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Purpose: Assessment of the absorption, metabolism and excretion of [(14)C]-lenalidomide in healthy male subjects following a single oral dose., Methods: Six healthy male subjects were administered a single 25 mg oral suspension dose of [(14)C]-lenalidomide. Blood (plasma), semen and excreta were collected. Mass balance assessments were done by radioactivity measurements. Metabolite profiling and quantitation were accomplished using liquid chromatography with mass spectrometric and radiochemical detection., Results: [(14)C]-Lenalidomide was rapidly absorbed (T (max) 0.77-1.0 h), and the levels declined with a terminal half-life of approximately 3 h, with similar profiles for total blood and plasma radioactivity as well as plasma lenalidomide. The whole blood to plasma radioactivity exposure levels were comparable, suggesting equal distribution between plasma and blood cells. On average, 94% of the administered radioactivity was recovered within 10 days, with >88% recovered within 24 h. Urinary excretion was the primary route of elimination (90% of radioactive dose), with minor amounts excreted in feces (4%). Semen contained a small amount of the radioactive dose (0.0062%). Lenalidomide was the primary radioactive component in plasma (92% of the [(14)C]-area under the concentration-time curve) and urine (>90% of the radioactivity in urine). The remaining radioactivity was composed of primarily two metabolites: 5-hydroxy-lenalidomide and N-acetyl-lenalidomide, each accounting for less than 5% of the total radioactivity as well as lenalidomide levels in plasma and excreta., Conclusions: In summary, following oral administration, lenalidomide is highly absorbed and bioavailable, metabolized minimally, and eliminated predominantly via urinary excretion in the unchanged form in humans.

The formation of dihydroxythalidomide and glutathione (GSH) conjugate(s) of 5-hydroxythalidomide was investigated in chimeric mice modified with "humanized" liver: novel humanized TK-NOG mice were prepared by the introduction of thymidine kinase, followed by induction with ganciclovir, and human liver cells were transplanted. Following oral administration of racemic thalidomide (100 mg/kg), plasma concentrations of 5-hydroxy- and dihydroxythalidomide were higher in humanized mice than in controls. After administration of 5-hydroxythalidomide (10 mg/kg), higher concentrations of dihydroxythalidomide were detected. These results indicate that livers of humanized mice mediate thalidomide oxidation, leading to catechol and/or the GSH conjugate in vivo and suggest that thalidomide activation occurs.

Purpose: Cytochrome P450 (CYP)2C19 polymorphisms may partly explain the variability of thalidomide concentration and adverse drug effects by altering its metabolism. To compare the genetic and clinical factors responsible for the adverse effects and efficacy of thalidomide treatment, we investigated CYP2C19 genetic polymorphisms in Japanese subjects., Materials and Methods: Variations in the CYP2C19 gene in 6 patients treated with thalidomide were analyzed. The dosage of thalidomide, concentrations of (R)- and (S)-thalidomide in whole blood, and clinical laboratory test results were used as pharmacokinetic and pharmacodynamic indices. Using genomic DNA, CYP2C19*2 and *3 allele frequencies were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assays., Results: The frequencies of CYP2C19 PM and hetero EM (hetEM) genotypes in Japanese patients taking thalidomide were 2 (33.3%) and 4 (66.7%), respectively. The areas under the curve (AUC) of (R)-thalidomide were 3.42 and 5.33 μg·h/L, and those of (S)-thalidomide were 1.64 and 2.46 μg·h/L for hetEM and PM, respectively., Conclusions: This study provided new insights regarding the contribution of CYP2C19 gene variations to adverse responses to thalidomide. Genotyping of CYP2C19*2 and *3 can be considerably simplified by using KOD FX as a polymerase for prediction of adverse effects to thalidomide by the PCR-RFLP method. CYP2C19 PM patients tend to have high serum thalidomide concentrations.

Apremilast is a novel, orally available small molecule that specifically inhibits PDE4 and thus modulates multiple pro- and anti-inflammatory mediators, and is currently under clinical development for the treatment of psoriasis and psoriatic arthritis. The pharmacokinetics and disposition of [(14)C]apremilast was investigated following a single oral dose (20 mg, 100 μCi) to healthy male subjects. Approximately 58% of the radioactive dose was excreted in urine, while faeces contained 39%. Mean C(max), AUC(0-∞) and t(max) values for apremilast in plasma were 333 ng/mL, 1970 ng*h/mL and 1.5 h. Apremilast was extensively metabolized via multiple pathways, with unchanged drug representing 45% of the circulating radioactivity and <7% of the excreted radioactivity. The predominant metabolite was O-desmethyl apremilast glucuronide, representing 39% of plasma radioactivity and 34% of excreted radioactivity. The only other radioactive components that represented >4% of the excreted radioactivity were O-demethylated apremilast and its hydrolysis product. Additional minor circulating and excreted compounds were formed via O-demethylation, O-deethylation, N-deacetylation, hydroxylation, glucuronidation and/or hydrolysis. The major metabolites were at least 50-fold less pharmacologically active than apremilast. Metabolic clearance of apremilast was the major route of elimination, while non-enzymatic hydrolysis and excretion of unchanged drug were involved to a lesser extent.

Stable and orally bio-available pro-drugs of CPS11 were synthesized. They are active on human umbilical vein endothelial cell proliferation assay and tube formation assay. The therapeutic efficacy and safety of 4 as a single agent or combined with Taxol in the treatment of MX-1 human breast cancer xenograft were evaluated. Compound 4 as a single agent failed to produce an anti-tumor activity, while it significantly enhanced antitumor potency of Taxol., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

In several countries, including the US and in Europe, oral lenalidomide in combination with oral dexamethasone is approved for the treatment of multiple myeloma patients (aged ≥18 years) who have received at least one prior antimyeloma therapy. The key therapeutic mechanisms of action of lenalidomide (a thalidomide analog) reside in its immunomodulatory, antiproliferative, and anti-angiogenic properties. In patients with multiple myeloma, lenalidomide has dual effects, exerting a direct antitumor response by inhibiting proliferation and by inducing apoptosis of tumor cells. Lenalidomide also acts to enhance the immune system by inducing the activation of immune effector cells, such as T cells and natural killer cells, and inducing cytokine production. In the pivotal MM-009 and MM-010 phase III registration trials, treatment with lenalidomide plus dexamethasone was effective and had a manageable safety and tolerability profile in relapsed or refractory patients with multiple myeloma. In robust pharmacoeconomic analyses based on these trials, relative to dexamethasone, lenalidomide plus dexamethasone treatment met the assumed willingness-to-pay threshold for cost effectiveness from the UK and Scottish healthcare payer perspective in this patient population. The UK National Institute for Health and Clinical Excellence and the Scottish Medicines Consortium considered that the health economic case for lenalidomide plus dexamethasone treatment was demonstrated for patients who had received at least two prior antimyeloma therapies. In addition, in pharmacoeconomic analyses based on indirect comparisons of clinical efficacy, regulatory agencies in Norway and Sweden considered that lenalidomide plus dexamethasone treatment was cost effective relative to bortezomib in patients who have received at least one prior antimyeloma therapy. Furthermore, compared with placebo plus dexamethasone, treatment with lenalidomide plus dexamethasone significantly prolonged the median time to progression, increased overall response rates and prolonged overall survival, with significantly longer median time to progression and overall response rates observed for all subgroups of patients. Thus, combination therapy with lenalidomide plus dexamethasone provides a valuable option for the treatment of relapsed or refractory adult patients with multiple myeloma.

Fifty years ago, prescription of the sedative thalidomide caused a worldwide epidemic of multiple birth defects. The drug is now used in the treatment of leprosy and multiple myeloma. However, its use is limited due to its potent teratogenic activity. The mechanism by which thalidomide causes limb malformations and other developmental defects is a long-standing question. Multiple hypotheses exist to explain the molecular mechanism of thalidomide action. Among them, theories involving oxidative stress and anti-angiogenesis have been widely supported. Nevertheless, until recently, the direct target of thalidomide remained elusive. We identified a thalidomide-binding protein, cereblon (CRBN), as a primary target for thalidomide teratogenicity. Our data suggest that thalidomide initiates its teratogenic effects by binding to CRBN and inhibiting its ubiquitin ligase activity. In this review, we summarize the biology of thalidomide, focusing on the molecular mechanisms of its teratogenic effects. In addition, we discuss the questions still to be addressed.

