Gilberto Castañeda-Hernández

The role of biosimilars in the treatment of rheumatic diseases

The first biological therapeutics in rheumatology are approaching patent expiration, encouraging development of ‘follow-on’ versions, known as ‘biosimilars’. Biological agents range from simple replacement hormones to complex monoclonal antibodies and soluble receptors: large, intricate proteins with unique tertiary and quaternary structures that are inherently difficult to replicate. Post-translational modifications, such as glycosylation, may occur from changes in cell lines and/or manufacturing processes, resulting in products that are highly similar, but not identical, to approved ‘reference’ agents, hence, the term ‘biosimilar’, rather than ‘bioidentical’. Even minor modifications in manufacturing processes, which iteratively occur with reference products due to improvements in efficiency, scale up to meet commercial demands or changes in manufacturing sites, may alter biological function and/or immunogenicity, potentially changing their safety and efficacy profile. As biosimilars are now in randomised controlled trials for treatment of rheumatic diseases, rheumatologists face decisions regarding equipoise and will need to consider their clinical use versus reference products. A clear understanding of the inherent differences between reference antibodies and biosimilars, their clinical implications and the processes governing regulation, approval and clinical use of biosimilars, is paramount. A panel of international experts in the field of rheumatology recently convened to evaluate and discuss these issues.

Pharmacokinetic-Pharmacodynamic Modeling: Why?

At present, pharmacokinetic-pharmacodynamic (PK-PD) modeling has emerged as a major tool in clinical pharmacology to optimize drug use by designing rational dosage forms and dosage regimes. Quantitative representation of the dose-concentration-response relationship should provide information for prediction of the level of response to a certain level of drug dose. Several mathematical approaches can be used to describe such relationships, depending on the single dose or the steady-state measurements carried out. With concentration and response data on-phase, basic models such as fixed-effect, linear, log-linear, E(MAX), and sigmoid E(MAX) can be sufficient. However, time-variant pharmacodynamic models (effect compartment, acute tolerance, sensitization, and indirect responses) can be required when kinetics and response are out-of-phase. To date, methodologies available for PK-PD analysis barely suppose the use of powerful computing resources. Some of these algorithms are able to generate individual estimates of parameters based on population analysis and Bayesian forecasting. Notwithstanding, attention must be paid to avoid overinterpreted data from mathematical models, so that reliability and clinical significance of estimated parameters will be valuable when underlying physiologic processes (disease, age, gender, etc.) are considered.

Mechanisms involved in the cardiovascular alterations immediately after spinal cord injury.

The early cardiovascular effects resulting from an acute spinal cord injury (SCI) produced by a contusion procedure at T5-T6 were evaluated in anaesthetized rats. The mean arterial pressure (MAP) and heart rate (HR) were measured during one hour after the injury. A marked decrease in MAP and HR was observed immediately after injury, followed by an abrupt increase in MAP. These changes were observed between 3 and 9 min and the basal values were recovered after 20 min. Fall in the MAP and HR and increase in MAP induced by SCI were abolished by atropine. The interruption of the parasympathetic outflow by vagotomy also significantly diminished the fall and increase in MAP and the fall in HR. Likewise, pre-treatment with nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) completely abolished the effects produced by SCI. These data suggest that after SCI the decrement in MAP and HR was probably due to acetylcholine release from parasympathetic fibers and NO from endothelial source probably by a cholinergic stimulation. Additionally, the MAP increase observed was probably due to a reflex compensatory vasoconstriction.

Anti-tumor necrosis factor patent expiration and the risks of biocopies in clinical practice

Biosimilars that were not compared in clinical trials with the compound innovator are not true biosimilars (biocopies) and are associated with risks that the clinical rheumatologist should be aware of before generalized use. This article comments on various aspects surrounding the use of such biocopies in clinical rheumatology.

Acute spinal cord injury changes the disposition of some, but not all drugs given intravenously

Study design:Experimental laboratory investigations in paraplegic rats.Objective:In order to understand why acute spinal cord injury (SCI) changes the disposition of some, but not all drugs given intravenously (i.v.), pharmacokinetic parameters of drugs with different pharmacological properties were evaluated to determine the influence of SCI on physiological processes such as distribution, metabolism and excretion.Setting:Mexico City, Mexico.Methods:Rats were subjected to severe SCI (contusion) at T-9 level; pharmacokinetic studies of phenacetin, naproxen or gentamicin were performed 24u2009h after. These drugs were not chosen as markers because of their therapeutic properties, but because of their pharmacokinetic characteristics. Additional studies including plasma proteins, liver and renal function tests, and micro-vascular hepatic blood flow, were also performed at the same time after injury.Results:Acute SCI significantly reduced distribution of drugs with intermediate and low binding to plasma proteins (phenacetin 30% and gentamicin 10%, respectively), but distribution did not change when naproxen – a drug highly bound to plasma proteins (99%) – was used, in absence of changes in plasma proteins. Metabolism was significantly altered only for a drug with liver blood flow – limited clearance (phenacetin) and not for a drug with liver capacity-limited clearance (naproxen). The liver function test did not change, whereas the hepatic micro-vascular blood flow significantly decreased after SCI. Renal excretion, evaluated by gentamicin clearance, was significantly reduced as a consequence of SCI, without significant changes in serum creatinine.Conclusions:Changes in drug disposition associated to acute SCI are complex and generalization is not possible. They are highly dependent on each drug properties as well as on the altered physiological processes. Results motivate the quest for strategies to improve disposition of selective i.v. drugs during spinal shock, in an effort to avoid therapeutic failure.

