Review of Select NMEs

US Pharm. 2007;32(3):HS-5-HS-32.

New molecular entities (NMEs), as defined by the FDA, are new drug products that have as their active ingredient a chemical substance marketed for the first time in the United States. The following descriptions of the NMEs approved during the second half of 2006 detail the pharmacotherapeutic design and mechanism of action of each new drug. Also included is a summary of selected clinical data presented to the FDA in support of the manufacturer's new drug application (NDA). The FDA classifies NMEs on the basis of therapeutic potential (Table). NMEs classified as priority reviewed (P) represent significant improvement compared to marketed products in the treatment, diagnosis, or prevention of a disease. NMEs receiving standard review (S) are those that appear to have therapeutic qualities similar to those of one or more already marketed drugs.

This review is intended to be objective rather than evaluative in content. The information for each reviewed NME was obtained primarily from sources published prior to FDA approval. Experience clearly demonstrates that many aspects of a new drug's therapeutic profile, not detected in premarketing studies, surface after the drug is used in large numbers of patients. Studies have clearly demonstrated the appearance of "new" adverse reactions for many NMEs within two to three years of the drug becoming available. Many of these drugs may eventually acquire at least one black box warning for serious adverse drug reactions or are withdrawn from the market for safety reasons that were not recognized at the time of approval. Hence, while this review offers a starting point for learning about new drugs, it is essential that practitioners be vigilant of changes in a drug's therapeutic profile as reported by their own patients and in the pharmaceutical literature.

Posaconazole (Noxafil, Schering)

Introduction:^1-4 Oropharyngeal candidiasis (OPC) is an opportunistic mucosal infection caused by Candida species, in most cases Candida albicans. The four major forms of OPC are pseudomembranous, or thrush, consisting of white discrete plaques on an erythematous background, on the buccal mucosa, throat, tongue, or gingivae;  erythematous, consisting of smooth red patches on the hard or soft palate, dorsum of the tongue, or buccal mucosa; hyperplastic, consisting of white, firmly adherent patches or plaques, usually bilaterally distributed on the buccal mucosa; and denture-induced stomatitis, presenting as either a smooth or granular erythema confined to the denture-bearing area of the hard palate and often associated with angular cheilitis. Symptoms vary, ranging from no symptoms to a sore and painful mouth with a burning tongue and altered taste. OPC can also impair speech, nutritional intake, and quality of life.

Candida is found in the mouths of 31% to 60% of healthy people in developed countries, and denture stomatitis associated with Candida is present in 65% of denture wearers. OPC can affect up to 15% to 60% of people with hematologic or oncological malignancies during periods of immunosuppression. This condition is also seen in 7% to 48% of people with HIV infection and in over 90% of those with AIDS. Risk factors associated with symptomatic OPC, in addition to immunosuppression and hematologic disorders, include broad-spectrum antibiotic use, inhaled or systemic steroid use, xero­ stomia, diabetes, and the use of dentures, obturators, or orthodontic appliances. For most people, untreated candidiasis persists for months or years unless risk factors are treated or eliminated.

A number of therapeutic options are available for the treatment of OPC. Topical therapy with antifungal preparations, including nystatin lozenges or suspension or clotrimazole troches, usually suffices for mild forms of the disease. However, extensive disease, especially in patients with immunosuppression (from cancer or HIV/AIDS), and disease in which there are symptoms that suggest esophageal involvement (e.g., pain on swallowing) are best treated with systemic antifungal therapy; prolonged suppressive therapy may be required if the immunosuppressive condition does not remit. Historically, the primary systemic therapies applied for OPC employ an azole antifungal such as fluconazole, itraconazole, or ketoconazole. Although OPC is usually amenable to therapy with local or systemic antifungal drugs, failures of azole therapy for such infections have been reported, and relapse rates are high (30% to 50%). For example, fluconazole-refractory candidiasis reportedly occurs in 5% to10% of HIV-infected patients with low CD4+ counts who have received chronic treatment with fluconazole. Strains isolated during relapses are probably mutants of previously present susceptible strains of C albicans. Thus, there remains a need for new therapies to effectively treat OPC, especially in patients who are immunocompromised or have a hematologic disorder.

In September 2006, the FDA approved posaconazole (Figure) as an oral suspension for the treatment of OPC, including infections refractory to itraconazole and/or fluconazole. This action followed an approval earlier in the year for prevention of invasive Aspergillus and Candida infections in patients ages 13 and older who are at high risk of these infections due to being severely immunocompromised, such as hematopoietic stem cell transplant (HSCT) recipients with graft-versus-host disease (GVHD) or those with hematologic malignancies with prolonged neutropenia from chemotherapy. Invasive fungal infections are a leading cause of death in these high-risk populations.

Mechanism of Action:^2-5 Like other azole antifungals, posaconazole blocks the synthesis of ergosterol, a key component of the fungal cell membrane, through inhibition of the enzyme lanosterol 14-alpha-demethylase and the accumulation of methylated sterol precursors.

Posaconazole has demonstrated in vitroactivity against Aspergillus fumigatus and C albicans. However, correlation between the results of susceptibility studies and clinical outcomes has not been established, and interpretive criteria/breakpoints for posaconazole have not been established for any fungi. In immunocompetent and/or immunocompromised mice and rabbits with pulmonary or disseminated infection with A fumigatus, prophylactic administration of posaconazole was effective in prolonging survival and reducing mycological burden. Prophylactic posaconazole also prolonged survival of immunocompetent mice challenged with C albicans or Aspergillus flavus. Clinical isolates of C albicans and Candida glabrata with decreased posaconazole susceptibility were observed in oral samples taken during prophylaxis with posaconazole and fluconazole, suggesting a potential for resistance. These isolates also showed reduced susceptibility to other azoles, indicating possible cross-resistance between azoles.

