Review of Select NMEs 2008

US Pharm. 2008;33(10):HS5-HS17.

New molecular entities (NMEs), as defined by the FDA, are new drug products containing, as their active ingredient, a chemical substance marketed for the first time in the United States. The following descriptions of NMEs approved in 2007-2008 (TABLE) include a brief summary of the clinical and pharmacologic profile for each new drug, as well as selected pharmacokinetics, adverse reactions, drug interactions, and dosing information. This review is intended to be objective rather than evaluative in content. The information for each NME was obtained primarily from sources published prior to FDA approval. Experience has shown that many aspects of a new drug's therapeutic profile, such as adverse reactions, do not emerge until after the drug is used in large numbers of patients for several years. Hence, while this review offers a starting point for learning about new drugs, it is essential that practitioners become aware of changes in a drug's therapeutic profile over time.

Doripenem (Doribax, Johnson & Johnson)
Indication and Clinical Profile^1-3: Doripenem is a new carbapenem beta-lactam antibacterial approved for treatment of complicated intra-abdominal infections (cIAIs) and complicated urinary tract infections (cUTIs), including pyelonephritis. Approximately two million intra-abdominal procedures are performed in the U.S. annually, and cIAIs are a common cause of hospitalization following these surgeries. Urinary tract infections (UTIs) account for at least 40% of all hospital infections. Although many cases of UTI are uncomplicated, a significant proportion are classified as "complicated" because of anatomical abnormalities in the urinary tract, which make clearance of bacteria more difficult or cause kidney infection (pyelonephritis). Both cIAIs and cUTIs can be caused by a broad range of bacteria, many of which are resistant to multiple antibiotics.

The efficacy of doripenem for the treatment of cIAIs was evaluated in two identical controlled studies involving 946 adult patients who were treated with 500 mg of doripenem or with 1 g of meropenem administered IV every eight hours. After at least three days of therapy, patients were permitted to switch to oral amoxicillin 875 mg/clavulanate 125 mg twice daily, for a total of five to 14 days of IV and oral treatment. Doripenem was shown to be as effective as meropenem in clinical cure rates 25 to 45 days posttreatment.

The efficacy of doripenem for the treatment of cUTIs was evaluated in two multicenter studies involving 1,171 adult patients. In the first study, patients were treated with either 500 mg of doripenem IV (over 1 hour q8h) or with 250 mg levofloxacin IV every 24 hours. The second study was noncomparative but was otherwise of similar design. In both studies, patients were permitted to switch to oral levofloxacin (250 mg every 24 hours) after at least three days of IV therapy, for a total of 10 days of IV and oral treatment. Doripenem was as effective as levofloxacin with regard to the microbiological eradication rates 5 to 11 days posttreatment.

Pharmacology and Pharmacokinetics^1-3: Doripenem is a synthetic, parenteral carbapenem antibiotic. Like all other members of the beta-lactam class, this drug acylates and inactivates essential bacterial penicillin-binding proteins resulting in inhibition of cell wall biosynthesis and bacterial cell death. Like other carbapenems, doripenem is effective against a wide range of gram-positive and gram-negative pathogens often implicated in cIAI and cUTI including Escherichia coli, Bacteroides fragilis, viridans group streptococci, Proteus species, Klebsiella pneumoniae, and Pseudomonas aeruginosa. P. aeruginosa, a gram-negative bacterium with increasing multidrug resistance, is one of the leading causes of hospital-acquired (nosocomial) infections. In general, there are relatively few antibiotics available or in development to treat these life-threatening gram-negative infections.

The pharmacokinetics of doripenem (C_max and AUC) are linear over the therapeutic dose range, and there is no evidence of drug accumulation following multiple IV infusions in patients with normal renal function. Plasma protein binding is low (8%), and the median volume of distribution is 16.8 L, similar to extracellular fluid volume (18.2 L). Doripenem penetrates into several bodily fluids and tissues, including those at the site of infection.

