Anti-infliximab antibodies are already detectable in most patients with rheumatoid arthritis halfway through an infusioncycle: an open-label pharmacokinetic cohort study

Contains fulltext : 97636.pdf (publisher's version ) (Open Access)BACKGROUND: This study in patients with rheumatoid arthritis (RA) treated with infliximab describes prospectively the course of (anti)infliximab levels within an infusioncycle to assess at what moment patients develop low/no infliximab trough levels and/or detectable anti-infliximab levels. METHODS: Infliximab treated RA patients were included in this descriptive open-label cohort study. During one infusioncycle (anti-)infliximab levels were assessed just before and one hour after infusion, and subsequently at 50%, 75% and at the end of the infusioncycle (pre-infusion). RESULTS: 27 patients were included. The median infliximab levels decreased from 77.0 mg/l (p25-p75: 65-89) one hour after the infusion to pre-infusion levels of 0.0 mg/l (p25-p75: 0.0-3.1). In 7 (26%) patients pre-infusion anti-infliximab antibodies were detected; these antibodies were already present halfway through the infusioncycle in 5 of the 7 individuals. Patients with detectable pre-infusion anti-infliximab antibodies have significantly more often low/no infliximab levels (< 1 mg/l) halfway trough the infusioncycle (in 5/7 patients) compared to patients without detectable pre-infusion anti-infliximab antibodies (0/20 patients, p < 0.001). CONCLUSIONS: Most anti-infliximab forming patients have detectable anti-infliximab antibodies halfway through an infusioncycle, which implies that these patients are exposed to nontherapeutical infliximab levels during more than halve of their infusion cycle. As none of the patients without anti-infliximab antibodies had no/low-infliximab levels halfway through the infusioncycle, the presence of pre-infusion anti-infliximab antibodies seems a sensitive and specific predictor for no/low infliximab-levels

Requirements for generic anti-epileptic medicines: a regulatory perspective

Contains fulltext : 81660.pdf (publisher's version ) (Closed access

Evaluation of antiretroviral drug measurements by an interlaboratory quality control program.

Item does not contain fulltextSince 1999 an ongoing international interlaboratory quality control program has analyzed antiretroviral drugs in plasma. Results of the third round of this program are presented. Quality control samples were prepared by spiking drug-free plasma with varying concentrations of the currently available protease inhibitors and the nonnucleoside reverse transcriptase inhibitors efavirenz and nevirapine. Thirty-three laboratories participated in the program and were requested to analyze the quality control samples. Results were from 30 laboratories. Of all measurements, 82% were performed within 80%-120% accuracy limits. Only 3 laboratories performed all their measurements within these limits, and 12 participants reported at least 90% of their analyses within the acceptance range. Mean accuracy for low drug concentrations was worse than for medium and high concentrations. The percentage of satisfactory measurements for the 6 laboratories that participated for the third time in the program increased from 54% in the first round to 85% in the third round. The program revealed a large variability in the laboratories' ability to measure antiretroviral drugs accurately. This variability may have important implications for therapeutic drug monitoring of these drugs and for pharmacokinetic studies. Interlaboratory testing is useful to alert laboratories to previously undetected analytical problems

Switching to generic anti-epileptic medicines:A regulatory perspective

Introduction: Currently, there is a lot of discussion about whether generic substitution of anti-epileptic drugs (AEDs) with the same active moiety but from different manufacturers can take place safely. Many AEDs are considered to have a narrow therapeutic index, and the consequences of an epileptic attack are severe, in a physical, psychological and social respect. Therefore, there is ample ground to look critically at generic substitution of anti-epileptic medicines. In this context, the Dutch regulatory agency evaluated the exposureof generic AEDs and the occurrence of epilepsy related events. Methods: Reports received by the Dutch Pharmacovigilance Centre Lareb were screened for issues related to generic substitution of AEDs. Public literature dealing with generic substitution of AEDs was reviewed and checked for potential pharmacological issues related to generic substitution of AEDs. Finally, the exposures upon changing between different topiramate and gabapentin generics was evaluated based on internal bioequivalence data. Results: In only 26 of in total 2,103 reports in the Lareb database mentioning an AED as the suspected drug, a possible relationship was indicated with the substitution from a branded AED to a generic one. However, these data should be treated with care, since underreporting is a well-known phenomenon. The majority of publications on generic substitution of AEDs concerned potential instead of actual cases, with many publications based on surveys regarding prescribers' overall experience with switching. Potential issues raised in these publications relate to bioequivalence requirements, use of healthy volunteers instead of patients, variability in exposure, problems with medicine supply, and costs of adverse events. Overall, with very few exceptions, no differences in exposure upon generic substitution of AEDs were actually reported. Generic-generic substitution was also indicated as a potential problem. However, our investigations on topiramate and gabapentin generic-generic substitution indicated that this does not result in significant differences in exposure. Estimated ratios of AUC and Cmax upon substituting generics ranged from 94.1-113.1% and 91.2-103.1% for topiramate and from 95.6-114.9% and 92.5 111.5% for gabapentin, respectively. Conclusion: Overall, no evidence was found for a causal pharmacological relationship between switching to or between generic AEDs and the occurrence of epilepsy-related adverse events. Based on the strict requirements on generics, pharmacological differences between innovator and generic AEDs are considered unlikely, and have indeed hardly been reported. Alternative explanations for increased susceptibility to seizures with generic AEDs may be envisioned, like e.g., new or withdrawn co-medication, compliance, frequent switching, and differences in shape and colour of generics