Pharmacokinetics:^3,5 Posaconazole is absorbed with a median time to maximum plasma concentration (Tmax) of approximately three to five hours. Dose-proportional increases in plasma exposure (area under the curve [AUC]) to posaconazole were observed following single oral doses from 50 to 800 mg and following multiple-dose administration from 50 mg two times a day to 400 mg two times a day. No further increases in exposure were observed with dosages greater than 400 mg twice daily. In single-dose studies, the mean AUC and maximum plasma levels (Cmax) of posaconazole were approximately three times higher when administered with a nonfat meal or liquid nutritional supplement (14 g of fat) and about four times higher when administered with a high-fat meal (~50 g fat) relative to the fasted state. Thus, to ensure attainment of adequate plasma concentrations, it is recommended to administer posaconazole with food or a nutritional supplement. Posaconazole is highly protein-bound (>98%), predominantly to albumin, and has an apparent volume of distribution of 1,774 L, suggesting extensive extravascular distribution and penetration into the body tissues.

Posaconazole does not undergo any significant degree of oxidative (cytochrome P450 [CYP450]-mediated) metabolism but is conjugated to some degree by uridine diphosphate (UDP) glucuronidation (phase 2 enzymes). Posaconazole is eliminated primarily in the feces (71%), with the major component eliminated as parent drug (66% of dose). Renal clearance is a minor elimination pathway, with 13% of the dose excreted in urine in up to 120 hours. Excreted metabolites in both urine and feces account for about 17% of the administered posaconazole dose. The mean elimination half-life is 35 hours (range, 20 to 66 hours) with a total body clearance (CL/F) of 32 L/hour.

The pharmacokinetics of posaconazole are not altered significantly in mild (creatinine clearance [ClCr] 50 to 80 mL/min/1.73 m²) and moderate (ClCr 20 to 49 mL/min/1.73 m²) renal impairment. Thus, no dose adjustment is required in these patients. In patients with severe renal insufficiency (ClCr <20 mL/min/1.73 m²), the mean AUC was similar to that in patients with normal renal function, but the range of AUC estimates was highly variable. Due to variability in exposure, patients with severe renal impairment should be monitored closely for breakthrough fungal infections. Currently, there is inadequate pharmacokinetic data in patients with hepatic impairment to be able to determine if dose adjustment is necessary. Thus, it is recommended that posaconazole be used with caution in patients with hepatic impairment. The pharmacokinetic profile of posaconazole is not affected significantly by gender, race, or age.

Clinical Profile:^3,6-8 Posaconazole is indicated for prophylaxis of invasive Aspergillus and Candida infections in patients ages 13 and older who are at high risk due to a severely immunocompromised state. The efficacy of posaconazole in the prophylaxis of invasive fungal infections was demonstrated in two randomized, controlled studies (designated as study 1 and study 2) in more than 1,000 patients with severely immunocompromised immune systems. In both trials, aspergillosis was the most commonly observed breakthrough infection.

In study 1, patients with neutropenia receiving cytotoxic chemotherapy (n = 602) were randomized to receive posaconazole three times daily or pooled standard azole therapy (fluconazole oral suspension 400 mg once daily or itraconazole oral solution 200 mg twice daily). Results showed that posaconazole prophylactic therapy yielded a reduction in treatment failure, compared to fluconazole/itraconazole, as defined by a composite end point of breakthrough invasive fungal infections, death, and use of systemic antifungal drugs (27% vs. 42%). Posaconazole was associated with lower rates of proven or probable invasive fungal infections (2% vs. 8%), a reduced number of breakthrough Aspergillus infections (1% vs. 7%), and decreased all-cause mortality rates at 100 days postrandomization (14% vs. 21%).

Study 2 compared posaconazole suspension (200 mg three times daily) with fluconazole capsules (400 mg once daily) for invasive fungal-infection prophylaxis in allogenic HSCT recipients with GVHD (n = 600). In this trial, posaconazole was shown to significantly reduce the rate of proven or probable invasive fungal infections and related mortality at 16 weeks (5% vs. 9% and 3% vs. 5%, respectively).

More recently, the FDA has approved posaconazole for the treatment of OPC, including OPC refractory to itraconazole and/or fluconazole, based on results primarily from two additional trials. One trial, designated as study 3, was a randomized, controlled, evaluator-blinded study in HIV-infected patients with OPC in which the majority of subjects were infected with C albicans. Patients were treated with posaconazole or fluconazole oral suspension, both drugs administered as 100 mg twice daily for one day, followed by 100 mg once daily for 13 days). Clinical and mycological outcomes were assessed after 14 days of treatment and at four weeks after the end of treatment. Patients who received at least one dose of study medication and had a positive oral swish culture of Candida species at baseline were included in the analyses. Posaconazole therapy achieved similar rates of clinical success (complete or partial resolution of all ulcers and/or plaques and symptoms) and mycological eradication (absence of colony-forming units) at 14 days, compared to fluconazole (91.7% vs. 92.5% and 52.1% vs. 50.0%, respectively). Clinical and mycological relapse rates at four weeks posttherapy were also comparable between groups (29.0% vs. 35.1% and 55.6% vs. 63.7%, respectively).

