US Pharm. 2007;32(10):HS-3-HS-13.

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 first half of 2007 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 review (P) represent significant improvement in comparison 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 indicated 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 Many of these drugs may eventually acquire at least one black box warning for serious adverse drug reactions or are withdrawn from the market for safety reasons that were not recognized at the time of approval.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.

Histrelin Acetate (Supprelin LA, Indevis Pharmaceuticals)

Indication and Clinical Profile:1-4 Central precocious puberty (CPP) is the premature development of body characteristics that normally occur during puberty. In females, this is usually defined as younger than 8 years, and in males, younger than 9 years. Signs of early puberty include breast enlargement in girls and the appearance of hair in the genital area in boys and girls. Children with CPP also show significantly advanced bone age that can result in diminished adult height attainment as well as an increased likelihood of psychosocial problems. About 6,000 American children have this condition, with 2,000 new cases diagnosed each year.

Histrelin acetate is indicated specifically for the treatment of children with CPP and was developed as an orphan product. Orphan status provides incentives for companies to develop products for use in conditions that afflict fewer than 200,000 people annually. FDA approval was based on the results of two open-label, single-arm clinical studies (study 1 and study 2). Study 1 enrolled 11 pretreated female subjects, ages 3.7 to 11 years. Study 2 enrolled 36 subjects (33 females and three males), ranging in age from 4.5 to 11.6 years. Sixteen of these subjects were pretreated, and 20 were treatment naïve. End points were similar in both trials and included measurements of the suppression of gonadotropins (luteinizing hormone [LH] and follicle-stimulating hormone [FSH]) and gonadal sex steroids (estrogen in girls, testosterone in boys). Additional assessments were clinical (evidence of stabilization or regression of signs of puberty) or gonadal steroid dependent (bone age, linear growth). In study 2, the primary measure of efficacy was LH suppression, defined as a peak LH of <4 mIU/mL following stimulation with the gonadotropin-releasing hormone (GnRH) analog leuprolide acetate. In both trials, the end points were achieved. In study 2, suppression of LH was induced in all treatment-naïve subjects and maintained in all pretreated subjects one month after implantation and continued through month 12. Secondary efficacy assessments indicated stabilization of disease. In addition, in study 2, estradiol suppression was present in 100% of the females through month 9 and was 97% at month 12. Testosterone suppression was maintained in the three pretreated males.

Pharmacology and Pharmacokinetics:1,2 Continuous administration of the GnRH agonist histrelin acetate causes a reversible down-regulation of the GnRH receptors in the pituitary gland and desensitization of the pituitary gonadotropes. These inhibitory effects result in decreased levels of LH and FSH that, in turn, cause a reduction in ovarian (estrone and estradiol) and testicular (testosterone and dihydrotestosterone) steroidogenesis. Based on this mechanism, initial exposure to histrelin acetate results in a transient increase in circulating levels of LH and FSH and in the concentration of gonadal steroids.

In clinical trials, implantation of histrelin acetate provided average maximum serum histrelin concentrations of 0.43 ng/mL--a level expected to maintain gonadotropins at prepubertal levels. There was no apparent pharmacokinetic difference between naïve subjects who received a luteinizing hormone–releasing hormone (LHRH) agonist and subjects previously treated with an LHRH agonist.

Adverse Reactions and Dug Interactions:1-4 During the early phase of histrelin acetate therapy, gonadotropins and sex steroids rise above baseline because of the natural stimulatory effect of the drug (see Pharmacology section). Therefore, an increase in clinical signs and symptoms may be observed initially. The most commonly reported adverse reaction (occurring in about 50% of patients) was implant site reactions, including scarring, bruising, soreness, pain, tingling, itching, and swelling. In 22% of the girls, light vaginal bleeding occurred during the first month. Other infrequent effects included headache and nausea and vomiting. Although not reported with histrelin acetate, serious and life-threatening allergic reactions have occurred with GnRH. No formal drug–drug, drug–food, or drug–herb interaction studies were performed. Results of diagnostic tests of pituitary gonadotropic and gonadal functions conducted during and after histrelin acetate therapy may be affected.

Dosage and Administration: 1 Histrelin acetate is supplied as a sterile, nonbiodegradable, diffusion-controlled reservoir drug delivery system (hydron implant technology) that contains 50 mg of active drug. The implant is inserted subcutaneously in the inner aspect of the upper arm and delivers approximately 65 mcg of histrelin acetate per day over 12 months. The implant must be removed after 12 months of therapy. (The implant has been designed to allow a few additional weeks of histrelin acetate release in order to enable flexibility of medical appointments.) When an implant is removed, another implant may be inserted to continue therapy. Discontinuation of therapy should be considered at the discretion of the physician and at the appropriate time point for the onset of puberty (about age 11 for females and age 12 for males).

