Jonathan Bullman

The effects of the TRPV1 antagonist SB-705498 on TRPV1 receptor-mediated activity and inflammatory hyperalgesia in humans.

Abstract TRPV1 is a cation channel activated by a range of noxious stimuli and highly expressed in nociceptive fibres. TRPV1 receptors are involved in pain and sensitisation associated with tissue injury and inflammation; hence, TRPV1 antagonists are potentially useful for the treatment of such pain states. SB‐705498 is a potent, selective and orally bioavailable TRPV1 antagonist with demonstrated efficacy in a number of preclinical pain models. In this first‐time‐into‐human study, we have investigated the pharmacodynamic and antihyperalgesic activity of SB‐705498. The compound was safe and well tolerated at single oral doses up to 400 mg. In a cohort of 19 healthy volunteers, we used a randomised placebo‐controlled single‐blind cross‐over design to assess the effects of SB‐705498 (400 mg) on heat‐evoked pain and skin sensitisation induced by capsaicin or UVB irradiation. Compared with placebo, SB‐705498 reduced the area of capsaicin‐evoked flare (P = 0.0047). The heat pain threshold on non‐sensitised skin was elevated following SB‐705498 (estimated difference from placebo [95% confidence intervals]: 1.3 °C [0.07, 2.53], P = 0.019). Following capsaicin sensitisation, the heat pain threshold and tolerance were similar between SB‐705498 and placebo. However, SB‐705498 increased heat pain tolerance at the site of UVB‐evoked inflammation (estimated difference from placebo: 0.93 °C [0.25, 1.6], P = 0.0054). The magnitude of the pharmacodynamic effects of SB‐705498 appeared to be related to plasma concentration. These results indicate that SB‐705498, at a clinically safe and well‐tolerated dose, has target‐specific pharmacodynamic activity in humans. These data provide the first clinical evidence that a TRPV1 antagonist may alleviate pain and hyperalgesia associated with inflammation and tissue injury.

A randomized, controlled study to investigate the analgesic efficacy of single doses of the cannabinoid receptor-2 agonist GW842166, ibuprofen or placebo in patients with acute pain following third molar tooth extraction.

ObjectivesTo evaluate the postoperative analgesic efficacy of GW842166, a noncannabinoid CB2 agonist, in patients undergoing third molar tooth extraction. MethodsThis randomized, double-blind, placebo-controlled study compared the analgesic efficacy of single doses of GW842166 (100 or 800 mg) or ibuprofen with placebo in patients undergoing extraction of at least 1 fully or partially impacted third molar tooth. Eligible participants were dosed preoperatively within 1 hour of surgery. Participants allocated to active comparator received a second dose of ibuprofen (400 mg), 4 hours after the first 800 mg dose. Participants in the GW842166 and placebo groups received placebo at 4 hours. Procedures for the assessment of efficacy included a visual analog scale and verbal rating scale for scoring pain up to 10 hours postsurgery, duration of analgesia, patient global evaluation, proportion of patients requiring rescue medication, and elapsed time to rescue analgesia. Analysis of covariance was used to compare efficacy variables. Patient global evaluation was analyzed using Wilcoxon rank-sum tests and time to data was analyzed using the log-rank test. ResultsIbuprofen was significantly more effective than placebo across all endpoints. Trends for an improvement in pain scores for GW842166 800 mg failed to be of either clinical or statistical significance. GW842166 100 mg showed little separation from placebo. There was no evidence for any beneficial adjunctive effect after coadministration of rescue analgesia with GW842166. All treatments were well tolerated. DiscussionIn comparison to ibuprofen, single doses of GW842166 (100 and 800 mg) failed to demonstrate clinically meaningful analgesia in the setting of acute dental pain.

Analgesic efficacy and safety of the novel p38 MAP kinase inhibitor, losmapimod, in patients with neuropathic pain following peripheral nerve injury: a double-blind, placebo-controlled study

Inhibitors of p38 mitogen‐activated protein kinase are undergoing evaluation as a novel class of anti‐rheumatic drugs, by virtue of their ability to suppress the production of pro‐inflammatory cytokines. Emerging data suggests that they may also attenuate peripheral or central sensitization in neuropathic pain. A double‐blind, placebo‐controlled study was undertaken to evaluate the analgesic efficacy of losmapimod (GW856553), a novel p38α/β inhibitor, in subjects with neuropathic pain following traumatic peripheral nerve injury.

