We aimed to assess the plasma and urine concentrations of beta2-agonists and evaluate the difference between three routes of administration in trained adults in order to distinguish doping from prevention of exercise-induced asthma. Ten young healthy Caucasian male subjects received during a four treatment period study: 1) inhaled salbutamol (S(I)) 2 x 100 microg t.i.d. for 3 days, 2) inhaled formoterol (F(I)) 2 x 12 microg b.i.d. for 3 days, 3) a single subcutaneous injection of salbutamol (S(S)) 0.5 mg, and 4) salbutamol 2 x 2 mg t.i.d. orally for 3 days (S(O)). Blood samples were taken during the first and the third day of experimentation at baseline, 30 min, 1 h, 2 h, 4 h and 6 h after administration; additional blood samples were drawn at 15 min for S(I), S(S) and F(I) and at 12 h for F(I). Urinary samples were collected at baseline, 2 h, 4 h, 6 h and 12 h after administration. Urinary concentrations were 20 to almost 50 times higher after S(O) than after S(I). Mean urinary concentration after S(O) increased to above 800 ng.mL(-1) within the two hours and above 1000 ng.mL(-1) at 6 to 12 hours post-drug administration. Urinary concentrations after S(S) were maximal during the first 2 hours (mean: 340 +/- 172 ng.mL(-1)). Plasma concentrations were very low, whatever the routes of administration. Results showed that we could eliminate the use of S(I) (authorized) and S(S) administration when individual urinary concentrations are higher than 230 ng.mL(-1) and 615 ng.mL(-1), respectively. Therefore, at rest, the cut-off value used to discriminate therapeutic from doping salbutamol intake could be fixed at 250 ng.mL(-1) instead of the 1000 ng.mL(-1) still authorized by international committees.

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Aims/Background To evaluate relative bioavailability and plasma pharmacokinetic (PK) profile of single oral doses of zolpidem modified‐release (MR) formulations (10 mg and 12.5 mg) compared to standard zolpidem 10 mg. Methods 24 healthy, Caucasian, male volunteers (18–45 years old) received single oral doses of zolpidem MR 10 mg and 12.5 mg, or standard zolpidem 10 mg via a randomized, open‐label, crossover study. Blood sample (n=18) were collected up to 16h postdose. PK parameters were determined by noncompartmental analysis: Cmax, tmax, t1/2z, AUC, MRT, and half‐value duration (HVD). Comparisons between treatments were performed by ANOVA (α=0.05). Results The initial absorption phase of zolpidem MR formulations was as fast as that of standard zolpidem with no significant difference in tmax. With zolpidem MR 12.5 mg, Cmax values were moderately lower (ratio of 0.82) compared with standard zolpidem and plasma concentrations were maintained above those observed with standard zolpidem for a longer period of time, and particularly from 3 to 6h postdose. This was confirmed by an increase of the HVD from 2.3h for standard zolpidem to 4.6h for zolpidem MR 12.5 mg. The mean terminal half‐life was similar with all 3 formulations. Conclusion These results show that this new zolpidem MR formulation provides the appropriate PK characteristics to extend plasma concentration into the middle of the night (3–6 h postdose), while retaining the same tmax and terminal half‐life. Clinical Pharmacology & Therapeutics (2005) 77, P44–P44; doi:

Despite the small sample size, based on the results of healthy, elderly volunteers, a single MDZ plasma measurement taken at 6 h post-oral administration may represent an accurate marker of CYP3A phenotype. This single-time-point method could be used safely for predicting drug-drug or diet interactions and identifying individuals with genetic polymorphism that affect CYP3A activity.

Objective: This trial evaluated the efficacy and safety of GZ389988A, a tropomyosin receptor kinase A (TrkA) inhibitor, in subjects with painful knee osteoarthritis (OA). Method: In this single center, double-blind, placebo-controlled and randomized trial, 104 subjects with moderate-to-severe knee OA pain were enrolled to receive a single intra-articular (IA) injection of either GZ389988A or placebo. Efficacy measures were assessed over 12 weeks and included walking pain (Western Ontario and McMaster Universities Osteoarthritis Index [WOMAC] A1), overall knee pain, WOMAC A, B, C and total score, Patient Global Impression of Change (PGIC), OMERACT-OARSI responder rate and rescue medication use. Adverse events (AEs) were monitored up to 24 weeks. Results: The primary efficacy endpoint was met with a between-group difference of À7.49 (VAS 0e100) on WOMAC A1 changes over 4 weeks (P < 0.05 favoring GZ389988A). The secondary outcome on WOMAC A1 changes over 12 weeks had a between-group difference of À6.78 (P ¼ 0.064). Among weekly assessments, statistically significant greater improvement in the GZ389988A group was observed in WOMAC A1, overall knee pain and/or WOMAC A at weeks 2e5. Although not statistically significant, improvements over placebo on pain and WOMAC C persisted over 12 weeks. Greater AE incidence was observed in the GZ389988A group including transient and self-limited injection joint inflammatory reactions with a spike of acetaminophen intake within the first week post-injection. Conclusion: IA injection of TrkA inhibitor GZ389988A in knee OA subjects reduced pain with a numerically functional gain and an acceptable safety profile. (ClinicalTrials.gov, NCT02845271).