WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Numerous cocktails using concurrent administration of several cytochrome P450 (CYP) isoform‐selective probe drugs have been reported to investigate drug–drug interactions in vivo.• This approach has several advantages: characterize the inhibitory or induction potential of compounds in development toward the CYP enzymes identified in vitro in an in vivo situation, assess several enzymes in the same trial, and have complete in vivo information about potential CYP‐based drug interactions. WHAT THIS STUDY ADDS • This study describes a new cocktail containing five probe drugs that has never been published.• This cocktail can be used to test the effects of a new chemical entity on multiple CYP isoforms in a single clinical study: CYP1A2 (caffeine), CYP2C9 (warfarin), CYP2C19 (omeprazole), CYP2D6 (metoprolol), and CYP3A (midazolam) and was designed to overcome potential liabilities of other reported cocktails.AIMS To assess the pharmacokinetics (PK) of selective substrates of CYP1A2 (caffeine), CYP2C9 (S‐warfarin), CYP2C19 (omeprazole), CYP2D6 (metoprolol) and CYP3A (midazolam) when administered orally and concurrently as a cocktail relative to the drugs administered alone.METHODS This was an open‐label, single‐dose, randomized, six‐treatment six‐period six‐sequence William's design study with a wash‐out of 7 or 14 days. Thirty healthy male subjects received 100 mg caffeine, 100 mg metoprolol, 0.03 mg kg−1 midazolam, 20 mg omeprazole and 10 mg warfarin individually and in combination (cocktail). Poor metabolizers of CYP2C9, 2C19 and 2D6 were excluded. Plasma samples were obtained up to 48 h for caffeine, metoprolol and omeprazole, 12 h for midazolam, 312 h for warfarin and the cocktail. Three different validated liquid chromatography tandem mass spectrometry methods were used. Noncompartmental PK parameters were calculated. Log‐transformed Cmax, AUClast and AUC for each analyte were analysed with a linear mixed effects model with fixed term for treatment, sequence and period, and random term for subject within sequence. Point estimates (90% CI) for treatment ratios (individual/cocktail) were computed for each analyte Cmax, AUClast and AUC.RESULTS There was no PK interaction between the probe drugs when administered in combination as a cocktail, relative to the probes administered alone, as the 90% CI of the PK parameters was within the prespecified bioequivalence limits of 0.80, 1.25.CONCLUSION The lack of interaction between probes indicates that this cocktail could be used to evaluate the potential for multiple drug–drug interactions in vivo.

AIMCannabinoid receptor type 1 (CB1) antagonists have been developed for the treatment of obesity and associated risk factors. Surinabant is a high affinity CB1 antagonist in vitro. The aim of this study was to assess the magnitude of inhibition by surinabant of CNS effects and heart rate induced by D 9 -tetrahydrocannabinol (THC) in humans. METHODSThis was a double-blind, placebo-controlled, randomized, four period six sequence crossover study. Thirty healthy young male occasional cannabis users (<1 per week) were included. A single oral dose of surinabant (5, 20 or 60 mg) or placebo was administered followed 1.5 h later by four intrapulmonary THC doses (2, 4, 6 and 6 mg) or vehicle, administered at 1 h intervals. The wash-out period was 14-21 days. Subjective and objective pharmacodynamic (PD) measurements were performed. A population PK-PD model for THC and surinabant quantified PK and PD effects. RESULTSSurinabant 20 and 60 mg inhibited all THC-induced PD effects in a similar range for both doses with inhibition ratios ranging from 68.3% (95% CI = 32.5, 104.2; heart rate) to 91.1% (95% CI = 30.3, 151.8; body sway). IC50 ranged from 22.0 ng ml -1 [relative standard error (RSE) = 45.2%; body sway] to 58.8 ng ml -1 (RSE = 44.2%; internal perception). Surinabant 5 mg demonstrated no significant effects. CONCLUSIONSThe dose-related inhibition by surinabant, without any effect of its own, suggests that this compound behaves as a CB1 receptor antagonist in humans at these concentrations. A single surinabant dose between 5 to 20 mg and above was able to antagonize THC-induced effects in humans. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Rimonabant was the first cannabinoid receptor type 1 (CB1) inverse agonist that reached the market. However, with the doses used in patients, it caused severe side effects. We wanted to investigate the dose-effect profile and the effective dose range of surinabant, a new CB1 antagonist in healthy subjects. WHAT THIS STUDY ADDS• This study provides insight into the effective surinabant dose range in healthy subjects using a D 9 -tetrahydrocannabinol (THC) challenge test. Surinabant is able to inhibit various tests, such as heart rate, body sway and feeling high. In our model, surinabant is already maximally effective at single doses of 20 mg, and possibly even below.