Doripenem is not a substrate for hepatic CYP450 enzymes. A small amount of metabolism to an inactive ring-opened metabolite occurs primarily via renal dehydropeptidase-I. Doripenem is primarily eliminated unchanged by the kidneys by both glomerular filtration and tubular secretion. The mean plasma terminal elimination half-life of doripenem is approximately one hour. At therapeutic doses, 70% and 15% of the dose is excreted in the urine as unchanged drug and the ring-opened metabolite, respectively, within 48 hours. Less than 1% of the total dose is eliminated in the feces.

No dosage adjustment of doripenem appears necessary based on gender, race, or age or in patients with normal renal function. However, based on the clearance profile, dosage adjustment is necessary in patients with moderate (CrCl 31-50 mL/min) and severe (CrCl <30 mL/min) renal impairment. Presently, there is insufficient information to make dosage adjustment recommendations in patients on hemodialysis or with hepatic impairment.

Adverse Reactions^1-3: The most common adverse reactions (>=5%) observed in clinical trials with doripenem included headache, nausea, diarrhea, rash, and phlebitis. Serious, potentially fatal hypersensitivity reactions have been reported occasionally in patients treated with beta-lactam antibiotics. Therefore, before doripenem therapy is instituted, it should be determined if a patient has had a previous hypersensitivity reaction to other beta-lactam drugs (e.g., carbapenems, cephalosporins, penicillins) or other allergens. Nearly all antibacterial agents have been reported to cause Clostridium difficile–associated diarrhea (CDAD), ranging from mild diarrhea to fatal colitis. If CDAD is suspected or confirmed, antibiotic use should be discontinued and appropriate treatment measures implemented. Doripenem is a Pregnancy Category B drug and should be used with caution while nursing. The safety and effectiveness in pediatric patients have not been established.

Drug Interactions^1-3: Significant reductions in serum valproic acid concentrations have been reported in patients receiving carbapenem antibiotics, resulting in concerns about loss of seizure control. It appears that carbapenem antibiotics may inhibit valproic acid glucuronide hydrolysis, and thereby enhance its elimination. Thus, serum valproic acid concentrations should be monitored frequently after initiating therapy with any carbapenem, or alternative antibacterial or anticonvulsant therapy be considered. Probenecid, an inhibitor of active tubular secretion, causes an increase in plasma concentrations of doripenem, and thus concurrent use is not recommended.

Dosage and Administration^1-3: To reduce the development of drug-resistant bacteria and maintain effectiveness, doripenem (and all antibacterials) should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria, preferably documented by culture and susceptibility data. Doripenem is supplied in single-use, clear glass vials containing 500 mg of sterile doripenem powder. The recommended dosage for indicated infections is 500 mg administered every eight hours by IV infusion over one hour, in patients 18 years of age or older. The duration of therapy for intra-abdominal infections is five to 14 days, and 10 days for cUTIs. For patients with significant renal impairment, dosage reduction is recommended. Patients with an estimated CrCl >=30 to <50 mL/min should receive 250 mg every eight hours, while those with a CrCl between 10 and 30 mL/min should receive 250 mg every 12 hours. Full details for preparations of IV solutions are provided in the manufacturer's literature.

Rilonacept (Arcalyst, Regeneron Pharmaceuticals)
Indication and Clinical Profile^4,5: Rilonacept is approved for the long-term treatment of two cryopyrin-associated periodic syndromes (CAPS) in patients aged 12 years or older. Specifically, it is approved for the familial cold auto-inflammatory syndrome (FCAS) and Muckle-Wells syndrome (MWS) forms of the disease. CAPS are inherited disorders caused by mutations in the nucleotide-binding domain, leucine rich family, pyrin domain containing 3 (NLRP-3) gene, which encodes the protein cryopyrin. Cryopyrin regulates the protease caspase-1 and controls activation of interleukin-1 beta (IL-1ß). Mutations in NLRP-3 can cause an overactive inflammasome, resulting in excessive levels of activated IL-1ß, which causes inflammation, joint pain, rash or skin lesions, fever and chills, eye redness or pain, and fatigue. The FCAS and MWS disorders are extremely rare, affecting about 300 people in the U.S. MWS is associated with more severe inflammation and amyloidosis and may include hearing loss or deafness.