A second study (designated as study 4) was a noncomparative study of posaconazole oral suspension in HIV-infected subjects with OPC that was refractory to treatment with fluconazole or itraconazole. An episode of OPC was considered refractory if there was a lack of improvement or a worsening of OPC after a standard course of therapy with fluconazole at doses ?100 mg/day for at least 10 consecutive days or itraconazole 200 mg/day for at least 10 consecutive days, and treatment with fluconazole or itraconazole had not been discontinued for more than 14 days prior to treatment with posaconazole. Of the 199 subjects enrolled in this study, 89 subjects met these criteria for refractory infection. Forty-five subjects with refractory OPC were treated with posaconazole 400 mg twice daily for three days, followed by 400 mg once a day for 25 days, with an option for further treatment during a three-month maintenance period. Following a dosing amendment, 44 more subjects were treated with posaconazole 400 mg twice daily for 28 days. The efficacy of posaconazole was assessed by the clinical success (cure or improvement) rate after four weeks of treatment. The clinical success rate was 74.2% (66/89). The clinical success rates for both the original and amended dosing regimens were similar (73.3% and 75.0%, respectively).

Adverse Reactions:^3,6-8 To date, the safety of posaconazole has been assessed in more than 2,000 patients in clinical trials. The most commonly reported adverse events associated with posaconazole are fever (45%), gastrointestinal (GI) effects (27% to 42%; e.g., diarrhea, nausea, vomiting, abdominal pain, constipation), hypokalemia (30%), headache (28%), coughing (24%), rigors (20%), dyspnea (20%), rash (19%), hypertension (18%), fatigue (17%), and blood disorders (20% to 29%; e.g., anemia, neutropenia, thrombocytopenia). Rare cases of hepatic reactions (e.g., mild-to-moderate elevations in alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase, total bilirubin, and/or clinical hepatitis) have also been reported in association with posaconazole. Thus, liver function tests should be evaluated at the beginning and during the course of posaconazole therapy.

Serious, or medically significant, rare treatment-related adverse events reported during clinical trials with posaconazole have been adrenal insufficiency, allergic, and/or hypersensitivity reactions. In addition, rare cases of hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, and pulmonary embolus have been seen primarily among patients who had received concomitant cyclosporine or tacrolimus for the management of transplant rejection or GVHD. During clinical development, there was a single case of torsade de pointes in a patient taking posaconazole. This report involved a seriously ill patient with multiple confounding, potentially contributory risk factors, such as a history of palpitations, recent cardiotoxic chemotherapy, hypokalemia, and hypomagnesemia.

Drug Interactions:^3,6-8 A number of azole antifungals, such as ketoconazole, depend on an acidic environment for optimal dissolution and absorption from the GI tract. Therefore, drugs that decrease gastric acid secretion (e.g., antacids, H₂ -antagonists, proton pump inhibitors) can impair absorption of some azoles. No clinically significant effects on bioavailability or plasma concentrations were observed when posaconazole was administered with an antacid, proton pump inhibitor, or H₂-antagonist other than cimetidine. Since cimetidine significantly reduces posaconazole absorption, its concurrent use should be avoided.

Posaconazole is primarily metabolized via UDP glucuronidation (phase 2 metabolism) and is a substrate for p-glycoprotein efflux pump. Therefore, inhibitors or inducers (rifabutin, phenytoin) of these clearance pathways may affect posaconazole plasma concentrations. Clinical studies and in vitro studies with human hepatic microsomes indicate that posaconazole is an inhibitor of cytochrome enzymes, particularly the CYP3A4 isozyme. Therefore, posaconazole has the potential to increase plasma concentrations of other drugs that are predominantly inactivated by CYP3A4 metabolism. This can be particularly significant when the other drug is a CYP3A4 substrate with a narrow therapeutic index, such as cyclosporine, tacrolimus, midazolam, rifabutin, and phenytoin. Based on this potential interaction, drug dosages may need to be reduced at the initiation of posaconazole treatment, and blood concentrations may need to be monitored frequently during, and at discontinuation of, posaconazole administration. The manufacturer's literature should be consulted for specific dosing and monitoring recommendations when initiating posaconazole therapy in patients receiving other drugs.

Dosage and Administration: ³ Posaconazole is supplied as an oral suspension in 4-oz. (123-mL) amber glass bottles containing 105 mL of suspension (40 mg of posaconazole per milliliter). The product should be shaken well before use and administered as 400 mg (10 mL) twice a day for OPC. Duration of therapy should be based on the severity of the patient's underlying disease and clinical response. A measured dosing spoon is provided, marked for doses of 2.5 and 5 mL. To enhance oral absorption and optimize plasma concentrations, the drug should be administered with a full meal or with a liquid nutritional supplement in patients who cannot eat a full meal. Patients who experience severe diarrhea or vomiting should be monitored closely for breakthrough fungal infections. In addition, coadministration of drugs that can decrease the plasma concentrations of posaconazole should be generally  avoided unless the benefit outweighs the risk. If such drugs are necessary, patients should be monitored closely for breakthrough fungal infections. The duration of therapy is based on recovery from neutropenia or immunosuppression.

No dosage adjustment is recommended for patients with renal dysfunction. However, due to the high variability in exposure, patients with severe renal impairment should be monitored closely for breakthrough fungal infections. The pharmacokinetic data in subjects with hepatic impairment were not sufficient to determine if dosage adjustment is necessary in patients with hepatic dysfunction. It is recommended that posaconazole be used with caution in patients with hepatic impairment.


