Valacyclovir clinical pharmacology

# Clinical Pharmacology

## Pharmacokinetics
The pharmacokinetics of valacyclovir and acyclovir after oral administration of VALTREX 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.
Absorption and Bioavailability: After oral administration, valacyclovir hydrochloride is rapidly absorbed from the gastrointestinal tract and nearly completely converted to acyclovir and Lvaline by first-pass intestinal and/or hepatic metabolism.
The absolute bioavailability of acyclovir after administration of VALTREX is 54.5%  9.1% as determined following a 1gram oral dose of VALTREX and a 350mg intravenous acyclovir dose to 12 healthy volunteers. Acyclovir bioavailability from the administration of VALTREX 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 VALTREX to healthy adult volunteers are presented in Table 3. There was a less than doseproportional increase in acyclovir maximum concentration (Cmax) and area under the acyclovir concentrationtime curve (AUC) after singledose and multipledose administration (4 times daily) of VALTREX 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.

## 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 Lvaline by firstpass 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 singledose administration of 1 gram of VALTREX, 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 VALTREX to 12 healthy subjects was approximately 255  86 mL/min which represents 42% of total acyclovir apparent plasma clearance.
The plasma elimination halflife of acyclovir typically averaged 2.5 to 3.3 hours in all trials of VALTREX in subjects with normal renal function.

## Specific Populations
Reduction in dosage is recommended in patients with renal impairment .
Following administration of VALTREX to subjects with ESRD, the average acyclovir halflife is approximately 14 hours. During hemodialysis, the acyclovir halflife is approximately 4 hours. Approximately onethird of acyclovir in the body is removed by dialysis during a 4hour hemodialysis session. Apparent plasma clearance of acyclovir in subjects on dialysis was 86.3  21.3 mL/min/1.73 m2 compared with 679.16  162.76 mL/min/1.73 m2 in healthy subjects.
Administration of VALTREX to subjects with moderate (biopsyproven cirrhosis) or severe (with and without ascites and biopsyproven cirrhosis) liver disease indicated that the rate but not the extent of conversion of valacyclovir to acyclovir is reduced, and the acyclovir halflife is not affected. Dosage modification is not recommended for patients with cirrhosis.
In 9 subjects with HIV-1 disease and CD4+ cell counts less than 150 cells/mm3 who received VALTREX 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.
After single-dose administration of 1 gram of VALTREX in healthy geriatric subjects, the halflife 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 multipledose oral administration of VALTREX in geriatric subjects varied with renal function. Dose reduction may be required in geriatric patients, depending on the underlying renal status of the patient .
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 . Acyclovir pharmacokinetic parameter estimates following a 20mg/kg dose are provided in Table 4.

## Drug Interactions
When VALTREX is coadministered with antacids, cimetidine and/or probenicid, digoxin, or thiazide diuretics in patients with normal renal function, the effects are not considered to be of clinical significance (see below). Therefore, when VALTREX 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 VALTREX (1 gram) were unchanged by coadministration of a single dose of antacids (Al3+ or Mg++).
Cimetidine: Acyclovir Cmax and AUC following a single dose of VALTREX (1 gram) increased by 8% and 32%, respectively, after a single dose of cimetidine (800 mg).
Cimetidine Plus Probenecid: Acyclovir Cmax and AUC following a single dose of VALTREX (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 VALTREX 1 gram 3 times daily, and the pharmacokinetics of acyclovir after a single dose of VALTREX (1 gram) was unchanged by coadministration of digoxin (2 doses of 0.75 mg).
Probenecid: Acyclovir Cmax and AUC following a single dose of VALTREX (1 gram) increased by 22% and 49%, respectively, after probenecid (1 gram).
Thiazide Diuretics: The pharmacokinetics of acyclovir after a single dose of VALTREX (1 gram) were unchanged by coadministration of multiple doses of thiazide diuretics.