Purpose: A phase I trial of lenalidomide was performed in children with recurrent, refractory, or progressive primary CNS tumors to estimate the maximum-tolerated dose (MTD) and to describe the toxicity profile and pharmacokinetics., Patients and Methods: Lenalidomide was administered by mouth daily for 21 days, repeated every 28 days. The starting dose was 15 mg/m(2)/d orally, and the dose was escalated according to a modified continuous reassessment method. Correlative studies included pharmacokinetics obtained from consenting patients on course 1, day 1, and at steady-state (between days 7 and 21)., Results: Fifty-one patients (median age, 10 years; range, 2 to 21 years) were enrolled. Forty-four patients were evaluable for dose finding, and 49 patients were evaluable for toxicity. The primary toxicity was myelosuppression, but the MTD was not defined because doses up to 116 mg/m(2)/d were well-tolerated during the dose-finding period. Two objective responses were observed (one in thalamic juvenile pilocytic astrocytoma and one in optic pathway glioma) at dose levels of 88 and 116 mg/m(2)/d. Twenty-three patients, representing all dose levels, received ≥ six cycles of therapy. Pharmacokinetic analysis demonstrated that the lenalidomide area under the concentration-time curve from 0 to 24 hours and maximum plasma concentration increased with dosage over the range studied., Conclusion: Lenalidomide was tolerable in children with CNS tumors at doses of 116 mg/m(2)/d during the initial dose-finding period. The primary toxicity is myelosuppression. Antitumor activity, defined by both objective responses and long-term stable disease, was observed, primarily in patients with low-grade gliomas.

Purpose: To determine the maximum-tolerated or recommended phase II dose, dose-limiting toxicities (DLTs), pharmacokinetics (PK), and immunomodulatory effects of lenalidomide in children with recurrent or refractory solid tumors or myelodysplastic syndrome (MDS)., Patients and Methods: Cohorts of children with solid tumors received lenalidomide once daily for 21 days, every 28 days at dose levels of 15 to 70 mg/m(2)/dose. Children with MDS received a fixed dose of 5 mg/m(2)/dose. Specimens for PK and immune modulation were obtained in the first cycle., Results: Forty-nine patients (46 solid tumor, three MDS), median age 16 years (range, 1 to 21 years), were enrolled, and 42 were fully assessable for toxicity. One patient had a cerebrovascular ischemic event of uncertain relationship to lenalidomide. DLTs included hypercalcemia at 15 mg/m(2); hypophosphatemia/hypokalemia, neutropenia, and somnolence at 40 mg/m(2); and urticaria at 55 mg/m(2). At the highest dose level evaluated (70 mg/m(2)), zero of six patients had DLT. A maximum-tolerated dose was not reached. No objective responses were observed. PK studies (n = 29) showed that clearance is faster in children younger than 12 years of age. Immunomodulatory studies (n = 26) showed a significant increase in serum interleukin (IL) -2, IL-15, granulocyte-macrophage colony-stimulating factor, natural killer (NK) cells, NK cytotoxicity, and lymphokine activated killer (LAK) cytoxicity, and a significant decrease in CD4(+)/CD25(+) regulatory T cells., Conclusion: Lenalidomide is well-tolerated at doses up to 70 mg/m(2)/d for 21 days in children with solid tumors. Drug clearance in children younger than 12 years is faster than in adolescents and young adults. Lenalidomide significantly upregulates cellular immunity, including NK and LAK activity.

Purpose: To evaluate the safety and activity of 6 months of treatment with lenalidomide at 5 or 25 mg/d in nonmetastatic biochemically relapsed prostate cancer., Experimental Design: Sixty men with non-castrate, nonmetastatic, biochemically relapsed prostate cancer were stratified by prostate-specific antigen (PSA) doubling time, surgery/radiation therapy, prior androgen deprivation therapy (ADT), and randomized to lenalidomide 5 mg (n = 26) or 25 mg/d (n = 34) for 3 weeks repeated monthly for 6 months or until dose-limiting toxicity or disease progression. Toxicity was evaluated monthly, and PSAs and X-rays/scans every 6 months. Study size was determined to detect a progression rate of 40% at 6 months in either arm with 85% power (compared with a rate of 80% in the population receiving no treatment). Changes in PSA slopes were calculated using the regression of the log PSA for each patient before and during the initial 6 months and compared by t test., Results: Baseline variables were balanced between arms. Grade 3/4 toxicity rates were 12% (n = 3) with 5 mg and 29% (n = 10) with 25 mg (P = 0.1), most commonly neutropenia (five patients, all on 25 mg). Two patients per arm had thromboembolic events. The change in PSA slope was greater with 25 mg versus 5 mg [-0.172 (-0.24 to -0.11) versus -0.033 (-0.11 to 0.04); P = 0.005]. With a mean follow-up of 31.4 months (range 14-44), five patients on 25 mg and one patient on 5 mg remain on the study., Conclusions: Lenalidomide has acceptable toxicity and is associated with long-term disease stabilization and PSA declines. Randomized studies evaluating conventional clinical disease end points in this patient population are planned., (©2010 AACR.)

We conducted a multicenter, open-label study to investigate the safety, efficacy, and pharmacokinetics of lenalidomide in Japanese patients with relapsed or refractory multiple myeloma The study was composed of the "monotherapy phase", a dose-escalation phase, to determine the tolerability to single agent lenalidomide and the "combination phase" to determine the safety and obtain preliminary data on the efficacy of lenalidomide plus dexamethasone. The primary end points were the tolerability to 25 mg lenalidomide and safety. Nine and six patients were enrolled in the monotherapy phase and the combination phase, respectively. Since 25 mg of monotherapy treatment did not satisfy the DLT criteria, this dose was employed in the combination phase. The major adverse event was myelosuppression. At the planned interim analysis (median study duration, 26.3 weeks), grade 3 or grade 4 neutropenia was observed with high frequency (66.7%). However, all adverse events observed were clinically manageable. In the combination cohort, the overall response rate (> or =PR) was 100%. The pharmacokinetics of lenalidomide showed rapid absorption and elimination after both single and multiple doses. In conclusion, 25 mg of lenalidomide was given safely as a single agent or in combination with dexamethasone in Japanese patients. The good efficacy of the combination therapy was also demonstrated in this study.

Lenalidomide is a thalidomide analog and an immunomodulatory drug with demonstrated efficacy in various hematological malignancies. The distribution of lenalidomide into semen was evaluated in healthy subjects. Twenty-four male subjects were randomized into 4 equal groups for semen collection. All subjects received lenalidomide 25 mg once daily for 4 days. After the last dose, a single semen sample was collected from subjects, at approximately 2, 24, 72, and 168 hours for groups 1, 2, 3, and 4, respectively, and serial blood sampling was performed for 24 hours in all groups. The mean lenalidomide concentration in semen was 478 ng/mL at 2 hours and 10.0 ng/mL at 24 hours, which was higher than was the corresponding drug concentration in plasma (219 ng/mL at 2 hours and undetectable at 24 hours) but roughly paralleled the time course in plasma for drug elimination. The mean amount of lenalidomide was 1379 ng/ejaculate at 2 hours and 35 ng/ejaculate at 24 hours. The maximal drug content in a single ejaculate was <2000 ng (<0.01% of the daily 25-mg dose). Lenalidomide was undetectable in semen at 72 and 168 hours. Therefore, lenalidomide is essentially eliminated from seminal reservoirs by 72 hours postdose.