Safety, Pharmacokinetic, and Functional Effects of the Nogo-A Monoclonal Antibody in Amyotrophic Lateral Sclerosis: A Randomized, First-In-Human Clinical Trial

The neurite outgrowth inhibitor, Nogo-A, has been shown to be overexpressed in skeletal muscle in amyotrophic lateral sclerosis (ALS); it is both a potential biomarker and therapeutic target. We performed a double-blind, two-part, dose-escalation study, in subjects with ALS, assessing safety, pharmacokinetics (PK) and functional effects of ozanezumab, a humanized monoclonal antibody against Nogo-A. In Part 1, 40 subjects were randomized (3∶1) to receive single dose intravenous ozanezumab (0.01, 0.1, 1, 5, or 15 mg/kg) or placebo. In Part 2, 36 subjects were randomized (3∶1) to receive two repeat doses of intravenous ozanezumab (0.5, 2.5, or 15 mg/kg) or placebo, approximately 4 weeks apart. The primary endpoints were safety and tolerability (adverse events [AEs], vital signs, electrocardiogram (ECG), and clinical laboratory tests). Secondary endpoints included PK, immunogenicity, functional endpoints (clinical and electrophysiological), and biomarker parameters. Overall, ozanezumab treatment (0.01–15 mg/kg) was well tolerated. The overall incidence of AEs in the repeat dose 2.5 mg/kg and 15 mg/kg ozanezumab groups was higher than in the repeat dose placebo group and repeat dose 0.5 mg/kg ozanezumab group. The majority were considered not related to study drug by the investigators. Six serious AEs were reported in three subjects receiving ozanezumab; none were considered related to study drug. No study drug-related patterns were identified for ECG, laboratory, or vital signs parameters. One subject (repeat dose 15 mg/kg ozanezumab) showed a weak, positive anti-ozanezumab-antibody result. PK results were generally consistent with monoclonal antibody treatments. No apparent treatment effects were observed for functional endpoints or muscle biomarkers. Immunohistochemical staining showed dose-dependent co-localization of ozanezumab with Nogo-A in skeletal muscle. In conclusion, single and repeat dose ozanezumab treatment was well tolerated and demonstrated co-localization at the site of action. These findings support future studies with ozanezumab in ALS. Trial Registration ClinicalTrials.gov NCT00875446 GSK-ClinicalStudyRegister.com GSK ID 111330

Lack of Pharmacokinetic Interaction between Oxcarbazepine and Lamotrigine

Epilepsy and bipolar disorder are commonly treated by combination drug therapy, such as lamotrigine and oxcarbazepine. To ensure the safety of this combination, information on pharmacokinetics and tolerability must be available. The objective of study was to evaluate the pharmacokinetics and tolerability of coadministered lamotrigine and oxcarbazepine in healthy subjects. This randomized, single-blind, parallel-group study comprised three cohorts: lamotrigine (200 mg daily) plus oxcarbazepine (600 mg twice daily), lamotrigine (200 mg daily) plus placebo, and oxcarbazepine (600 mg twice daily) plus placebo. Serial blood samples were collected at steady state to determine serum concentrations of lamotrigine and plasma concentrations of oxcarbazepine and its active metabolite 10-monohydroxy metabolite (MHD). Pharmacokinetic parameters were determined by noncompartmental methods. Tolerability was monitored through adverse event reports, clinical laboratory results, vital signs, and electrocardiograms. A total of 47 male volunteers received study drugs. At steady state, lamotrigine AUC(0–24) and Cmax were not significantly affected by oxcarbazepine cotherapy, nor were MHD AUC(0–12) and Cmax significantly affected by lamotrigine cotherapy. The most common adverse events, headache, dizziness, nausea, and somnolence, occurred more frequently during lamotrigine and oxcarbazepine combination therapy than during the monotherapy. No significant changes in clinical laboratory parameters, vital signs, or electrocardiograms were reported. In conclusion, the combination of lamotrigine and oxcarbazepine does not require dose adjustments based on pharmacokinetic data. However, it is important to recognize that the combination therapy was associated with more frequent adverse events.

Pharmacokinetic profile of a new form of sumatriptan tablets in healthy volunteers

SUMMARY Objective: Rapid delivery of migraine-specific medication to its site(s) of action is thought to be crucial in preventing or minimizing sensitization of central pain pathways and thereby in optimizing pain-free outcomes in patients with migraine. Sumatriptan has been developed as a new tablet formulation to enhance the rate of systemic drug delivery by improving tablet disintegration and drug dispersion relative to those of conventional tablets. These enhanced formulation characteristics may be beneficial during occurrences of the gastric stasis that can accompany migraine. Methods: This randomized, open-label, 4-way crossover study (n = 32) was conducted to determine whether the new formulation of sumatriptan 50 and 100 mg is bioequivalent to sumatriptan conventional tablets and to compare the pharmacokinetic profiles of the new formulation and the conventional tablet during the early (0–2 h) post-dose interval in healthy volunteers. Pharmacokinetics during the early post-dose interval are important in determining a drugs onset of action, an important parameter to patients with migraine. Results: The results confirm that the new formulation of sumatriptan and sumatriptan conventional tablets are bioequivalent as demonstrated by the finding that the 90% confidence intervals for the sumatriptan area under the concentration time curve to infinity and to the last evaluable time point (AUC0–∞ and AUC0–t, respectively) and maximum plasma concentration (Cmax) fell within the predetermined bounds defining bioequivalence (0.80–1.25) for both doses. Pharmacokinetic parameters measured early (0–2 h) after dosing reveal slightly faster absorption, on average, of the new sumatriptan formulation than sumatriptan conventional tablets although high intersubject variability was observed. For the new sumatriptan formulation, AUC0–2 (AUC up to 2h post-dose) was, on average, 1% greater (50 mg) and 8% greater (100 mg) and maximal sumatriptan levels were attained, on average, 10 min earlier (50 mg) and 15 min earlier (100 mg) compared with the conventional tablet. Other measures including AUC0–0.5 (AUC to 30 min post-dose), times to achieve sumatriptan concentrations of 5 and 10 ng/mL, and mean percentage Cmax 15, 20 and 30 min post-dose demonstrate an observable improvement in rate of drug absorption for the new form of sumatriptan compared with conventional tablets. Conclusion: The new form of sumatriptan is bioequivalent to sumatriptan conventional tablets and is absorbed more quickly than conventional tablets.

Effects of lamotrigine and phenytoin on the pharmacokinetics of atorvastatin in healthy volunteers

Purpose:  Statins and antiepileptic drugs (AEDs) are frequently coprescribed to individuals with hypercholesterolemia and new‐onset seizures. Statins are metabolized by the cytochrome P450 (CYP) enzyme system. Interactions between statins and agents that undergo CYP metabolism are common. In this study, the effects of two commonly prescribed AEDs, lamotrigine and phenytoin, with different routes of metabolism (CYP3A4 versus glucuronic acid conjugation) on atorvastatin pharmacokinetics were evaluated.

Safety and efficacy of ozanezumab in patients with amyotrophic lateral sclerosis : a randomised, double-blind, placebo-controlled, phase 2 trial

BACKGROUND Neurite outgrowth inhibitor A (Nogo-A) is thought to have a role in the pathophysiology of amyotrophic lateral sclerosis (ALS). A monoclonal antibody against Nogo-A showed a positive effect in the SOD1G93A mouse model of ALS, and a humanised form of this antibody (ozanezumab) was well tolerated in a first-in-human trial. Therefore, we aimed to assess the safety and efficacy of ozanezumab in patients with ALS. METHODS This randomised, double-blind, placebo-controlled, phase 2 trial was done in 34 centres in 11 countries. Patients aged 18-80 years with a diagnosis of familial or sporadic ALS were randomly assigned (1:1), centrally according to a computer-generated allocation schedule, to receive ozanezumab (15 mg/kg) or placebo as intravenous infusions over 1 h every 2 weeks for 46 weeks, followed by assessments at week 48 and week 60. Patients and study personnel were masked to treatment assignment. The primary outcome was a joint-rank analysis of function (ALS Functional Rating Scale-Revised) and overall survival, analysed at 48 weeks in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01753076, and with GSK-ClinicalStudyRegister.com, NOG112264, and is completed. FINDINGS Between Dec 20, 2012, and Nov 1, 2013, we recruited 307 patients, of whom 303 were randomly assigned to receive placebo (n=151) or ozanezumab (n=152). The adjusted mean of the joint-rank score was -14·9 (SE 13·5) for the ozanezumab group and 15·0 (13·6) for the placebo group, with a least squares mean difference of -30·0 (95% CI -67·9 to 7·9; p=0·12). Overall, reported adverse events, serious adverse events, and adverse events leading to permanent discontinuation of study drug or withdrawal from study were similar between the treatment groups, except for dyspepsia (ten [7%] in the ozanezumab group vs four [3%] in the placebo group), depression (11 [7%] vs five [3%]), and diarrhoea (25 [16%] vs 12 [8%]). Respiratory failure was the most common serious adverse event (12 [8%] vs seven [5%]). At week 60, the number of deaths was higher in the ozanezumab group (20 [13%]) than in the placebo group (16 [11%]), mainly as a result of respiratory failure (ten [7%] vs five [3%]). Two deaths were considered related to the study drug (bladder transitional cell carcinoma in the ozanezumab group and cerebrovascular accident in the placebo group). INTERPRETATION Ozanezumab did not show efficacy compared with placebo in patients with ALS. Therefore, Nogo-A does not seem to be an effective therapeutic target in ALS. FUNDING GlaxoSmithKline.

