Quantitative Prediction of CYP3A4‐ and CYP3A5‐Mediated Drug Interactions

We verified a physiologically‐based pharmacokinetic (PBPK) model to predict cytochrome P450 3A4/5‐mediated drug‐drug interactions (DDIs). A midazolam (MDZ)–ketoconazole (KTZ) interaction study in 24 subjects selected by CYP3A5 genotype, and liquid chromatography and mass spectroscopy quantification of CYP3A4/5 abundance from independently acquired and genotyped human liver (n = 136) and small intestinal (N = 12) samples, were conducted. The observed CYP3A5 genetic effect on MDZ systemic and oral clearance was successfully replicated by a mechanistic framework incorporating the proteomics‐informed CYP3A abundance and optimized small intestinal CYP3A4 abundance based on MDZ intestinal availability (FG) of 0.44. Furthermore, combined with a modified KTZ PBPK model, this framework recapitulated the observed geometric mean ratio of MDZ area under the curve (AUCR) following 200 or 400 mg KTZ, which was, respectively, 2.7–3.4 and 3.9–4.7‐fold in intravenous administration and 11.4–13.4 and 17.0–19.7‐fold in oral administration, with AUCR numerically lower (P > 0.05) in CYP3A5 expressers than nonexpressers. In conclusion, the developed mechanistic framework supports dynamic prediction of CYP3A‐mediated DDIs in study planning by bridging DDIs between CYP3A5 expressers and nonexpressers

Combining Cognitive-Behavioral Therapy and Milnacipran for Fibromyalgia: A Feasibility Randomized-controlled Trial

To evaluate the feasibility of a randomized-controlled trial (RCT) and to obtain estimates of the effects of combined cognitive behavioral therapy (CBT) and milnacipran for the treatment of fibromyalgia (FM)

Research to Encourage Exercise for Fibromyalgia (REEF): Use of motivational interviewing design and method

Fibromyalgia (FM), defined as the presence of both chronic widespread pain and the finding of 11/18 tender points on examination, is an illness associated with major personal and societal burden. Supervised aerobic exercise is an important treatment modality to improve patient symptoms. Unfortunately, adherence to an exercise regimen after a structured supervised program is disappointingly low. Since FM is a chronic illness, studies are needed to test strategies that would enhance exercise adherence in these individuals. Individuals who are able to adhere to exercise almost always maintain the symptomatic benefits of exercise. The objective of this paper was to describe the protocol of the Research to Encourage Exercise for Fibromyalgia (REEF). REEF is a randomized attention-controlled trial that seeks to test the efficacy of 6 sessions of telephone delivered motivational interviewing (MI) that targets exercise adherence to improve FM-relevant clinical outcomes (i.e., physical function and pain severity). The trial has recently completed enrolling 216 subjects, and randomization has resulted in well-balanced groups. Details on the study design, MI program, and treatment fidelity are provided in the paper. Outcome assessments at week 12, week 24 and week 36 will test the immediate, intermediate and long-term effects of exercise-based MI on adherence (as measured by the Community Health Activities Model Program for Seniors/CHAMPS and accelerometer) and clinical outcomes. When completed, REEF will determine whether exercise-based MI could be utilized as a management strategy to sustain the clinical benefits of exercise for FM

Research to Encourage Exercise for Fibromyalgia (REEF): Use of Motivational Interviewing, Outcomes From a Randomized-controlled Trial

Objectives Regular exercise is associated with important benefits in patients with fibromyalgia (FM). Unfortunately, long-term maintenance of exercise after a structured program is rare. The present study tested the efficacy of Motivational Interviewing (MI) to promote exercise and improve symptoms in patients with FM. Methods 216 patients with FM were randomized to 6 MI sessions (n=107) or an equal number of FM self-management lessons (education control/EC, n=109). Co-primary endpoints were an increase of 30 minutes in moderate-vigorous physical activity and improvement in the Fibromyalgia Impact Questionnaire-Physical Impairment (FIQ-PI) score, assessed at pre-treatment, post-treatment, and 3- and 6-month follow-up. Secondary outcomes included clinically meaningful improvements in FIQ score, pain severity ratings, and a 6-minute walk test. Results There were no significant treatment group differences in either co-primary endpoint at 6-month follow-up. However, more MI participants than controls exhibited meaningful improvements in FIQ score at 6-month follow-up (62.9% vs. 49.5%, p=0.06). Compared to EC subjects, MI subjects also displayed a larger increment in their 6-minute walk test (43.9 vs. 24.8 meters, p=0.03). Additionally, MI was superior to EC in increasing the number of hours of physical activity immediately post-intervention and in reducing pain severity both immediately after the intervention and at 3-month follow-up. Conclusions Despite a lack of benefits on long term outcome, MI appears to have short-term benefits with respect to self-report physical activity and clinical outcomes. This is the first study in FM that explicitly addresses exercise maintenance as a primary aim

The interaction between St John\u27s wort and an oral contraceptive.

OBJECTIVES: The popular herbal remedy St John\u27s wort is an inducer of cytochrome P450 (CYP) 3A enzymes and may reduce the efficacy of oral contraceptives. Therefore we evaluated the effect of St John\u27s wort on the disposition and efficacy of Ortho-Novum 1/35 (Ortho-McNeil Pharmaceutical, Inc, Raritan, NJ), a popular combination oral contraceptive pill containing ethinyl estradiol (INN, ethinylestradiol) and norethindrone (INN, norethisterone). METHODS: Twelve healthy premenopausal women who were using oral contraception (\u3e3 months) received a combination oral contraceptive pill (Ortho-Novum 1/35) for 3 consecutive 28-day menstrual cycles. During the second and third cycles, the participants received 300 mg St John\u27s wort 3 times a day. The serum concentrations of ethinyl estradiol (day 7), norethindrone (day 7), follicle-stimulating hormone (days 12-16), luteinizing hormone (days 12-16), progesterone (day 21), and intravenous and oral midazolam (days 22 and 23) were determined in serial blood samples. The incidence of breakthrough bleeding was quantified during the first and third cycles. RESULTS: Concomitant use of St John\u27s wort was associated with a significant (P.05). Breakthrough bleeding occurred in 2 of 12 women in the control phase compared with 7 of 12 women in the St John\u27s wort phase. The oral clearance of midazolam after St John\u27s wort dosing was greater in women who had breakthrough bleeding (215.9 +/- 66.5 L/h) than in those who did not (97.5 +/- 37.2 L/h) (P =.005). CONCLUSION: St John\u27s wort causes an induction of ethinyl estradiol-norethindrone metabolism consistent with increased CYP3A activity. Women taking oral contraceptive pills should be counseled to expect breakthrough bleeding and should consider adding a barrier method of contraception when consuming St Johns wort