Valaciclovir pharmacokinetics and molecular data

Pharmacokinetics
Mechanism of antiviral action Antiviral activities Drug resistance Absorption/bioavailability Distribution Metabolism Elimination End-stage renal disease Geriatrics Pediatrics Liver disease HIV disease

Mechanism of antiviral action
Valacyclovir hydrochloride is rapidly converted to acyclovir which has demonstrated antiviral activity against herpes simplex virus types 1 (HSV-1) and 2 (HSV-2) and varicella-zoster virus (VZV) both in vitro and in vivo. The inhibitory activity of acyclovir is highly selective due to its affinity for the enzyme thymidine kinase (TK) encoded by HSV and VZV. This viral enzyme converts acyclovir into acyclovir monophosphate,a nucleotide analogue. The monophosphate is further converted into diphosphate by cellular guanylate kinase and into triphosphate by a number of cellular enzymes. In vitro, acyclovir triphosphate stops replication of herpes viral DNA. This is accomplished in 3 ways: 1) competitive inhibition of viral DNA polymerase, 2) incorporation and termination of the growing viral DNA chain, and 3) inactivation of the viral DNA polymerase. The greater antiviral activity of acyclovir against HSV compared with VZV is due to its more efficient phosphorylation by the viral TK. Return to top

Antiviral activities
The quantitative relationship between the in vitro susceptibility of herpesviruses to antivirals and the clinical response to therapy has not been established in humans, and virus sensitivity testing has not been standardized. Sensitivity testing results, expressed as the concentration of drug required to inhibit by 50% the growth of virus in cell culture (IC50), vary greatly depending upon a number of factors. Using plaque-reduction assays, the IC50 against herpes simplex virus isolates ranges from 0.02 to 13.5 mcg/mL for HSV-1 and from 0.01 to 9.9 mcg/mL for HSV-2. The IC50 for acyclovir against most laboratory strains and clinical isolates of VZV ranges from 0.12 to 10.8 mcg/mL. Acyclovir also demonstrates activity against the Oka vaccine strain of VZV with a mean IC50 of 1.35 mcg/mL. Return to top

Drug resistance
Resistance of HSV and VZV to acyclovir can result from qualitative and quantitative changes in the viral TK and/or DNA polymerase. Clinical isolates of VZV with reduced susceptibility to acyclovir have been recovered from patients with AIDS. In these cases, TK-deficient mutants of VZV have been recovered. Resistance of HSV and VZV to acyclovir occurs by the same mechanisms. While most of the acyclovir-resistant mutants isolated thus far from immunocompromised patients have been found to be TK-deficient mutants, other mutants involving the viral TK gene (TK partial and TK altered) and DNA polymerase have also been isolated. TK-negative mutants may cause severe disease in immunocompromised patients. The possibility of viral resistance to valacyclovir (and therefore, to acyclovir) should be considered in patients who show poor clinical response during therapy. Return to top

Absorption/bioavailability
The absolute bioavailability of acyclovir after administration of Valaciclovir is 54.5% ± 9.1% as determined following a 1-gram oral dose of Valaciclovir and a 350-mg intravenous acyclovir dose to 12 healthy volunteers. Acyclovir bioavailability from the administration of Valaciclovir is not altered by administration with food (30 minutes after an 873 Kcal breakfast, which included 51 grams of fat). There was a lack of dose proportionality in acyclovir maximum concentration (Cmax) and area under the acyclovir concentration-time curve (AUC) after single-dose administration of 100 mg, 250 mg, 500 mg, 750 mg, and 1 gram of Valaciclovir to 8 healthy volunteers. The mean Cmax (± SD) was 0.83 (± 0.14), 2.15 (± 0.50), 3.28 (± 0.83), 4.17 (± 1.14), and 5.65 (± 2.37) mcg/mL, respectively; and the mean AUC (± SD) was 2.28 (± 0.40), 5.76 (± 0.60), 11.59 (± 1.79), 14.11 (± 3.54), and 19.52 (± 6.04) hr•mcg/mL, respectively. There was also a lack of dose proportionality in acyclovir Cmax and AUC after the multiple-dose administration of 250 mg, 500 mg, and 1 gram of Valaciclovir administered 4 times daily for 11 days in parallel groups of 8 healthy volunteers. The mean Cmax (± SD) was 2.11 (± 0.33), 3.69 (± 0.87), and 4.96 (± 0.64) mcg/mL, respectively, and the mean AUC (± SD) was 5.66 (± 1.09), 9.88 (± 2.01), and 15.70 (± 2.27) hr•mcg/mL, respectively. There is no accumulation of acyclovir after the administration of valacyclovir at the recommended dosage regimens in healthy volunteers with normal renal function. Return to top