Dasatinib (Sprycel, Bristol-Myers Squibb)

Introduction and Mechanism of Action:^9-11 Chronic myelogenous leukemia (CML) is a cancer of blood cells characterized by replacement of the bone marrow with malignant, leukemic cells called blast cells. As the number of blast cells increases in the blood and bone marrow, there is a decrease in white blood cells, red blood cells, and platelets. This may result in infections, anemia, and bleeding, as well as in bone pain and pain or a feeling of fullness below the ribs on the left side. The number of blast cells in the blood and bone marrow and the severity of symptoms determine the phase of CML. The three phases of CML are chronic, accelerated, and blastic. In chronic-phase CML, fewer than 10% of the cells in the blood and bone marrow are blast cells; in the accelerated phase, 10% to 19% are blast cells. In blastic-phase CML, 20% or more of the cells in the blood or bone marrow are blast cells. Blastic transformation may be myeloid, lymphoid, undifferentiated, or mixed, with myeloid blast crisis being about two times more common than lymphoid. A blast crisis consists of fatigue, fever, and an enlarged spleen that occur during the blastic phase. Diagnosis of the CML phase is important to determine therapy.

CML is usually diagnosed by finding a specific chromosomal abnormality, the Philadelphia (Ph) chromosome, named after the city where it was first recorded. The Ph chromosome is the result of the exchange of genetic material between the long arms of chromosomes 9 and 22, a process referred to as translocation. This exchange brings together two genes: the BCR (breakpoint cluster region) gene on chromosome 22 and the proto-oncogene ABL (Abelson leukemia virus) on chromosome 9. The resulting hybrid gene BCR-ABL codes for a fusion protein with tyrosine kinase activity, which activates signal transduction pathways, leading to uncontrolled cell growth.

Imatinib, an orally available ABL kinase inhibitor, can induce hematologic and cytogenetic remission in all stages of CML, as well as in Ph-positive acute lymphoblastic leukemia (Ph+ALL), with minimal toxicity. Imatinib is now first-line therapy for newly diagnosed CML. However, resistance to imatinib has become increasingly important. Furthermore, nearly all patients with chronic-phase CML have persistent disease, measurable by polymerase chain reaction and indicative of a reservoir of residual leukemia cells that may be a source of relapse. Relapse during imatinib treatment is most often caused by mutations in the kinase domain of BCR-ABL that interfere with imatinib binding.

Dasatinib, approved in mid-2006, is an orally available ABL kinase inhibitor that differs from imatinib in that it can bind to both the active and inactive conformations of the ABL kinase domain (Figure). Dasatinib also inhibits a distinct spectrum of kinases that overlaps with the array of enzymes that imatinib inhibits. Since it has less stringent binding requirements than those of imatinib, dasatinib has activity against many imatinib-resistant kinase domain mutations of BCR-ABL at nanomolar concentrations. By targeting these kinases, dasatinib inhibits the overproduction of leukemia cells in the bone marrow of patients with CML and Ph+ALL and allows normal red cell, white cell, and blood platelet production to resume. In cell-line models of CML and ALL, dasatinib inhibited 18 of 19 imatinib-resistant BCR-ABL mutations within a narrow concentration range, similar to that required to block wild-type BCR-ABL. The only exception is a single mutation deep within the ATP-binding pocket of the ABL tyrosine kinase (T315I) that confers a high degree of resistance to imatinib and dasatinib and to the imatinib analogue AMN-107, presumably as a result of steric hindrance caused by replacement of threoninewith the bulkier isoleucine residue.

Pharmacokinetics: ¹¹ Maximum plasma concentrations (Cmax) of dasatinib are observed between 0.5 and six hours (Tmax) following oral administration. Dasatinib exhibits dose-proportional increases in AUC and linear elimination characteristics over the dosage range of 15 to 240 mg/day. While consumption of a high-fat meal can result in a modest increase (14%) in the mean AUC, this effect is not believed to be clinically relevant.

Dasatinib has an apparent volume of distribution of 2,505 L, suggesting that the drug is extensively distributed in the extravascular space. Binding of dasatinib and its active metabolite (see below) to human plasma proteins in vitro was approximately 96% and 93%, respectively, with no concentration dependence over the range of 100 to 500 ng/mL.

Dasatinib is extensively metabolized in humans, primarily by CYP3A4, resulting in formation of the active metabolite. In human liver microsome assays, dasatinib is a weak, time-dependent inhibitor of CYP3A4. The exposure of the active metabolite, which is equipotent to dasatinib, represents only about 5% of the dasatinib AUC, suggesting that this metabolite is unlikely to have a major role in the drug's therapeutic profile. Other dasatinib metabolites are formed by the action of flavin-containing monooxygenase 3 (FMO-3) and uridine diphosphate-glucuronosyl-transferase (UGT) enzymes, and these metabolites appear to be pharmacologically inactive.

Approximately 4% and 85% of the administered dose of dasatinib is recovered in the urine and feces, respectively, within 10 days. The parent drug accounts for 0.1% and 19% of the administered dose in urine and feces, respectively, with metabolites being the remainder of the dose. The overall mean terminal half-life of dasatinib is three to five hours. In adults, the pharmacokinetics of dasatinib are not significantly altered by age or gender. The pharmacokinetics of dasatinib have not been evaluated in pediatric patients. In addition, no clinical studies have been performed with dasatinib in patients with impaired hepatic or renal function. Since less than 4% of dasatinib and its metabolites are excreted via the kidney, renal function is not expected to significantly influence drug exposure.

