146: Optimizing Simvastatin Dosing in Patients Post-gastric Bypass Surgery Using a Population PK/PD Link Approach

Statement of Purpose, Innovation or Hypothesis: The alterations of gastric bypass surgeries to the gastrointestinal anatomy and physiology can potentially change drug exposure and response. Roux-en-Y gastric bypass (RYGB), involves creating a small stomach pouch, bypassing part of the small intestine, and rerouting the digestive tract. Our primary objective is to evaluate the impact of RYGB on the pharmacokinetics (PK) of simvastatin lactone (SV) and its active metabolite, simvastatin hydroxy acid (SVA). By elucidating these changes, we aim to determine whether dose adjustments are necessary and, if warranted, optimize the dose for patients post-RYGB.

Description of Methods & Materials: The study comprised patients who had undergone gastric bypass surgery and morbidly obese age-matched individuals without a previous history of RYGB. All participants received a single oral dose of 40 mg of simvastatin and CYP3A4 in vivo activity was investigated using midazolam as a probe drug. Plasma concentration data on SV and SVA were analyzed using the nonlinear mixed-effect modeling approach and the stochastic approximation expectation maximization algorithm. Age, body size metrics, CYP3A4 in vivo activity, and genotypes for major enzymes and transporters (SLCO1B1, SLCO2B1, and CYP3A5) were tested as potential covariates. A population pharmacokinetic-pharmacodynamic (PK/PD) link approach was employed for optimal dosing simulation.

Data & Results: A parent-metabolite model with first-order absorption, 2-compartment for SV and 1-compartment for SVA, linear elimination, unidirectional conversion from SV to SVA, and enterohepatic circulation best described the data. The RYGB surgery reduced the oral bioavailability of SV by approximately 40% compared to non-operated, and consequently, decreased the AUC_0-τ of SV. The genotype SLCO1B1 521TC (heterozygous) increased the AUC_0-τ of SVA by 98%, while 521CC (homozygous variant) increased by 260%. Simulations of multiple doses from 10 to 80 mg of simvastatin show that RYGB surgery patients achieve a similar exposure compared to non-surgery patients when increasing the dose by 2-fold. When linking the SVA plasma levels to LDL-cholesterol levels using a turnover model, our simulations indicated that for a fixed dose patients who underwent a gastric bypass surgery were less likely to achieve the statin treatment goal, defined as 20-25% LDL-C baseline reduction for low-intensity statins (simvastatin 10 mg, p-value = 0.00013) and 30-49% LDL-C baseline reduction for moderate-intensity statins (simvastatin 20-40mg, p-value = 0.00018 and 0.00032, respectively). Simulations with a 2-fold increase in dose show a similar response for surgery patients when compared to patients with no history of RYGB for 10 mg (p-value = 1.0), 20 mg (p-value = 0.88), and 40 mg (p-value = 1.0).

Interpretation, Conclusion or Significance: In summary, individuals who have undergone gastric bypass surgery show decreased exposure-response to simvastatin. RYGB patients might benefit from doubling the dose or adding a non-statin drug to achieve the same response and prevent adverse events. In future endeavors, we plan to integrate a disease model to accommodate the impact of weight loss induced by RYGB on LDL-C levels in conjunction with the surgery’s effect on pharmacokinetics. This combined approach will enable us to formulate time-dependent recommendations for statin utilization following RYGB procedures.

Disclosures: The authors declare that there are no conflict of interest.

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