the main driving force for the distribution of pomalidomide into the seminal reservoirs. Simulation results suggest that pomalidomide was undetectable in semen 48 hours after stopping dosing. Conclusion: Based on the results from this study, the pomalidomide prescribing information approved by the US Food and Drug Administration includes a statement that “pomalidomide is present in the semen of patients receiving the drug. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 4 weeks after discontinuing POMALYST, even if they have undergone a successful vasectomy. Male patients taking POMALYST must not donate sperm.” Keywords: pomalidomide, distribution, semen, teratogen, kinetics

1. The absorption, distribution, metabolism and excretion (ADME) of enasidenib were studied following a single oral dose of [14C]enasidenib to rats (10 mg/kg; 100 μCi/kg) and healthy volunteers (100 mg; 318 nCi). 2. Enasidenib was readily absorbed, extensively metabolized and primarily eliminated via the hepatobiliary pathway. Enasidenib-derived radioactivity was widely distributed in rats. Excretion of radioactivity was approximately 95% to 99% of the dose from rats in 168 hours post-dose and 82.4% from human volunteers in 504 hours post-dose. In rat bile, approximately 35% to 42% of the administered dose was recovered, with less than 5% of the dose excreted as the parent drug. Renal elimination was a minor pathway, with < 12% of the dose excreted in rat urine and < 10% of the dose excreted in human urine. 3. Enasidenib was the prominent radioactive component in rat and human systemic circulation. Enasidenib was extensively metabolized in rats and human volunteers through N-dealkylation, oxidation, direct glucuronidation, and combinations of these pathways. Glucuronidation was the major metabolic pathway in rats while N-dealkylation was the prominent metabolic pathway in human volunteers. All human metabolites were detected in rats.

Purpose Lenalidomide, a weak substrate of P-glycoprotein (P-gp) in vitro, is an oral anticancer drug eliminated predominantly via renal excretion as unchanged compound. The role of P-gp in lenalidomide disposition and the associated clinical relevance were evaluated. Methods Two phase I, crossover studies were conducted in healthy volunteers. In Study 1, subjects received lenalidomide (10 mg × 7 days) alone or with the P-gp substrate digoxin (0.5 mg on Day 5). In Study 2, subjects received lenalidomide (a single 25 mg dose) alone, the P-gp inhibitor quinidine (300–600 mg twice-daily × 5 days) plus lenalidomide (on Day 4), the P-gp inhibitor/substrate temsirolimus (a single 25 mg dose) alone, or lenalidomide plus temsirolimus. Pharmacokinetic and safety data were collected for lenalidomide and the co-administrated drugs. Results There were no significant changes in the maximum concentration (Cmax) and area under the plasma concentration–time curve (AUC) of lenalidomide when co-administered with quinidine, digoxin, or temsirolimus. Neither the rate nor the capacity of lenalidomide renal excretion was affected by quinidine or temsirolimus, in addition lenalidomide absorption rate and bioavailability remained unchanged. Furthermore, lenalidomide had no significant effect on blood Cmax and AUC of temsirolimus and its active metabolite sirolimus (also a P-gp inhibitor/substrate). The Cmax of digoxin was slightly higher (+14 %) when administered with lenalidomide versus placebo. There were no other changes in digoxin pharmacokinetics upon co-administration with lenalidomide. No remarkable safety findings were observed. Conclusions There are no clinically significant pharmacokinetic interactions between lenalidomide and substrates or inhibitors of P-gp.

The effect of lenalidomide on the corrected QT (QTc) interval was evaluated in healthy men and extended to patients based on the lenalidomide concentration–QTc (C–QTc) relationship. A rigorous assessment of the effect of lenalidomide on QTc intervals was conducted in healthy volunteers who each received, in randomized order, a single oral dose of 10 mg lenalidomide, 50 mg lenalidomide, 400 mg moxifloxacin (positive control) and placebo. Plasma lenalidomide exposure was compared between healthy volunteers and patients with multiple myeloma or myelodysplastic syndromes. In healthy volunteers, moxifloxacin produced the expected significant prolongation in QTcI (individual correction). For lenalidomide 10 mg and 50 mg, the time-matched changes from placebo in the baseline-adjusted least-squares mean QTcI were 450 ms or change from baseline >60 ms after lenalidomide administration. Similar results were seen with QT interval data corrected by Fridericia and Bazett methods. The C–QTc analysis yielded no significant association between lenalidomide concentrations and QTcI changes up to 1522 ng/mL; this range was close to that observed in patients receiving lenalidomide doses up to 50 mg, including those with reduced drug clearance due to renal impairment. In conclusion, single doses of lenalidomide up to 50 mg were not associated with prolonged QTc intervals in healthy males. The C–QTc analysis further assured that lenalidomide doses up to 50 mg are not expected to prolong QTc intervals in patients.

