Authors: François Gimenez¹; Estelle Foeillet¹; Olivier Bourdon¹; Steve Weller²; Christophe Garret³; Roselyne Bidault³; Eric Singlas¹

Source: Clinical Pharmacokinetics, Volume 43, Number 10, 2004 , pp. 685-692(8)

Publisher: Adis International

Abstract:

Objective: To investigate a potential pharmacokinetic interaction between mycophenolate mofetil (MMF) and aciclovir or valaciclovir.

Study design and participants: Fifteen healthy subjects were enrolled in a prospective, randomised, open-label, single-dose, cross-over study conducted at a single centre. Subjects received each of the following five oral treatments: (i) aciclovir 800mg alone; (ii) valaciclovir 2g alone; (iii) MMF 1g alone; (iv) valaciclovir 2g + MMF 1g; and (v) aciclovir 800mg + MMF 1g. The following pharmacokinetic parameters were estimated for aciclovir, mycophenolic acid (MPA) and its inactive glucuronide metabolite (MPAG) from the plasma concentration-time data using noncompartmental methods: area under the concentration-time curve from zero to infinity (AUC), terminal elimination half-life (t_½z), peak concentration (C_max) and time to C_max (t_max). The renal clearance (CL_R) of aciclovir was also calculated. These parameters were compared when aciclovir or valaciclovir were coadministered with MMF relative to aciclovir, valaciclovir or MMF given alone.

Results and discussion: Aciclovir C_max, t_max and AUC were significantly increased by 40%, 0.38 hour and 31%, respectively, following coadministration of aciclovir and MMF, whereas aciclovir t_½z was significantly decreased by 11%. Following coadministration of valaciclovir and MMF, aciclovir pharmacokinetic parameters were not significantly modified except for t_max (about 0.5 hour shorter with MMF). MPA and MPAG pharmacokinetic parameters were not significantly modified following coadministration of MMF with valaciclovir or aciclovir except for MPAG AUC, which was decreased by 12% with valaciclovir. Our results are similar to those reported in the literature, except for MPAG AUC. In urine, following coadministration of aciclovir and MMF, aciclovir CL_R was significantly decreased by 19%. Competition between MPAG and aciclovir for renal tubular secretion could partly explain this phenomenon. Following coadministration of valaciclovir and MMF, aciclovir CL_R was not significantly modified.

Conclusion: In healthy subjects, interactions are observed after coadministration of MMF and aciclovir, but the extent of the interactions is unlikely to be of clinical significance. These interactions should be investigated in patients with abnormal renal function.

Keywords: Immunosuppressants, drug interactions; Drug interactions; Immunosuppressants, pharmacokinetics; Mycophenolate mofetil, pharmacokinetics; Mycophenolate mofetil, drug interactions; Antivirals, drug interactions; Antivirals, pharmacokinetics; Aciclovir, pharmacokinetics; Aciclovir, drug interactions; Valaciclovir, drug interactions; Valaciclovir, pharmacokinetics

Document Type: Research article

Affiliations: 1: 1 Pharmacie Clinique, Hôpital Necker-Enfants Malades, Paris, France 2: 2 GlaxoSmithKline Inc., Research Triangle Park, North Carolina, USA 3: 3 GlaxoSmithKline, Marly-Le-Roi, France

Publication date: 2004-01-01

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