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Therapeutic protein-drug interaction assessment for daclizumab high-yield process in patients with multiple sclerosis using a cocktail approach.
Tran, JQ, Othman, AA, Wolstencroft, P, Elkins, J
British journal of clinical pharmacology. 2016;(1):160-7
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Abstract
AIMS: To characterize the potential effect of daclizumab high-yield process (DAC HYP), a monoclonal antibody that blocks the high-affinity interleukin-2 receptors for treatment of multiple sclerosis, on activity of cytochrome P450 (CYP) enzymes. METHODS Twenty 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 mixed-effects model. RESULTS The 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. CONCLUSIONS DAC HYP treatment in patients with multiple sclerosis had no effect on CYP 1A2, 2C9, 2C19, 2D6 and 3A activity.
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Positive association of vitamin D receptor gene variations with multiple sclerosis in South East Iranian population.
Narooie-Nejad, M, Moossavi, M, Torkamanzehi, A, Moghtaderi, A
BioMed research international. 2015;:427519
Abstract
Among the factors postulated to play a role in MS susceptibility, the role of vitamin D is outstanding. Since the function of vitamin D receptor (VDR) represents the effect of vitamin D on the body and genetic variations in VDR gene may affect its function, we aim to highlight the association of two VDR gene polymorphisms with MS susceptibility. In current study, we recruited 113 MS patients and 122 healthy controls. TaqI (rs731236) and ApaI (rs7975232) genetic variations in these two groups were evaluated using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. All genotype and allele frequencies in both variations showed association with the disease status. However, to find the definite connection between genetic variations in VDR gene and MS disease in a population of South East of Iran, more researches on gene structure and its function with regard to patients' conditions are required.
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Polyphenon E, non-futile at neuroprotection in multiple sclerosis but unpredictably hepatotoxic: Phase I single group and phase II randomized placebo-controlled studies.
Lovera, J, Ramos, A, Devier, D, Garrison, V, Kovner, B, Reza, T, Koop, D, Rooney, W, Foundas, A, Bourdette, D
Journal of the neurological sciences. 2015;(1-2):46-52
Abstract
OBJECTIVES Phase I (PhI): assess the safety of Polyphenon E in people with multiple sclerosis (MS) and determine the futility of Polyphenon E as a neuroprotective agent. Correlate plasma levels of EGCG with neuroprotective effects. Phase II (PhII): Further assess safety and confirm the neuroprotective effects of Polyphenon E. DESIGN PhI: single group futility study. PhII: parallel group randomized double-blind placebo-controlled study. PARTICIPANTS Recruitment area (both studies): LSU MS Center, New Orleans, LA and general public from surrounding areas. Inclusion criteria (both studies): 1) MS per 2005 McDonald criteria; 2) relapsing remitting or secondary progressive MS; 3) stable for six months prior to enrollment on either no therapy or glatiramer acetate (GA) for the PhI study and on either on GA or Interferon β for the PhII study. Exclusion criteria (both studies): 1) complete bone marrow ablation or alentuzumab use at any time; 2) mitoxantrone, cyclophosphamide, natalizumab or fingolimod use in the prior nine months; 3) liver problems or significant medical problems. INTERVENTIONS PhI: Polyphenon E, a green tea extract containing 50% of the antioxidant Epigallocatechin-gallate (EGCG), two capsules twice daily (200mg of EGCG per capsule; total daily dose 800mg) for six months. PhII: Polyphenon E or matching placebo capsules, same dose for one year. Only the research pharmacist knew treatment assignment and she randomized participants (one-to-one, stratified by GA or Interferon β, blocks of 4 or 6). Outcome evaluators did not discuss side effects with participants. OUTCOME MEASURES PhI: 1) adverse events (AE); 2) futility: decrease in N-acetyl aspartate (NAA) from baseline to six months of 10% or more; 3) association between EGCG plasma levels and change in NAA. PhII: 1) AEs; 2) difference in the rate of change of NAA-levels over twelve months.We measured NAA using a point resolved magnetic resonance spectroscopic imaging sequence (TE30/TR2000) on a 10cm×10cm×1cm volume of interest (VOI) located just superior to the lateral ventricles. The field of view was 16×16 resulting in 1cm(3) voxels. We quantified NAA and creatine/phosphocreatine (Cr) levels using LCModel for post-processing. RESULTS PhI: Ten participants enrolled and completed all assessments with no serious AEs. One discontinued therapy due to grade (G) I abnormal liver function tests (LFTs). We included all participants in the analysis. NAA adjusted for creatine increased by 10% [95% CI(3.4%,16.2%), p<0.01] rejecting the futility endpoint. PhII: Thirteen participants enrolled and twelve started treatment. The DSMB stopped the study because 5/7 participants on Polyphenon E had abnormal LFTs (G I, and 1G III). Median time to onset of abnormal LFTs was 20 weeks [Inter-Quartile Range (IQR) (10,23)]. Only two participants completed the six-month visit, so we could not analyze the NAA levels. PhI participants took capsules from lot 189I1107 while 6/7 PhII participants