S470 Development and Utilization of a Pharmacokinetic/Pharmacodynamic Model for Vonoprazan to Assess the Relationship Between Dose, Exposure, and pH Holding Time Ratio

Abstract

Introduction: Vonoprazan, a potassium-competitive acid blocker, suppresses gastric acid secretion rapidly and potently over prolonged periods. Gastric acid suppression is key to the healing and maintenance of erosive esophagitis (EE) and the eradication of Helicobacter pylori infection. The daily fraction of time that gastric pH is >4 (the pH >4 holding time ratio [HTR]) is critical for healing of EE; pH >6 HTR is important for eradication of H. pylori infection. Here, we develop and utilize a pharmacokinetic (PK)/pharmacodynamic (PD) model to investigate the relationship between vonoprazan treatment and intragastric pH HTR. Methods: Data from prior Phase 1 single and multiple dose studies with pH measurements were pooled. An existing population PK model was used to estimate individual model parameters and predict PK profiles for study participants on each day with pH measurements. The area under the concentration-time curve between 0 and 24 hours post-dose (AUC0–24h) was merged with pH HTR PD study data. Three direct link PK/PD models characterizing the relationship between AUC0–24h and HTRs for pH >4, >5, and >6 were then derived. The models were used to simulate pH HTRs with between-subject variability; results were summarized as mean and 80% prediction intervals. Results: Data from 245 participants in five different Phase 1 studies were used to derive the PK/PD model. Demographics: 95.1% male; 50.6% Japanese; 49.4% Western. The estimates and 95% confidence intervals for all model parameters are shown in Table. Simulations showed that vonoprazan 20 mg once-daily (QD) and 20 mg twice-daily (BID) are predicted to give pH >4 HTRs of 89.7% and 98.1%, respectively, by Day 7 (Figure). HTRs for pH >6 were 53.1% for vonoprazan 20 mg QD and 75.3% for BID. Conclusion: These results indicate that vonoprazan provides high, dose-dependent pH HTRs and, therefore, consistent, dose-dependent control of 24-hour intragastric acidity. These pH HTRs may explain the high EE healing rates and, when combined with antimicrobials, H. pylori eradication rates seen with vonoprazan in clinical trials.Figure 1.: Predicted Mean and 80% Prediction Interval pH Holding Time Ratio at Days 0 (pre-treatment), 1, 7 and 14. BID, twice daily; QD, once daily. Table 1. - Estimates and 95% CIs for Model Parameters Parameter Role pH >4 Estimate (95% CI) pH >5 Estimate (95% CI) pH >6 Estimate (95% CI) E0 TV (logit) -2.74 (3.77%)(-2.84 to -2.64) -3.18 (1.56%)(-3.27 to -3.09) -3.48 (0.514%)(-3.54 to -3.42) Asian-effect (%) -12.8 (-17.3 to -8.41) -9.23 (-12.7 to -5.74) -5.63 (-8.11 to -3.15) BSV 0.388 (0.310 to 0.465) 0.276 (0.192 to 0.361) 3.16e-05 (-0.286 to 0.286) EC50 TV (ng/mL) 48.2 (43.9 to 52.4) 58.8 (53.1 to 64.5) 99.5 (86.2 to 113) gamma 1.39 (1.20 to 1.58) 1.34 (1.17 to 1.52) 1.62 (1.30 to 1.94) Weight effect (1/kg) 1.50 (0.803 to 2.19) 1.81 (1.19 to 2.44) - BSV 0.319 (0.259 to 0.379) 0.310 (0.252 to 0.368) 0.235 (0.102 to 0.368) Emax TV (logit) 4.80 (102%)(4.53 to 5.07) 4.83 (102%)(4.44 to 5.23) 2.17 (91.9%)(1.65 to 2.70) Weight effect (1/kg) - - -0.0187 (-0.0265 to -0.0108) BSV 1e-04 (6.80e-05 to 0.000132) 1e-04 (5.42e-05 to 0.000146) 0.781 (0.505 to 1.06) ET50 TV (days) 0.432 (0.384 to 0.481) 0.427 (0.369 to 0.485) 0.348 (0.274 to 0.422) delta 1 (fixed) 1 (fixed) 1 (fixed) RUV add.err. (logit) 0.528 (0.475 to 0.580) 0.545 (0.493 to 0.596) 0.498 (0.457 to 0.539) E0 and Emax were estimated on the logit-scale as the pH holding time ratios were logit-transformed; back-transformed estimates on the original percent scale are given for these parameters in round brackets. add.err., additive error; BSV, between subject variability; CI, confidence interval; E0, baseline effect; Emax, theoretical maximum effect achieved at infinite exposure and time; EC50, exposure (AUC) required to achieve 50% of maximum effect (Emax); ET50, time required to achieve 50% of maximum effect; RUV, residual unexplained variability; TV, typical value.