Pharmacology Journal

Valaciclovir (Valtrex^™ ), the l-valyl ester of aciclovir, is licensed for the treatment of herpes zoster (shingles), a disease occurring commonly in the elderly. After oral administration, valaciclovir is rapidly converted to aciclovir with a bioavailability 3–5 times greater than from oral aciclovir. Aciclovir is renally eliminated with tubular secretion forming a significant component. Probenecid, which inhibits organic anion secretion in the renal tubule, decreases the renal clearance of aciclovir. Both probenecid and cimetidine, which inhibit tubular cation secretion, decrease aciclovir renal clearance following oral valaciclovir..

Digoxin, a drug of low therapeutic index, is commonly prescribed in the elderly. In most patients more than 80% of digoxin is excreted unchanged in the urine. Interactions with drugs which affect digoxin renal clearance have been identified, some of which may be due to effects on tubular secretion. As there is the potential for an interaction between digoxin and aciclovir following oral valaciclovir, we have studied the pharmacokinetics of the drugs alone and in combination in healthy volunteers.

Subjects

Twelve healthy volunteers (seven males, five females) of mean age 31  years (range 22–44 years) and mean weight 75  kg (range 51–99  kg) participated in the study. Exclusion criteria included evidence of a cardiac conduction disorder on a 12-lead ECG and an estimated creatinine clearance <70  ml  min⁻¹. All subjects gave written informed consent, and the protocol was approved by the Wellcome Protocol Review Committee and the King’s Healthcare Research Ethics Committee.

Study design

This open, randomized, four-period crossover study was carried out at the Wellcome Clinical Investigations Unit, King’s College Hospital, London. Volunteers fasted overnight prior to drug administration on the first blood sampling day. Oral valaciclovir, 1000  mg, was administered on one occasion, and on another, with digoxin, 0.75  mg being given 12  h before and 0.75  mg being given with valaciclovir. Digoxin was not dosed to steady state because of the ethical concerns of giving multiple doses to healthy volunteers. Blood was sampled before and 15, 30, 45 and 60  min and 1.5, 2.0, 2.5, 3.0, 4.0, 5.0, 6.0, 8.0 and 12  h after the valaciclovir dose for plasma aciclovir assay. Urine was also collected up to 12  h, weighed and a 10  ml aliquot was frozen at −20°  C for aciclovir assay.

Digoxin was administered as 2×0.75  mg doses alone on one occasion, and on another, with oral valaciclovir, 1000  mg three times daily for 8 days, with valaciclovir started 12  h before the first digoxin dose. The valaciclovir daily dose was that recommended for the treatment of shingles. Blood samples were taken before and 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 4.0, 6.0, 8.0, 12, 24, 32, 48, 72, 96 and 168  h following the second digoxin dose for plasma digoxin assay. Urine was collected up to 24  h after the second digoxin dose, weighed, and a 10  ml aliquot was frozen at −20°  C for digoxin assay.

Adverse experiences were recorded, 12-lead ECGs were performed before dosing and at 24  h after the second digoxin dose, and continuous lead II ECG monitoring was performed on all subjects for 24  h after digoxin doses.

Assays

Plasma and urine aciclovir determinations were made using double antibody radioimmunoassay (r.i.a.), which is a modification of the original method. The lower limits of quantitation (LLOQs) were 0.01  μg  ml⁻¹ (0.04  μm ) for plasma and 0.025  μg  ml⁻¹ (0.11  μm ) for urine, with separate inter- and intra-assay precision shown by coefficients of variation (CVs) of <10% for plasma and <11% for urine.

Plasma and urine digoxin determinations were made using a competitive r.i.a. procedure (Phoenix International Life Sciences Inc.). The LLOQ was 0.10  ng  ml⁻¹ for both plasma and urine, with combined inter- and intra-assay precision shown by CVs of ≤10% for plasma and ≤12% for urine.

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‘cl12\Pharmacokinetic and statistical analysis

‘ol17\‘cc20p0,1,10,12\‘eh‘nd8\‘tageqend‘tagNon-compartmental pharmacokinetic parameters were determined for plasma aciclovir and digoxin. The area under the plasma concentration-time curve from zero to the last measurable plasma concentration AUC(0, t ) was estimated by the linear trapezoidal rule. AUC(0, ∞) was calculated as AUC(0, t )+Ct/λ_z where C_t is the last quantifiable concentration at time t. λ_z was obtained by log linear regression, using the terminal portion of the log of the concentration-time curve. Digoxin C_max and AUC(0, ∞) were corrected for pre-dose concentration (C₀ ) as the plasma profile after the second dose was not at steady state (half-life of approximately 40  h). Digoxin AUC(0, 24  h ) was also measured, but was not corrected. The elimination half-life (t_1/2 ) was calculated as ln 2/λ_z. The apparent volume of distribution, V_z/F, was calculated as Dose. AUC(0, ∞)/λ_z. The aciclovir dose was calculated from the molar equivalents in the valaciclovir dose. Urinary recovery (Ae) was calculated as the product of urine concentrations and weights (assuming density of 1  g  ml⁻¹ ). Renal clearance (CL_R ) was calculated as Ae/AUC where Ae is the amount of drug excreted unchanged in urine, and AUC and Ae were measured over 12 and 24  h for aciclovir and digoxin respectively.

Pharmacokinetic parameters following digoxin or valaciclovir alone or in combination were subjected to analysis of variance. All parameters except t_max were log-transformed prior to analysis. Data were back-transformed to provide a point estimate with 95% confidence interval (CI) for the ratio in pharmacokinetic parameters between treatments. Differences between t_max medians were estimated (with 95% CIs) using a method based on the Wilcoxon Signed Rank test.

Filed under: Clinical Pharmacology