Clinical Profile:^11,12 FDA approval of dasatinib was based on four single-arm, multicenter studies that investigated the safety and efficacy of the drug in the treatment of imatinib-resistant or imatinib-intolerant CML and Ph+ALL. These trials were all ongoing at the time of approval. In all four trials, subjects received 70 mg of dasatinib twice daily. Each study investigated the drug in the treatment of a single disease subclass (see below).

A chronic-phase CML study enrolled 186 patients with imatinib-resistant (68%) or -intolerant (32%) chronic-phase CML. Patients received treatment for a median of 5.6 months (ranging from 0.03 to 8.3 months). Results yielded efficacy in the trial's primary end point, with dasatinib producing major cytogenetic response (MCyR) in 45% of subjects, including complete cytogenic response (CCyR, defined as 0% Ph+ cells detected) in 33% of subjects. Furthermore, complete hematologic response (CHR) was achieved in 90% of subjects.

An accelerated-phase CML study enrolled 107 patients with imatinib-resistant (93%) or -intolerant (7%) accelerated-phase CML. These patients received treatment for a median of 5.5 months (range, 0.2 to 10.1 months). Results yielded efficacy in the trialprimary end point, with dasatinib producing major hematologic response (MaHR) in 59% of subjects, including CHR in 33% and no evidence of leukemia (NEL) in 26%. In addition, MCyR was achieved in 31% of subjects, including CCyR in 21%.

The myeloid blast–phase CML trial enrolled 74 patients with imatinib-resistant (92%) or intolerant (8%) myeloid blast–phase CML. Subjects received therapy for a median of 3.5 months (range, 0.03 to 9.2 months). Results yielded efficacy in the trial's primary end point, with dasatinib producing MaHR in 32% of subjects, including CHR in 24% and NEL in 8%. In addition, MCyR was achieved in 30% of subjects, including CCyR in 27%.

The lymphoid blast–phase CML study enrolled 42 patients with imatinib-resistant (92%) or -intolerant (8%) lymphoid blast–phase CML, and 36 patients with imatinib-resistant (94%) or -intolerant (6%) Ph+ALL. CML subjects received treatment for a median of 2.8 months (range, 0.1 to 6.4 months), and Ph+ALL subjects received treatment for a median of 3.2 months (range, 0.2 to 8.1 months). Dasatinib produced MaHR in 31% of CML subjects and 42% of Ph+ ALL subjects, including CHR in 26% and 31% of subjects and NEL in 5% and 11% of subjects, respectively. In addition, MCyR was achieved in 50% and 58% of subjects, including CCyR in 58% and 58% of subjects, respectively.

Adverse Reactions:^11,12 In clinical trials to date that involve 911 patients with leukemia (one phase I and five phase II clinical studies), the majority of dasatinib-treated patients experienced adverse drug reactions. The drug was discontinued for adverse reactions in 6% of patients in chronic-phase, 5% in accelerated-phase, and 11% in myeloid blast–phase CML and in 6% in lymphoid blast–phase CML or Ph+ALL. The most frequently reported adverse effects included fluid retention events (e.g., pleural effusion), GI effects (diarrhea, nausea, abdominal pain, and vomiting) and bleeding events. Fluid retention was severe in 9% of patients, including pleural and pericardial effusions. Severe ascites, generalized edema, and severe pulmonary edema were reported in 1% of trial patients. Fluid retention was typically managed by supportive care measures such as diuretics or short courses of steroids. Patients who develop symptoms suggestive of pleural effusion (dyspnea or dry cough) should be evaluated by chest x-ray. Severe pleural effusion may require oxygen therapy and thoracentesis.

Treatment with dasatinib is associated with severe chronic toxicity criteria grade 3/4 thrombocytopenia, neutropenia, and anemia, which occur more frequently in patients with advanced CML or Ph+ALL than in patients with chronic-phase CML. Myelosuppression was reported in patients with normal baseline laboratory values, as well as in patients with preexisting laboratory abnormalities. Complete blood counts should be performed weekly for the first two months and then monthly thereafter, or as clinically indicated. In clinical studies, myelosuppression was managed by interruption, dosage reduction, or discontinuation of dasatinib therapy. Hematopoietic growth factor has been used in patients with persistent myelosuppression.

Dasatinib-induced platelet dysfunction and thrombocytopenia may result in severe hemorrhage. Severe GI hemorrhage occurred in 7% of trial patients and generally required treatment interruptions and transfusions. Severe central nervous system hemorrhage, including fatalities, occurred in 1%. Other cases of severe hemorrhage occurred in 4% of patients. Therefore, caution is advised when using dasatinib in patients who are also required to take medications that inhibit platelet function or anticoagulants.

In clinical trials, nine patients receiving dasatinib had QTc prolongation as an adverse event. Therefore, this drug should be administered with caution in patients who have or may develop prolongation of QTc, such as patients with hypokalemia, hypomagnesemia, or congenital long QT syndrome, as well as patients taking antiarrhythmic drugs, other medicinal products that lead to QT prolongation, or cumulative high-dose anthracycline therapy. Hypokalemia or hypomagnesemia should be corrected prior to initiation of dasatinib therapy.

Grade 3/4 elevations of transaminases or bilirubin were reported in all patients treated with dasatinib, with increased frequency in patients with myeloid– or lymphoid–blast CML or Ph+ALL. These elevations were managed with dose reduction or interruption of therapy. Grade 3/4 hypocalcemia was reported in patients with all phases of CML but with an increased frequency in patients with myeloid– or lymphoid–blast CML or Ph+ALL. Patients with hypocalcemia often had recovery with oral calcium supplementation.

Dasatinib is not recommended for use in pregnant women or those contemplating pregnancy, since the drug may cause fetal harm (pregnancy category D). Sexually active male or female patients taking dasatinib should use adequate contraception.