Counseling Points and Precautions:1 Histrelin should not be used in children younger than 2 years or in women who are or may become pregnant, since the drug may cause harm to the fetus. Patients who receive the histrelin implant should keep the arm clean and dry, should not swim or bathe for 24 hours, and avoid heavy play or exercise that uses the implanted arm for seven days. After the implant site incision has healed, patients may return to normal activities. After 12 months, the implant must be removed and a new implant may be inserted to continue treatment. It may be necessary to perform an ultrasound or MRI to locate the implant prior to removal.

Eculizumab (Soliris, Alexion Pharmaceuticals)

Indication and Clinical Profile:5-7 Paroxysmal nocturnal hemoglobinuria (PNH) is a rare blood disorder that occurs due to hematopoietic stem cell mutation, resulting in a lack of protective complement-regulating surface membrane proteins on red and white blood cells as well as on platelets. Patients with PNH are unable to synthesize the glycosyl-phosphatidylinositol anchor glycolipid that binds surface proteins to cell membranes and protects the cell from destructive substances called terminal complement. The disease causes the hemolysis of blood cells resulting in dark urine, hemolytic anemia, pancytopenia, pulmonary hypertension, and thrombosis of large veins typically hepatic, abdominal, cerebral, and subdermal. PNH is not inherited, affects men and women of all races equally, and can occur at any age (median age of diagnosis, 35 to 40 years). The median survival is about 10.3 years, with some patients surviving up to 25 years and documented reports of spontaneous remission. Until recently, PNH was treated with symptom management with transfusions and supplements for anemia, anticoagulants for thrombosis, immunosuppressants or steroids for low cell counts, and bone marrow transplantion. Eculizumab (Soliris) was approved in March 2007 for the treatment of PNH to reduce hemolysis. It is the first complement inhibitor approved in the U.S.

Pharmacology and Pharmacokinetics:5,6 Eculizumab is a recombinant humanized monoclonal IgG2/4-kappa antibody that binds specifically with high affinity to the complement protein C5. Binding to C5 inhibits its cleavage to C5a and C5b proteins, preventing the generation of the terminal complement complex C5b-9 and inhibiting intravascular hemolysis. The clearance of eculizumab in a typical 70-kg PNH patient is 22 mL/hour, with a volume of distribution of 7.7 L and an average half-life of 272 hours. The mean peak and trough serum concentrations were 194 and 97 mcg/mL, respectively.

Adverse Reactions and Drug Interactions:5 In clinical trials, the most significant adverse event in terms of severity in patients receiving eculizumab was meningococcal infections, with two patients experiencing meningococcal sepsis. Overall, the most common adverse events (? 10% overall and greater than placebo) occurring in clinical trials included headache, nasopharyngitis, back pain, and nausea. Serious adverse reactions occurred in 9% of the treated patients in the placebo-controlled study. These reactions included progression of PNH and infections. Approximately 16% of patients in the single-arm and long-term exposure study experienced serious adverse events, which included viral infection, headache, anemia, and pyrexia. No drug interaction studies have been performed with eculizumab to date.

Dosage and Administration: 5,7 Eculizumab is supplied in a 300-mg, single-use vial containing 30 mL of 10 mg/mL sterile solution that must be refrigerated and protected from light until time of use. Patients treated with eculizumab must receive a meningococcal vaccine at least two weeks before the initiation of eculizumab therapy and revaccinated according to current guidelines. The eculizumab solution must be diluted with the appropriate diluent to a final admixture concentration of 5 mg/mL before intravenous (IV) infusion. It may not be administered as an IV push or bolus injection. The final 5 mg/mL infusion volume is 120 mL for a 600-mg dose or 180 mL for a 900-mg dose. The admixture should be allowed to adjust to room temperature and be visually inspected for particles or discoloration before being administered. It is stable at room temperature for 24 hours after preparation. The recommended eculizumab dosage is 600 mg every seven days for the first four weeks, followed by 900 mg for the fifth dose seven days later, then 900 mg every 14 days thereafter. The admixture should be administered by the recommended time points or within two days of each time point. The infusion should occur over 35 minutes. It may be stopped or slowed if adverse reactions occur, but total infusion time should not exceed two hours. After the completion of the infusion, the patient should be monitored for at least one hour for signs and symptoms of an infusion reaction. If therapy is discontinued, patients should be monitored for eight weeks for serious hemolysis and serum lactate dehydrogenase levels.

