Candace Bramson

Efficacy and safety of tanezumab in the treatment of chronic low back pain.

Summary Intravenous tanezumab produces clinically and statistically superior analgesic efficacy compared to placebo and naproxen, with few adverse events in patients with chronic low back pain. Abstract Increased nerve growth factor levels are associated with chronic pain conditions, including chronic low back pain (LBP). This study examined safety and analgesic efficacy of tanezumab, a humanized anti‐nerve growth factor antibody, in adults with chronic LBP. Patients received intravenous tanezumab 200 &mgr;g/kg plus oral placebo (n = 88), intravenous placebo plus oral naproxen 500 mg twice a day (n = 88), or intravenous placebo plus oral placebo (n = 41). Primary outcome was average LBP intensity (aLBPI) at Week 6. Secondary outcomes were proportion of patients with ≥30% or ≥50% reduction in aLBPI, Roland–Morris Disability Questionnaire and Brief Pain Inventory–short form scores, Patients’ Global Assessment of LBP, Patients’ Global Evaluation of study medication, and rescue medication use. Mean aLBPI change from baseline to Week 6 was greater with tanezumab vs naproxen (P = 0.004) and placebo (P < 0.001). Greater proportions of patients reported ≥30% and ≥50% reduction in aLBPI with tanezumab vs naproxen (P ≤ 0.013) and placebo (P < 0.001), and greater improvements in Roland–Morris Disability Questionnaire (P < 0.001) and other secondary outcomes except rescue medication use. Tanezumab was associated with adverse events (AEs) of abnormal peripheral sensation that were generally mild and resolved before study completion; however, there were no serious AEs. Nine patients (4 of whom were tanezumab‐treated) discontinued due to AEs. In conclusion, tanezumab resulted in analgesic efficacy that was clinically and statistically superior to placebo and naproxen in patients with chronic LBP. Tanezumab clinical development is on regulatory hold due to AEs in osteoarthritis patients.

Efficacy and safety of tanezumab versus naproxen in the treatment of chronic low back pain

&NA; Tanezumab provides significantly greater improvement in pain, function, and global scores versus placebo and naproxen in patients with chronic low back pain. &NA; Tanezumab is a humanized monoclonal antibody that specifically inhibits nerve growth factor as a treatment for chronic pain. This phase IIB study investigated the efficacy and safety of tanezumab for chronic low back pain vs placebo and naproxen. Patients (N = 1347) received intravenous tanezumab (5, 10, or 20 mg every 8 weeks), naproxen (500 mg twice daily), or placebo. The primary efficacy end point was mean change in daily average low back pain intensity (LBPI) from baseline to week 16. Secondary end points included mean change from baseline to week 16 in the Roland Morris Disability Questionnaire and Patient’s Global Assessment (PGA) of low back pain. Tanezumab 10 and 20 mg had similar efficacy profiles and significantly improved LBPI, Roland Morris Disability Questionnaire, and PGA scores vs both placebo and naproxen (P ≤ .05). Tanezumab 5 mg provided improvement of PGA scores vs placebo (P ≤ .05), and naproxen resulted in significant improvement of LBPI vs placebo (P ≤ .05). Adverse event incidence was comparable across tanezumab doses but higher than with placebo or naproxen. Arthralgia, pain in extremity, headache, and paresthesia were the most commonly reported adverse events by tanezumab‐treated patients. The most frequently reported adverse events resulting in discontinuation of tanezumab treatment were arthralgia and paresthesia; the highest frequency was observed with tanezumab 20 mg (both 1.4%). Serious adverse event incidence was similar across treatments. In conclusion, tanezumab provided significantly greater improvement in pain, function, and global scores vs placebo and naproxen in patients with chronic low back pain.