Drug Interactions:^11,12 Dasatinib is a substrate for CYP3A4. Therefore, drugs that inhibit this isozyme (e.g., ketoconazole, itraconazole, erythromycin, cla­ rithromycin, ritonavir, atazanavir, indinavir, nefazodone, nelfinavir, saquinavir, and telithromycin) may increase dasatinib concentrations. Concomitant use of such drugs with dasatinib should be avoided. If systemic administration of a potent CYP3A4 inhibitor cannot be avoided, close monitoring for toxicity and dosage reduction should be considered. Drugs that induce CYP3A4 (e.g., dexamethasone, phenytoin, carbamazepine, and phenobarbital) may decrease dasatinib concentrations. Alternative agents with less enzyme-induction potential should be used, or a dosage increase of dasatinib should be considered. St. John's wort (Hypericum perforatum ) may decrease dasatinib plasma concentrations unpredictably; thus, patients taking dasatinib should not take St. John's wort.

In addition to functioning as a substrate, dasatinib is a time-dependent inhibitor of CYP3A4. Therefore, other drugs that are CYP3A4 substrates and have a narrow therapeutic index (e.g., alfentanil, astemizole, terfenadine, cisapride, cyclosporine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus, or the ergot alkaloids ergotamine and dihydroergotamine) should be administered with caution in patients treated with dasatinib.

The solubility of dasatinib in the GI tract is pH-dependent, and long-term suppression of gastric acid secretion by use of H₂ blockers (e.g., famotidine) or proton pump inhibitors (e.g., omeprazole) is likely to reduce dasatinib exposure. Concomitant use of H₂ blockers or proton pump inhibitors with dasatinib is therefore not recommended, and the use of antacids may be considered. If antacids are used, they should be administered at least two hours before or after the dose of dasatinib. Simultaneous administration of dasatinib and antacids should be avoided.

Dosage and Administration:¹¹ Dasatinib is available as 20, 50, and 70 mg white to off-white, biconvex, round, film-coated tablets. The recommended dosage is 140 mg per day administered orally in two divided doses (70 mg twice daily), one in the morning and one in the evening with or without a meal. Tablets should not be crushed or cut; they should be swallowed whole. A dosage increase or reduction of 20-mg increments per dose is recommended based on individual safety and tolerability.

CYP3A4 inducers such as rifampin may decrease dasatinib plasma concentrations (see Drug Interactions section). Selection of an alternate concomitant medication with no or minimal enzyme-induction potential is recommended. If dasatinib must be administered with a strong CYP3A4 inhibitor, a dosage decrease to 20 to 40 mg daily should be considered. If the dosage of dasatinib is increased, the patient should be monitored for toxicity.

In clinical studies of adult patients with CML and Ph+ALL, dosage escalation to 90 mg twice daily (chronic-phase CML) or 100 mg twice daily (advanced-phase CML and Ph+ALL) was allowed in patients who did not achieve a hematologic or cytogenetic response at the recommended dosage. In clinical studies, myelosuppression was managed by dose interruption, dosage reduction, or discontinuation of therapy. Hematopoietic growth factor has been used in patients with resistant myelosuppression. Guidelines for dosage modifications are provided in the manufacturer's literature.

If a severe nonhematologic adverse reaction develops with dasatinib use, treatment must be withheld until the event has resolved or improved. Treatment can then be resumed as appropriate at a reduced dosage, depending on the initial severity of the event.

Vorinostat (Zolinza, Merck)

Introduction and Mechanism of Action:^13-16 Non-Hodgkin's lymphomas (NHLs) are subclassified into two grades based on growth rates. Low-grade lymphomas are usually slow-growing, while high-grade lymphomas tend to grow more quickly. Cutaneous T-cell lymphoma (CTCL) is a rare, low-grade lymphoma that accounts for one in 20 of all NHL cases. It occurs most frequently in people between 40 and 60 years of age and affects up to 20,000 patients in the United States, with another 1,500 new cases reported each year. Unlike other forms of NHL, CTCL mainly affects the skin. It is caused by the uncontrolled growth of T cells. Normal T cells function by regulating immune response to infection and other foreign antigens. In CTCL, the malignant T cells accumulate and are deposited in the skin.The most common subtypes of CTCL are mycosis fungoides (MF) and Sézary syndrome (SS). CTCL is considered SS when large areas of the skin are affected and large numbers of abnormal lymphocytes (Sézary cells) are also found in the blood and lymph nodes. In some patients, there are no plaques or tumors, but the whole skin can be red, thickened, swollen, and sore (erythroderma). MF represents those forms of CTCL when the blood is not affected.

Clinically, CTCL is staged based on the degree of skin, lymph node, and visceral tissue involvement and the presence of circulating Sézary cells, tumors, or erythroderma. Using this system, CTCL is classified as: (1) stage Ia or limited patch/plaque MF involving <10 % body surface area; (2) stage Ib or generalized patch/plaque MF involving ?10% body surface area; (3) stage IIb or tumor stage MF; and (4) stage III or erythrodermic MF/SS. In the early stage, small, raised, red patches appear on the skin, commonly on the breast and buttocks, although they can appear anywhere. At this stage, the disease often looks like a common skin condition such as eczema or psoriasis. In the plaque or infiltrative stages, irregularly shaped red patches (plaques) form. Although any part of the body may be affected, the buttocks, skin folds, and face are particularly common locations. There may be permanent hair loss from the affected areas if the plaques are left untreated. In the tumor stage, raised tumors appear on the skin and may become deep sores (ulcerate). At this stage, the cancer may have also affected the lymph nodes and, rarely, internal organs such as the liver, lungs, and spleen. CTCL does not necessarily progress through all three stages, and only a small proportion of patients progress to this stage; most never progress beyond the first stage.

