First-in-human randomized clinical trials of the safety and efficacy of tanezumab for treatment of chronic knee osteoarthritis pain or acute bunionectomy pain.

INTRODUCTION: The neurotrophin nerve growth factor has a demonstrated role in pain transduction and pathophysiology. OBJECTIVES: Two randomized, double-blind, placebo-controlled, phase 1 studies were conducted to evaluate safety, tolerability, and analgesic efficacy of single doses of tanezumab, a humanized anti-nerve growth factor monoclonal antibody, in chronic or acute pain. METHODS: In the first study (CL001), patients with moderate to severe pain from osteoarthritis (OA) of the knee received a single intravenous infusion of tanezumab (3-1000 µg/kg) or placebo in a dose-escalation (part 1; N = 42) or parallel-arm (part 2; N = 79) study design. The second study (CL002) was a placebo-controlled dose-escalation (tanezumab 10-1000 µg/kg; N = 50) study in patients undergoing bunionectomy surgery. RESULTS: Adverse event rates were generally similar across treatments. Most adverse events were generally mild to moderate in severity and no patients discontinued as a result of adverse events. Adverse events of abnormal peripheral sensation were more common with higher doses of tanezumab (≥100 µg/kg) than with placebo. These were generally mild to moderate in severity. Tanezumab provided up to 12 weeks of effective analgesia for OA knee pain, with statistically significant improvements at doses ≥100 µg/kg (P < 0.05). By contrast, no trend for analgesic activity was found when tanezumab was administered 8 to 16 hours before bunionectomy. CONCLUSIONS: The demonstration of a favorable safety profile and clinical efficacy in OA pain supports clinical development of tanezumab as a potential treatment for chronic pain conditions.

Pharmacokinetics and Pharmacodynamics of Anacetrapib Following Single Doses in Healthy, Young Japanese and White Male Subjects.

Anacetrapib is a cholesteryl ester transfer protein (CETP) inhibitor being developed for the treatment of mixed dyslipidemia. The aim of the study was to evaluate the pharmacokinetic, pharmacodynamic, and safety characteristics of anacetrapib following single doses in healthy, young Japanese men. In a double-blind, randomized, placebo-controlled, 3-panel, single-rising-dose study, 6 healthy young Japanese male or white male subjects (aged 19 to 44 years) received single oral doses of 5 to 500 mg anacetrapib, and 2 received placebo. Plasma and urine drug concentrations were measured 0-168 hours postdose, and plasma CETP inhibition was measured 0-24 hours postdose. Urinary anacetrapib levels were all below quantitation limits. Plasma concentrations of anacetrapib increased approximately less than dose-proportionally. Consumption of a traditional Japanese breakfast prior to dosing increased the plasma pharmacokinetics of anacetrapib in Japanese subjects compared with fasted conditions, to a similar extent as in white subjects. CETP activity measured over 0-24 hours postdose resulted in significant inhibition. Anacetrapib was generally well tolerated, and there were no serious adverse experiences. No clinically meaningful differences in PK and CETP inhibition parameters were found between Japanese and white subjects.

Phase-0/microdosing studies using PET, AMS, and LC-MS/MS: a range of study methodologies and conduct considerations. Accelerating development of novel pharmaceuticals through safe testing in humans - a practical guide.

INTRODUCTION: Phase-0 studies, including microdosing, also called Exploratory Investigational New Drug (eIND) or exploratory clinical trials, are a regulatory framework for first-in-human (FIH) trials. Common to these approaches is the use and implied safety of limited exposures to test articles. Use of sub-pharmacological doses in phase-0/microdose studies requires sensitive analytic tools such as accelerator mass spectrometer (AMS), Positron Emission Tomography (PET), and Liquid Chromatography Tandem Mass Spectrometry (LC-MS/MS) to determine drug disposition. Areas covered: Here we present a practical guide to the range of methodologies, design options, and conduct strategies that can be used to increase the efficiency of drug development. We provide detailed examples of relevant developmental scenarios. Expert opinion: Validation studies over the past decade demonstrated the reliability of extrapolation of sub-pharmacological to therapeutic-level exposures in more than 80% of cases, an improvement over traditional allometric approaches. Applications of phase-0/microdosing approaches include study of pharmacokinetic and pharmacodynamic properties, target tissue localization, drug-drug interactions, effects in vulnerable populations (e.g. pediatric), and intra-target microdosing (ITM). Study design should take into account the advantages and disadvantages of each analytic tool. Utilization of combinations of these analytic techniques increases the versatility of study designs and the power of data obtained.

Evaluation of pharmacokinetic parameters and dipeptidyl peptidase-4 inhibition following single doses of sitagliptin in healthy, young Japanese males.

AIMS: Sitagliptin is a selective inhibitor of dipeptidyl peptidase-4 (DPP-4) used to treat type 2 diabetes. The present aim was to evaluate pharmacokinetic (PK), pharmacodynamic (PD) and safety characteristics of sitagliptin following single doses in healthy, young Japanese males. METHODS: In this alternating two-panel, randomized, controlled double-blind study, six healthy Japanese male subjects (aged 20-46 years) in each panel received single oral doses of 5-400mg sitagliptin and two received placebo. Plasma and urine drug concentrations were measured from 0-48h post dose and plasma DPP-4 inhibition from 0-24h post dose. The results were compared with historical data from young, healthy non-Japanese males. RESULTS: Plasma concentrations of sitagliptin increased approximately in proportion to dose; maximum concentrations occurred 2-6h post-dose. The mean apparent terminal half-life for plasma sitagliptin was 9-14h, with the half-life slightly decreasing as the dose increased. The mean dose fraction excreted unchanged in the urine was 0.73-1.00. Ingestion of a traditional Japanese breakfast prior to dosing had only a minor effect on PK parameters. After correction for dilution and competition effects during assay, doses of sitagliptin ≥50mg resulted in weighted average DPP-4 inhibition from 0-24h post-dose >94% (without correction, >78%). No clinically meaningful differences in PK and DPP-4 inhibition parameters were found between Japanese and non-Japanese subjects. Sitagliptin was generally well tolerated and there were no serious adverse experiences or episodes of hypoglycaemia. CONCLUSIONS: The PK and PD findings from this study are consistent with once daily dosing of sitagliptin in Japanese patients with type 2 diabetes.