Lenalidomide is an immunomodulatory drug with efficacy in various hematological malignancies. The purpose of these studies was to evaluate the single-dose pharmacokinetics of lenalidomide, including dose proportionality, food effect, and racial sensitivity.Three studies were conducted including a total of 58 healthy subjects: a randomized, single-blind, alternating group, single-ascending dose study; a randomized, two-way crossover food effect study; and a randomized, double-blind, two-group, within-subject, single-ascending dose study.Oral absorption of lenalidomide was rapid and the maximum plasma concentration (C (max)) was observed approximately 1 h post-dose. Co-administration with a high-fat meal reduced the area under the concentration-time curve (AUC) and C (max) by approximately 20 and 50 %, respectively, and delayed time to C (max) (t (max)) by 1.63 h. However, phase III trials were dosed without regard to food; therefore, clinical relevance of the food effect was minimal. The terminal elimination half-life (t (½)) was 3-4 h at doses up to 50 mg and was not affected by food. The AUC and C (max) were proportional to lenalidomide single doses (5-400 mg), and total and renal clearance were dose-independent. The R- to S-lenalidomide ratio in plasma was stable over time, approximately 45-55 % of total drug. There were no differences in pharmacokinetic parameters, dose-exposure relationship, or enantiomeric ratio, between Japanese and Caucasian subjects.Lenalidomide displayed linear pharmacokinetics from doses 5-400 mg in healthy subjects. Although food reduced bioavailability, this was not considered clinically relevant. Lenalidomide was generally well tolerated in both ethnic groups.

This study was conducted to characterize the pharmacokinetic and safety profile of rabeprazole sodium tablets in children and adolescents with gastroesophageal reflux disease (GERD).This was a multicenter, open-label, single- and multiple-dose study in subjects aged 12 to 16 years with GERD. Subjects were stratified by age (12-14 years and 14-16 years) and were randomized to receive oral rabeprazole 10 or 20 mg/d over 5 or 7 days (to accommodate weekends). The pharmacokinetic parameters calculated included C(max), T(max), AUC, t(1/2), and apparent oral clearance (day 5/7 only). Blood samples for pharmacokinetic determinations were obtained on study days 1, 2, and 5 (or 7) and at discharge on day 6 (or 8). Safety assessments, including adverse events (AEs), were performed at all study visits.Twenty-four subjects were enrolled in the study (12 in each dose group); they were predominantly white, had a mean age of 14.2 years, and had a mean body mass index of 24.3 kg/m(2) (the 90th percentile for adolescents of this age in the United States). Mean age and weight did not differ significantly between the 2 dose groups. On day 1, C(max) was significantly greater in the rabeprazole 20-mg group compared with the rabeprazole 10-mg group (P = 0.024); on day 5/7, both AUC and C(max) were significantly greater in the rabeprazole 20-mg group compared with the rabeprazole 10-mg group (P = 0.005 and P = 0.007, respectively). Within-period comparisons for both groups indicated that the AUC and C(max) for rabeprazole and its thioether metabolite did not differ significantly from day 1 to day 5/7. In addition, the T(max) and t(1/2) were relatively unchanged from day 1 to day 5/7 in both dose groups. Treatment-emergent signs and symptoms occurred in 11 subjects, 6 in the 10-mg group and 5 in the 20-mg group. The most frequently reported AEs were headache and nausea (16.7% and 8.3%, respectively). No statistically significant differences were observed between dose groups in terms of the number of subjects with AEs.Rabeprazole 10 and 20 mg were well tolerated in these children and adolescents with GERD. The results of the pharmacokinetic analyses of single and multiple oral doses indicated no apparent accumulation of rabeprazole or its thioether metabolite with the 10-mg dose. There was, however, a suggestion of accumulation with multiple dosing of rabeprazole 20 mg, which requires confirmation in larger studies.

Purpose To investigate the pharmacokinetics and disposition of [14C]pomalidomide following a single oral dose to healthy male subjects. Methods Eight subjects were administered a single 2 mg oral suspension of [14C]pomalidomide. Blood (plasma), urine and feces were collected. Mass balance of radioactivity and the pharmacokinetics of radioactivity, pomalidomide and metabolites were determined. Metabolite profiling and characterization was performed. The enzymes involved in pomalidomide metabolism and the potential pharmacological activity of metabolites were evaluated in vitro. Results Mean recovery was 88 %, with 73 and 15 % of the radioactive dose excreted in urine and feces, respectively, indicating good oral absorption. Mean Cmax, AUC0−∞ and tmax values for pomalidomide in plasma were 13 ng/mL, 189 ng*h/mL and 3.0 h. Radioactivity and pomalidomide were rapidly cleared from circulation, with terminal half-lives of 8.9 and 11.2 h. Pomalidomide accounted for 70 % of the circulating radioactivity, and no circulating metabolite was present at >10 % of parent compound. Pomalidomide was extensively metabolized prior to excretion, with excreted metabolites being similar to those observed in circulation. Clearance pathways included cytochrome P450-mediated hydroxylation with subsequent glucuronidation (43 % of the dose), glutarimide ring hydrolysis (25 %) and excretion of unchanged drug (10 %). 5-Hydroxy pomalidomide, the notable oxidative metabolite, was formed primarily via CYP1A2 and CYP3A4. The hydroxy metabolites and hydrolysis products were at least 26-fold less pharmacologically active than pomalidomide in vitro. Conclusions Following oral administration, pomalidomide was well absorbed, with parent compound being the predominant circulating component. Pomalidomide was extensively metabolized prior to excretion, and metabolites were eliminated primarily in urine.