The anticancer agent docetaxel shows significant inter-individual variation in its pharmacokinetic and toxicity profile. Thalidomide is an active anticancer agent and also shows wide pharmacological variation. Past pharmacogenetic research has not explained this variation. Patients with prostate cancer enrolled in a randomized phase II trial using docetaxel and thalidomide versus docetaxel alone were genotyped using the Affymetrix DMET 1.0 platform, which tests for 1256 genetic variations in 170 drug disposition genes. Genetic polymorphisms were analyzed for associations with clinical response and toxicity. In all, 10 single-nucleotide polymorphisms (SNPs) in three genes were potentially associated with response to therapy: peroxisome proliferator-activated receptor-delta (PPAR-delta), sulfotransferase family, cytosolic, 1C, member 2 (SULT1C2) and carbohydrate (chondroitin 6) sulfotransferase 3 (CHST3). In addition, 11 SNPs in eight genes were associated with toxicities to treatment: spastic paraplegia 7 (pure and complicated autosomal recessive) (SPG7), CHST3, cytochrome P450, family 2, subfamily D, polypeptide 6 (CYP2D6), N-acetyltransferase 2 (arylamine N-acetyltransferase) (NAT2), ATP-binding cassette, sub-family C (CFTR/MRP), member 6 (ABCC6), ATPase, Cu++ transporting, alpha polypeptide (ATP7A), cytochrome P450, family 4, subfamily B, polypeptide 1 (CYP4B1) and solute carrier family 10 (sodium/bile acid cotransporter family), member 2 (SLC10A2). Genotyping results between drug metabolizing enzymes and transporters (DMET) and direct sequencing showed >96% of concordance. These findings highlight the role that non-CYP450 metabolizing enzymes and transporters may have in the pharmacology of docetaxel and thalidomide.

Lenalidomide is an immunomodulatory agent recently reported to be effective in the treatment of transfusion-dependent anemia due to low- or intermediate-1 risk myelodysplastic syndromes (MDS) associated with a deletion 5q (del 5q) cytogenetic abnormality. We conducted a multicenter, single-arm clinical trial to evaluate the safety and efficacy of lenalidomide in Japanese patients with anemia in low- or intermediate-1 risk MDS associated with the del 5q cytogenetic abnormality. Eleven patients (5 with transfusion-dependent anemia; 6 with transfusion-independent symptomatic anemia) received once daily oral administrations of 10 mg of lenalidomide for 21 consecutive days in a 28-day treatment cycle. The efficacy was assessed by the IWG criteria. At an interim analysis after > or =24 weeks of therapy, hemoglobin increase was noted in all 11 patients, with a median increase of 6.0 g/dL (range, 0.9-10.9) from the baseline. All transfusion-dependent patients achieved transfusion independence. Histopathologic and cytogenetic improvement was also noted. Neutropenia and thrombocytopenia were the most common adverse events related to lenalidomide. The adverse events were manageable, and no patients experienced serious adverse events or adverse events requiring treatment discontinuation. The results indicate that lenalidomide can be a useful agent for treating Japanese patients with anemia associated with low- or intermediate-1 risk MDS with the del 5q cytogenetic abnormality.

Objectives of this study were to determine the maximum tolerated dose and to characterize the side effect profile and pharmacokinetics of lenalidomide in patients with advanced refractory solid tumors. Patients were treated on a modified Fibronacci dose escalation scheme with an oral daily dose of lenalidomide. A total of 45 patients with 8 different tumor types were accrued. Doses administered included 5, 10, and 20 mg continuous daily doses, every 28 days (n = 15), later modified to intermittent doses of 15, 20, 25, 30, 35, and 40 mg, with a 21 days-on and 7 days-off schedule, due to observed side effects. Lenalidomide exhibited a linear pharmacokinetics over a wide range of doses with the mean half-life of 3.9 hours. The renal function affected lenalidomide clearance, resulting in 50% reduction in patients with mild renal impairment compared with patients with normal function (CL/F = 243 mL/min). Stable disease was documented in 12 of 44 evaluable patients, of whom 9 patients had prostate cancer. Most frequent grade 1 and 2 toxicities included fatigue, nausea, pruritus/rash, neutropenia, and neuropathy. Grade 3/4 events were predominantly hematologic. Lenalidomide was well tolerated up to a 35-mg/d intermittent dosing schedule at doses higher than previously indicated for hematologic malignancies.

To obtain approval from the Ministry of Health, Labor and Welfare of Japan, a phase II study was conducted to assess the pharmacokinetics and pharmacodynamics of thalidomide along with its efficacy and safety in Japanese patients with multiple myeloma. Between 2005 and 2006, 42 patients were enrolled, and 37 patients met eligibility criteria. Of the 37 patients, 3 were excluded from efficacy analysis because of short duration of thalidomide administration (<4 weeks). The overall response rate was 35.3% (12/34), including partial response of 14.7% (5/34) and minimal response of 20.6% (7/34). The adverse events observed in high frequency (>40%) were leukopenia, neutropenia, drowsiness, dry mouth, and constipation. Grade 3 neutropenia was observed in nine cases. Peripheral neuropathy and eruption were observed in about one-quarter of the patients. Deep vein thrombosis was not observed. At a single oral dose of thalidomide (100 mg), the C (max) was 1.68 +/- 0.41 microg/ml, T (max) was 4.54 +/- 1.71 h, T (1/2) was 4.86 +/- 0.44 h, and AUC was 15.87 +/- 3.05 microg h/ml. Low-dose thalidomide was an effective and tolerable treatment for Japanese patients with relapsed/refractory myeloma. Leukopenia and neutropenia were the most serious adverse events. The pharmacokinetics was similar to those observed in Caucasian patients.

Background: Initial analysis of the combination melphalan, prednisone, plus lenalidomide (MPR) showed significant antimyeloma activity in patients with untreated multiple myeloma, with neutropenia and thrombocytopenia as the most frequent side effects. This updated analysis reassessed the kinetics of neutropenia and thrombocytopenia as well as the safety and efficacy of MPR., Patients and Methods: A total of 21 patients with newly diagnosed myeloma received melphalan 0.18 mg/kg on days 1-4, prednisone 2 mg/kg on days 1-4, and lenalidomide 10 mg daily on days 1-21 for nine 28-day cycles, followed by maintenance therapy with lenalidomide 10 mg daily on days 1-21., Results: Grade 3/4 neutropenia occurred in 52% of the patients, and granulocyte colonystimulating factor was administered in 43%. The mean neutrophil counts at the start of each MPR cycle, during nadir, and after 6 months of maintenance were 2.69 x 109/L, 1.43 x 109/L, and 2.11 x 109/L, respectively. Grade 3/4 thrombocytopenia occurred in 24% of the patients. Platelet transfusions were required by 1 patient (5%) with a platelet count of 16 x 109/L; however, no thrombocytopenia-associated bleeding was reported. The mean platelet counts at the start of each cycle, during nadir, and after 6 months of maintenance were 174 x 109/L, 121 x 109/L, and 158 x 109/L, respectively. Median follow-up was 29.6 months, median progression-free survival was 28.5 months, and 2-year overall survival was 91%., Conclusion: MPR is a promising regimen with manageable hematologic toxicity.

The serum concentration of thalidomide in multiple myeloma (MM) patients with renal insufficiency has not been investigated in Japan. We examined the serum concentration of thalidomide 12 and 16 hours after administration in 5 patients with MM (one with normal renal function and four with renal insufficiency, including one on hemodialysis (HD)) taking 100-200 mg/day. Concentrations 12 and 16 hours after administration corresponded to those before and after HD, respectively, in the patient on HD. The thalidomide concentration was not significantly increased by renal insufficiency. We could not detect any correlation between the concentration of thalidomide and its clinical effect. Since the elimination of thalidomide during HD seems to be greater than during the same period on a non-HD day, it was suggested that thalidomide could be eliminated by HD. The concentrations 12 hours after administration were similar with or without HD. From these results, even in Japanese patients, the thalidomide dosage need not be modified for renal insufficiency and HD.

