Evaluation of pharmacokinetic interactions after oral administration of mycophenolate mofetil and valaciclovir or aciclovir to healthy subjects.
OBJECTIVE
To investigate a potential pharmacokinetic interaction between mycophenolate mofetil (MMF) and aciclovir or valaciclovir.


METHODS
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 800 mg alone; (ii) valaciclovir 2 g alone; (iii) MMF 1 g alone; (iv) valaciclovir 2 g + MMF 1 g; and (v) aciclovir 800 mg + MMF 1 g. 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 infinity), terminal elimination half-life (t1/2z), peak concentration (Cmax) and time to Cmax (tmax). The renal clearance (CLR) 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.


CONCLUSIONS
Aciclovir Cmax, tmax and AUC infinity were significantly increased by 40%, 0.38 hour and 31%, respectively, following coadministration of aciclovir and MMF, whereas aciclovir t1/2z was significantly decreased by 11%. Following coadministration of valaciclovir and MMF, aciclovir pharmacokinetic parameters were not significantly modified except for tmax (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 infinity, 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 CLR 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 CLR was not significantly modified.


CONCLUSIONS
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.
Gimenez
François
F
Pharmacie Clinique, Hôpital Necker-Enfants Malades, Paris, France. francois.gimenez@nck.ap-hop-paris.fr
Foeillet
Estelle
E
Bourdon
Olivier
O
Weller
Steve
S
Garret
Christophe
C
Bidault
Roselyne
R
Singlas
Eric
E
D000212:Acyclovir / Q000031:analogs & derivatives* / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000328:Adult; D000998:Antiviral Agents / Q000493:pharmacokinetics* / Q000494:pharmacology*; D019540:Area Under Curve; D002853:Chromatography, Liquid; D018592:Cross-Over Studies; D004347:Drug Interactions; D020719:Glucuronides / Q000378:metabolism; D006207:Half-Life; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics* / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000077483:Valacyclovir; D014633:Valine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics* / Q000494:pharmacology*
D000998:Antiviral Agents; D020719:Glucuronides; D007166:Immunosuppressive Agents; D014633:Valine; D009173:Mycophenolic Acid; D000077483:Valacyclovir; D000212:Acyclovir