Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.
Evaluation of Drug-Drug Interactions of Sodium Oxybate: Results from Pharmacokinetic/Pharmacodynamic Studies with Duloxetine, Lorazepam, and Tramadol.
Eller, Mark, Halladay, Whitney, Madrid, Annette
Clinical trials have demonstrated the efficacy and tolerability of sodium oxybate (SXB) for fibromyalgia treatment. Since polypharmacy is common in fibromyalgia, we evaluated SXB for interactions with three drugs commonly used by fibromyalgia patients.
Three phase 1 studies characterized the pharmacokinetics (PK) and pharmacodynamics (PD) of SXB (2.25 g single dose) with duloxetine (60 mg/day for 4 days; N=24), lorazepam (2 mg single dose; N=18), and extended release tramadol (100 mg/day for 5 days; N=19) in healthy volunteers. Drugs were administered individually and in combination with SXB in a double-blind, placebo-controlled, crossover design. Blood sampling at pre-defined time points enabled estimation of PK parameters for drugs administered alone and combined with SXB. Assessment of PD interactions at pre-defined time points included subject self-assessment of sleepiness/alertness (100 mm visual analogue scale [VAS]; 0=very alert to 100=very sleepy) and the Digit Symbol Substitution Test (DSST) for cognition and attention. Tolerability was evaluated based on the occurrence of adverse events (AEs), physical examination including vital signs, laboratory, and clinical tests including 12-lead electrocardiograms.
Subjects were Caucasian (>=95%), mean age was similar across studies (3133 years); the proportion of females varied (duloxetine, 54%; tramadol, 47%; lorazepam, 39%). The PK of each drug was consistent with established profiles; no statistically or clinically significant PK effects were observed for any of the drugs when administered in combination with SXB. The PD paralleled the PK profile of individual drugs. SXB+duloxetine and SXB+tramadol resulted in increases in sleepiness VAS scores that were similar to SXB alone. Sleepiness VAS scores with SXB+lorazepam were higher than when each drug was administered individually (p<0.05) and had a later and more prolonged peak than SXB alone. SXB alone peaked earlier (1.5 hours) than lorazepam alone (4 hours), and declined more rapidly. Compared to administration of the single agents, decreases in DSST scores with co-administration were only consistently seen with SXB+duloxetine (generally significant across time points vs duloxetine alone, and significant vs SXB alone at 1.5 hours only; p<0.05). All AEs were mild to moderate. One discontinuation, due to ventricular extrasystole in a patient administered tramadol, was not related to study medication.
The PK, PD, and tolerability profiles suggest that the combination of SXB with duloxetine or tramadol are not likely to result in clinically relevant effects. Sleepiness ratings increased when SXB and lorazepam were combined.
To cite this abstract, please use the following information:
Eller, Mark, Halladay, Whitney, Madrid, Annette; Evaluation of Drug-Drug Interactions of Sodium Oxybate: Results from Pharmacokinetic/Pharmacodynamic Studies with Duloxetine, Lorazepam, and Tramadol. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :801