Alternative Pharmacokinetic Metrics in Single-Dose Studies to Ensure Bioequivalence of Prolonged-Release Products at Steady State—A Case Study
Víctor Mangas-Sanjuán,
Marta Simón,
Esperanza González-Rojano,
Dolores Ochoa,
Francisco Abad-Santos,
Manuel Román,
Mercedes Ramos,
Carlos Govantes,
Alfredo García-Arieta
Affiliations
Víctor Mangas-Sanjuán
Department of Pharmacy and Pharmaceutical Technology and Parasitology, University of Valencia, 46100 Valencia, Spain
Marta Simón
Laboratorios Normon, 28760 Madrid, Spain
Esperanza González-Rojano
Clinical Pharmacology Department, Hospital Universitario Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), 28040 Madrid, Spain
Dolores Ochoa
Clinical Pharmacology Department, Hospital Universitario de La Princesa, Instituto Teófilo Hernando, Instituto de Investigación Sanitaria la Princesa (IIS-IP), 28006 Madrid, Spain
Francisco Abad-Santos
Clinical Pharmacology Department, Hospital Universitario de La Princesa, Instituto Teófilo Hernando, Instituto de Investigación Sanitaria la Princesa (IIS-IP), 28006 Madrid, Spain
Manuel Román
Clinical Pharmacology Department, Hospital Universitario de La Princesa, Instituto Teófilo Hernando, Instituto de Investigación Sanitaria la Princesa (IIS-IP), 28006 Madrid, Spain
Mercedes Ramos
Laboratorios Normon, 28760 Madrid, Spain
Carlos Govantes
Laboratorios Normon, 28760 Madrid, Spain
Alfredo García-Arieta
División de Farmacología y Evaluación Clínica, Departamento de Medicamentos de Uso Humano, Agencia Española de Medicamentos y Productos Sanitarios, 28022 Madrid, Spain
(1) Background: this article investigates which PK metrics in a single-dose study (concentration at the end of posology interval, Cτ, partial areas under the curve, pAUCs, or half-value duration, HVD) are more sensitive and less variable for predicting the failure of a prolonged-release product at steady-state that was the bioequivalent for Cmax, AUC0-t and AUC0-inf, in the single-dose study; (2) Methods: a cross-over study was performed in 36 subjects receiving desvenlafaxine 100 mg prolonged-release tablets. Conventional (Cmax, AUC0-t and AUC0-inf) and additional (Cτ, pAUCs and HVD) PK metrics were considered after single-dose conditions. Predicted PK metrics at steady state (AUC0-τ, Cmax,ss, and Cτ,ss) were derived using a population PK model approach; (3) Results: the existing differences in the shape of the concentration–time curves precluded to show equivalence for Cτ,ss in the simulated study at steady state. This failure to show equivalence at steady state was predicted by Cτ, pAUCs and HVD in the single-dose study. Cτ was the most sensitive metric for detecting the different shape, with a lower intra-subject variability than HVD; (4) Conclusions: conventional PK metrics for single-dose studies (Cmax, AUC0-t and AUC0-inf) are not enough to guarantee bioequivalence at steady state for prolonged-release products.