Over the past 5 years, lenalidomide (Revlimid, Celgene Co., Summit, NJ, USA), a member of a class of drugs termed immunomodulatory drugs, has emerged as a significant weapon in the arsenal of cancer-therapeutics. It is a lead therapeutic in multiple myeloma and del-5q myelodysplastic syndromes and has also been trialed for acute leukaemia and chronic lymphocytic leukaemia, relapsed or refractory Hodgkin's lymphoma, T-cell non-Hodgkin's lymphoma, prostate cancer, non-small cell lung cancer, malignant melanoma, renal cancer, advanced ovarian and peritoneal carcinoma. The most significant development for lenalidomide has been its FDA approval (US and Europe) for previously treated multiple myeloma in combination with dexamethasone. The following review describes key clinical and mechanistic breakthroughs that have made lenalidomide a leading cancer therapeutic.

Thalidomide is an important advance in the treatment of multiple myeloma. In Japan thalidomide is now on the approval step for the treatment of multiple myeloma. The drug has some bothersome side effects such as defect of organogenesis, neuropathy, constipation and fatigue, but is likely more effective than standard chemotherapy and is changing multiple myeloma treatment. At this moment, Japanese patients must import the thalidomide preparations from Mexico, Britain and elsewhere, but after approval, they patients will be able to get the new Japanese thalidomide capsules. In order to determine appropriate amounts of Japanese thalidomide capsules in the treatment of multiple myeloma, we compared the dissolution profile and plasma thalidomide concentrations of Japanese and British capsules and Mexican tablets. The dissolution test was performed according to the Japanese and the United States Pharmacopoeia. The pharmacokinetic data for Japanese capsules were obtained from the clinical trial in Japanese subjects and compared with those data published for other formulations. The dissolution rate of the Japanese capsule was the fastest, followed by British and Mexican formulations. The pharmacokinetic profiles of Japanese and British capsules were similar, while the 100 mg Japanese thalidomide capsule demonstrated a 1.6-fold higher maximum plasma concentration than the 200 mg Mexican thalidomide tablet (1.7 vs. 1.1 microg/ml), greatly shortened t(max) (4.5 vs. 6.2 h), and the apparent half life was only one-third of the Mexican tablet (4.8 vs. 13.5 h). A comparison of the dissolution and the pharmacokinetic absorption profiles demonstrated a rank-order correlation. Physicians and pharmacists should be aware of the probable alteration in plasma thalidomide concentration when switching to the Japanese capsule, especially from the Mexican tablet, and should monitor clinical response carefully.

Background: After the tragic events in the early 1960s, thalidomide has re-emerged as therapeutic for multiple myeloma (MM). It was first approved for the treatment of erythema nodosum leprosum, and is now under evaluation for hematologic and non-hematologic disorders. Its complex mechanism of action is not fully understood; however extensive preclinical studies in MM have revealed its antiangiogenic and immunomodulatory properties., Objective: In this review, we focus on the importance and toxicity of thalidomide in today's clinical use., Methods: Key preclinical and clinical trials available as well as data on the pharmacokinetics and pharmacodynamics of thalidomide in humans are summarized., Conclusions: Thalidomide is widely used as first-line treatment and in relapsed/refractory MM. The most common side effects are fatigue, constipation and peripheral neuropathy, and careful monitoring is required to avoid fetal exposure.

Objective: To evaluate the clinical and biological activity of apremilast in patients with severe plaque-type psoriasis., Research Design and Methods: Apremilast, a phosphodiesterase-4 inhibitor, inhibits in vitro activity of multiple inflammatory factors implicated in the pathogenesis of psoriasis. Patients received 20 mg apremilast orally for 29 days. Immunohistological analysis was conducted on lesional-skin biopsies for psoriasis-associated inflammatory markers. Lipopolysaccharide-stimulated tumor necrosis factor-alpha levels were evaluated in blood. Psoriasis Area and Severity Index (PASI), static Physician's Global Assessment, and Body Surface Area were used to monitor disease severity., Results: There were 19 patients enrolled in this study, of whom 17 completed the study. Epidermal thickness was reduced by a mean of 20.5% from baseline to day 29. Among the responders, T cells were reduced by 28.8% and 42.6% in the dermis and epidermis, respectively. Similarly, CD11c cells were reduced by 18.5% and 40.2% in the dermis and epidermis, respectively. Fourteen of the 19 (73.7%) patients demonstrated an improvement in their PASI scores., Limitations: This was a small, single-arm, open-label pilot study; therefore there was neither a placebo nor a comparison group., Conclusion: Apremilast demonstrated biological activity and improved psoriasis clinical efficacy scores in patients with severe plaque-type psoriasis. The majority of adverse events were mild in nature. Two adverse events (fatigue and dizziness) were judged by the investigator to be moderate and related to apremilast. In addition, there were no clinically-relevant abnormal laboratory test results in subjects treated with apremilast for 29 days.

Thalidomide's reported ability to inhibit tumor angiogenesis has led to clinical trials determining its effectiveness in combating various types of cancer. Since thalidomide exhibits low oral bioavailability due to limitations in solubility, inclusion complexation using sulfobutyl ether-7 beta-cyclodextrin was used to improve the delivery of thalidomide. Our main goals were to increase the solubility, bioavailability as well as chemical stability of thalidomide through complexation with anionic beta-cyclodextrin, to characterize the complex in solid state using differential scanning calorimetry, X-ray powder diffractometry, and to explore thalidomide's antitumorigenic and antiangiogenesis potential when administered orally as free and in combination with cyclodextrin to experimental animals. The aqueous solubility and aqueous alkaline stability of thalidomide was markedly increased by the SBE7betaCD complexation. Thalidomide administered orally in combination with SBE7betaCD, led to a significant delay in tumor formation as a result of improved cellular drug absorption, distribution through solubilization in experimental animals. The improved pharmacological efficacy of the thalidomide-cyclodextrin complex compared to free thalidomide in mouse melanoma model suggest that such a delivery system may be useful for the improved therapeutics of thalidomide, in vivo.

The present study investigated the effect of renal impairment and hemodialysis on the pharmacokinetics of lenalidomide following a single 25-mg oral dose in 30 subjects aged 39 to 76 years. A single 25-mg dose was well tolerated by renally impaired subjects. Renal impairment did not alter the oral absorption, protein binding, or nonrenal elimination of lenalidomide. Mean urinary recovery of unchanged lenalidomide was 84% of the dose in subjects with normal renal function (creatinine clearance [CL(Cr)] > 80 mL/min), and it declined to 69%, 38%, and 43% in subjects with mild (50 < or = CL(Cr) < or = 80 mL/min), moderate (30 < or = CL(Cr) < 50 mL/min), and severe (CL(Cr) < 30 mL/min) renal impairment, respectively. The differences in pharmacokinetic parameters between normal renal function and mild renal impairment were minor to modest (11%-32%). As renal impairment progressed to moderate, severe, or end-stage renal disease, total and renal lenalidomide clearance decreased drastically, area under the concentration-time curve increased by approximately 185% to 420%, and t((1/2)) was prolonged by approximately 6 to 12 hours. A 4-hour hemodialysis removed 31% of lenalidomide in the body. Therefore, lenalidomide dose adjustments should be considered for patients with CL(Cr) < 50 mL/min, and the recommendations are given for the starting doses.

Purpose: Inhibition of angiogenesis represents a promising new therapeutic strategy for treating primary malignant brain tumors. Lenalidomide, a potent analogue of the antiangiogenic agent thalidomide, has shown significant activity in several hematologic malignancies, and therefore we chose to explore its tolerability and activity in patients with primary central nervous system tumors., Experimental Design: A phase I interpatient dose escalation trial of lenalidomide in patients with recurrent primary central nervous system tumors was conducted., Results: Thirty-six patients were accrued to the study, of which 28 were evaluable for toxicity, the primary end point of the trial. We show that lenalidomide can be given safely up to doses of 20 mg/m(2), with the only toxicity being a probable increased risk of thromboembolic disease. Pharmacokinetic studies reveal good bioavailability, linear kinetics, and no effects of enzyme-inducing antiepileptic drugs on the metabolism of lenalidomide. No objective radiographic responses were seen in any of the treated patients. In the group of 24 patients with recurrent glioblastoma, the median time to tumor progression was <2 months and only 12.5% of patients were progression-free at 6 months., Conclusion: Lenalidomide is well tolerated in patients with recurrent glioma in doses up to 20 mg/m(2). Treatment may be associated with an increased risk of thromboembolic disease. Preliminary data suggest that single agent activity may be limited in patients with recurrent glioblastoma at the doses evaluated although larger studies will be needed to confirm these observations.

