Bernard Bannwarth

Clinical Pharmacokinetics of Low-Dose Pulse Methotrexate in Rheumatoid Arthritis

SummaryLow-dose pulse methotrexate has emerged as one of the most frequently used slow-acting, symptom-modifying antirheumatic drugs in patients with rheumatoid arthritis (RA) because of its favourable risk-benefit profile.Methotrexate is a weak bicarboxylic acid structurally related to folic acid. The most widely used methods for the analysis of methotrexate are immunoassays, particularly fluorescence polarisation immunoassay. After oral administration, the drug is rapidly but incompletely absorbed. Since food does not significantly affect the bioavailability of oral methotrexate in adult patients, the drug may be taken regardless of meals. There is a marked interindividual variability in the extent of absorption of oral methotrexate. Conversely, the intraindividual variability is moderate even over a long time period. Intramuscular and subcutaneous injections of methotrexate result in comparable pharmacokinetics, suggesting that these routes of administration are interchangeable.A mean protein binding to serum albumin of 42 to 57% is usually reported. Again, the unbound fraction exhibits a large interindividual variability. The steady-state volume of distribution is approximately 1 L/kg. Methotrexate distributes to extravascular compartments, including synovial fluid, and to different tissues, especially kidney, liver and joint tissues. Finally, the drug is transported into cells, mainly by a carrier-mediated active transport process.Methotrexate is partly oxidised by hepatic aldehyde oxidase to 7-hydroxy-methotrexate. This main, circulating metabolite is over 90% bound to serum albumin. Both methotrexate and 7-hydroxy-methotrexate may be converted to polyglutamyl derivatives which are selectively retained in cells. Methotrexate is mainly excreted by the kidney as intact drug regardless of the route of administration. The drug is filtered by the glomeruli, and then undergoes both secretion and reabsorption processes within the tubule. These processes are differentially saturable, resulting in possible nonlinear elimination pharmacokinetics. The usually reported mean values for the elimination half-life and the total body clearance of methotrexate are 5 to 8 hours and 4.8 to 7.8 L/h, respectively. A positive correlation between methotrexate clearance and creatinine clearance has been found by some authors.Finally, the pharmacokinetics of low-dose methotrexate appears to be highly variable and largely unpredictable even in patients with normal renal and hepatic function. Furthermore, studies in patients with juvenile rheumatoid arthritis provide evidence of age-dependent pharmacokinetics of the drug. These features must be considered when judging the individual clinical response to methotrexate therapy.Various drugs currently used in RA may interact with methotrexate. Aspirin might affect methotrexate disposition to a greater extent than other nonsteroidal anti-inflammatory drugs without causing greater toxicity. Corticosteroids do not interfere with the pharmacokinetics of methotrexate, whereas chloroquine may reduce the gastrointestinal absorption of the drug. Folates, especially folic acid, have been shown to reduce the adverse effects of methotrexate without compromising its efficacy in RA. Finally, both trimethoprim-sulfamethoxazole (cotrimoxazole) and probenecid lead to increased toxicity of methotrexate, and hence should be avoided in patients receiving these drugs.A relationship between oral dosage and efficacy has been found in the range 5 to 20mg methotrexate weekly. The plateau of efficacy is attained at approximately 10 mg/m2/week in most patients. No clear relationship between pharmacokinetic parameters and clinical response has been demonstrated. Overall, the dosage must be individualised because of interindividual variability in the dose-response curve. This variability is probably related, at least in part, to the wide interindividual variability in the disposition of the drug.

Fibromyalgia syndrome in the general population of France: A prevalence study

OBJECTIVEnTo estimate the prevalence of fibromyalgia (FM) syndrome in the French general population.nnnMETHODSnA validated French version of the London Fibromyalgia Epidemiology Study Screening Questionnaire (LFESSQ) was administered via telephone to a representative community sample of 1014 subjects aged over 15 years, selected by the quota method. A positive screen was defined as: (1) meeting the 4-pain criteria alone (LFESSQ-4), or (2) meeting both the 4-pain and 2-fatigue criteria (LFESSQ-6). To estimate the positive predictive value of LFESSQ-4 and LFESSQ-6, this questionnaire was submitted to a sample of rheumatology outpatients (n=178), who were then examined by a trained rheumatologist to confirm or exclude the diagnosis of FM according to the 1990 American College of Rheumatology criteria. The prevalence of FM in the general population was estimated by applying the predictive positive value to eligible community subjects (i.e., positive screens).nnnRESULTSnIn the community sample, 9.8% and 5.0% screened positive for LFESSQ-4 and LFESSQ-6, respectively. Among rheumatology outpatients, 47.1% screened positive for LFESSQ-4 and 34.8% for LFESSQ-6 whereas 10.6% were confirmed FM cases. Based on positive screens for LFESSQ-4, the prevalence of FM was estimated at 2.2% (95% CI 1.3-3.1) in the French general population. The corresponding figure was 1.4 % (95% CI 0.7-2.1) if positive screens for LFESSQ-6 were considered.nnnCONCLUSIONnOur findings suggest that FM is also a major cause of widespread pain in France since a point prevalence of 1.4% would translate in approximately 680,000 patients.