took capsules from a new lot (L0206306). Both lots had similar levels of EGCG but differed in the levels of minor catechins. There were no significant differences between the lots on participants' median free EGCG plasma levels at either 3h or 8h as well as conjugated EGCG levels at 3h (all p>0.4, Wilcoxon exact test). Free EGCG levels at 8h correlated with changes in NAA adjusted by water content. A 1ng/ml higher EGCG plasma concentration correlated with a 0.9% increase in NAA[95% CI(0.5%,1.4%), visit*level interaction F=14.4, p<0.001]. However, EGCG plasma concentrations did not correlate with NAA adjusted by creatine (1ng/ml higher EGCG was associated with 0.02%,[95% CI(-0.27%,0.3%) change in NAA, p>0.5]). There was a trend towards an increase in creatine levels (referenced to water content) from baseline to exit (1 5% increase, [95% CI(-6%,17%), p=0.4]). The free EGCG levels at 8hours correlated significantly with change in creatine levels (1ng/ml higher EGCG level at 8h was associated with a 1.1% increase in creatine [95% CI(0.6%,1.6%)]). Thus it is possible that the discrepancy between the correlation of the EGCG 8h levels with NAA changes referenced to water and the 8h EGCG levels with NAA changes referenced to creatine was due to a change in creatine among the subjects with higher EGCG levels. Conjugated 3h and 8h levels and free 3h levels did not correlate with NAA changes (all p >0.5). CONCLUSIONS/CLASSIFICATION OF EVIDENCE Class III evidence: Polyphenon E at a dose of 400mg of EGCG twice a day is not futile at increasing brain NAA levels. Class I evidence: some lots of Polyphenon E have a high risk of hepatotoxicity. FUNDING National Center for Complementary and Alternative Medicine K23AT004433, National Multiple Sclerosis Society RG4816-A-1 and National Institute of General Medical Sciences 1 U54 GM104940. Mitsui Norin provided Polyphenon E and placebo and their representative reviewed the manuscript prior to publication. Mitsui Norin was not involved in other aspects of the study. The decision to submit the manuscript remained with the investigators. REGISTRATION NCT00836719 and NCT01451723
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Subcutaneous interferon Beta-1a in pediatric multiple sclerosis: a retrospective study.
Tenembaum, SN, Banwell, B, Pohl, D, Krupp, LB, Boyko, A, Meinel, M, Lehr, L, Rocak, S, Cantogno, EV, Moraga, MS, et al
Journal of child neurology. 2013;(7):849-56
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Abstract
To expand current knowledge, we examined the safety and tolerability of subcutaneous interferon β-1a in patients with pediatric-onset multiple sclerosis. Records from 307 patients who had received at least 1 injection of subcutaneous interferon β-1a for demyelinating events when aged younger than 18 years were reviewed. Overall, 168 (54.7%) patients had at least 1 prespecified medical event related to or under close monitoring with subcutaneous interferon β-1a or specific to pediatric patients, 184 (59.9%) had nonserious medical events related to treatment or of unknown causality, and 12 (3.9%) had serious medical events irrespective of causality. The most common laboratory abnormalities were increased alanine (74/195; 37.9%) and aspartate aminotransferase levels (59/194; 30.4%). Annualized relapse rates were 1.79 before treatment and 0.47 during treatment. In conclusion, adult doses of subcutaneous interferon β-1a (44 and 22 μg, 3 times weekly) were well tolerated in pediatric patients and were associated with reduced relapse rates.
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Diffusion tensor imaging of the optic nerve in multiple sclerosis: association with retinal damage and visual disability.
Smith, SA, Williams, ZR, Ratchford, JN, Newsome, SD, Farrell, SK, Farrell, JA, Gifford, A, Miller, NR, van Zijl, PC, Calabresi, PA, et al
AJNR. American journal of neuroradiology. 2011;(9):1662-8
Abstract
BACKGROUND AND PURPOSE There is a well-known relationship between MS and damage to the optic nerve, but advanced, quantitative MR imaging methods have not been applied to large cohorts. Our objective was to determine whether a short imaging protocol (< 10 minutes), implemented with standard hardware, could detect abnormal water diffusion in the optic nerves of patients with MS. MATERIALS AND METHODS We examined water diffusion in human optic nerves via DTI in the largest MS cohort reported to date (104 individuals, including 38 optic nerves previously affected by optic neuritis). We also assessed whether such abnormalities are associated with loss of visual acuity (both high and low contrast) and damage to the retinal nerve fiber layer (assessed via optical coherence tomography). RESULTS The most abnormal diffusion was found in the optic nerves of patients with SPMS, especially in optic nerves previously affected by optic neuritis (19% drop in FA). DTI abnormalities correlated with both retinal nerve fiber layer thinning (correlation coefficient, 0.41) and loss of visual acuity, particularly at high contrast and in nerves previously affected by optic neuritis (correlation coefficient, 0.54). However, diffusion abnormalities were overall less pronounced than retinal nerve fiber layer thinning. CONCLUSIONS DTI is sensitive to optic nerve damage in patients with MS, but a short imaging sequence added to standard clinical protocols may not be the most reliable indicator of optic nerve damage.