A number of treatments can be used for CTCL; therapy selection often depends on the stage or extent of skin involvement. Although treatment for early or localized patch-stage MF may result in a cure, the practical aim of therapy is generally to achieve and maintain clinical remission, decrease morbidity, and palliate advanced disease. Therapeutic modalities include topical therapy, phototherapy, photopheresis (extracorporeal photochemotherapy), radiation therapy, immunotherapy, chemotherapy, or newer agents such as antitumor vaccines and antibody fusion toxins. Commonly used topical agents include high-potency topical cortico­ steroids, carmustine, and mechlorethamine (nitrogen mustard). Phototherapy may consist of psoralen with ultraviolet A photochemotherapy (PUVA), ultraviolet-B (UVB) broadband (280 to 320 nm), and, more recently, narrowband (TL-01-311 nm) UVB. Electron beam radiation has been used locally and for total-body irradiation. Systemic drug therapies include interferons (mostly alpha-interferon), retinoids, methotrexate, and other drugs. Photopheresis has been employed for erythrodermic MF or SS. All of these treatments can be used as monotherapy, and some have been used in combination or in sequence.

Vorinostat was approved by the FDA in 2006 as a new therapy for cutaneous manifestations of CTCL in patients who have progressive, persistent, or recurrent disease on or following two systemic therapies (Figure). This drug has a novel mechanism of action, functioning as an inhibitor of a number of histone deacetylase (HDAC) isozymes. The HDACs catalyze the removal of acetyl groups from the lysine residues of proteins, including histones and transcription factors. In some cancer cells, there is an overexpression of HDACs or an aberrant recruitment of HDACs to oncogenic transcription factors, causing hypoacetylation of core nucleo­ somal histones. Hypoacetylation of histones is associated with a condensed chromatin structure and repression of gene transcription. Inhibition of HDAC activity allows for the accumulation of acetyl groups on the histone lysine residues, resulting in an open chromatin structure and transcriptional activation. In vitro, vorinostat inhibits the enzymatic activity of histone deacetylase isozymes HDAC1, HDAC2, HDAC3 (class I), and HDAC6 (class II) at nanomolar concentrations (IC₅₀ <86 nM) and causes the accumulation of acetylated histones. This is believed to induce cell cycle arrest and/or apoptosis of some transformed cells.

Vorinostat will be made accessible to patients through Merck's Accessing Coverage Today (ACT) program. ACT is a three-part program designed specifically to assist patients in obtaining vorinostat, offer help with insurance reimbursement issues, and provide support for qualified individuals who lack insurance coverage for the drug. Patients without coverage may be eligible for Merck's Patient Assistance Program, which allows them to receive vorinostat free of charge. Merck is also contributing to foundations that provide copay assistance to qualified individuals.

Pharmacokinetics:¹⁶ In clinical trials, oral administration of a single 400-mg dose of vorinostat with a high-fat meal, resulted in peak serum concentrations (Cmax) of 1.2 ± 0.62 µM, median Tmax of 4 (2 to 10) hours, and AUC of 5.5 ± 1.8 µM•hr. In the fasting state, there was a modest decrease in the extent of absorption (4.2 ± 1.9 µM•hr) and increase in the rate of absorption (Tmax 1.5 hours), but these differences are not expected to be clinically significant. At steady state in the fed-state, oral administration of multiple 400-mg doses of vorinostat resulted in a mean AUC and Cmax and a median Tmax of 6.0 ± 2.0 µM•hr and 1.2 ± 0.53 µM and 4 (0.5 to 14) hours, respectively. Vorinostat is approximately 71% bound to human plasma proteins over the concentration range of 0.5 to 50 µg/mL.

In vitro studies using human liver microsomes indicate negligible biotransformation of vorinostat by CYP450   isozymes. Instead, vorinostat is metabolized by direct O -glucuronidation and hydrolysis, followed by beta-oxidation, to yield 4-anilino-4-oxobutanoic acid. Both metabolites are pharmacologically inactive. Compared to the parent drug, the mean steady-state serum exposures in humans of the O-glucuronide of vorinostat and 4-anilino-4-oxobutanoic acid metabolite are fourfold and 13-fold higher, respectively. Less than 1% of the oral dose of vorinostat is recovered in the urine unchanged, indicating that renal excretion does not have a role in the elimination of this drug. The mean urinary recovery of two pharmacologically inactive metabolites at steady state was approximately 16% of the dose as the O-glucuronide of vorinostat and 36% of the dose as 4-anilino-4-oxobutanoic acid. The total urinary recovery of vorinostat and these two metabolites averaged 52 ± 13.3% of the dose. The mean terminal half-life was approximately two hours for both vorinostat and the O-glucuronide metabolite, while that of the 4-anilino-4-oxobutanoic acid metabolite was 11 hours.

The pharmacokinetics of vorinostat do not appear to be vary significantly based on gender, race, or age. Vorinostat was not evaluated in patients younger than 18 years or in patients with hepatic or renal impairment. However, renal excretion does not have an impact in the elimination of vorinostat.

