Clinical Pharmacokinetics of Acyclovir

Laskin, Oscar L.

doi:10.2165/00003088-198308030-00001

Cited by 127 publications

(58 citation statements)

References 57 publications

(32 reference statements)

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“…This value is in the range of F values estimated for adults (20% for the 200-mg dose, 12% for the 800-mg dose) for various pharmaceutical forms (tablets, solution, etc.) (11,24). From a practical point of view, it implies that for a given dosing regimen, mean acyclovir concentrations are about eight times lower after oral administration than after intravenous administration to the same patients, so that doses administered by the oral route must be about eight times higher than those administered by the intravenous route to ensure the same exposure.…”

Section: Discussionmentioning

confidence: 99%

“…Numerous previous pharmacokinetic studies have shown that acyclovir disposition is adequately described by a one-compartment (oral route) or a twocompartment (intravenous route) open model with first-order rate constants (2,11,14). Therefore, only these pharmacokinetic models were considered.…”

Section: Methodsmentioning

confidence: 99%

“…Elaboration of the covariate model was based on the following rationale. Acyclovir is primarily eliminated by the renal route, by glomerular filtration and tubular secretion (11). Because of knowledge of the evolution of renal function after birth, acyclovir clearance was expected to exhibit a linear or hyperbolic relationship with age and especially with PCA.…”

Section: Methodsmentioning

confidence: 99%

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Pharmacokinetics of Oral Acyclovir in Neonates and in Infants: a Population Analysis

Tod

Lokiec

Bidault

et al. 2001

Antimicrob Agents Chemother

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Acyclovir is approved for the treatment of herpes simplex virus (HSV) and varicella-zoster virus (VZV)infections in children by the intravenous and oral routes. However, its use by the oral route in children younger than 2 years of age is limited due to a lack of pharmacokinetic data. The objectives of the present study were to determine the typical pharmacokinetics of an oral suspension of acyclovir given to children younger than 2 years of age and the interindividual variabilities in the values of the pharmacokinetic parameters in order to support the proposed dosing regimen (24 mg/kg of body weight three times a day for patients younger than 1 month of age or four times a day otherwise). Children younger than age 2 years with HSV or VZV infections were enrolled in a multicenter study. Children were treated for at least 5 days with an acyclovir oral suspension. