Population pharmacokinetics of tanezumab in phase 3 clinical trials for osteoarthritis pain

AimsThe aims were to 1) develop the pharmacokinetics model to describe and predict observed tanezumab concentrations over time, 2) test possible covariate parameter relationships that could influence clearance and distribution and 3) assess the impact of fixed dosing vs. a dosing regimen adjusted by body weight.MethodsIndividual concentration–time data were determined from 1608 patients in four phase 3 studies conducted to assess efficacy and safety of intravenous tanezumab. Patients received two or three intravenous doses (2.5, 5 or 10 mg) every 8 weeks. Blood samples for assessment of tanezumab PK were collected at baseline, 1 h post‐dose and at weeks 4, 8, 16 and 24 (or early termination) in all studies. Blood samples were collected at week 32 in two studies. Plasma samples were analyzed using a sensitive, specific, validated enzyme‐linked immunosorbent assay.ResultsA two compartment model with parallel linear and non‐linear elimination processes adequately described the data. Population estimates for clearance (CL), central volume (V ₁), peripheral volume (V ₂), inter‐compartmental clearance, maximum elimination capacity (VM) and concentration at half‐maximum elimination capacity were 0.135 l day^–1, 2.71 l, 1.98 l, 0.371 l day^–1, 8.03 μg day^–1 and 27.7 ng ml^–1, respectively. Inter‐individual variability (IIV) was included on CL, V ₁, V ₂ and VM. A mixture model accounted for the distribution of residual error. While gender, dose and creatinine clearance were significant covariates, only body weight as a covariate of CL, V ₁ and V ₂ significantly reduced IIV.ConclusionsThe small increase in variability associated with fixed dosing is consistent with other monoclonal antibodies and does not change risk : benefit.     

膝骨性关节炎慢性疼痛的机制及其综合治疗进展

膝骨关节炎(KOA)是慢性疼痛最常见的原因之一,其治疗仅限于对乙酰氨基酚、非甾体抗炎药和物理治疗等,全膝关节置换术是解决关节疼痛的最终选择。因此,对于KOA疼痛的产生机制需进一步了解,以希望找到更好的治疗方法。     

抗神经生长因子单克隆抗体Tanezumab

目前在对疼痛和骨关节炎之类的炎症的治疗中多联合使用非甾体类解热镇痛抗炎药（NSAIDs）与硫酸吗啡等阿片类药物,但这些药物可能对某些病人无效或能引起复杂的不良反应,如胃肠道溃疡和呼吸抑制,因而亟待开发更为安全有效的治疗药物。神经生长因子（NGF）是一种在超敏反应的发生和异常性疼痛的产生中具有关键作用的递质。大量临床前研究表明：阻止NGF与其受体的相互作用,     

Anti-nerve growth factor antibodies for the treatment of low back pain

ABSTRACT

Introduction

The treatment of chronic low back pain (cLBP) often involves multimodal pharmacologic and non-pharmacologic strategies. There remain shortcomings with these tools with regards to both effect size and side effects.     

Pain and Palliative Care Pharmacotherapy Literature Summaries and Analyses

ABSTRACT

Timely and important studies are reviewed and commentaries provided by leading palliative care clinicians. Symptoms, interventions, and treatment-related adverse events addressed in this issue are effective management of cancer pain; validity of multiple self-reported pain assessment scales in medically ill populations; sleep duration and mortality in older adults; depression and survival in metastatic breast cancer patients; safety and effectiveness of tanezumab for osteoarthritis pain of the knee; and plotting the functional trajectory of certain patients with end-stage renal disease.     

New investigational drugs for the treatment of neuropathic pain

Introduction: Neuropathic pain (NP) is a chronic condition that arises from a lesion or dysfunction of the somatosensory nervous system. However, there are several new targets and novel technologies in the pipeline to address this unmet medical need.

Areas covered: In this review, the authors briefly discuss a direction of the development of agents that could be potentially used in NP treatment. Special attention is paid to 1.7-selective voltage-gated sodium channels, N-type voltage-gated calcium channels, angiotensin II (Ang II) AT₂ receptors and nerve growth factor (NGF) as promising targets for new drugs. Furthermore, the article also presents and discusses, in detail, the results of Phase II clinical studies with the AT₂ receptor antagonist ? EMA401 in NP (the results of Phase II clinical trials of other described compounds are not available, yet).

Expert opinion: There is a real hope that new drugs for NP may be available soon. This hope is based on advancing methods of genomics, developing new targets and more efficient drug screening. Some forms of direct influence on voltage-gated ion channels have a place in the treatment of NP, while the development of entirely novel Ang II AT₂ receptor antagonists or NGF inhibitors may be available for many chronic pain sufferers in the foreseeable future.