Population pharmacokinetic analysis of tacrolimus in Mexican paediatric renal transplant patients: role of CYP3A5 genotype and formulation

AIMSnThe aims of this study were (i) to develop a population pharmacokinetic (PK) model of tacrolimus in a Mexican renal transplant paediatric population (nu2009=u200953) and (ii) to test the influence of different covariates on its PK properties to facilitate dose individualization.nnnMETHODSnPopulation PK and variability parameters were estimated from whole blood drug concentration profiles obtained at steady-state using the non-linear mixed effect modelling software NONMEM® Version 7.2.nnnRESULTSnTacrolimus PK profiles exhibited high inter-patient variability (IPV). A two compartment model with first order input and elimination described the tacrolimus PK profiles in the studied population. The relationship between CYP3A5 genotype and tacrolimus CL/F was included in the final model. CL/F in CYP3A5*1/*1 and *1/*3 carriers was approximately 2- and 1.5-fold higher than in CYP3A5*3/*3 carriers (non-expressers), respectively, and explained almost the entire IPV in CL/F. Other covariates retained in the final model were the tacrolimus dose and formulation type. Limustin® showed markedly lower concentrations than the rest of the formulations.nnnCONCLUSIONSnPopulation PK modelling of tacrolimus in paediatric renal transplant recipients identified the tacrolimus formulation type as a significant covariate affecting the blood concentrations and confirmed the previously reported significant effect of CYP3A5 genotype on CL/F. It allowed the design of a proposed dosage based on the final model that is expected to help to improve tacrolimus dosing.

Changes in renal function during acute spinal cord injury: implications for pharmacotherapy

Study design:Laboratory investigation in rats submitted to experimental spinal cord injury (SCI).Objective:To characterize changes in renal function during acute SCI.Methods:Sprague Dawley rats were subjected to severe spinal cord contusion at T8 level or to laminectomy as control. Twenty-four hours after spine surgery, clearance assessments of a single dose of iohexol (120u2009mgu2009kg−1) or of p-aminohippuric acid (PAH, 100u2009mgu2009kg−1) were used to evaluate glomerular filtration rate (GFR) and tubular secretion (TS), respectively. Blood sampling was used to determine concentrations of both compounds by high-performance liquid chromatography for pharmacokinetic measurements.Results:Iohexol clearance decreased significantly after injury, which resulted in increased concentrations and half-life of iohexol in blood; PAH clearance remained unchanged.Conclusion:GFR but not TS is altered during spinal shock. These observations should be of interest to professionals caring for early cord-injured patients, in order to prevent toxicity and therapeutic failure when administering drugs eliminated by the kidney.

Decreased cyclosporine exposure during the remission of nephrotic syndrome

In this paper, we report the pharmacokinetics changes observed in seven children with steroid-resistant nephrotic syndrome (SRNS). They received cyclosporine A (CsA) microemulsion 6xa0mg/kg/day and, one week later, they were admitted to perform a 12-h pharmacokinetic profile with eight time sample points. The pharmacokinetic profile was repeated at 24xa0weeks of treatment, when all patients achieved remission. Blood concentration against time curves were constructed for each patient at weeks 1 and 24 of CsA treatment. Peak concentrations (Cmax) and the time needed to reach peak concentrations (tmax) were directly determined from these plots. The area under the curve (AUC) was estimated by the trapezoidal rule. There was a statistically significant difference of the AUC, trough levels, and tmax between weeks 1 and 24, with a decrease of AUC from 5,211xa0ng*h/ml in week 1 to 3,289xa0ng*h/ml in week 24, the trough levels decreased from 157xa0ng/ml to 96xa0ng/ml, and the tmax decreased from 1.85xa0h to 1.00xa0h. The higher CsA bioavailability during the nephrotic state has to be considered when managing patients, since the target AUC cannot be the same throughout the treatment.

Peri-Infusional Adverse Reactions to Rituximab in Patients with Non-Hodgkin's Lymphoma

BACKGROUND AND AIMSnRituximab is effective in the treatment of B-cell lymphoid malignances and some autoimmune diseases. Most patients receiving the first infusion of rituximab experience symptoms that decrease with subsequent infusions. It is assumed that the first dose of rituximab should be infused slowly during a 6-h period and during 4-h periods subsequently. The aim of the study was to evaluate the frequency and severity of adverse reactions to rituximab in patients with non-Hodgkins lymphoma.nnnMETHODSnThis was an intensive pharmacovigilance prospective, observational, open labeled, multicenter cohort study conducted in 12 hospitals. Adults requiring treatment with rituximab (375 mg/m(2) body surface area) alone or with chemotherapy were included. Adverse reactions were graded according to the National Cancer Institute scale, whereas causality was established using the Naranjo algorithm. Infusions were classified as fast (0-90 min) and slow (>91 min). Fast infusions were used to analyze the associated adverse reactions.nnnRESULTSnWe included 550 adult patients. Total infusion episodes were 1,749 and 52 adverse reactions were reported in 22 patients (4%). Thirty-one of 52 adverse reactions occurred during the first infusion. The risk of adverse reactions was lower with the fast infusions (10/52 adverse reactions [19.23%]). All adverse effects were mild. Twenty-three adverse effects were possibly related to rituximab.nnnCONCLUSIONSnRituximab can be infused at a fast rate without an increase in adverse reactions. Peri-infusional adverse reactions are similar to those described for other populations but the incidence rate is lower. Rituximab has a favorable safety profile in patients with non-Hodgkins lymphoma.

Volume Transmission and Pain Perception

Volume transmission (VT) is the diffusion through the brain extracellular fluid of neurotransmitters released at points that may be remote from the target cells with the resulting activation of extrasynaptic receptors. VT appears to play multiple roles in the brain in normal and abnormal activity, brain plasticity and drug actions. The relevance of VT to pain perception has been explored in this review.