Clinical Profile:^16-18 The efficacy of vorinostat in the treatment of CTCL was assessed in two open-label studies (study 1 and study 2) involving 107 patients. In both studies, patients were treated until disease progression or intolerable toxicity. In study 1, patients with advanced CTCL that was progressive, persistent, or recurrent during or following two systemic therapies were treated with vorinostat 400 mg once daily. The median age of patients was 60 years (51% male, 49% female). Approximately 18% of patients had stage Ib or IIa CTCL, and 82% had stage IIb and higher CTCL. The primary end point was response rate as determined by a modified Severity Weighted Assessment Tool (SWAT) measuring the percentage of total-body surface area involvement. Efficacy was measured as a complete clinical response (CCR), defined as no evidence of disease, or a partial response, defined as a ?50% decrease in SWAT skin assessment score compared with baseline. The overall objective response rate was 29.7% in all patients treated with vorinostat. In patients with stage IIb and higher CTCL, the overall objective response rate was 29.5%, and one patient with stage IIb CTCL achieved a CCR. Secondary endpoints in this study included time to objective response, time to progression, and duration of objective response. In the study, the median time to response was less than two months (55 days) in all patients. However, in rare cases, it took up to six months for patients to achieve an objective response to vorinostat. The median duration of response was not reached, since the majority of responses continued at the time of analysis but was estimated to exceed six months in all patients. The median time to progression approached five months (148 days) in all patients, based on a criterion for tumor progression of a 25% increase in SWAT score from the nadir.

In study 2, patients with CTCL who were refractory or intolerant to one or more treatments were assigned to one of three dosing cohorts. Patients in cohort 1 received 400 mg once daily, while those in cohort 2 received 300 mg twice daily three days a week, and those in cohort 3 received 300 mg twice daily for 14 days, followed by a seven-day rest. Patients in cohort 3 received a maintenance regimen of 200 mg twice daily during the rest period if no response was observed after 14 days of full dosing. The primary efficacy end point in the study was objective response, as measured by the seven-point Physician's Global Assessment scale. In all patients treated, the objective response was 24.2% in the overall population, 25% in patients with stage IIb or higher, and 36.4% in patients with SS. The overall response rates were 30.8%, 9.1%, and 33.3% in cohorts 1, 2, and 3, respectively.

Adverse Reactions:^16-18 In the two single-arm clinical studies described above, the most common side effects, regardless of causality, included fatigue (52%), diarrhea (52%), nausea (41%), taste alteration (28%), low platelet count (26%), anorexia (24%), weight loss (21%), and muscle spasms (20%). The most common serious adverse events, also regardless of causality, were pulmonary embolism (4.7%), squamous cell carcinoma (3.5%), and anemia (2.3%). The GI adverse effects may require management with antiemetic and antidiarrheal medications. Preexisting nausea, vomiting, and diarrhea should be adequately controlled before initiating therapy. Furthermore, because of the risk of dehydration from GI effects, patients should be instructed to drink as least 2 L of fluid per day to maintain adequate hydration during vorinostat therapy.

Since treatment with vorinostat can cause dose-related thrombocytopenia and anemia, platelet counts and hemoglobin should be monitored closely. If platelet counts and/or hemoglobin are reduced during treatment, the dose of vorinostat should be reduced or therapy should be discontinued. In addition, since pulmonary embolism and deep vein thrombosis have been reported in patients taking vorinostat, health care providers should be alert to the signs and symptoms of these events, particularly in patients with a prior history of thromboembolic events.

Serum glucose levels should be monitored, especially in diabetic or potentially diabetic patients, because hyperglycemia has been observed in some patients on vorinostat. Adjustment of diet and/or therapy for hyperglycemia may be required. Baseline electrolytes and ECGs should be determined, and these parameters should be monitored periodically during vorinostat treatment, since this drug has been associated with QTc prolongation and electrolyte abnormalities. Any electrolyte abnormality (e.g., hypokalemia or hypomagnesemia) should be corrected prior to initiation of vorinostat therapy.

While there are no adequate controlled studies of vorinostat in pregnant women, animal studies suggest that this drug has the potential to cause harm to the fetus. Therefore, if vorinostat is used during pregnancy, or if the patient becomes pregnant while taking vorinostat, the patient should be apprised of the potential hazard to the fetus (pregnancy category D).

Drug Interactions:^16-18 Vorinostat is not metabolized via the CYP isozymes and does not appear to inhibit or induce these enzymes at therapeutic concentrations. Therefore, vorinostat is not expected to interact when coadministered with drugs that are known CYP substrates, inhibitors, or inducers. However, no formal clinical studies have been conducted to evaluate potential cytochrome-based drug interactions with vorinostat.

Prolongation of prothrombin time and international normalized ratio were observed in patients receiving vorinostat concomitantly with coumarin-derivative anticoagulants. Thus, prothrombin time and international normalized ratio should be carefully monitored in patients using vorinostat and coumarin concurrently. In addition, severe thrombocytopenia and GI bleeding have been reported with concomitant use of vorinostat and other HDAC inhibitors, such as valproic acid. Platelet counts should be monitored every two weeks for the first two months of therapy.

Dosing and Administration: ¹⁶ Vorinostat is supplied as 100 mg white, opaque, hard gelatin capsules. These capsules should not be opened or crushed. The recommended dosage is 400 mg once daily with food. If a patient is intolerant to therapy, the dosage may be reduced to 300 mg once daily with food. The dosage may be further reduced to 300 mg once daily with food for five consecutive days each week, as necessary. No information is available in patients with renal or he­ patic impairment. However, since vorinostat is cleared primarily by metabolism, patients with hepatic impairment should be treated with caution. Treatment may be continued as long as there is no evidence of progressive disease or unacceptable toxicity.

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