The approval of rilonacept was based on results from a two-part trial designated as Part A and Part B. In Part A, patients received a 320-mg loading dose of rilonacept followed by 160 mg/wk or placebo for six weeks. In Part B, all patients received rilonacept 160 mg/wk for nine weeks and were then randomized to either rilonacept 160 mg/wk or placebo for an additional nine weeks. The trial also included a 24-week, open-label treatment extension phase; enrolled patients received rilonacept 160 mg/wk. For both parts of the study, patients completed a daily questionnaire to rate the severity (0-10, none to very severe) of the primary symptoms of CAPS. In Part A, the mean symptom score reductions from baseline to end point among rilonacept recipients was 2.4 versus a 0.5 among placebo recipients. The mean symptom change among rilonacept patients in Part B of the trial was 0.1 versus a 0.9 difference among placebo-treated patients. Most patients indicated improvement in symptom scores within several days of initiating rilonacept therapy. Rilonacept therapy was associated with a 20-mg/L reduction from baseline in mean C-reactive protein (CRP) levels versus a 2-mg/L reduction with placebo, and mean serum amyloid A (SAA) levels were reduced by 56 mg/L versus no change among placebo-treated patients. Reductions in mean symptom scores, serum CRP, and SAA levels were maintained for one year or less among patients who received rilonacept in the extension phase of these trials.

Pharmacology and Pharmacokinetics^4,5: Rilonacept acts as a soluble decoy receptor that binds the excessive IL-1‚ formed in CAPS, thereby preventing its interaction with cell surface receptors and significantly reducing the inflammation associated with disease. Rilonacept also binds IL-1a and IL-1 receptor antagonist (IL-1ra) with reduced affinity. The equilibrium dissociation constants for rilonacept binding to IL-1ß, IL-1a, and IL-1ra are reported to be 0.5 pM, 1.4 pM, and 6.1 pM, respectively.

Rilonacept is administered subcutaneously (SC), and steady state is reached by six weeks. Gender, age, and body weight (50-120 kg) do not appear to have a significant effect on trough levels. The effect of race could not be assessed because only Caucasian patients participated in the clinical study (reflecting disease epidemiology). No pharmacokinetic data are available in patients with hepatic or renal impairment.

Adverse Reactions^4,5: The most commonly reported side effects associated with use of rilonacept include injection-site reactions, upper respiratory infections, cough, and hypoesthesia. Infections appear to result from the IL-1 blocking actions of the drug that interfere with immune response. Some patients receiving rilonacept experienced serious, life-threatening infections. Thus, patients with active or chronic infections should not be treated with rilonacept, and patients should receive all recommended vaccinations before initiating treatment with this drug. Rilonacept is a Pregnancy Category C drug. Live vaccines should not be administered concurrently with rilonacept.

Drug Interactions^4,5: Specific drug interaction studies have not been conducted with rilonacept. However, concurrent administration of drugs that block IL-1 with a TNF-blocking agent (e.g., etanercept, infliximab, adalimumab) has been associated with an increased risk of serious infections and an increased risk of neutropenia; thus, it is not recommended. In addition, the concomitant administration of rilonacept and other agents that block IL-1 or its receptors (IL-1ra) is not recommended.

Increased levels of cytokines, including interleukins during chronic inflammation, can suppress the formation of CYP450 enzymes. Thus, it is expected that exposure to drugs that bind to IL-1, such as rilonacept, could result in normalization of CYP450 enzyme levels. This may be clinically relevant for CYP450 substrates with a narrow therapeutic index, where the dose is individually adjusted (e.g., warfarin) and may require monitoring and dosage adjustment.

Dosage and Administration^4,5: The first injection of rilonacept should be performed under the supervision of a qualified health care professional. If patients or caregivers are to administer rilonacept, they should be instructed on aseptic reconstitution and methods of administration. Rilonacept is supplied in single-use, 20-mL glass vials containing 220 mg of the drug as a lyophilized powder. The recommended dosage for patients aged 18 years or older is a 320-mg loading dose (delivered as two 2-mL SC injections of 160 mg on the same day, administered in different injection sites), followed by 160 mg/wk administered as a single 2-mL SC injection. The recommended dosage of rilonacept for patients aged 12 to 17 years is a 4.4-mg/kg loading dose (maximum 320 mg), delivered as one or two SC injections (maximum single-injection volume 2 mL). Pediatric patients should be treated with 2.2 mg/kg/wk delivered as a single SC injection (maximum 2 mL).

