A Single Dose of Baicalin Has No Clinically Significant Effect on the Pharmacokinetics of Cyclosporine A in Healthy Chinese Volunteers.

Ruijuan Liu,Xin Tian,Uwe Fuhr,Shuaibing Liu,Jingyao Wei,Jiali Zhang,Ji Zhang,Yuanyuan Chang,Xiaojian Zhang,Xia Li,Max Taubert

doi:10.3389/fphar.2019.00518

Abstract

Despite its narrow therapeutic window and large interindividual variability, cyclosporine A (CsA) is the first-line therapy following organ transplantation. Metabolized mainly by CYP3A and being a substrate of P-glycoprotein (P-gp), CsA is susceptible to drug–drug interactions. Baicalin (BG) is a drug used for adjuvant therapy of hepatitis in traditional Chinese medicine. Since its aglycone baicalein (B) inhibits CYP3A and P-gP, co-administration might affect CsA pharmacokinetics. This study investigated the effect of BG on CsA pharmacokinetics. In a two-period study, 16 healthy volunteers received a single 200 mg oral CsA dose alone (reference period) or in combination with 500 mg BG (test period). Pharmacokinetic evaluation of CsA was carried out using non-compartmental analysis (NCA) and population pharmacokinetics (popPK). Treatments were compared using the standard bioequivalence method. Based on NCA, 90% CIs of AUC and Cmax test-to-reference ratios were within bioequivalence boundaries. In the popPK analysis, a two-compartment model (clearance/F 62.8 L/h, central and peripheral volume of distribution/F 254 L and 388 L) with transit compartments for absorption appropriately described CsA concentrations. No clinically relevant effect of 500 mg BG co-administration on CsA pharmacokinetics was identified and both treatments were well tolerated.

Highlights

As an immunosuppressant drug, cyclosporine A (CsA) has been widely used in transplantation since the early 1980s (Colombo and Ammirati, 2011)
An early study in rats which directly investigated the effects of Scutellaria radix decoction, BG, or B on CsA pharmacokinetics provided mixed findings: the decoction reduced exposure to oral but not to intravenous CsA, while BG and even more so B increased exposure to oral CsA (Lai et al, 2004). These results indicate that co-medication with BG might alter the pharmacokinetics of CsA in humans and indicate that any respective drug–drug interaction (DDI) may be mediated by several mechanisms
An effect of BG was introduced on the following pharmacokinetic parameters of the final model of CsA with Eq 1: number of transit compartments (N), mean transit time (MTT), absorption rate constant (Ka), apparent clearance (CL/F), Vc/F, Vp/F

Summary

Introduction

Cyclosporine A (CsA) has been widely used in transplantation since the early 1980s (Colombo and Ammirati, 2011). CsA remained a first-line therapy for patients with solid organ transplantation. CsA has a narrow therapeutic range and large interindividual pharmacokinetic variability. While underexposure might cause graft versus host disease (Rogosheske et al, 2014) and acute rejection episodes, overexposure might result in toxicity (Bardazzi et al, 2018). CsA is categorized as a biopharmaceutical classification system (BSC) class II drug due to low solubility and high permeability (Onoue et al, 2010).

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Discussion

Conclusion