Leiden University Medical Center Pharmacy and Toxicology Department using the TAG CYP2D6 Kit v3 (Luminex Corporation, Den Bosch, The Netherlands). CYP2D6-haplotypes and copy number variants were determined.19 Adverse Events Side effects were evaluated on an 11-point visual analog scale (0 to 10) for the following items: nausea (none to severe), sedation (none to most intense), dizziness (none to most severe), lightheadedness (none to most severe), drug likability (5 was equivocal, under 5 was do not like, over 5 was like). Additionally, we scored occurrence vomiting (yes/no). These items were queried at baseline, t = 45 min, and subsequently at 1-h intervals until t = 345 min after drug administration. Also, adverse effects spontaneously reported by the participant or observed by the investigators were recorded. Data Analysis Data analysis was performed in several steps. First, ˙VE55 or ventilation at an extrapolated end-tidal PCO2 of 55 mmHg (units l/min) was calculated from the slope of the ventilatory response to hypercapnia. The slope was determined in R (the R-Foundation for Statistical Computing, www.r-project.org) by fitting all ventilation-end-tidal Pco2 data points of the linear part of the ventilatory response to hypercapnia curve to the equation S = Ventilation(t)/[end-tidal Pco2(t) – B], where S is the slope of the ventilatory response to hypercapnia and B the apneic threshold or extrapolated end-tidal Pco2 at zero ventilation; this process was automated in R.20 Next, the population pharmacokinetic data were analyzed, followed by a population pharmacokinetic–pharmacodynamic analysis using ˙VE55, the main endpoint of the study, as pharmacodynamic input to the model. Pharmacokinetic-Pharmacodynamic Analysis The pharmacokinetics and pharmacodynamics of oliceridine and morphine were analyzed with NONMEM VII (Icon Plc., USA), a software package for nonlinear mixed-effects modeling, using a population approach. Although measured in plasma, morphine-6-glucuronide was not included in the analyses, because previous studies indicated a rather low potency of morphine-6-glucuronide on generating respiratory effects in individuals with a normal renal function with a potency ratio of approximately 1:20 for depression of isohypercapnic ventilation and 1:50 for isocapnic hypoxic ventilation.21 The pharmacokinetic data were analyzed using three-compartment models. The following analysis sequence was applied: initialization using iterative two-stage, parameter 70
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