124: A Drug-Drug Interaction Study to Evaluate the Impact of Coadministration of AZD0780 on Rosuvastatin Exposure in Healthy Participants

Statement of Purpose, Innovation or Hypothesis: AZD0780 is an oral, small molecule PCSK9 inhibitor in development for hypercholesterolemia. Statins, including rosuvastatin, are the standard of care in this patient population.  In vitro data suggest AZD0780 is a BCRP, OATP1B1, and OATP1B3 inhibitor and these transporters are involved in rosuvastatin disposition.  We conducted a clinical study to evaluate the potential of AZD0780 to perpetrate a drug interaction with rosuvastatin.

Description of Methods & Materials: An open-label, 2-period, 2-sequence, cross-over study was conducted whereby 16 healthy participants were randomized to two treatment arms; A-single dose 20mg rosuvastatin alone (fasting state) or B-single dose 20mg rosuvastatin plus 100mg AZD0780 (fasting state).   There was a minimum of a 14 day washout between periods.  Plasma pharmacokinetics (PK) samples were taken serially through 48 hours for both rosuvastatin and AZD0780 (treatment B only). Coproporphyrin I (CP-I), a sensitive endogenous biomarker of hepatic OATP1B transporter function, plasma concentrations were also measured in each period. This exploratory analysis was to aid in differentiation of BCRP versus OATP1B1/OATP1B3 inhibition effect of AZD0780, if any, on rosuvastatin exposure. Rosuvastatin and AZD0780 PK parameters were derived using standard noncompartmental methods with primary parameters being AUC_inf, AUC_last, and C_max. Treatment effects were determined using a mixed effects model of the natural log-transformed PK parameters with treatment, period, and sequence as fixed effects and sequence within-participant as a random effect. Standard safety and tolerability endpoints were collected; laboratory evaluations, ECGs, vital signs, AE collection, and physical exams.

Data & Results: There was no impact of coadministration of AZD0780 on rosuvastatin total exposure parameters (GMR (90% CI) for AUC_inf 1.06 (0.918, 1.23) and AUC_last 1.08  (0.942, 1.24)). Although C_max was statistically higher with coadministration of AZD0780, GMR (90% CI) 1.23 (1.11, 1.36), this increase is not clinically relevant. AZD0780 exposures were generally as expected relative to previous data. Based on graphical analysis, there was no clear trend of increased CP-I concentrations with treatment B (with AZD0780) compared to treatment A (without AZD0780). There were no deaths, other SAEs, or AEs leading to withdrawal from the study. No clinically relevant trends were observed for laboratory results, vital signs, physical examinations, and ECGs and no safety concerns were raised.

Interpretation, Conclusion or Significance: Rosuvastatin and AZD0780 may be coadministered. AZD0780 is unlikely to perpetrate DDIs mediated by BCRP and OATP1B1/OATP1B3.

Disclosures: All authors are or were at the time of this work employees of AstraZeneca and may own stock in AstraZeneca.

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Additional Information/Authors: None