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BackgroundThe total effect of a medication is the sum of its drug effect, placebo effect (meaning response), and their possible interaction. Current interpretation of clinical trials' results assumes no interaction. Demonstrating such an interaction has been difficult due to lack of an appropriate study design.Methods180 adults were randomized to caffeine (300 mg) or placebo groups. Each group received the assigned intervention described by the investigators as caffeine or placebo, in a randomized crossover design. 4-hour-area-under-the-curve of energy, sleepiness, nausea (on 100 mm visual analog scales), and systolic blood pressure levels as well as caffeine pharmacokinetics (in 22 volunteers nested in the caffeine group) were determined. Caffeine drug, placebo, placebo-plus-interaction, and total effects were estimated by comparing outcomes after, receiving caffeine described as placebo to receiving placebo described as placebo, receiving placebo described as caffeine or placebo, receiving caffeine described as caffeine or placebo, and receiving caffeine described as caffeine to receiving placebo described as placebo, respectively.ResultsThe placebo effect on area-under-the-curve of energy (mean difference) and sleepiness (geometric mean ratio) was larger than placebo-plus-interaction effect (16.6 [95% CI, 4.1 to 29.0] vs. 8.4 [-4.2 to 21.0] mm*hr and 0.58 [0.39 to 0.86] vs. 0.69 [0.49 to 0.97], respectively), similar in size to drug effect (20.8 [3.8 to 37.8] mm*hr and 0.49 [0.30 to 0.91], respectively), and its combination with the later was larger than total caffeine effect (29.5 [11.9 to 47.1] mm*hr and 0.37 [0.22 to 0.64]). Placebo-plus-interaction effect increased caffeine terminal half-life by 0.40 [0.12 to 0.68] hr (P = 0.007).ConclusionsDrug and placebo effects of a medication may be less than additive, which influences the interpretation of clinical trials. The placebo effect may increase active drug terminal half-life, a novel mechanism of placebo action.Trial RegistrationClinicalTrials.gov identification number - NCT00426010.

BackgroundThe extents of generic-reference and generic-generic average bioequivalence and intra-subject variation of on-market drug products have not been prospectively studied on a large scale.MethodsWe assessed bioequivalence of 42 generic products of 14 immediate-release oral drugs with the highest number of generic products on the Saudi market. We conducted 14 four-sequence, randomized, crossover studies on the reference and three randomly-selected generic products of amlodipine, amoxicillin, atenolol, cephalexin, ciprofloxacin, clarithromycin, diclofenac, ibuprofen, fluconazole, metformin, metronidazole, paracetamol, omeprazole, and ranitidine. Geometric mean ratios of maximum concentration (Cmax) and area-under-the-concentration-time-curve, to last measured concentration (AUCT), extrapolated to infinity (AUCI), or truncated to Cmax time of reference product (AUCReftmax) were calculated using non-compartmental method and their 90% confidence intervals (CI) were compared to the 80.00%–125.00% bioequivalence range. Percentages of individual ratios falling outside the ±25% range were also determined.ResultsMean (SD) age and body-mass-index of 700 healthy volunteers (28–80/study) were 32.2 (6.2) years and 24.4 (3.2) kg/m2, respectively. In 42 generic-reference comparisons, 100% of AUCT and AUCI CIs showed bioequivalence, 9.5% of Cmax CIs barely failed to show bioequivalence, and 66.7% of AUCReftmax CIs failed to show bioequivalence/showed bioinequivalence. Adjusting for 6 comparisons, 2.4% of AUCT and AUCI CIs and 21.4% of Cmax CIs failed to show bioequivalence. In 42 generic-generic comparisons, 2.4% of AUCT, AUCI, and Cmax CIs failed to show bioequivalence, and 66.7% of AUCReftmax CIs failed to show bioequivalence/showed bioinequivalence. Adjusting for 6 comparisons, 2.4% of AUCT and AUCI CIs and 14.3% of Cmax CIs failed to show bioequivalence. Average geometric mean ratio deviation from 100% was ≤3.2 and ≤5.4 percentage points for AUCI and Cmax, respectively, in both generic-reference and generic-generic comparisons. Individual generic/reference and generic/generic ratios, respectively, were within the ±25% range in >75% of individuals in 79% and 71% of the 14 drugs for AUCT and 36% and 29% for Cmax.ConclusionsOn-market generic drug products continue to be reference-bioequivalent and are bioequivalent to each other based on AUCT, AUCI, and Cmax but not AUCReftmax. Average deviation of geometric mean ratios and intra-subject variations are similar between reference-generic and generic-generic comparisons.Trial registration ClinicalTrials.gov identifier: NCT01344070 (registered April 3, 2011).Electronic supplementary materialThe online version of this article (doi:10.1186/s40360-017-0182-1) contains supplementary material, which is available to authorized users.

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Several high-performance liquid chromatography (HPLC) methods have been described for the determination of caffeine in human plasma. However, none have been cross validated using synthetic plasma. The present study describes a simple and reliable HPLC method for the determination of the caffeine level in human plasma. Synthetic plasma was used to construct calibration curves and quality control samples to avoid interference by caffeine commonly present in donor's human plasma. After deproteination of plasma samples with perchloric acid, caffeine and antipyrine (internal standard, IS) were separated on a Waters Atlantis C18 column using a mobile phase of 15 mM potassium phosphate (pH 3.5) and acetonitrile (83:17, v/v), and monitored by photodiode array detector, with the wavelength set at 274 nm. The relationship between caffeine concentrations and peak area ratio (caffeine-IS) was linear over the range of 0.05-20 μg/mL. Inter-run coefficient of variation was ≤ 5.4% and ≤ 6.0% and bias was ≤ 3% and ≤ 7% using human and synthetic plasma, respectively. Mean extraction recovery from human plasma of caffeine and the IS was 91% and 86%, respectively. Caffeine in human plasma was stable for at least 24 h at room temperature or 12 weeks at -20 °C, and after three freeze-thaw cycles. The method was successfully applied to monitor caffeine levels in healthy volunteers with correction of caffeine levels using the mean ratio of the slopes of the calibration's curves constructed using human and synthetic plasma.