Bioavailability of Amlodipine Besylate/Atorvastatin Calcium Combination Tablet

The bioequivalence of combination tablets containing amlodipine besylate/atorvastatin calcium with coadministered matching doses of amlodipine besylate and atorvastatin calcium tablets was investigated in randomized, 2‐way crossover studies in healthy volunteers (N = 126). Subjects received a single dose of the amlodipine/atorvastatin tablet or coadministered matching doses of amlodipine and atorvastatin at the highest (10/80 mg; n = 62) and lowest (5/10 mg; n = 64) dose strengths. Atorvastatin geometric mean ratios for maximum plasma concentration (Cmax) and area under the plasma concentration–time curve (AUC) for the highest and lowest dose strengths were 94.1 and 98.8, and 104.5 and 103.8, respectively. Amlodipine geometric mean ratios for Cmax and AUC for the highest and lowest dose strengths were 100.8 and 103.4, and 100 and 102.7, respectively. The 90% confidence intervals for all comparisons were within 80% to 125%, demonstrating bioequivalence for amlodipine and atorvastatin at both dose strengths. Use of amlodipine/atorvastatin combination tablets may provide a more integrated approach to treatment of cardiovascular risk.

Exploring the Role of Tanezumab as a Novel Treatment for the Relief of Neuropathic Pain

OBJECTIVE Evaluate efficacy and safety of tanezumab, a humanized monoclonal antibody against nerve growth factor, in neuropathic pain. DESIGN Two randomized controlled trials. SUBJECTS Patients with pain due to diabetic peripheral neuropathy (DPN) or postherpetic neuralgia (PHN). METHODS In the DPN study, patients received subcutaneous tanezumab 20 mg or placebo on Day 1 and Week 8. Evaluations included change from baseline in average DPN pain (primary endpoint), Patients Global Assessment of DPN, and safety (including neuropathy assessments). Due to a partial clinical hold limiting enrollment and treatment duration, the prespecified landmark analysis was modified post hoc from Week 16 to Week 8. In the PHN study, patients received intravenous tanezumab 50 μg/kg, tanezumab 200 μg/kg, or placebo on Day 1. Evaluations included change from baseline in average daily pain (primary endpoint), Brief Pain Inventory-short form, Patients Global Assessment of pain from PHN, and safety. RESULTS Mean DPN pain reduction from baseline to Week 8 was greater with tanezumab vs placebo (P = 0.009); differences in Patients Global Assessment of DPN were not significant (P > 0.05). Neither tanezumab dose resulted in significant differences vs placebo in efficacy in PHN (P > 0.05), although tanezumab 200 μg/kg provided some benefit. Neuropathy assessments showed no meaningful changes. CONCLUSIONS Tanezumab provided effective pain reduction in DPN. In PHN, only the highest tanezumab dose reduced pain; treatment differences were not significant. No new safety concerns were observed despite preexisting neuropathy.

Effect of Food on the Bioavailability of Amlodipine Besylate/Atorvastatin Calcium Combination Tablet

T aimed at simultaneously reducing blood pressure and lipid levels can substantially reduce the occurrence of cardiovascular events. A tablet containing the antihypertensive amlodipine besylate and the lipid-lowering drug atorvastatin calcium has been developed in 11 different combination dose strengths based on currently approved dosages of amlodipine besylate and atorvastatin calcium. Amlodipine is an oral calcium channel blocker (CCB) indicated for the treatment of hypertension and angina, and atorvastatin is a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor indicated for the treatment of dyslipidemia. A previous study demonstrated that combining the 2 agents in a single tablet does not affect the bioavailability of either drug under fasting conditions. When amlodipine alone is administered with food, its bioavailability is unaffected. When atorvastatin alone is administered with food, the rate and extent of atorvastatin absorption are reduced by approximately 25% and 9%, respectively. This study investigated the effect of a high-fat meal on the bioavailability of a combination tablet containing amlodipine/atorvastatin 10/80 mg in healthy volunteers. The highest dose strength available was selected because it is more likely to demonstrate any effect of food on absorption than is lower dose strengths.