Distribution
The binding of valacyclovir to human plasma proteins ranged from 13.5% to 17.9%. Return to top

Metabolism
After oral administration, valacyclovir hydrochloride is rapidly absorbed from the gastrointestinal tract. Valacyclovir is converted to acyclovir and L-valine by first-pass intestinal and/or hepatic metabolism. Acyclovir is converted to a small extent to inactive metabolites by aldehyde oxidase and by alcohol and aldehyde dehydrogenase. Neither valacyclovir nor acyclovir is metabolized by cytochrome P450 enzymes. Plasma concentrations of unconverted valacyclovir are low and transient, generally becoming non-quantifiable by 3 hours after administration. Peak plasma valacyclovir concentrations are generally less than 0.5 mcg/mL at all doses. After single-dose administration of 1 gram of Valaciclovir, average plasma valacyclovir concentrations observed were 0.5, 0.4, and 0.8 mcg/mL in patients with hepatic dysfunction, renal insufficiency, and in healthy volunteers who received concomitant cimetidine and probenecid, respectively. Return to top

Elimination
The pharmacokinetic disposition of acyclovir delivered by valacyclovir is consistent with previous experience from intravenous and oral acyclovir. Following the oral administration of a single 1-gram dose of radiolabeled valacyclovir to 4 healthy subjects, 45.60% and 47.12% of administered radioactivity was recovered in urine and feces over 96 hours, respectively. Acyclovir accounted for 88.60% of the radioactivity excreted in the urine. Renal clearance of acyclovir following the administration of a single 1-gram dose of Valaciclovir to 12 healthy volunteers was approximately 255 ± 86 mL/min which represents 41.9% of total acyclovir apparent plasma clearance. The plasma elimination half-life of acyclovir typically averaged 2.5 to 3.3 hours in all studies of Valaciclovir in volunteers with normal renal function. Return to top

End-stage renal disease
Following administration of Valaciclovir to volunteers with ESRD, the average acyclovir half-life is approximately 14 hours. During hemodialysis, the acyclovir half-life is approximately 4 hours. Approximately one third of acyclovir in the body is removed by dialysis during a 4-hour hemodialysis session. Apparent plasma clearance of acyclovir in dialysis patients was 86.3 ± 21.3 mL/min/1.73 m2, compared with 679.16 ± 162.76 mL/min/1.73 m2 in healthy volunteers. Reduction in dosage is recommended in patients with renal impairment. Return to top

Geriatrics
After single-dose administration of 1 gram of Valaciclovir in healthy geriatric volunteers, the half-life of acyclovir was 3.11 ± 0.51 hours, compared with 2.91 ± 0.63 hours in healthy volunteers. The pharmacokinetics of acyclovir following single- and multiple-dose oral administration of Valaciclovir in geriatric volunteers varied with renal function. Dose reduction may be required in geriatric patients, depending on the underlying renal status of the patient. Return to top

Pediatrics
Valacyclovir pharmacokinetics have not been evaluated in pediatric patients. Return to top

Liver disease
Administration of Valaciclovir to patients with moderate (biopsy-proven cirrhosis) or severe (with and without ascites and biopsy-proven cirrhosis) liver disease indicated that the rate butnot the extent of conversion of valacyclovir to acyclovir is reduced, and the acyclovir half-life is not affected. Dosage modification is not recommended for patients with cirrhosis. Return to top

HIV disease
In 9 patients with HIV disease and CD4 cell counts <150 cells/mm3 who received Valaciclovir at a dosage of 1 gram 4 times daily for 30 days, the pharmacokinetics of valacyclovir and acyclovir were not different from that observed in healthy volunteers. Return to top