Simulations The results of the simulation study are given in Figure 4.7 on page 85. They show the effect of multiple dosing aimed at a steady state in effect to maximal depression of 65% of baseline isohypercapnic ventilation. Irrespective of genotype (oliceridine), the differences in pharmacokinetic and pharmacodynamic properties result in less variation in the effectsite concentrations for morphine (difference between peaks and valleys 1 ng/ml) versus oliceridine (5 ng/ml) and variation in ventilation for morphine (difference between peaks and valleys 2% of baseline) versus oliceridine (7%). For morphine, in a 24-h period, the total drug dose given is 27 mg, which is made up of an initial bolus dose of 10 mg followed by 17 1-mg doses. For oliceridine in normal and poor metabolizers, the initial bolus dose was 1.5 mg followed by 20 doses of 0.5 mg in normal metabolizers (total dose given 11.5 mg) and 11 doses of 0.5 mg in poor metabolizers (total dose 7 mg). This indicates that less oliceridine was needed in poor than in normal metabolizers to induce a similar level of respiratory depression. Adverse Effects All reported and observed adverse effects are given in Table 4.3 on page 86. At low dose and high dose, the total number of events was similar between opioids. Most frequently reported events were dizziness, lightheadedness, somnolence, and horizontal vertigo after oliceridine administration, and nausea, lightheadedness, dizziness, and somnolence following morphine (all occurring on at least 8 visits). The queried adverse events are given in Figure 4.8 on page 87. It shows the more protracted occurrence of events after morphine than oliceridine. 84
RkJQdWJsaXNoZXIy MTk4NDMw