An early rationale for using thalidomide to treat erythema nodosum leprosum had been based on some reports that it suppresses tumor necrosis factor-alpha (TNF-alpha). However, in vivo and in vitro studies have yielded variable results, having shown that thalidomide can either enhance or suppress TNF-alpha. Since the course of circulating cytokines like TNF-alpha after infusion of endotoxin into volunteers is reproducible and characteristic, we investigated the effect of thalidomide on endotoxin-induced synthesis of TNF-alpha, interleukin (IL)-6, and IL-8. The cytokine response from 18 placebo-treated subjects who had undergone the endotoxin challenge were pooled with a placebo-treated subject from the current study and were compared with 4 subjects who received thalidomide (100 mg) every 6 h for 5 doses before endotoxin challenge. Thirty minutes after the last dose of thalidomide or placebo, volunteers were infused with 4-ng/kg endotoxin. Plasma was collected and assayed for cytokines by enzyme-linked immunosorbent assay. Endotoxin evoked the synthesis of the cytokines in all volunteers. The peak response for TNF-alpha was 1.5 h, 2.5 h for IL-8, and 3.0 h for IL-6. Thalidomide did not significantly delay the release of cytokines into the circulating blood. At the peak response, thalidomide reduced the concentration of the cytokines in the plasma. Using the area under the dose response curve (AUC(0 to 24) h), thalidomide reduced the AUC for IL-6 by 56%, for IL-8 by 30%, and TNF-alpha by 32%. In this model, thalidomide did not suppress TNF-alpha or IL-8, but it did suppress IL-6 at 4-h postinfusion with lipopolysaccharide (P=0.004), at 6 h (P=0.014), at 12 h (P=0.001), and at 16 h (P=0.012).

Purpose: This phase II study evaluated the combination of semaxanib, a small molecule tyrosine kinase inhibitor of vascular endothelial growth factor (VEGF) receptor-2, and thalidomide in patients with metastatic melanoma to assess the efficacy, tolerability, pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of the combination., Patients and Methods: Patients with metastatic melanoma, who had failed at least one prior biologic and/or chemotherapeutic regimen, were treated with escalating doses of thalidomide combined with a fixed dose of semaxanib., Results: Twelve patients were enrolled and received 44 courses of semaxanib at the fixed dose of 145 mg/m2 intravenously twice-weekly in combination with thalidomide, commencing at 200 mg daily with intrapatient dose escalation as tolerated. Treatment with semaxanib was initiated 1 day before thalidomide in the first course, permitting the assessment of the PKs of semaxanib alone (course 1) and in combination with thalidomide (course 2). The principal toxicities included deep venous thrombosis, headache, and lower extremity edema. Of ten patients evaluable for response, one complete response lasting 20 months and one partial response lasting 12 months were observed. Additionally, four patients had stable disease lasting from 2 to 10 months. The PKs of semaxanib were characterized by drug exposure parameters comparable to those observed in single-agent phase II studies, indicating the absence of major drug-drug interactions. Maximum semaximib plasma concentration values were 1.2-3.8 microg/ml in course 1 and 1.1-3.9 microg/ml in course 2. The mean terminal half-life was 1.3 ( +/- 0.31) h. Biological studies revealed increasing serum VEGF concentrations following treatment in patients remaining on study for more than 4 months., Conclusion: The combination of semaxanib and thalidomide was feasible and demonstrated anti-tumor activity in patients with metastatic melanoma who had failed prior therapy. Further evaluations of therapeutic strategies that target multiple angiogenesis pathways may be warranted in patients with advanced melanoma and other malignancies.

Purpose: Nuclear factor-kappaB (NF-kappaB) activation induces resistance to irinotecan. Preclinically, thalidomide and COX-2 inhibitors reduce NF-kappaB activation. We tested the feasibility of combining irinotecan with thalidomide and thalidomide/celecoxib in patients with refractory malignancies., Patients/methods: The study was conducted in two parts. First, the optimal dose of thalidomide (400 or 200 mg daily) in combination with irinotecan 125 mg/m(2) days 1 and 8 every 3 weeks was determined. In the second part, celecoxib 400 mg twice-daily was added to irinotecan/thalidomide. Pharmacokinetics of irinotecan and thalidomide alone or concurrently were evaluated. Tumor necrosis factor alpha, beta-fibroblast growth factor, and NF-kappaB activation were measured in blood mononuclear cells (PBMC). No CYP450 enzyme inducers/inhibitors were allowed., Results: Thirty-six patients were enrolled: Eleven received thalidomide 400 mg, 13 thalidomide 200 mg and 12 thalidomide 400 mg and celecoxib, with irinotecan. For the two-drug combination, there was a higher rate of moderate/severe diarrhea/myelosuppression with thalidomide 200 mg. Thus thalidomide 400 mg was combined with celecoxib. The triple combination resulted in similar toxicity as the doublet with the lower thalidomide dose. Concurrent administration of irinotecan/thalidomide did not influence pharmacokinetics. Anti-tumor responses occurred in two patients and prolonged stabilization in eight others. NF-kappaB activation increased over time. Patients experiencing tumor response or prolonged stabilization had lower NF-kappaB activation, albeit not statistically significant (P = 0.124)., Conclusions: The combination of thalidomide/irinotecan is safe and devoid of PK interactions. Thalidomide 400 mg appeared more suitable for combination, whereas the addition of celecoxib did not improve tolerability. Tumor-specific studies in patients with lesser prior treatment will be necessary to establish the therapeutic impact of the combinations.

Thalidomide is currently under evaluation as an anti-angiogenic agent in cancer treatment, alone and in combination with cytotoxic agents. Thalidomide is a racemate with known pharmacologic and pharmacokinetic enantioselectivity. In a previous study with thalidomide combination chemotherapy, we found evidence of anti-tumour synergy. In this study, we examined whether the synergy involved altered pharmacokinetics of thalidomide enantiomers. Adult female F344 rats were implanted with 9L gliosarcoma tumours intracranially, subcutaneously (flank), or both. Effectiveness of oral thalidomide alone, and with intraperitoneal BCNU or cisplatin combination chemotherapy, was assessed after several weeks treatment. Presumed pseudo steady-state serum, tumour and other tissues, collected after treatment, were assayed for R- and S-thalidomide by chiral HPLC. Both serum and tissue concentrations of R-thalidomide were 40-50% greater than those of S-thalidomide. Co-administration of BCNU or cisplatin with thalidomide did not alter the concentration enantioselectivity. Poor correlation of concentration with subcutaneous anti-tumour effect was found for individual treatments, and with all treatments for intracranial tumours. The consistency of the enantiomer concentration ratios across treatments strongly suggests that the favourable antitumour outcomes from interactions between thalidomide and the cytotoxic agents BCNU and cisplatin did not have altered enantioselectivity of thalidomide pharmacokinetics as their basis.