Assessment of the time needed to attain steady state is a key pharmacokinetic objective during drug development. Traditional approaches for assessing steady state include ANOVA-based methods for comparing mean plasma concentration values from each sampling day, with either a difference or equivalence test. However, hypothesis-testing approaches are ill suited for assessment of steady state. This paper presents a nonlinear mixed effects modelling approach for estimation of steady state attainment, based on fitting a simple nonlinear mixed model to observed trough plasma concentrations. The simple nonlinear mixed model is developed and proposed for use under certain pharmacokinetic assumptions. The nonlinear mixed modelling estimation approach is described and illustrated by application to trough data from a multiple dose trial in healthy subjects. The performance of the nonlinear mixed modelling approach is compared to ANOVA-based approaches by means of simulation techniques.

BACKGROUND Rimonabant is the first selective CB1 blocker developed for the management of multiple cardiometabolic risk factors in overweight/obese patients. AIMS To assess the pharmacokinetics (PK) of rimonabant after repeated oral doses in healthy and obese subjects. METHODS PK was assessed in healthy young non‐obese males in a randomized, double‐blind, placebo‐controlled, ascending dose study after 3, 10, 20, 40 and 60 mg once‐daily doses for 21 days (N=8 active, 2 placebo/group). PK was assessed in young obese subjects (BMI≥<>30 kg/m2) in an open label study after 20 mg once‐daily doses for 21 days (N=8/gender). Blood was sampled after the first and last dose for full PK profiles and at pre‐dose on specified days. Plasma was analyzed for rimonabant with a validated LC‐MS/MS method. RESULTS Mean (SD) non‐compartmental PK parameters of rimonabant on Day 21 are: (See Table) Subjects Dose (mg) N Cmax (ng/mL) tmaxa (h) AUC0–24 (ng.h/mL) t1/2z (h) tssb (days) Healthy3857.9 (23.1)1.51 (1.00, 2.00)665 (323)210 (132)Healthy108118 (42.2)2.01 (1.50, 3.00)1480 (446)180 (110)12.7 (20.2)Healthy208196 (28.1)2.00 (1.50, 6.00)2960 (268)216 (96.2)Obese2016188 (51.7)2.00 (1.00, 4.00)2480 (605)376 (163)25.5 (48.9)Healthy408326 (92.5)3.00 (2.00, 5.98)4830 (1360)193 (73.3)12.7 (20.2)Healthy608416 (90.6)3.50 (1.50, 6.02)6760 (1560)151 (59.3) CONCLUSIONS Rimonabant exhibits no major deviation from dose proportionality up to 20 mg (therapeutic dose range), after which there is a less than dose‐proportional increase in exposure. Obese subjects have a longer t1/2z (16 days) than non‐obese subjects (6 to 9 days) due to a larger peripheral volume of distribution. Gender has no effect on rimonabant PK. Clinical Pharmacology & Therapeutics (2005) 79, P50–P50; doi:

Background:Teriflunomide, a once-daily oral immunomodulator approved for treatment of relapsing-remitting multiple sclerosis, is eliminated slowly from plasma. If necessary to rapidly lower plasma concentrations of teriflunomide, an accelerated elimination procedure using cholestyramine or activated charcoal may be used. The current bioanalytical assay for determination of plasma teriflunomide concentration requires laboratory facilities for blood centrifugation and plasma storage. An alternative method, with potential for greater convenience, is dried blood spot (DBS) methodology. Analytical and clinical validations are required to switch from plasma to DBS (finger-prick sampling) methodology.Methods:Using blood samples from healthy subjects, an LC-MS/MS assay method for quantification of teriflunomide in DBS over a range of 0.01–10 mcg/mL was developed and validated for specificity, selectivity, accuracy, precision, reproducibility, and stability. Results were compared with those from the current plasma assay for determination of plasma teriflunomide concentration.Results:Method was specific and selective relative to endogenous compounds, with process efficiency ∼88%, and no matrix effect. Inaccuracy and imprecision for intraday and interday analyses were <15% at all concentrations tested. Quantification of teriflunomide in DBS assay was not affected by blood deposit volume and punch position within spot, and hematocrit level had a limited but acceptable effect on measurement accuracy. Teriflunomide was stable for at least 4 months at room temperature, and for at least 24 hours at 37°C with and without 95% relative humidity, to cover sampling, drying, and shipment conditions in the field. The correlation between DBS and plasma concentrations (R2 = 0.97), with an average blood to plasma ratio of 0.59, was concentration independent and constant over time.Conclusions:DBS sampling is a simple and practical method for monitoring teriflunomide concentrations.