Targeting Nerve Growth Factor (NGF) for Pain Management: What Does the Future Hold for NGF Antagonists?

It is unanimously accepted that there is an unmet need for pain medications that are both effective and safe. Unfortunately, no really novel analgesics have been approved over the past three decades. In view of both experimental and clinical evidence of a major role for nerve growth factor (NGF) in the generation and maintenance of a wide range of pain states, drug discovery efforts focusing on the development of anti-NGF agents have aroused particular interest. Several humanized anti-NGF monoclonal antibodies (mAbs) have entered clinical trials as potential analgesics. In this respect, tanezumab is at an advanced stage of clinical development while fulranumab, fasinumab and ABT-110, previously known as PG110, are in early phases of clinical development. This Current Opinion article aims at describing the rationale for targeting NGF for pain, reviewing the analgesic efficacy and safety of anti-NGF agents based on data from fully published studies, conference abstracts, and the US Food and Drug Administration (FDA) website, and discussing the possible future of these agents in managing chronic pain. Anti-NGF mAbs produced significant pain relief and functional improvement in patients with osteoarthritis of the knee and/or hip. Conversely, studies in non-specific lower back pain generated mixed results; overall, this condition appeared to be less responsive to anti-NGF agents than osteoarthritis. Finally, there was no conclusive evidence of the effectiveness of anti-NGF mAbs in some types of chronic visceral or neuropathic pain. Furthermore, these studies raised safety concerns about anti-NGF mAbs. As a class, these drugs may cause or worsen peripheral neuropathies. But the most problematic issue—which prompted the FDA to place studies of these compounds on clinical hold in 2010—was rapid joint destruction leading to joint replacement surgery. The aetiologies of these side effects have been much debated and their pathophysiology is poorly understood. After an Arthritis Advisory Committee meeting held in March 2012, pharmaceutical companies negotiated with the FDA on the conditions for restarting clinical studies. Although the FDA lifted its clinical hold, there remain many unresolved issues about the long-term efficacy and safety of anti-NGF mAbs. While acknowledging that the future of these drugs is unforeseeable, it appears that they may not be the safe and effective painkillers that have been awaited for decades.

EULAR recommendations for the management of knee osteoarthritis. Report of a task force of the Standing Committee for International Clinical Studies Including Therapeutic Trials.

UNLABELLEDnA task force for the EULAR standing committee for clinical trials determined the methodological and logistical approach required for the development of evidence-based guidelines for treatment of knee osteoarthirits (OA).nnnMETHODSnThe first stage was the selection of treatment modalities to be considered. The second stage comprised a search of the databases of all European-language publications. All of the relevant studies were quality scored. The third stage involved determination of key clinical propositions by expert consensus employing a Delphi approach. The final stage involved ranking of these propositions according to the available evidence. A second set of propositions relating to a future research agenda was determined by expert consensus.nnnRESULTSnSeven hundred and forty-four studies presented outcome data of the effects of specific treatments on knee OA. Quantitative analysis of treatment effect was possible in only 61 studies. Recommendations for the management of knee OA based on currently available data and expert opinion are presented. Proposals for a future research agenda are highlighted.nnnCONCLUSIONSnThese are the first clinical guidelines on knee OA to combine an evidence-based approach and a consensus approach across a wide range of treatment modalities. It is apparent that only certain clinical propositions are supported by substantial research-based evidence. There is thus an urgent need for future well-designed trials to address key clinical questions.

Relationship between lipophilicity and binding to human serum albumin of arylpropionic acid non-steroidal anti-inflammatory drugs

A possible relationship between lipophilicity and binding to human serum albumin was investigated for 11 arylpropionate non-steroidal anti-inflammatory drugs. The lipophilic parameter was determined by a reversed-phase high-performance liquid chromatographic procedure as the capacity factor (k). The binding of arylpropionic acids to human serum albumin was studied in vitro by equilibrium dialysis. For each compound, a Scatchard analysis was performed considering two classes of binding sites characterized by high- and low-affinity constants, K1 and K2, respectively. A linear relationship was found between lipophilicity and binding parameters, n1K1 (r = 0.88, P < 0.0005) and n2K2 (r = 0.96, P < 0.0002). These results suggest the role of hydrophobic interactions in the binding of arylpropionic acids to human serum albumin.

Simultaneous Measurement of Flurbiprofen, Ibuprofen, and Ketoprofen Enantiomer Concentrations in Plasma Using L-Leucinamide as the Chiral Coupling Component

Abstract A high performance liquid chromatographic method was developed for the quantitation of the R- and S- enantiomers of 2-arylpropionic acid namely flurbiprofen, ibuprofen and ketoprofen, in plasma. The procedure involved extraction of drugs and internal standard from acidified plasma into dichloromethane. After evaporation of the organic layer, the compounds were derivatized with L-leucinamide after addition of ethyl chloroformate as the coupling reagent. The former diastereoisomeric amides were chromatographied at ambient temperature on a reversed phase column using 0.06M KH2PO4–acetonitrile–triethylemine (51:49:0.1) as the mobile phase pumped at a flow rate of 1.8 ml/min. This assay allowed determination of 0.1μg/ml of both R- and S- enantiomers with an acceptable precision (maximum coefficient of variation of 7.5%) using a 0.5-ml plasma sample.