This multicenter, open-label, randomized phase 2 study evaluated 2 dose regimens of lenalidomide for relapsed, refractory myeloma. Seventy patients were randomized to receive either 30 mg once-daily or 15 mg twice-daily oral lenalidomide for 21 days of every 28-day cycle. Patients with progressive or stable disease after 2 cycles received dexamethasone. Analysis of the first 70 patients showed increased grade 3/4 myelo-suppression in patients receiving 15 mg twice daily (41% versus 13%, P = .03). An additional 32 patients received 30 mg once daily. Responses were evaluated according to European Group for Blood and Marrow Transplantation (EBMT) criteria. Overall response rate (complete, partial, or minor) to lenalidomide alone was 25% (24% for once-daily and 29% for twice-daily lenalidomide). Median overall survival in 30-mg once-daily and twice-daily groups was 28 and 27 months, respectively. Median progression-free survival was 7.7 months on once-daily versus 3.9 months on twice-daily lenalidomide (P = .2). Dexamethasone was added in 68 patients and 29% responded. Time to first occurrence of clinically significant grade 3/4 myelosuppression was shorter in the twice-daily group (1.8 vs 5.5 months, P = .05). Significant peripheral neuropathy and deep vein thrombosis each occurred in only 3%. Lenalidomide is active and well tolerated in relapsed, refractory myeloma, with the 30-mg once-daily regimen providing the basis for future studies as monotherapy and with dexamethasone.

Thalidomide has been used for the treatment of refractory multiple myeloma, the dosage in Japan is lower than in other countries; however, there is little information on the pharmacokinetics and their relationship with the drug response. The aim of this study was to characterize the pharmacokinetics of low-dose thalidomide in Japanese patients with refractory multiple myeloma, and to examine the relationship between pharmacokinetics and adverse events. On the first and second days, a 100 mg capsule was administered to 8 Japanese patients after breakfast and blood samples were obtained. The plasma concentrations were measured using HPLC and analyzed based on a one-compartment model. If intolerable adverse events were not observed for 14 d, the dose was increased to 200 mg. The average apparent volume of distribution (Vd/F), apparent total clearance (CL/F) and area under the plasma concentration-time curve from 0 to infinity (AUC0-infinity), which were 45.3 l, 5.5 l/h and 21.7 microg.h/ml, respectively, with smaller Vd/F and CL/F and larger AUC0-infinity than in Caucasian populations. This pharmacokinetic difference may explain the dose difference between Japan and other countries. Adverse events were associated with AUC0-infinity, which was best correlated with plasma concentration at 12 h after administration. The 12-h time point was suggested to be a capable indicator for "safety-oriented" therapeutic drug monitoring of thalidomide.

Purpose: To evaluate the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), and pharmacokinetics of thalidomide in patients with advanced hepatocellular carcinoma (HCC)., Methods: Patients with advanced HCC who were not feasible for definitive local therapy were eligible. Patients were enrolled in a cohort of three to receive thalidomide twice daily for 1 week to determine the MTD. Intra-patient dose escalation was permitted. Pharmacokinetic studies were performed at the first dose level and repeated at the second dose level of each patient., Results: Fifteen patients were accrued at four dose levels with the starting dose range 100-400 mg/day. Two patients at 400 mg/day experienced DLT (grade 3 angioedema and dyspnea, respectively). The MTD of twice-daily schedule was determined as 300 mg/day. The mean steady-state maximal blood concentration and mean steady-state area under the curve had a trend toward positive correlation, but non-linear proportionate, to the daily dose of thalidomide. Pharmacokinetic parameters are comparable for patients of Child-Pugh's A and B. Apparent mild, transient drug-induced transaminitis was early onset, self-limited, which occurred in 30.7% of patients. Serum hepatitis B or C viral titers was largely not affected., Conclusion: The absorption and elimination of thalidomide are not significantly different in HCC patients with compensated or decompensated hepatic dysfunction.

The clinical use of irinotecan (CPT-11) is hindered by dose-limiting diarrhea and myelosuppression. Recent clinical studies indicate that thalidomide, a known tumor necrosis factor-alpha inhibitor, ameliorated the toxicities induced by CPT-11. However, the mechanisms for this are unknown. This study aimed to investigate whether combination of thalidomide modulated the toxicities of CPT-11 using a rat model and the possible role of the altered pharmacokinetic component in the toxicity modulation using in vitro models. The toxicity model was constructed by treatment of healthy rats with CPT-11 at 60 mg/kg per day by intravenous (i.v.) injection. Body weight, acute and delayed-onset diarrhea, blood cell counts, and macroscopic and microscopic intestinal damages were monitored in rats treated with CPT-11 alone or combined therapy with thalidomide at 100 mg/kg administered by intraperitoneal (i.p.) injection. Single dose and 5-day multiple-dose studies were conducted in rats to examine the effects of concomitant thalidomide on the plasma pharmacokinetics of CPT-11 and its major metabolites SN-38 and SN-38 glucuronide (SN-38G). The effect of CPT-11 on thalidomide's pharmacokinetics was also checked. Rat liver microsomes and a rat hepatoma cell line, H4-II-E cells, were used to study the in vitro metabolic interactions between these two drugs. H4-II-E cells were also used to investigate the effect of thalidomide and its hydrolytic products on the transport of CPT-11 and SN-38. In addition, the effect of thalidomide and its hydrolytic products on rat plasma protein binding of CPT-11 and SN-38 was examined. Administration of CPT-11 by i.v. for 4 consecutive days to rats induced significant body weight loss, decrease in neutrophil and lymphocyte counts, severe acute- and delayed-onset diarrhea, and intestinal damages. These toxicities were alleviated when CPT-11 was combined with thalidomide. In both single-dose and 5-day multiple-dose pharmacokinetic study, coadministered thalidomide significantly increased the area under the plasma concentration-time curve (AUC) of CPT-11, but the AUC and elimination half-life (t(1/2)) of SN-38 were significantly decreased. However, CPT-11 did not significantly alter the pharmacokinetics of thalidomide. Thalidomide at 25 and 250 microM and its hydrolytic products at a total concentration of 10 microM had no significant effect on the plasma protein binding of CPT-11 and SN-38, except for that thalidomide at 250 microM caused a significant increase in the unbound fraction (f(u)) of CPT-11 by 6.7% (P < 0.05). The hydrolytic products of thalidomide (total concentration of 10 microM), but not thalidomide, significantly decreased CPT-11 hydrolysis by 16% in rat liver microsomes (P < 0.01). The formation of both SN-38 and SN-38G from CPT-11, SN-38 glucuronidation, or intracellular accumulation of both CPT-11 and SN-38 in H4-II-E cells followed Michaelis-Menten kinetics with the one-binding site model being the best fit for the kinetic data. Coincubation or 2-hr preincubation of thalidomide at 25 microM and 250 microM and its hydrolytic products at 10 microM did not show any significant effects on CPT-11 hydrolysis and SN-38 glucuronidation. However, preincubation of H4-II-E cells with thalidomide (250 microM), its hydrolytic products (total concentration of 10 microM), or phthaloyl glutamic acid (one major thalidomide hydrolytic product, 10 microM) significantly increased the intracellular accumulation of SN-38, but not CPT-11 (P < 0.01). The dose-limiting toxicities of CPT-11 were alleviated by combination with thalidomide in rats and the pharmacokinetic modulation by thalidomide may partially explain its antagonizing effects on the toxicities of CPT-11. The hydrolytic products of thalidomide, instead of the parental drug, modulated the hepatic hydrolysis of CPT-11 and intracellular accumulation of SN-38, probably contributing to the altered plasma pharmacokinetics of CPT-11 and SN-38. Further studies are needed to explore the role of both pharmacokinetics and pharmacodynamic components in the protective effect of thalidomide against the toxicities of CPT-11.

