1566. Population Pharmacokinetics of Voriconazole: Serum Albumin Status as a Novel Marker of Clearance and Dosage Optimization

Background Voriconazole (VRCZ) is a first-line agent for the treatment of invasive aspergillosis. In this study, we report the first study on population pharmacokinetics (PPK) of VRCZ in Thai patients. Methods A PPK study was performed by combining blood VRCZ data from intensive pharmacokinetic (PK) sampling and trough concentration. A non-linear mixed-effect model with FOCE ELS optimization by Phoenix NLME was used. Validity of the model was confirmed by bootstrap, visual predictive check (VPC) and goodness-of-fit (GOF) plot. Recommended dosage regimens based on albumin level of patient were simulated. Results One hundred and six patients using oral VRCZ were included. Eighty-eight patients had the phenotype results which were 43, 37, and 8 of extensive metabolizer (EM), intermediate metabolizer (IM) and poor metabolizer (PM), respectively. The linear one-compartment model with first-order absorption and elimination by fixing Ka value at 1.0 well described the data. CYP2C19 phenotypes did not influence any PK parameter during the covariate model building, then all 106 patients were included in the model construction. The final model was V (Liter) = θ V × (Actual body weight/55) θ1 × exp (η V), CL (L/hr) = θ CL × (albumin/28) θ2 × (logGGT/2.4)θ3 × exp (η CL), Table 1. Estimated clearance (CL) and volume of distribution (V) values were 7.33 L hour−1and 439.69 L, respectively. VPC (Figure 1) and 96% of 1000 succeeded bootstrap results (Table1) showed a good consistency to the observed data. Serum albumin had more impact correlation across all patients with CL, R2 = 0.18, P ≤ 0.001. Patient with serum albumin 30 g/L had CL lower than patient having serum albumin > 30 g/L, P = 0.0007, irrespective of PM status because of there were all phenotypes which distributed across two groups; %EM: %IM: %PM for 55: 38.3: 6.6 and 48:36:16, respectively. Dosing simulation (Table 2) found that patient having albumin 30 g/L required a lower daily maintenance dose to achieve any trough level. Conclusion Serum albumin is a novel marker influencing VRCZ CL. Therapeutic drug monitoring with this dosing regimen could be another practical option for more specialized patient condition. Disclosures All authors: No reported disclosures.