Long-term safety and effectiveness of tanezumab as treatment for chronic low back pain

Summary Tanezumab provides sustained effectiveness, is generally safe, and may be a promising long‐term treatment for chronic low back pain. ABSTRACT A noncontrolled, randomized, multicenter study (NCT00924664) evaluated long‐term safety and effectiveness of tanezumab in patients with chronic low back pain following a randomized placebo‐ and active‐controlled parent study that evaluated analgesic efficacy. Patients were randomized to tanezumab 10 mg (n = 321) or 20 mg (n = 527) administered at 8‐week intervals via 3 intravenous injections followed by 4 subcutaneous injections. Effectiveness analyses included change from parent study baseline in Brief Pain Inventory Short Form, Roland Morris Disability Questionnaire, and Patient’s Global Assessment of low back pain. Safety assessments included adverse event documentation, physical/neurological examinations, and laboratory tests. Mean treatment duration during the extension study was 194 and 202 days with tanezumab 10 and 20 mg, respectively. Both tanezumab doses provided similar and sustained improvements in all effectiveness outcomes. The most frequently reported adverse events were arthralgia, paresthesia, and hypoesthesia. Adverse events initially described as osteonecrosis were reported in 6 patients (tanezumab 10 mg, n = 2; tanezumab 20 mg, n = 4); 9 additional patients (tanezumab 10 mg, n = 7; tanezumab 20 mg, n = 2) underwent total joint replacement (TJR). A blinded, independent adjudication committee reviewed all 6 patients with reported osteonecrosis and 4 of the 9 patients undergoing TJR. Adjudication outcomes were osteonecrosis (n = 0), worsening osteoarthritis (n = 5; 1 rapidly progressive), and another diagnosis or indeterminate (n = 5). Tanezumab 10 mg had better tolerability than tanezumab 20 mg, and may represent an effective long‐term treatment for chronic low back pain.

A Single‐Dose Pharmacokinetic Study of Lasofoxifene in Healthy Volunteers and Subjects With Mild and Moderate Hepatic Impairment

Lasofoxifene, a selective estrogen receptor modulator for osteoporosis management, is metabolized primarily by hepatic oxidation and conjugation. This study compared the pharmacokinetics of 0.25 mg lasofoxifene in subjects with mild (Child‐Pugh grade A, n = 6) or moderate (Child‐Pugh grade B, n = 6) hepatic impairment and healthy volunteers (n = 6). Analysis of variance was used to calculate 90% confidence intervals for the ratios (impaired/healthy) of least squares mean log maximum plasma concentration (Cmax) and area under the curve (AUC) values. Lasofoxifene pharmacokinetics was similar between healthy and mild hepatic impairment subjects: ratios of Cmax and AUC from 0 to infinity (AUC[0‐∞]) were 101% (75.0–138) and 95.5% (77.9–117), respectively. In subjects with moderate hepatic impairment, ratios of Cmax and AUC[0‐∞] were 121% (89.6–165) and 138% (112–169), respectively; mean terminal half‐life was 252 hr compared to 193 hr in healthy subjects. Dose adjustment should not be required for subjects with mild to moderate hepatic impairment.

Effect of lasofoxifene on the pharmacokinetics of digoxin in healthy postmenopausal women.

Lasofoxifene is in late‐stage development for the prevention and treatment of osteoporosis. Digoxin is commonly prescribed for arrhythmias and congestive heart failure, has a narrow therapeutic index, and may be coadministered with lasofoxifene. This study was conducted to determine the effect of lasofoxifene (4‐mg loading dose on day 11 followed by 0.5 mg/d on days 12–20) on the steady‐state pharmacokinetics of digoxin (0.25 mg/d on days 1–20) in 12 healthy postmenopausal women. On days 10 and 20, blood and urine samples were collected for 24 hours to determine digoxin concentrations. The 90% confidence interval (CI) of least squares mean ratio for maximum concentration (Cmax) and area under the plasma concentration‐time curve (AUC) was calculated. Lasofoxifene had no effect on digoxin plasma pharmacokinetics with a ratio (90% CI) of 95.4% (84.6%–107%) and 103% (97.7%–108%) for Cmax and AUC0–24, respectively. The ratio of the percentage of dose eliminated unchanged in urine in 24 hours was 127% (116% to 142%). Coadministration of lasofoxifene had no effect on the steady‐state pharmacokinetics of digoxin.