Precautions and Counseling Points:5 The use of eculizumab is contraindicated in patients with unresolved serious Neisseria meningitidis infection and in patients who are not currently vaccinated against N meningitidis. Meningococcal infections may still occur even with vaccination. Patients should be monitored for early signs and symptoms of meningococcal infections and be treated with antibiotics if necessary. Discontinuation of eculizumab therapy should be considered during the treatment of serious meningococcal infections. Caution should be exercised when using eculizumab in patients who have any systemic infection. Eculizumab is FDA pregnancy category C and should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus. It is not known whether eculizumab is excreted in breast milk, and caution should be used when administered to nursing women. The safety and efficacy of eculizumab in children younger than 18 years have not been established.

Lapatinib (Tykerb, GlaxoSmithKline)

Indication and Clinical Profile:8-11 Lapatinib is indicated specifically in combination with capecitabine for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress human epidermal receptor type 2 (HER2) and who have received prior therapy, including an anthracycline, a taxane, and trastuzumab. FDA approval was based on the results of one clinical trial involving 399 subjects with tumors overexpressing HER2 in locally advanced or met­ a­ static breast cancer that was progressing after prior treatment, which included anthracyclines, taxanes, and trastu­zumab. Subjects were randomized to receive either lapatinib 1,250 mg once daily (continuously) plus capecitabine 2,000 mg/m2/day on days 1 to 14 every 21 days, or to receive capecitabine alone at a dosage of 2,500 mg/m2 /day on days 1 to 14 every 21 days. The primary end point was time to progression (TTP), defined as time from randomization to tumor progression or death related to breast cancer. The median TTP was 23.9 weeks for the combination treatment, compared to 18.3 weeks for capecitabine alone, for a response rate of 31.8% versus 17.4%, respectively.

Pharmacology and Pharmacokinetics:8,9 Tyrosine kinases are enzymes that provide a central switch mechanism in cellular signal transduction pathways and as such are involved in many cellular processes (e.g., cell proliferation, metabolism, survival, and apoptosis). Several specific tyrosine kinases are known to be activated in cancer cells and to drive tumor growth and progression. Blocking tyrosine kinase activity therefore represents a rational approach to cancer therapy. Therapeutic strategies include blocking kinase-substrate interaction, inhibiting the enzyme's adenosine triphosphate–binding site, and blocking extracellular tyrosine kinase receptors on tumor cells. Several tyrosine kinase inhibitors (TKIs), including gefitinib (Iressa) and trastuzumab (Herceptin), have been approved as anticancer agents.

The erbB (or HER) family of transmembrane tyrosine kinase receptors, especially receptors erbB1 (or epidermal growth factor receptor [EGFR]) and erbB2 (or HER2), has been identified as an important therapeutic target in a number of cancers. HER2, for example, is overexpressed in roughly 20% to 30% of patients with aggressive breast cancer, while EGFR is overexpressed in several solid tumors. Lapatinib is an orally active TKI that targets both erbB1 and erbB2 receptors. Its dual mode of action differs from existing TKIs, such as gefitinib and trastuzumab, which are single EGFR and HER2 receptor inhibitors, respectively. It is hoped that dual TKIs may help to address the problem of drug resistance that can arise following treatment with single-receptor inhibitors.

Lapatinib is incompletely and variably absorbed from the gastrointestinal tract. Peak plasma concentrations (Cmax) are achieved approximately four hours after administration, and steady state is achieved within six to seven days with repeated dosing. Lapatinib AUC (area under the curve) values are approximately three- and fourfold higher, and Cmax is approximately 2.5- and threefold higher when administered with a low-fat (5% fat, 500 calories) or high-fat (50% fat, 1,000 calories) meal, respectively. Lapatinib is highly bound (>99%) to albumin and alpha-1 acid glycoprotein. The drug is a substrate for the transporters breast cancer resistance protein (BCRP, ABCG2) and P-glycoprotein (Pgp, ABCB1). Lapatinib has also been shown in vitro to inhibit these efflux transporters, as well as the hepatic uptake transporter OATP 1B1.

Lapatinib undergoes extensive metabolism, primarily by cytochrome P-450 (CYP) 3A4 and CYP3A5, with minor contributions from CYP2C19 and CYP2C8 to a variety of oxidation metabolites. None of these metabolites account for more than 14% of the dose recovered in the feces or more than 10% of lapatinib concentration in plasma. The terminal phase half-life following a single dose is 14.2 hours; accumulation with repeated dosing indicates an effective half-life of 24 hours. Elimination of lapatinib is predominantly through metabolism by CYP3A4/5 with negligible (<2%) renal excretion. Recovery of parent drug in feces accounts for a median of 27% (range, 3% to 67%) of an oral dose. The effects of age, gender, or race on the pharmacokinetics of lapatinib have not been investigated.

Adverse Reactions:9-11 In clinical trials, adverse events leading to discontinuation were similar in the lapatinib-capecitabine combination arm versus capecitabine alone, with a rate of 14%. Most commonly reported adverse effects were gastrointestinal (diarrhea, nausea, and vomiting), dermatologic (palmar-plantar erythrodysesthesia and rash), and fatigue. Diarrhea was the most common adverse reaction, resulting in discontinuation.