Reporting Format for Economic Evaluation: Part I: Application to the Dutch Healthcare System

This article presents the first version of the reporting format for economic valuation that was created in 1995 by a multidisciplinary taskforce. The members of this taskforce come from a broad spectrum of backgrounds within the healthcare field and participated in the exercise voluntarily. The format presented should be understood as the preferred Dutch structure for the reporting of any study on economic evaluation. In view of the many areas of contention that exist within the field, this format only gives normative directions in those areas in which consensus exists, as evidenced by the current published international guidelines. A regular review and adaptation of this format will be needed to reflect advances in the field.Pharmacoeconomics, Health-economics, Clinical-trial-design, Data-collection

Influence of chemical structure on hypersensitivity reactions induced by antiepileptic drugs:the role of the aromatic ring

OBJECTIVE: Antiepileptic drugs (AEDs) can cause various 'idiosyncratic' hypersensitivity reactions, i.e. the mechanism by which AEDs induce hypersensitivity is unknown. The aim of this study was to assess whether the presence of an aromatic ring as a commonality in chemical structures of AEDs can explain symptoms of hypersensitivity. METHODS: Between January 1985 and January 2007, all adverse drug reactions (ADRs) reported to the Netherlands Pharmacovigilance Centre Lareb related to AEDs as suspected drugs were included in this study. ADRs were analysed using a case/non-case design. Cases were defined as those patients with ADRs involving symptoms of hypersensitivity. Non-cases were patients with all other ADR reports. Symptoms of hypersensitivity were classified according to the Gell and Coombs classification (type I-IV) and the organ involved (e.g. cutaneous, hepatic). AEDs were classified as aromatic anticonvulsant if their chemical structure contained at least one aromatic ring. All other AEDs were classified as non-aromatic. We assessed the strength of the association between aromatic AEDs versus non-aromatic AEDs and reported hypersensitivity reactions with logistic regression analysis and expressed these as reporting odds ratios (RORs). RESULTS: In total, 303 cases of hypersensitivity associated with the use of AEDs were reported. Aromatic AEDs were suspected in 64.4% of these reports versus 41.3% (574/1389) of the non-hypersensitivity reports. A significant ROR of 2.15 (95% CI 1.63, 2.82) was found for aromatic AEDs and all hypersensitivity reactions. Aromatic AEDs were significantly associated with immunoglobin E-mediated type I hypersensitivity reactions (ROR 2.15; 95% CI 1.23, 3.78) and T-cell-mediated type IV reactions (ROR 6.06; 95% CI 3.41, 10.75). Type II and III reactions did not show an association. Cutaneous symptoms represented 39.9% of the hypersensitivity-related ADRs. Aromatic AEDs were significantly associated with cutaneous hypersensitivity reactions (ROR 5.81; 95% CI 3.38, 9.99). CONCLUSION: This study confirms that the presence of an aromatic ring as a common feature in chemical structures of AEDs partly explains apparent 'idiosyncratic' hypersensitivity reactions. Symptoms of hypersensitivity were reported twice as frequently with aromatic AEDs than with non-aromatic AEDs. Strong associations for aromatic AEDs versus non-aromatic AEDs were found for T-cell-mediated (type IV) reactions, as well as for cutaneous reactions