Ixabepilone (Ixempra, Bristol-Myers Squibb)
Indication and Clinical Profile^6-8: Ixabepilone was approved for use in combination with another cancer drug, capecitabine, for the treatment of patients with metastatic or locally advanced breast cancer resistant to treatment with an anthracycline (doxorubicin or epirubicin) and a taxane (paclitaxel or docetaxel), or whose cancer is taxane resistant and for whom further anthracycline therapy is contraindicated. The drug is also approved as monotherapy for the treatment of metastatic or locally advanced breast cancer in patients whose tumors are resistant or refractory to anthracyclines, taxanes, and capecitabine. About 180,000 new cases of breast cancer are diagnosed in the U.S. each year. Metastatic breast cancer is the most advanced stage of breast cancer and has the potential to spread to almost any region of the body.

The efficacy of ixabepilone in combination with capecitabine was assessed in a multicenter trial in which patients were assigned either to IV ixabepilone (40 mg/m² every 3 weeks) plus capecitabine (1,000 mg/m² twice daily for 2 weeks) followed by one week of rest or to capecitabine (1,250 mg/m² twice daily) for two weeks followed by one week of rest. Eligible patients (n = 752) had been treated previously with anthracyclines and taxanes and had demonstrated tumor progression or resistance to these agents. Patients in the combination therapy group received a median of five treatment cycles. The combination treatment prolonged progression-free survival compared to capecitabine alone (5.7 months vs. 4.1 months), with a statistically significant 25% decrease in the risk of disease progression. An objective response rate was observed in more than twice as many subjects in the combination group compared to control (34.7% vs. 14.3%). The median duration of response was 6.4 months versus 5.6 months.

The efficacy of ixabepilone as monotherapy was assessed in a single-arm trial in which ixabepilone was administered at a dosage of 40 mg/m² over three hours every three weeks. Eligible patients (n = 126) had tumors that had recurred or progressed after two or more chemotherapy regimens including an anthracycline, a taxane, and capecitabine. Patients received a median of four treatment cycles. Independent radiologic review demonstrated clinically significant tumor shrinkage in 12% of the ixabepilone-treated patients, with a median duration of response of 6.0 months.

Pharmacology and Pharmacokinetics^6-8: Ixabepilone is a semisynthetic analog of epothilone B. It binds directly to ß-tubulin subunits on microtubules, resulting in suppression of the dynamic instability of aß-II and aß-II microtubules. This arrests the cells in the G2-M phase of the cell cycle and induces tumor cell apoptosis. In addition to direct antitumor activity, ixabepilone also has antiangiogenic activity. Ixabepilone is active in xenografts that are resistant to multiple agents including taxanes, anthracyclines, and vinca alkaloids and has demonstrated synergistic antitumor activity in combination with capecitabine in vivo.

The pharmacokinetics of ixabepilone appear to be linear at therapeutic doses. The mean volume of distribution of 40 mg/m² ixabepilone at steady state is in excess of 1,000 L, and plasma protein binding ranges from 67% to 77%. Ixabepilone is extensively metabolized by hepatic CYP3A4 oxidation. More than 30 inactive metabolites are excreted into urine and feces, and no single metabolite accounts for more than 6% of the administered dose. Approximately 86% of the dose is eliminated within seven days in feces (65% of the dose) and in urine (21% of the dose), primarily as metabolites. Ixabepilone has a terminal elimination half-life of approximately 52 hours. The pharmacokinetics of ixabepilone are not significantly altered by gender, race, or age.

