AIMSTo characterize the potential effect of daclizumab high-yield process (DAC HYP), a monoclonal antibody that blocks the highaffinity interleukin-2 receptors for treatment of multiple sclerosis, on activity of cytochrome P450 (CYP) enzymes. METHODSTwenty patients with multiple sclerosis received an oral cocktail of probe substrates of CYP1A2 (caffeine 200 mg), CYP2C9 (warfarin 10 mg/vitamin K 10 mg), CYP2C19 (omeprazole 40 mg), CYP2D6 (dextromethorphan 30 mg) and CYP3A (midazolam 5 mg) on two sequential occasions: 7 days before and 7 days after subcutaneous administration of DAC HYP 150 mg every 4 weeks for three doses. Serial pharmacokinetic blood samples up to 96 h post dose and 12-h urine samples were collected on both occasions. Area under the curve (AUC) for caffeine, S-warfarin, omeprazole and midazolam, and urine dextromethorphan to dextrorphan ratio were calculated. Statistical analyses were conducted on log-transformed parameters using a linear mixedeffects model. RESULTSThe 90% confidence intervals (CIs) for the geometric mean ratio (probe substrate with DAC HYP/probe substrate alone) for caffeine AUC from 0-12 h (0.93-1.15), S-warfarin AUC from 0 to infinity (AUC[0-inf]) (0.95-1.06), omeprazole AUC(0-inf) (0.88-1.13) and midazolam AUC(0-inf) (0.89-1.15) were within the no-effect boundary of 0.80-1.25. The geometric mean ratio for urine dextromethorphan to dextrorphan ratio was 1.01, with the 90% CI (0.76-1.34) extending slightly outside the no-effect boundary, likely due to high variability with urine collections and CYP2D6 activity. CONCLUSIONSDAC HYP treatment in patients with multiple sclerosis had no effect on CYP 1A2, 2C9, 2C19, 2D6 and 3A activity. British Journal of Clinical Pharmacology WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Therapeutic proteins that modulate cytokine activities can indirectly influence expression of cytochrome P450 (CYP) isoenzymes by affecting cytokine concentrations, and consequently may alter CYP-mediated metabolism of small molecule drugs when given in combination. Interleukin-2 (IL-2) and its modulators have been implicated in CYP-mediated drug interactions.• Daclizumab high-yield process (HYP) is a humanized monoclonal antibody that selectively blocks the alpha subunit (CD25) of the high-affinity IL-2 receptors and is being developed for treatment of multiple sclerosis.• Daclizumab HYP treatment increases systemic IL-2 levels. WHAT THIS STUDY ADDS• The study demonstrates that repeated administration of daclizumab HYP to patients with multiple sclerosis has no effect on the metabolic activity of the evaluated CYP enzymes.• Results provide important clinical information on impact of cytokine modulators on CYP activities, contributing to the clinical database to guide future recommendation on therapeutic protein-drug interaction assessment.

BackgroundDaclizumab high-yield process (DAC HYP), a humanized immunoglobulin G1 monoclonal antibody specific for the α subunit (CD25) of the high-affinity interleukin-2 receptor, has demonstrated efficacy for treatment of relapsing forms of multiple sclerosis in Phase II and III clinical trials.ObjectiveTo characterize the pharmacokinetics (PK) of DAC HYP following repeated administration of the 150 mg subcutaneous (SC) dose every 4 weeks (q4wk), the proposed clinical regimen in patients with relapsing-remitting multiple sclerosis (RRMS).MethodsTwenty-six patients with RRMS received DAC HYP 150 mg SC q4wk for a total of six doses. Serial PK blood samples were collected over the first and last dosing intervals and trough PK samples were collected between these doses. Blood samples for immunogenicity assessment were collected throughout the study. Serum DAC HYP levels and anti-DAC HYP antibodies were characterized using validated immunoassays. PK parameters were estimated using noncompartmental analysis.ResultsDAC HYP showed slow SC absorption with a median time to reach maximum observed concentration (Cmax) value of ~1 week. Steady state was reached by the fourth injection. At steady state, DAC HYP mean serum Cmax, minimum observed concentration (Cmin), and area under the concentration–time curve within a dosing interval (AUCtau) values were 29.1 µg/mL, 14.9 µg/mL, and 638 µg · day/mL, respectively, with intersubject variability of 35%–40%. The AUC accumulation ratio was ~2.5 at steady state. DAC HYP had a long elimination half-life of ~22 days and low apparent clearance (0.274 L/day). Nine patients tested positive for anti-DAC HYP antibodies, with no impact on DAC HYP clearance in this limited data set.ConclusionThe PK of DAC HYP in patients with RRMS are consistent with those previously reported in healthy volunteers. The half-life of ~3 weeks and the low fluctuations in peak and trough concentrations of serum DAC HYP support the once-monthly SC dosing regimen.

A study has been conducted in general practice comparing two brands of lozenges, Merocaine (Merrell) and Tyrozets, (M.S.D.), in the management of acute sore throat and pharyngitis. Eighty-eight patients entered the between-patient study and each completed a diary card covering symptoms experienced and dosage used for each of the two drugs. The doctor reported upon the appearance of the throat and added antibiotics in cases of necessity, which was approximately for one-third of patients. Merocaine proved to be significantly superior to Tyrozets in producing rapid pain relief (within 15 minutes) and reduction of faucial and pharyngeal injection.

Forty patients in general practice with rheumatoid arthritis or osteoarthritis were identified as suffering from moderate pain and tenderness and moderate stiffness in excess of 30 minutes. After discontinuation of non-steroidal anti-inflammatory drugs for 2 weeks, a crossover study was conducted comparing the benefits of flufenamic acid, 100 mg, four times daily with placebo. At the same time, paracetamol at a dose up to 8 x 500 mg daily, could be used for pain which the patient judged to be unrelieved. Thirty-four patients completed the two 3-week test periods and twenty-one patients were improved in relation to morning stiffness and pain by flufenamic acid and twelve patients by placebo--a difference greater than would have occurred by chance (p = 0.05). At the same time, paracetamol consumption was reduced significantly fron a mean of 91.29 tablets to 60.68 tablets for each 3-week period. Side-effects occurred in ten patients on placebo and fifteen patients on flufenamic acid. One patient on each medication had to discontinue for multiple side-effects. Diarrhoea occurred in two patients on flufenamic acid and in one patient on placebo. Flufenamic acid is clearly effective and side-effects do not occur more often than would be expected by chance when compared with placebo.

A double-blind study of terfenadine and placebo in 110 patients suffering from hay fever (confirmed by skin tests) was conducted. A novel technique was applied using an escape envelope containing a reference drug which could be taken under controlled conditions if, after 48 hours, the patient experienced no relief. Significantly more patients on placebo opened the envelope than patients taking the active drug. Terfenadine was demonstrated to be an effective drug in hay fever and produced no more drowsiness than placebo.