A randomized, placebo-controlled trial of the analgesic efficacy and safety of the p38 MAP kinase inhibitor, losmapimod, in patients with neuropathic pain from lumbosacral radiculopathy.

Objectives:Preclinical studies have demonstrated involvement of p38 mitogen-activated protein kinase signaling pathways in the development of persistent pain after peripheral nerve injury. A double-blind, randomized, placebo-controlled study was undertaken to evaluate the analgesic efficacy of losmapimod (GW856553), a novel p38&agr;/&bgr; inhibitor, in patients with chronic neuropathic pain due to lumbosacral radiculopathy. Materials and Methods:A total of 144 patients with at least moderate baseline pain intensity (average daily score of ≥4 on an 11-point pain intensity numeric rating scale) were randomized to receive losmapimod, 7.5 mg bid orally or placebo. All patients underwent a blinded placebo run-in period for 7 days before receiving losmapimod/placebo for 28 days. Efficacy and safety evaluations were undertaken weekly. Results:The adjusted mean treatment difference for the change from baseline to week 4 in numeric rating scale was −0.36 U (95% confidence interval, −0.84, 0.13; P=0.149) in favor of losmapimod over placebo; this was not considered clinically meaningful. Statistically significant differences in favor of losmapimod were observed, however, for several secondary endpoints of emotional, physical, and social functioning: Oswestry Disability Index; Profile of Mood States total score; Short-Form 36 Health Survey physical functioning, bodily pain, general health, role emotional, social functioning, and vitality domains; and Short-Form 36 physical, and mental components. There were no unexpected findings related to safety or tolerability following treatment with losmapimod. Discussion:Losmapimod could not be differentiated from placebo in terms of analgesia. The lack of response could reflect insufficient losmapimod levels in the spinal cord or differences between lumbosacral radiculopathy and animal models of neuropathic pain.

Characterising the plasma-target occupancy relationship of the neurokinin antagonist GSK1144814 with PET

GSK1144814 is a potent, insurmountable antagonist at human NK1 and NK3 receptors. Understanding the relationship between plasma pharmacokinetics and receptor occupancy in the human brain, was crucial for dose selection in future clinical studies. GSK1144814 occupancy data were acquired in parallel with the first-time-in-human safety and tolerability study. [11C]GR-205171 a selective NK1 receptor PET ligand was used to estimate NK1 occupancy at several time-points following single dose administration of GSK1144814. The time-plasma concentration–occupancy relationship post-single dose administration was assessed, and used to predict the plasma concentration–occupancy relationship following repeat dose administration. Repeat dose predictions were tested in a subsequent cohort of subjects examined following approximately 7 and 14 days dosing with GSK1144814. GSK1144814 was shown to demonstrate a dose-dependent occupancy of the NK1 receptor with an estimated in vivo EC50 ~0.9 ng/mL in the human brain. A direct relationship was seen between the GSK1144814 plasma concentration and its occupancy of the brain NK1 receptor, indicating that in future clinical trials the occupancy of brain receptors can be accurately inferred from the measured plasma concentration. Our data provided support for the further progression of this compound and have optimised the likely therapeutic dose range.