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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 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., Results and Discussion: 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., 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.

Antiviral drug interactions are a particular problem among immuno-compromised patients because these patients are often receiving multiple different drugs, i.e. antiretroviral drugs and drugs effective against herpesvirus. The combination of zidovudine and other antiretroviral drugs with different adverse event profiles, such as didanosine, zalcitabine and lamivudine, appears to be well tolerated and no relevant pharmacokinetic interactions have been detected. The adverse effects of didanosine and zalcitabine (i.e. peripheral neuropathy and pancreatitis) should be taken into account when administering these drugs with other drugs with the same tolerability profile. Coadministration of zidovudine and ganciclovir should be avoided because of the high rate of haematological intolerance. In contrast, zidovudine and foscarnet have synergistic effect and no pharmacokinetic interaction has been detected. No major change in zidovudine pharmacokinetics was seen when the drug was combined with aciclovir, famciclovir or interferons. However, concomitant use of zidovudine and ribavirin is not advised. Although no pharmacokinetic interaction was documented when didanosine was first administered with intravenous ganciclovir, recent studies have shown that concentration of didanosine are increased by 50% or more when coadministered with intravenous or oral ganciclovir. The mechanism of this interaction has not been elucidated. Lack of pharmacokinetic interaction was demonstrated between foscarnet and didanosine or ganciclovir. Clinical trials have shown that zidovudine can be administered safely with paracetamol (acetaminophen), nonsteroidal anti-inflammatory drugs, oxazepam or codeine. Inhibition of zidovudine glucuronidation has been demonstrated with fluconazole, atovaquone, valproic acid (valproate sodium), methadone, probenecid and inosine pranobex; however, the clinical consequences of this have not been fully investigated. No interaction has been demonstrated with didanosine per se but care should be taken of interaction with the high pH buffer included in the tablet formulation. Drugs that need an acidic pH for absorption (ketoconazole, itraconazole but not fluconazole, dapsone, pyrimethamine) or those that can be chelated by the ions of the buffer (quinolones and tetracyclines) should be administered 2 hours before or 6 hours after didanosine. Very few interaction studies have been undertaken with other antiviral drugs. Coadministration of zalcitabine with the antacid 'Maalox' results in a reduction of its absorption. Dapsone does not influence the disposition of zalcitabine. Cotrimoxazole (trimethoprim-sulfamethoxazole) causes an increase in lamivudine concentrations by 43%. Saquinavir, delavirdine and atevirdine appeared to be metabolised by cytochrome P450 and interactions with enzyme inducers or inhibitors could be anticipated. Some studies showed that interferons can reduce drug metabolism but only a few studies have evaluated the pathways involved. Further studies are required to better understand the clinical consequences of drug interactions with antiviral drugs. Drug-drug interactions should be considered in addition to individual drug clinical benefits and safety profiles.

Cardiovascular diseases occur frequently in patients with renal failure. Any pharmacokinetic impairment in these diseases should be considered when individualizing drug therapy. The pharmacokinetics of new cardiovascular drugs in uraemic patients are reviewed: alpha- and beta-blocking agents, ACE inhibitors, centrally acting antihypertensive agents, calcium antagonists, antiarrhythmic agents and inotropic agents. Guidelines are proposed for adjustment of dosage regimens as a function of renal impairment. Renal or extrarenal elimination of drugs and their metabolites, and the activity of the latter, are taken into account. The disposition of new drugs such as flestolol, alacepril, delapril, propafenone, milrinone or enoximone, is not well documented in patients with renal failure. Further characterizations of the elimination of these compounds are needed and the potential therapeutic or toxic effects of the metabolites require evaluation to determine whether the dosage needs to be adjusted. Until such investigations are performed, those drugs should not be used in uraemic patients; if no therapeutic alternative is available, clinical controls are necessary at regular intervals. Relationships between pharmacological or therapeutic effects and drug plasma concentrations should be evaluated for such long term use drugs. The knowledge of a plasma concentration therapeutic window is important to provide information which will be useful in determining appropriate drug dosage in renal failure.