Due to potential cardiac toxicity with HER2 (erbB2) inhibitors, left ventricular ejection fraction (LVEF) was monitored in clinical trials at about eight-week intervals. LVEF decreases were defined as signs or symptoms of deterioration in left ventricular cardiac function that are grade 3 or higher based on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) or as a ? 20% decrease in LVEF relative to baseline, which is below the institution's lower limit of normal. Among 198 patients who received lapatinib/capecitabine treatment, three experienced grade 2 and one had grade 3 LVEF adverse reactions.

Drug Interactions:9-11 Concomitant administration of lapatinib with capecitabine did not substantially alter the pharmacokinetics of either agent (or the metabolites of capecitabine). Lapatinib undergoes extensive metabolism by CYP3A4. Thus, concomitant administration of strong inhibitors (e.g., ketoconazole) or inducers (e.g., carbamazepine) of CYP3A4 alter lapatinib concentrations significantly. Concurrent administration of ketoconazole resulted in about a 3.6-fold increase in AUC, and the half-life increased to 1.7-fold of control. Concomitant use of the CYP3A4 inducer carbamazepine resulted in a 72% reduction in lapatinib AUC. Thus, dosage adjustment of lapatinib should be considered for patients who must receive concomitant therapy with strong inhibitors or strong inducers of CYP3A4 enzymes.

Lapatinib inhibits CYP3A4 and CYP2C8 in vitro at clinically relevant concentrations. Thus, caution is advised, and dosage reduction of the concomitant substrate drug should be considered when dosing lapatinib concurrently with medications with narrow therapeutic windows that are substrates of CYP3A4 or CYP2C8. Lapatinib does not appear to significantly inhibit CYP1A2, CYP2C9, CYP2C19, CYP2D6, or UGT enzymes. Since lapatinib is a substrate of the efflux transporter Pgp, ABCB1; thus, caution should be exercised if it is administered with other drugs that inhibit Pgp (e.g., ritonavir, cyclosporine, verapamil).

Dosage and Administration: 9 Lapatinib is supplied as a 250-mg tablet. The recommended initial dosage is 1,250 mg (five tablets) orally once daily on days 1 to 21 continuously in combination with capecitabine 2,000 mg/m2/day (administered orally in two doses approximately 12 hours apart) on days 1 to 14 in a repeating 21-day cycle. Dividing the daily dose is not recommended. The drug should be taken on an empty stomach, at least one hour before or one hour after eating. Lapatinib should be discontinued in patients with decreased LVEF that is grade 2 or greater according to the NCI CTCAE scale and in patients with an LVEF that drops below the institution's lower limit of normal. Treatment may be restarted at a reduced daily dose (1,000 mg) after a minimum of two weeks if the LVEF recovers to normal and the patient is asymptomatic. Patients with severe hepatic impairment should have their dosage reduced. The concomitant use of potent CYP3A4 inhibitors and inducers should be avoided. If a grade 2 NCI CTCAE toxicity occurs, discontinuation or interruption of lapatinib may be considered. Treatment can resume at 1,250 mg/day when toxicity improves to grade 1 or less.

Counseling Points and Precautions:9-11 Before initiating lapatinib, patients should be assessed to determine if they have heart disease, liver disease, or a history of long QT syndrome. Patients should also be asked if they are using antibiotics, ulcer medications, seizure medications, HIV or AIDS medications, herbal supplements, heart or blood pressure medication, or an antidepressant. Lapatinib is FDA pregnancy category D and thus should not be used during pregnancy. Patients are advised to use an effective form of birth control while taking this medication. It is not known whether lapatinib passes into breast milk or if it could harm a nursing baby. Therefore, caution is advised in breast-feeding. Patients should be counseled to stop using the drug and call their physician if they have serious side effects, such as severe diarrhea or vomiting or uneven heart rate with extreme dizziness or fainting.

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5. Soliris [package insert]. Cheshire, CT: Alexion Pharmaceuticals Inc.; 2007.
6. Hillmen P, Young NS, Schubert J, et al. The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria. N Eng J Med. 2006;355:1233-1243.
7. Besa EC, Talavera F, Conrad M, et al. Paroxysmal nocturnal hemoglobinuria. eMedicine from WebMD, May 18, 2007. Available at: /topic2696.htm#section~Followup.
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9. TYKERB [package insert]. Research Triangle Park, NC: Glaxo­ SmithKline; 2007.
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11. Konecny GE, Pegram MD, Venkatesan N, et al. Activity of the dual kinase inhibitor lapatinib (GW572016) against HER-2-overexpressing and trastuzumab-treated breast cancer cells. Advances Cancer Res. 2006;66:1630-1639.

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