Thalidomide is a racemate with potentially different pharmacokinetics and pharmacodynamics of the component (+)-(R)- and (-)-(S)-thalidomide enantiomers. As part of a project on the adjunctive effects of thalidomide and cytotoxic agents, a method for the chiral separation and quantitation of thalidomide was developed and validated. Thalidomide in relevant serum and tissue homogenate samples was stabilized by buffering with an equal volume of citrate-phosphate buffer (pH 2, 0.2M), and stored at -80 degrees C pending assay. The thalidomide enantiomers, extracted from the samples with diethyl ether, were well separated on a chiral HPLC column of vancomycin stationary phase and a mobile phase of 14% acetonitrile in 20 mM ammonium formate adjusted to pH 5.4; their concentrations were determined with phenacetin as internal standard at 220 nm detection. Over a thalidomide concentration range of 0.1-20 microg/ml, assay precision was 1-5% (CV) for both enantiomers, and calibration curves were linear with all correlation coefficients being >0.99. The estimated limit of quantification for both enantiomers was 0.05 microg/ml with 0.2-0.6 ml serum samples. Thalidomide in rat and human serum, acidified and stored as described above, was found to be chemically and chirally stable over 1 year. The method has been successfully applied to serum samples from human patients undergoing thalidomide treatment for mesothelioma, and to serum, blood and tissue samples from a laboratory rodent model using transplanted 9l gliosarcoma. Enantioselectivity in thalidomide pharmacokinetics has been found, thereby reinforcing the need for considering the relevance of chirality in thalidomide pharmacology.

Multiple myeloma is an incurable bone marrow cancer, the treatment of which is notoriously difficult. Only modest advances have been achieved using complex polychemotherapeutic regimens, transplant strategies and supportive therapy. In 1999, when new drugs for myeloma were urgently needed, thalidomide was introduced and opened up a completely new line of therapy for the disease. Although the mechanism of action is not yet completely understood, thalidomide has demonstrated efficacy in patients with refractory, relapsed myeloma, even in late-stage cases. This article reviews the current knowledge of thalidomide in myeloma treatment, focusing especially on the possible mechanisms of action, clinical results and adverse events of this drug.

In this study, we prepared 2-(2,6-dioxopiperidin-3-yl)-4-[(18)F]fluoroisoindole-1,3-dione (4-[(18)F]fluorothalidomide; [(18)F]1) for the in vivo studies of angiogenesis. Radiochemical synthesis of [(18)F]1 was carried out by labeling 4-trimethylammoniumthalidomide trifluoromethanesulfonate with nBu(4)N[(18)F]F in dimethyl sulfoxide (DMSO), followed by reverse-phase HPLC purification. Decay-corrected radiochemical yield of [(18)F]1 was 50-60%, with an effective specific activity of 42-120 GBq/micromol (end of synthesis). Incubation of the radioligand with human umbilical vein endothelial cells (HUVEC-C; American Type Culture Collection) showed a time-dependent increase in the uptake of the radioligand, and the uptake was inhibited by 8-11% in the presence of 10 microM thalidomide, indicating nonspecific binding of the radioligand. Positron emission tomography (PET) images of mice implanted with tumors in their right flanks revealed a marked accumulation of radioactivity in the livers, kidneys and bladders of the mice, and brain uptake appeared at approximately 40 min after injection. However, no radioactivity uptake was detected in the implanted tumor. Thin-layer chromatography (TLC), HPLC and LC-MS analyses of mouse liver microsomal metabolites of [(18)F]1 and 1 with or without nicotinamide adenine dinucleotide phosphate (NADPH) clearly revealed that the radioligand did not go through metabolic activation but underwent nonenzymatic hydrolysis at physiological pH. Therefore, these results would appear to indicate that [(18)F]1 may not be suitable for the in vivo studies of angiogenesis at least in mice, although it was reported that thalidomide and/or its hydrolysis products may be responsible for its activity in humans.

Recurrent Aphthous Ulceration (RAU) is an inflammatory ulcerative disease of unknown etiology. Although RAU are common in the general population, people with HIV disease may have ulcers that are large and painful and take a long time to heal. Local and systemic steroid therapy has been the traditional method of treatment for recurrent lesions. Recent studies have shown that systemic thalidomide therapy has the best efficacy in the treatment of major RAU in HIV-seropositive patients. Two case histories of complete resolution of the RAU are presented. We have included recommended guidelines for prescribing thalidomide according to the System for Thalidomide Education and Prescribing Safety (STEPS) Program.

Background: Multiple myeloma accounts for 10% of all haematologic malignancies worldwide. In Europe, over 10,000 new cases and nearly 8000 deaths were attributed to multiple myeloma in 2000. Unlike other malignancies, in which surgery and radiation are important treatment modalities, myeloma is exclusively treated with stem cell transplantation and drug therapy, requiring pharmacists to stay abreast of new developments. The melphalan-prednisolone and vincristine-doxorubicin-dexamethasone (VAD) regimens, which have been standard treatments for multiple myeloma over the past few decades, have yielded responses without real survival benefits. Transplantation utilizing high-dose chemotherapy has produced the only meaningful survival benefits for patients with multiple myeloma, but many patients are not candidates for this aggressive treatment option. More effective therapies for multiple myeloma are needed., Objective: To address the mechanisms of action, safety, and efficacy of novel approaches to the treatment of myeloma involving bortezomib, thalidomide and its analogues, lenalidomide and CC-4047 (Actimid), and arsenic trioxide as single agents or in combination regimens., Data Sources: Published preclinical and primary clinical trial results, as well as scientific or clinical meeting abstracts. The author determined the relevance and subsequent inclusion of the data., Conclusions: Bortezomib is approved in the US and Europe as single-agent therapy for the treatment of relapsed or refractory multiple myeloma. Thalidomide, its analogues, and arsenic trioxide have demonstrated activity and are under investigation in this disease. Further clinical trials of the efficacy and toxicity of these novel agents are ongoing and will further define optimal combinations and sequencing with conventional therapies.

A rapid and sensitive system of liquid chromatography coupled with microdialysis was developed for the simultaneous determination of unbound thalidomide in rat blood, brain and bile for pharmacokinetic study. Microdialysis probes were concurrently inserted into the jugular vein toward the right atrium, the brain striatum and the bile duct of the anesthetized Sprague-Dawley rats for biological fluid sampling after the administration of thalidomide (5 mg kg(-1)) through the femoral vein. Thalidomide and dialysates were separated using a Zorbax ODS C(18) column and a mobile phase comprising acetonitrile-methanol-0.1 mm 1-octanesulufonic acid (32:3:65, v/v/v, pH 5.3) at flow rate of 1 mL min(-1). The UV wavelength was set at 220 nm. The concentration-response relationship was linear (r(2)>0.995) over a concentration range of 0.025--25 microg mL(-1). The intra-assay and inter-assay precision and accuracy of thalidomide fell within 7%. The average in vivo recoveries were 0.31+/- 0.02,0.046+/- 0.004 and 0.57+/- 0.02 (n=6), respective to the dialysates of blood, brain and bile, with thalidomide at concentrations 2, 5 and 10 microg mL(-1). The disposition of thalidomide in the blood, brain and bile fluid suggests that there is a rapid thalidomide exchange and equilibration between the blood and brain systems. In addition, thalidomide undergoes hepatobiliary excretion., (Copyright (c) 2005 John Wiley & Sons, Ltd.)

A sensitive and simple high performance liquid chromatography (HPLC) method was developed and validated for the determination of thalidomide in rat plasma. Chromatography was accomplished with a reversed-phase Hypersil C18 column. Mobile phase consisted of acetonitrile-10 mM ammonium acetate buffer (pH 5.50) (28:72, v/v), at a flow rate of 0.8 ml/min. Thalidomide was monitored by ultraviolet detector at 220 nm and it gave a linear response as a function of concentration over 0.02-50 microM. The limit of quantitation in rat plasma was 0.50 ng (0.02 microM plasma concentration) with an aliquot of 20 microl. Results from a 3-day validation study indicated that this method allows for simple and rapid quantitation of thalidomide with excellent accuracy and reliability. Using this validated assay, the effect of coadministered irinotecan (CPT-11) on the plasma pharmacokinetics of thalidomide in rats was determined. Coadministration of CPT-11 (intravenously, 60 mg/kg) increased the maximum plasma concentration (C(max)) and area under the plasma concentration-time curve (AUC(0-10h)) of thalidomide by 32.29 and 11.66%, respectively, as compared to the control, but none of the effect of CPT-11 was of statistical significance (P > 0.05). Concomitant CPT-11 also caused a 10.04% decrease in plasma clearance (CL) and 14.51% decrease in volume of distribution (V(d)) (P > 0.05). These results suggest that coadministered CPT-11 did not significantly alter the plasma pharmacokinetics of thalidomide in rats. Further studies are warranted to explore the pharmacokinetic and pharmacodynamic interactions between CPT-11 and thalidomide.