Many drugs are eliminated via the renal route and the usual dose must be modified in patients with severe renal impairment. This review is an attempt to supply physicians with the more recent data on pharmacokinetic studies of new drugs administered in uraemic patients. The review is in 2 parts: the first indicates the results of studies on the pharmacokinetics of antibiotic agents, antifungal, antiviral and antiulcer drugs, and nonsteroidal anti-inflammatory drugs. Special mention is made of epoetin (recombinant human erythropoietin). It was not possible to give all the information collected from the recent literature: since mild renal failure has little effect on the fate of a drug, pharmacokinetic data obtained in patients with a creatinine clearance (CLCR) of more than 50 ml/min has been omitted. Both the text and tables give recommendations for treating patients with moderate renal insufficiency (CLCR of about 50 ml/min), more severe renal impairment (CLCR between 10 and 50 ml/min) and end-stage renal failure with a very low creatinine clearance (below 10 ml/min). It was not possible to give uniform recommendations (i.e. reducing the dose while maintaining the same interval, or giving the same dose and prolonging the interval). This article follows the recommendations of the authors, which may vary for drugs in similar classes.

The pharmacokinetics of fleroxacin and its metabolites following a single oral dose of fleroxacin 400mg were examined in 6 healthy subjects and 24 patients with various degrees of renal insufficiency. Plasma and urine samples, collected at various times after administration, were assayed by high performance liquid chromatography (HPLC). In healthy subjects, Cmax was 6.8 +/- 0.7 mg/L; tmax = about 1h, t1/2 = 14 +/- 2h, total clearance = 4.86 +/- 0.72 L/h and the percentage of unchanged fleroxacin excreted in urine in 48 hours was 48 +/- 4% (HPLC). Plasma concentrations of metabolites were very low and accounted for no more than 5% of the levels of unchanged fleroxacin. In uraemic patients Cmax did not change, whatever the degree of renal failure; tmax was increased in patients with a glomerular filtration rate below 0.6 L/h, and Vd/f was independent of the severity of renal failure. These data suggest that bioavailability of the drug is unchanged. In uraemic patients t1/2 was prolonged and AUC multiplied by a factor of 2 to 3. A linear relationship was found between total and renal clearances of fleroxacin and creatinine clearance. Accumulation of N-demethyl-fleroxacin and N-oxide-fleroxacin was very high in uraemic patients, due to slow formation of these metabolites and decreased urinary elimination. Dialysance of fleroxacin and of its metabolites was approximately 3.6 to 4.8 L/h. These findings suggest that fleroxacin dosage may need to be reduced in patients with severe renal disease; in haemodialysed patients, treated every 2 days, a single dose of fleroxacin 400mg is recommended at the end of each dialysis session.

The pharmacokinetics of fleroxacin and its main metabolites, N-demethyl-fleroxacin and N-oxide-fleroxacin, were studied in 12 elderly patients aged 63 to 88 years. Plasma and urine samples collected at different times after drug administration were analysed by a specific reverse phase high performance liquid chromatography (HPLC) method. The peak plasma concentration (Cmax) of fleroxacin was 15.6 +/- 1.6 mg/L, time to Cmax (tmax) was about 3h, elimination half-life (t1/2) was 16 +/- 1h and the percentage of unchanged fleroxacin excreted in urine was 39 +/- 3% of the dose. The plasma concentrations of metabolites were very low and accounted for no more than 4% of the concentration of unchanged fleroxacin. Plasma parameters were mainly correlated with age and weight; urinary parameters were correlated with creatinine clearance. Compared with results in younger normal patients, no significant change in the t1/2 of fleroxacin or metabolites was observed. Assuming that the bioavailability (f) is complete, the apparent volume of distribution (Vd/f) was lower in elderly (0.9 +/- 0.1 L/kg) than in younger patients (1.3 +/- 0.1 L/kg) and a 2-fold decrease in apparent total clearance (CL/f) was noted (2.58 +/- 0.42 vs 4.86 +/- 0.72 L/h); plasma concentrations were consequently higher in elderly patients. Compared with patients with renal failure, the pharmacokinetics of fleroxacin and metabolites in the elderly were similar to those of patients with mild to moderate renal insufficiency. On the basis of the findings of this single dose study, no major dosage adjustments are needed for patients of this age range except for those with creatinine clearance less than 30 ml/min.