The determination of bromazepam in plasma by reversed-phase high-performance liquid chromatography

A reversed-phase high-performance liquid chromatographic method has been developed for the determination of bromazepam, an anxiolytic benzodiazepine, in plasma. After a single-step extraction from alkalinized plasma with diethyl-ether in the presence of an internal standard (alpha-hydroxy-triazolam), the residues were chromatographed on a reversed-phase Nova Pak 5 microns C18 column, with a mobile phase of acetonitrile-water-triethylamine (700:300:4, v/v/v) adjusted to pH 7.4 with orthophosphoric acid. The limit of detection was 50 ng ml-1, using a 20 microliters injection with UV detection at 240 nm. Between-day and within-day relative standard deviations were lower than 6%. Studies of drug stability during sample storage at -20 degrees C and at +4 degrees C showed no degradation of bromazepam. However, bromazepam seemed to be degraded at ambient temperature, without any influence of light. This method is applied to the determination of bromazepam plasma levels in analytical toxicology.

Study of the lipophilicity of arylpropionic non-steroidal anti-inflammatory drugs. A comparison between LC retention data on a polymer-based column and octanol-water partition coefficients

Molecular lipophilicity can be expressed by log Pow or, more conveniently, by log kw, i.e., determined by the traditional shake-flask technique, or by reversed-phase high performance liquid chromatography (RP-HPLC). Moreover, the unionized form of solutes is usually taken as the reference state for the measurement of lipophilicity. This can be problematic for the RP-HPLC determination of lipophilicity of acidic compounds due to the limited pH operating range of silica bonded phases. The measured dissociation constant values (pKa) of the twelve arylpropionic non steroidal antiinflammatory drugs (NSAIDs) are comprised between 3.80 and 5.70; consequently, the lipophilicities of the unionized forms must be measured at pH below 2. Accordingly, their capacity factors (log kw) were determined on a column packed with a hydrophilic polymethacrylate gel having octadecyl groups. This RP-column allows separations at low pH values of the mobile phase. In practice, the values of log kw are obtained by a series of isocratic measurements at various compositions of binary acetonitrile-water eluents and extrapolation of the relationship between log k and volume fraction of organic solvent, φ, to 100% water. The 1-octanol-water partition coefficients (log Pow) of these NSAIDs were determined by the shake-flask technique using a conventional methodology. A significant linear relationship was obtained between log Pow and log kw with a slope close to unity, indicating similar intrinsic thermodynamic behaviour of these drugs for the two partitioning processes. This excellent correlation prompted us to validate this polymer-based column, to be useful for the determination of other acidic drug lipophilicity.

A pharmacokinetic and clinical assessment of tofacitinib for the treatment of rheumatoid arthritis

Introduction: Rheumatoid arthritis (RA) is a chronic painful and debilitating autoimmune disease. Although the outcome for patients with RA has improved markedly in the past decades, driven largely by the advent of biological disease-modifying antirheumatic drugs (DMARDs) and updated management strategies, adequate disease control cannot be achieved in a substantial proportion of patients. Since RA is a syndrome with different biological subsets, DMARDs, with a novel mechanism of action, may represent a valuable addition to the current armamentarium. Tofacitinib is a novel synthetic DMARD that selectively inhibits Janus kinases (JAKs), particularly JAK1 and JAK3. Areas covered: This review describes the pharmacokinetics of tofacitinib. Furthermore, the article summarizes and comments the drugs efficacy and safety profile in RA patients. The authors furthermore assess data derived from the FDAs RA development program. Expert opinion: Tofacitinib is an oral synthetic DMARD displaying linear pharmacokinetics. Metabolism, primarily mediated by CYP3A4, accounts for 70% of the total clearance of the drug; the remaining 30% are renally excreted. Tofacitinib monotherapy, or in combination with traditional DMARDs, has demonstrated its efficacy while having an acceptable safety profile in RA patients who have responded inadequately to current DMARDs, including TNF antagonists. In view of its undetermined benefit to risk ratio, in the real-world population, tofacitinib should, for now, only be prescribed to selected patients.

Determination of flunitrazepam in plasma by liquid chromatography

A reversed-phase liquid chromatographic method has been used to determine flunitrazepam in plasma. Extraction was simple and there was no need to hydrolyse the drug. Separation was achieved on a 150 x 3.9 mm i.d. column packed with 4-microns Nova Pack C18 using a mobile phase of water-acetonitrile-triethylamine (700:300:4, v/v/v) (adjusted to pH 7.5 with orthophosphoric acid). The method was shown to be rapid and reliable with a lower limit of detection of 5 ng ml-1. Results are reported of simple experiments on the effects of temperature and light on the stability of flunitrazepam in plasma kept on the laboratory bench.