Contribution of a heating element to topical anesthesia patch efficacy prior to vascular access: results from two randomized, double-blind studies.

CONTEXT: Pain associated with superficial procedures, including intravenous (IV) access procedures, should be prevented when possible, especially in children. OBJECTIVES: To evaluate a topical local anesthetic patch containing lidocaine 70 mg/tetracaine 70 mg with a heating element designed to warm the skin and facilitate rapid delivery of local anesthetics into the skin. The pilot study was designed to provide data to inform the design of the definitive study to evaluate the impact of controlled heat on the efficacy of the lidocaine/tetracaine patch (patch) when applied before IV cannulation. METHODS: Subjects in the pilot study were randomized to eight groups that varied by heated vs. unheated patch, 20 vs. 30 minute application, and 16 vs. 18 G catheter. Subjects in the definitive study were randomized in a double-blind manner to receive either the heated or unheated patch, 20 minutes before vascular access, using a 16 G catheter in the antecubital space of the arm. In both studies, the primary efficacy measure was subject-reported pain intensity using a visual analog scale. RESULTS: Pilot study: Subjects who received the heated patch (n=43) vs. the unheated patch (n=37) had lower mean pain intensity scores (14.7 vs. 23.5mm, P=0.04). Pain intensity scores did not differ significantly by application time, but the difference between the 16 and 18 G catheter groups approached statistical significance (22.8 vs. 14.9 mm, P=0.05). Definitive study: Mean pain intensity scores for the heated patch group (n=124) vs. the unheated patch group (n=126) were 14.2 and 20.5mm, respectively (P=0.006). CONCLUSION: Heated patches provided significantly better pain relief compared with unheated patches. All the subjects tolerated the patches well, with few adverse effects.

Use of accelerator mass spectrometry to measure the pharmacokinetics and peripheral blood mononuclear cell concentrations of zidovudine.

The remarkable sensitivity of accelerator mass spectrometry (AMS) is finding many new applications in pharmacology. In this study AMS was used to measure [(14)C]-Zidovudine (ZDV) concentrations at the drug's site of action (peripheral blood mononuclear cells, PBMCs) following a dose of 520 ng (less than one-millionth of the standard daily dose) to a healthy volunteer. In addition, the pharmacokinetics of this microdose were determined and compared to previously published parameters for therapeutic doses. Microdose ZDV pharmacokinetic parameters fell within reported 95% confidence intervals or standard deviations of most previously published values for therapeutic doses. Blood, urine, stool, saliva, and isolated PBMCs were collected periodically through 96 h postdose and analyzed for ZDV and metabolite concentrations. The results showed that ZDV is rapidly absorbed and eliminated, has one major metabolite, and is sequestered in PBMCs. (14)C mass balance assessments indicated a significant portion of ZDV remained after 96 h with a much prolonged elimination half-life. Results of this study demonstrate the usefulness of microdosing and AMS as a tool for studying the pharmacokinetic characteristics, including PBMC concentrations, of ZDV and underscore the value of AMS as a tool with which to perform pharmacokinetic and mass balance studies using trace amounts of radiolabeled compound.

Safety and pharmacokinetic profile of multiple escalating doses of (+)-calanolide A, a naturally occurring nonnucleoside reverse transcriptase inhibitor, in healthy HIV-negative volunteers.

BACKGROUND: (+)-Calanolide A is a naturally occurring nonnucleoside reverse transciptase inhibitor (NNRTI) that exhibits enhanced activity against HIV-1 isolates with the Y181C mutation and retains activity against HIV-1 isolates with dual Y181C and K103N mutations. Previous studies have demonstrated that (+)-calanolide A has a favorable safety profile in both animal and human subjects. METHOD: In this study, the safety and pharmacokinetics of multiple escalating doses of (+)-calanolide A were evaluated in a total of 47 healthy, HIV-seronegative individuals. RESULTS: All adverse events seen in the study were mild to moderate in intensity and were transient. The most common adverse events seen were headache, dizziness, nausea, and taste perversion (oily aftertaste). Laboratory abnormalities were determined to be clinically insignificant or unrelated to (+)-calanolide A administration. No dose-related pattern in adverse event or laboratory abnormality incidence was apparent. In all cohorts examined, administration of (+)-calanolide A produced highly variable plasma levels and absorption profiles. No accumulation of parent compound was seen over the 5-day treatment course, with the day 5 area under the curve (AUC) being approximately one half of that seen on the first day of dosing. Steady-state trough plasma levels were determined in the two highest dose cohorts (600 mg and 800 mg bid for 5 days). Mean elimination half-life in the two highest dosing cohorts combined was 15.5 hours in men and 35.2 hours in women. CONCLUSION: These pharmacokinetic properties, together with the benign safety profile, and unique in vitro resistance pattern warrant the continued development of this potential new antiviral agent.