Comparative Bioavailability of Two Formulations of Biopharmaceutical Classification System (BCS) Class IV Drugs: A Case Study of Lopinavir/Ritonavir

Abstract

Background: Lopinavir/ritonavir (LPV/r-A, Kaletra®), a fixed dose, co-formulated antiviral therapy for the treatment of HIV infection has been used worldwide for over two decades. Both active substances have low solubility in water and low membrane permeability. LPV/r-A tablets contain key excipients critical to ensuring acceptable bioavailability of lopinavir and ritonavir in humans. An established dog pharmacokinetic model demonstrated several generic LPV/r tablet formulations have significant oral bioavailability variability compared to LPV/r-A.

Methods: Analytical characterizations of LPV/r-B tablets were performed and a clinical study was conducted to assess the relative bioavailability of Kalidavir® (LPV/r-B) 400/100 mg tablets relative to Kaletra® (LPV/r-A) 400/100 mg tablets under fasting conditions.

Results: The presence of active substances were confirmed in LPV/r-B tablets in an apparent amorphous state at essentially the labeled amounts, and dissolution profiles were generally similar to LPV/r-A tablets. Excipients in the tablet formulation were found to be variable and deviate from the labeled composition. Lopinavir and ritonavir exposures (AUC) following LPV/r-B administration were approximately 90% and 20% lower compared to that of LPV/r-A.

Conclusions: LPV/r-B was not shown to be bioequivalent to LPV/r-A.

Keywords: ADME; Anti-infective; Bioavailability; Bioequivalence; Biopharmaceutics Classification system (BCS); Clinical pharmacokinetics; HIV; Lopinavir; Ritonavir.