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.     

Keeping Secrets or Educating Others: A Dyadic Analysis of Group Entitativity’s Influence on Spouses’ Label Management Connected to AATD

In 1963, Goffman argued that forming a group based on shared stigma may provide benefits. However, there is no empirical research on whether perception that a separate, unique, coherent group exists (i.e., group entitativity) influences coping, such as educating others or secrecy, for the stigmatized individual or his or her spouse. Further, little is known about how spouses influence each other in terms of promoting the education of others about a stigmatizing condition, especially when it comes to the role of believing that stigma-based groups, to which they may both belong, exist. This study provides a step toward bridging this gap in the research by applying the label management model in efforts to understand coping for couples in which one spouse is diagnosed with genetic mutations leading to alpha-1 antitrypsin deficiency (AATD). This study included 50 married couples in which one spouse is diagnosed with genetic mutations leading to alpha-1 antitrypsin deficiency (AATD). We found that group entitativity related to those with AATD counterbalanced the influence of genetic stigma on spouses’ intentions to keep the diagnosis secret or to educate others about it. Intrapersonal and interpersonal influences appeared among spouses. Attention is needed on the power of creating groups for stigmatized persons and their relatives. Indeed, people live within a dynamic world of group entities, and multiple social identities including spousal and familial. While attention has been paid to the diffusion of stigmas to loved ones, less has been paid to the uplift of group entities for them.     

Block of potassium channels and facilitation of acetylcholine release at the neuromuscular junction by the venom of the scorpion, Pandinus imperator

Venom from the scorpion Pandinus imperator potently and selectively blocks voltage-gated K+ channels in bullfrog neurones (Pappone, P. A. and Cahalan, M. D. 1987, J. Neurosci. 7, 3300-3305). Its effects on neuromuscular transmission have now been assessed. Twitch tension studies on chick biventer cervicis preparations showed that the venom (1 microgram/ml and above) significantly augmented responses to nerve but not muscle stimulation; there was little change in postjunctional sensitivity to cholinoceptor agonists or K+-induced depolarization. Electrophysiological studies on mouse triangularis sterni preparations revealed that the venom had no effect on spontaneous transmitter release, but increased evoked transmitter release. Extracellular recordings of nerve terminal action potentials showed that the venom selectively reduced the component of the waveform associated with K+ currents. These results confirm that this venom can selectively block neuronal K+ currents, and they show that this can facilitate the release of acetylcholine at the neuromuscular junction.     

Plasma uric acid in patients receiving anticonvulsant monotherapy

In newly diagnosed adult patients with epilepsy followed prospectively on monotherapy, carbamazepine and phenytoin were associated with a fall in plasma uric acid, but sodium valproate and phenobarbitone were associated with a rise in plasma uric acid. The mechanisms and significance of these findings are discussed.