Physiologically based Pharmacokinetic Model Validated to Enable Predictions Of Multiple Drugs in a Long-acting Drug-combination Nano-Particles (DcNP): Confirmation with 3 HIV Drugs, Lopinavir, Ritonavir, and Tenofovir in DcNP Products

J Pharm Sci. 2024 Jun;113(6):1653-1663. doi: 10.1016/j.xphs.2024.02.018. Epub 2024 Feb 20.

Abstract

Drug-Combination Nanoparticles (DcNP) are a novel drug delivery system designed for synchronized delivery of multiple drugs in a single, long-acting, and targeted dose. Unlike depot formulations, slowly releasing drug at the injection site into the blood, DcNP allows multiple-drug-in-combination to collectively distribute from the injection site into the lymphatic system. Two distinct classes of long-acting injectables products are proposed based on pharmacokinetic mechanisms. Class I involves sustained release at the injection site. Class II involves a drug-carrier complex composed of lopinavir, ritonavir, and tenofovir uptake and retention in the lymphatic system before systemic access as a part of the PBPK model validation. For clinical development, Class II long-acting drug-combination products, we leverage data from 3 nonhuman primate studies consisting of nine PK datasets: Study 1, varying fixed-dose ratios; Study 2, short multiple dosing with kinetic tails; Study 3, long multiple dosing (chronic). PBPK validation criteria were established to validate each scenario for all drugs. The models passed validation in 8 of 9 cases, specifically to predict Study 1 and 2, including PK tails, with ritonavir and tenofovir, fully passing Study 3 as well. PBPK model for lopinavir in Study 3 did not pass the validation due to an observable time-varying and delayed drug accumulation, which likely was due to ritonavir's CYP3A inhibitory effect building up during multiple dosing that triggered a mechanism-based drug-drug interaction (DDI). Subsequently, the final model enables us to account for this DDI scenario.

Keywords: HIV; Long-acting; Lopinavir; Mechanism-based inhibition; Nanoparticles; PBPK; Ritonavir; Tenofovir; Validation.

MeSH terms

  • Animals
  • Anti-HIV Agents* / administration & dosage
  • Anti-HIV Agents* / pharmacokinetics
  • Delayed-Action Preparations / pharmacokinetics
  • Drug Combinations*
  • Drug Delivery Systems / methods
  • Humans
  • Lopinavir* / administration & dosage
  • Lopinavir* / pharmacokinetics
  • Male
  • Models, Biological*
  • Nanoparticles*
  • Ritonavir* / administration & dosage
  • Ritonavir* / pharmacokinetics
  • Tenofovir* / administration & dosage
  • Tenofovir* / pharmacokinetics