Valacyclovir is an antiviral drug active against α-herpes viruses [see Microbiology ( 12.4)] .
The pharmacokinetics of valacyclovir and acyclovir after oral administration of valacyclovir have been investigated in 14 volunteer trials involving 283 adults and in 3 trials involving 112 pediatric subjects aged 1 month to less than 12 years.
Pharmacokinetics in Adults
Absorption and Bioavailability:After oral administration, valacyclovir hydrochloride is rapidly absorbed from the gastrointestinal tract and nearly completely converted to acyclovir and L-valine by first-pass intestinal and/or hepatic metabolism.
The absolute bioavailability of acyclovir after administration of valacyclovir is 54.5% ± 9.1% as determined following a 1-gram oral dose of valacyclovir and a 350-mg intravenous acyclovir dose to 12 healthy volunteers. Acyclovir bioavailability from the administration of valacyclovir is not altered by administration with food (30 minutes after an 873 Kcal breakfast, which included 51 grams of fat).
Acyclovir pharmacokinetic parameter estimates following administration of valacyclovir to healthy adult volunteers are presented in Table 3. There was a less than dose-proportional increase in acyclovir maximum concentration (C max) and area under the acyclovir concentration-time curve (AUC) after single-dose and multiple-dose administration (4 times daily) of valacyclovir from doses between 250 mg to 1 gram.
There is no accumulation of acyclovir after the administration of valacyclovir at the recommended dosage regimens in adults with normal renal function.
Table 3. Mean (±SD) Plasma Acyclovir Pharmacokinetic Parameters Following Administration of Valacyclovir to Healthy Adult Volunteers
aAdministered 4 times daily for 11 days.
ND = not done.
Distribution:The binding of valacyclovir to human plasma proteins ranges from 13.5% to 17.9%. The binding of acyclovir to human plasma proteins ranges from 9% to 33%.
Metabolism: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 valacyclovir, average plasma valacyclovir concentrations observed were 0.5, 0.4, and 0.8 mcg/mL in subjects with hepatic dysfunction, renal insufficiency, and in healthy subjects who received concomitant cimetidine and probenecid, respectively.
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, 46% and 47% of administered radioactivity was recovered in urine and feces, respectively, over 96 hours. Acyclovir accounted for 89% of the radioactivity excreted in the urine. Renal clearance of acyclovir following the administration of a single 1-gram dose of valacyclovir to 12 healthy subjects was approximately 255 ± 86 mL/min which represents 42% of total acyclovir apparent plasma clearance.
The plasma elimination half-life of acyclovir typically averaged 2.5 to 3.3 hours in all trials of valacyclovir in subjects with normal renal function.
Specific Populations
Patients with Renal Impairment:Reduction in dosage is recommended in patients with renal impairment [see Dosage and Administration ( 2.4), Use in Specific Populations ( 8.5, 8.6)].
Following administration of valacyclovir to subjects 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 subjects on dialysis was 86.3 ± 21.3 mL/min/1.73 m 2compared with 679.16 ± 162.76 mL/min/1.73 m 2in healthy subjects.
Patients with Hepatic Impairment:Administration of valacyclovir to subjects with moderate (biopsy-proven cirrhosis) or severe (with and without ascites and biopsy-proven cirrhosis) liver disease indicated that the rate but not 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.
Patients with HIV-1 Disease:In 9 subjects with HIV-1 disease and CD4+ cell counts less than 150 cells/mm 3who received valacyclovir 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 subjects.
Geriatric Patients:After single-dose administration of 1 gram of valacyclovir in healthy geriatric subjects, the half-life of acyclovir was 3.11 ± 0.51 hours compared with 2.91 ± 0.63 hours in healthy younger adult subjects. The pharmacokinetics of acyclovir following single- and multiple-dose oral administration of valacyclovir in geriatric subjects varied with renal function. Dose reduction may be required in geriatric patients, depending on the underlying renal status of the patient [see Dosage and Administration ( 2.4), Use in Specific Populations ( 8.5, 8.6)].
Pediatric Patients:Acyclovir pharmacokinetics have been evaluated in a total of 98 pediatric subjects (aged 1 month to less than 12 years) following administration of the first dose of an extemporaneous oral suspension of valacyclovir [see Adverse Reactions ( 6.2), Use in Specific Populations ( 8.4)] . Acyclovir pharmacokinetic parameter estimates following a 20-mg/kg dose are provided in Table 4.
Table 4. Mean (±SD) Plasma Acyclovir Pharmacokinetic Parameter Estimates Following First-Dose Administration of 20 mg/kg Valacyclovir Oral Suspension to Pediatric Subjects vs. 1-Gram Single Dose of Valacyclovir to Adults
aHistorical estimates using pediatric pharmacokinetic sampling schedule.
Drug Interaction Studies
When valacyclovir is coadministered with antacids, cimetidine and/or probenecid, digoxin, or thiazide diuretics in patients with normal renal function, the effects are not considered to be of clinical significance (see below). Therefore, when valacyclovir is coadministered with these drugs in patients with normal renal function, no dosage adjustment is recommended.
Antacids:The pharmacokinetics of acyclovir after a single dose of valacyclovir (1 gram) were unchanged by coadministration of a single dose of antacids (Al3 +or Mg ++).
Cimetidine:Acyclovir C maxand AUC following a single dose of valacyclovir (1 gram) increased by 8% and 32%, respectively, after a single dose of cimetidine (800 mg).
Cimetidine Plus Probenecid:Acyclovir C maxand AUC following a single dose of valacyclovir (1 gram) increased by 30% and 78%, respectively, after a combination of cimetidine and probenecid, primarily due to a reduction in renal clearance of acyclovir.
Digoxin:The pharmacokinetics of digoxin were not affected by coadministration of valacyclovir 1 gram 3 times daily, and the pharmacokinetics of acyclovir after a single dose of valacyclovir (1 gram) was unchanged by coadministration of digoxin (2 doses of 0.75 mg).
Probenecid:Acyclovir C maxand AUC following a single dose of valacyclovir (1 gram) increased by 22% and 49%, respectively, after probenecid (1 gram).
Thiazide Diuretics:The pharmacokinetics of acyclovir after a single dose of valacyclovir (1 gram) were unchanged by coadministration of multiple doses of thiazide diuretics.