A randomized double-blind, placebo-controlled efficacy and safety study of ALO-02 (extended-release oxycodone surrounding sequestered naltrexone) for moderate-to-severe chronic low back pain treatment.

Abstract The objective of this multicenter, double-blind, placebo-controlled, randomized withdrawal study was to evaluate the efficacy and safety of ALO-02, an abuse-deterrent formulation containing pellets of extended-release oxycodone hydrochloride (HCl) surrounding sequestered naltrexone HCl, compared with placebo in the treatment of moderate-to-severe chronic low back pain. An open-label titration period in which all patients received ALO-02 was followed by a double-blind treatment period where patients meeting treatment response criteria were randomized to either a fixed dose of ALO-02 or placebo. Daily average low back pain was assessed using an 11-point numeric rating scale (NRS)-Pain. Of the 663 patients screened, 410 received ALO-02 during the open-label conversion and titration period and 281 patients were randomized to the double-blind treatment period (n = 134, placebo; n = 147, ALO-02). Change in the mean NRS-Pain score from randomization baseline to the final 2 weeks of the treatment period was significantly different favoring ALO-02 compared with placebo (P = 0.0114). Forty-four percent of patients treated with placebo and 57.5% of patients treated with ALO-02 reported ≥30% improvement in weekly average NRS-Pain scores from screening to the final 2 weeks of the treatment period (P = 0.0248). In the double-blind treatment period, 56.8% of patients in the ALO-02 group and 56.0% of patients in the placebo group experienced a treatment-emergent adverse event (TEAE). The most common treatment-related TEAEs for ALO-02 during the treatment period were nausea, vomiting, and constipation, consistent with opioid therapy. ALO-02 has been demonstrated to provide significant reduction of pain in patients with chronic low back pain and has a safety profile similar to other opioids.

Intranasal administration of crushed ALO-02 (extended-release oxycodone with sequestered naltrexone): A randomized, controlled abuse-potential study in nondependent recreational opioid users.

ALO‐02 is an abuse‐deterrent formulation consisting of capsules filled with pellets of extended‐release oxycodone surrounding sequestered naltrexone. This randomized, double‐blind, placebo‐/active‐controlled, 4‐way crossover study examined the abuse potential of crushed ALO‐02 administered intranasally to healthy, nondependent, recreational opioid users. Following drug discrimination and naloxone challenge, eligible participants (n = 32) entered a 4‐way crossover treatment phase: crushed single dose of 1 of 2 placebos, ALO‐02 30 mg/3.6 mg (oxycodone/naltrexone) or oxycodone immediate‐release (IR) 30 mg. Primary end points were Drug Liking and High, measured on visual analog scales (VAS) summarized as maximum effect (Emax) and effect occurring over 2 hours postdose (AUE0–2 h). Crushed ALO‐02 resulted in significantly lower scores versus oxycodone IR on Drug Liking (Emax, 60.5 vs 92.8; AUE0–2 h, 105.4 vs 160.0, respectively) and High (Emax, 25.2 vs 86.9; AUE0–2 h, 27.1 vs 136.4, respectively; n = 28; P < .0001). Adverse events occurred most frequently with oxycodone IR, followed by ALO‐02, then placebo, and were considered mild and consistent with opioid therapy. Crushed ALO‐02 administered intranasally to nondependent recreational opioid users resulted in significantly lower scores on Drug Liking/High VAS and other positive subjective measures versus crushed oxycodone IR, suggesting less abuse potential. Demonstration of actual abuse deterrence in the real world requires further research.