Adverse Reactions^6-8: The most common adverse events associated with ixabepilone treatment include peripheral sensory neuropathy, fatigue/asthenia, nausea, myalgia/arthralgia, alopecia, diarrhea, palmar-plantar erythrodysesthesia syndrome, vomiting, stomatitis/mucositis, anorexia, musculoskeletal pain, constipation, abdominal pain, nail disorder, and myelosuppression (primarily manifested as neutropenia). In clinical trials, patients with hepatic impairment at baseline experienced greater toxicity with ixabepilone treatment, including occurrences of febrile neutropenia and severe adverse reactions. Thus, the drug carries a black box warning concerning toxicity in patients with moderate or severe hepatic impairment. A greater incidence of cardiac adverse reactions, including myocardial ischemia and ventricular dysfunction, was observed among ixabepilone-treated patients than among patients treated with capecitabine alone in clinical trials. Ixabepilone should not be taken by patients who have had severe allergic reactions to drugs that contain cremophor or its derivatives (e.g., polyoxyethylated castor oil). Ixabepilone should avoided in pregnancy and nursing (Pregnancy Category D).

Drug Interactions^6-8: Ixabepilone is a CYP3A4 substrate and thus has the potential to interact with other drugs that are inducers or inhibitors of this cytochrome isozyme. Ixabepilone does not inhibit CYP enzymes at therapeutic concentrations and is not expected to alter the plasma concentrations of other drugs. Coadministration of ixabepilone with potent CYP3A4 inhibitors (e.g., ketoconazole) can result in a significant increase in ixabepilone AUC. If alternative treatment cannot be administered, a dosage adjustment should be considered. The effect of mild or moderate inhibitors (e.g., erythromycin, fluconazole, verapamil) on exposure to ixabepilone has not been studied. Therefore, caution should be exercised when administering mild or moderate CYP3A4 inhibitors during treatment with ixabepilone.

Strong CYP3A4 inducers (e.g., dexa­ methasone, phenytoin, carbamazepine, rifampin, rifampicin, rifabutin, phenobarbital) may decrease ixabepilone concentrations, leading to subtherapeutic levels. St. John's wort may decrease ixabepilone plasma concentrations unpredictably and should be avoided. While capecitabine and ixabepilone may alter each other's AUC and C_max values, this interaction is not clinically significant.

Dosage and Administration^6-8: Ixabepilone is supplied as a single-use kit containing one vial of ixabepilone powder and one vial of diluent to be reconstituted for IV administration. All patients should be pretreated with a histamine H₁and H₂ antagonist approximately one hour before ixabepilone infusion to reduce the risk of hypersensitivity reactions. The recommended initial dosage is 40 mg/m² administered IV over three hours every three weeks. Doses for patients with body surface area exceeding 2.2 m² should be calculated based on 2.2 m². If toxicities occur, delay treatment and allow for recovery. If toxicities recur upon reinitiation, an additional dosage reduction of 20% is recommended. Patients with hepatic impairment receiving ixabepilone monotherapy require dose reductions based on aspartate aminotransferase (AST), alanine aminotransferase (ALT), and bilirubin levels. Dosage adjustment should be followed according to product labeling.

Nilotinib (Tasigna, Novartis)
Indication and Clinical Profile^9-11: Nilotinib is indicated for the treatment of chronic phase and accelerated phase Philadelphia chromosome–positive (Ph+) chronic myelogenous leukemia (CML) in adult patients resistant or intolerant to prior therapy that included imatinib. CML accounts for 15% of all leukemias in adults, and approximately 4,500 new cases of CML were diagnosed in 2007. An abnormal chromosome (Ph) is present in leukemic cells of the majority of CML patients. Imatinib is used for the treatment of newly diagnosed patients with Ph+ CML.

FDA approval of nilotinib was based on the results of a multicenter trial involving patients with imatinib-resistant or -intolerant CML with separate cohorts for chronic phase (CML-CP) and accelerated phase (CML-AP) disease. Overall, 280 CML-CP subjects with a minimum follow-up of six months and 105 CML-AP subjects with a minimum follow-up of four months were enrolled. A major cytogenetic response was observed in 40% of the subjects. Complete response was observed in 28%, and partial response was observed in 12% of this group. The efficacy end point in the CML-AP arm confirmed hematologic response, defined as either a complete hematologic response or no evidence of leukemia. A confirmed hematologic response was observed in 26%, with 18% showing a complete hematologic response and 8% showing no evidence of leukemia. Median duration of response had not been reached at the time of approval for either group. However, based on current data, 59% of the CML-CP subjects with a major cytogenetic response and 63% of CML-AP subjects with a confirmed hematologic response each had a duration of response of at least six months.

