4 Oliceridine respiratory effects Population Pharmacokinetic Analyses The average plasma concentrations of oliceridine, morphine, and morphine-6glucuronide are given in Figure 4.2 on page 76. Goodness-of-Fit plots (individual and population predicted versus measured data, conditional weighted residuals versus time, and normalized prediction discrepancy errors versus time) are given in Figure 4.3 on page 77; the population predicted pharmacokinetic outcomes and measured plasma concentrations of each individual of the four treatment arms are given in Figure 4.4 on page 78. Inspection of the data fits and Goodness-of-Fit plots indicate that the three-compartment models adequately described the data of both opioids. The estimated pharmacokinetic model parameter estimates are given in Table 4.1 on page 79. For all 4 treatment arms, the infusion rate parameter (D1) was not significantly different from 1, but its variability was significantly different from 0. Fixing it to zero had a marked effect on the remaining variability parameters and also on the population estimates. Therefore, including variability on D1 likely reduced the bias on all parameter estimates. The decrease in NONMEM’s objective function value was 141 and 139 points for morphine and oliceridine, respectively. Weight had an effect on the pharmacokinetic parameters via allometric scaling, indicated by a decrease in objective function value of 43 and 24 points for morphine and oliceridine, respectively. With respect to the CYP2D6 genotype, 10 subjects were classified as normal oliceridine metabolizers (2 functional alleles), 4 as intermediate metabolizer (heterozygous with one functional allele), 3 as poor metabolizer (with two alleles lacking activity due to *4/*4, *3/*4, and *4/*4 with *3 = 2549delA and *4 = 100C>T, 1661G>T, 1846G>A, 2850C>T, or 4180G>C) and 1 as ultrarapid metabolizer (more than two functional alleles).25 A significant difference in clearance (CL1) by about 50% was observed in the three poor oliceridine metabolizers. This caused higher plasma concentrations in these three subjects after both low- and high-dose oliceridine compared with the other participants (Fig 4.4 C and D on page 78). 75
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