After nearly decades of extinction as a sedative and antiemetic, thalidomide reemerged as the parent compound of a novel and promising class of therapeutics termed the immunomodulatory drugs (IMiDs). The analogues of thalidomide, CC-5013 (lenalidomide, Revlimid) and CC-4047 (Actimid) are more potent regulators of cellular immune and cytokine response while lacking some of the dose limiting side effects of the parent compound, such as neurologic toxicity. Preclinical data will be reviewed that outlines these drugs' effects on tumor necrosis alpha, interleukin 12, angiogenesis, and T-cell function. The evolution of the use of thalidomide as a therapeutic for diseases such as multiple myeloma and myelodysplastic syndrome and the promising initial results of the new IMiDs will be reviewed.

Studies in patients have indicated that the oral absorption of thalidomide is considerably variable at high doses (>200 mg/day). The aim of this study was to investigate the transport of racemic thalidomide using human colon cancer cell line (Caco-2) monolayers, which have been widely used to investigate drug permeability. A typical 21-day protocol was used to prepare Caco-2 monolayers. Thalidomide was determined by a validated high performance liquid chromatography method with ultraviolet detection. The integrity of Caco-2 monolayer was confirmed when the transepithelial electrical resistance (TEER) exceeded 300 Ohmz . cm2, and the leakage of 14C-manitol was <1% per hour. Uptake of thalidomide by Caco-2 cells was very limited (up to 2.1%). The transport of thalidomide appeared to be linear up to 1 hr. Our study indicated that the permeability coefficients (Papp) of thalidomide at 2.5-300 microM from the apical (AP) to basolateral (BL) and from BL to AP side was 2-6 x 10(-5) cm/sec, with a marked decrease in Papp values from AP to BL at increased thalidomide concentration. The transport of thalidomide was sodium-, temperature- and pH-dependent, as replacement of extracellular sodium chloride or reducing temperature and apical pH can result in significant decreases in the Papp values. Additional data indicated that transport of thalidomide is energy-dependent, as it was significantly (P < 0.05) inhibited by the ATP inhibitors, sodium azide and 2,4-dinitrophenol. In addition, DL-glutamic acid, cytidine, diprodomole, papaverine, quinidine, and cyclophosphamide significantly (P < 0.05) inhibited the transport of thalidomide, while the P-glycoprotein inhibitor verapamil and other nucleosides and nucleotides such as thymidine and guanine had no effect. These results indicated that thalidomide was rapidly transported by Caco-2 monolayers, and this might involve a saturable energy-dependent transporter.

The thalidomide analogue and immunomodulatory drug (IMiD) lenalidomide (CC-5013, REVLIMID) is emerging as a useful treatment for a number of cancers and has recently entered phase III trials for multiple myeloma. It has been suggested that the anti-tumor effect of lenalidomide is related to its anti-angiogenic potency. In this regard, we have previously shown that lenalidomide inhibits angiogenesis in both rat and human in vitro models but does not affect endothelial cell proliferation. We now show that oral administration of lenalidomide attenuates growth factor-induced angiogenesis in vivo; the rat mesenteric window assay was utilized to show that lenalidomide significantly inhibits vascularization in a dose-dependent manner. We also found that lenalidomide significantly inhibits growth factor-induced endothelial cell migration. This correlates with the inhibitory effect of lenalidomide on growth factor-induced Akt phosphorylation, thereby providing a potential mechanism for its anti-migratory and subsequent anti-angiogenic effects. These data further support the use of lenalidomide as an orally administered drug for the effective treatment of angiogenesis-dependent conditions, including cancer, and suggest a potential mechanism of action.

Thalidomide has anti-angiogenic and immunomodulatory activity, exhibiting antitumour effects in patients with multiple myeloma and, more rarely, in several other solid tumours. We evaluated the single-agent antitumour activity and toxicity profile of thalidomide in patients with metastatic malignant melanoma, as well as its plasma pharmacokinetics and pharmacodynamic effects [vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (b-FGF) levels]. A two-stage Gehan method was used with a stopping rule after 14 consecutive non-responding patients. Thalidomide was given orally at a daily dose of 200 mg/day, which was then escalated every 2 weeks by 200 mg/day as tolerated to a maximum of 800 mg/day. Patients were evaluated every 8 weeks for response using the World Health Organization (WHO)-27 criteria. Fourteen patients were enrolled and no objective responses were observed, with one stable disease and one mixed response. The dose-limiting toxicities were constipation, dizziness and somnolence. Other toxicities were oedema, neuropathy, dry skin, dry mouth, tremor and fatigue. The plasma pharmacokinetics of thalidomide were comparable with those of previous studies in normal volunteers and in patients with advanced prostate cancer. Serum levels of b-FGF and VEGF did not change significantly following drug administration. In conclusion, thalidomide showed poor activity, but acceptable toxicity, in patients with metastatic melanoma. Future studies should explore this agent in combination with other biological agents or cytotoxic agents, such as temozolomide.

A high-performance liquid chromatographic assay with MS detection has been developed for the quantitative determination of the anti-angiogenic agent CC-5013 in human plasma. Sample pretreatment involved liquid-liquid extraction with acetonitrile/1-chlorobutane (4:1, v/v) solution containing the internal standard, umbelliferone. Separation of the compounds of interest was achieved on a column packed with Waters C18 Nova-Pak material (4 microm particle size; 300 mm x 3.9 mm internal diameter) using acetonitrile, de-ionized water, and glacial acetic acid in ratios of 20:80:0.1 (v/v/v) (pH 3.5) delivered at an isocratic flow rate of 1.00 ml/min. Simultaneous MS detection was performed at m/z 260.3 (CC-5013) and m/z 163.1 (umbelliferone). The calibration curve was fit to a linear response-concentration data over a range of 5-1000 ng/ml using a weighting factor of 1/x. Values for accuracy and precision, obtained from four quality controls analyzed on three different days in replicates of five, ranged from 98 to 106% and from 5.5 to 15.5%, respectively. The method was successfully applied to study the pharmacokinetics of CC-5013 in a cancer patient receiving the drug as single daily dose.

Purpose: Tumor growth and metastasis is believed to depend on the tumor's ability to induce neovascularization. Recent studies have indicated that thalidomide inhibits angiogenesis. We performed a phase I and pharmacokinetic study of thalidomide with carboplatin in children with refractory solid tumors., Patients and Methods: Carboplatin was administered as a single intravenous dose once every 21 days at a target area under the concentration-time curve of 6 mg/mL.min. Thalidomide was administered daily by mouth. The initial dose level was 100 mg/m(2)/d with intrapatient dose escalation to a maximum dose of 300 mg/m(2)/d. The next cohort of patients started at a dose of 300 mg/m(2)/d, with intrapatient dose escalation to a maximum dose of 500 mg/m(2)/d. Standard response and adverse event criteria were used. Serial blood samples for thalidomide pharmacokinetics studies were obtained after the first dose., Results: Twenty-two patients received 56 cycles of therapy. The maximum tolerated thalidomide dose was 400 mg/m(2)/d. The dose-limiting toxicity was somnolence. There were no objective responses. Thalidomide's apparent clearance was 55 +/- 16 mL/min/m(2) and the terminal half-life was 5.9 +/- 2.8 hours. There was no evidence of dose-dependent pharmacokinetics in the narrow range studied., Conclusion: Thalidomide at a dose of 400 mg/m(2)/d can be safely administered to children with solid tumors in combination with carboplatin. Somnolence is the major toxicity. In addition, we have characterized the pharmacokinetic behavior of thalidomide in children. This study can serve as the basis for future investigation of thalidomide as an anticancer agent in children.