Pharmacology and Pharmacokinetics^9-11: Nilotinib is a signal transduction inhibitor of the BCR-ABL kinase, c-KIT, and platelet-derived growth factor (PDGF), all of which play a role in cell proliferation, cell migration, and angiogenesis. Nilotinib binds to and stabilizes the inactive conformation of the kinase domain of the ABL protein. In vitro, nilotinib inhibits BCR-ABL–mediated proliferation of murine leukemic cell lines and human cell lines derived from Ph+ CML patients. In vivo, nilotinib was shown to reduce tumor size in a murine BCR-ABL xenograft model.

Nilotinib is administered orally, and bioavailability increases significantly when given with a high-fat meal. Peak concentrations are reached three hours after oral administration. Serum protein binding is high (98%) and the blood-to-serum ratio of nilotinib is 0.68. Inter-patient variability in nilotinib AUC was 32% to 64%. The elimination half-life is estimated to be approximately 17 hours. The primary pathways of nilotinib metabolism include oxidation and hydroxylation, but the parent drug is the main circulating component in the serum. None of the metabolites appear to contribute significantly to the pharmacologic activity. More than 90% of the administered dose is eliminated within seven days, mainly in feces (93%). Parent drug accounted for 69% of the dose. The pharmacokinetics of nilotinib are not significantly altered by age, body weight, gender, or ethnic origin.

Adverse Reactions^9-11: In clinical trials, the most commonly reported adverse reactions (>10%) associated with nilotinib therapy were rash, pruritus, nausea, fatigue, headache, constipation, diarrhea, and vomiting. Less common, but more severe, adverse effects included thrombocytopenia, neutropenia, pneumonia, febrile neutropenia, leukopenia, intracranial hemorrhage, elevated lipase, and pyrexia. Nilotinib has been reported to cause concentration-dependent QT prolongation, prompting a black box warning for possible life-threatening irregular heartbeat and sudden death. Patients should consult with their physician about avoiding other medications that can cause heart problems when taking nilotinib. Women are advised to avoid breastfeeding or becoming pregnant while taking nilotinib (Pregnancy Category D).

Drug Interactions^9-11: Nilotinib is metabolized by CYP3A4, and concurrent administration of strong inhibitors (e.g., ketoconazole) or inducers (e.g., rifampicin) of this cytochrome isozyme have the potential to increase or decrease systemic exposure (i.e., AUC) to nilotinib. Nilotinib is also a competitive inhibitor of CYP3A4, CYP2C8, CYP2C9, CYP2D6, and UGT1A1 and therefore has the potential to increase the concentrations of drugs metabolized by these enzymes. Thus, caution should be exercised when coadministering nilotinib with drugs that are substrates for these CYP isozymes, and substrates such as warfarin that have a narrow therapeutic index should be avoided, if possible. Nilotinib may induce CYP2B6, CYP2C8, and CYP2C9, and thus has the potential to decrease the concentrations of drugs that are cleared by these isozymes. Nilotinib is a substrate for and inhibitor of human P-glycoprotein transporters, so caution should be exercised when it is used with other drugs that are substrates or inhibitors of this transporter.

Dosage and Administration^9-11: Nilotinib is supplied as 200-mg hard gelatin capsules in blister packs. The recommended initial dosage is 400 mg orally twice daily, at 12-hour intervals. No food should be consumed at least two hours before and one hour after administration of nilotinib. Treatment should continue as long as the patient does not show evidence of progression or unacceptable toxicity. Nilotinib may be given in combination with hematopoietic growth factors (e.g., eryth­ ropoietin), hydroxyurea, or anagrelide if clinically indicated. Dosage adjustments or modifications should be followed according to the product label for patients with ECGs with a QTc greater than 480 msec; for those with neutropenia and/or thrombocytopenia; for those with Grade 3 or greater elevations of serum lipase, amylase, bilirubin, or hepatic transaminases; and for patients with other clinically significant moderate or severe nonhematologic toxicities. The concomitant use of strong CYP3A4 inhibitors and strong CYP3A4 inducers with nilotinib should be avoided, if possible, or else dosage adjustment is required.

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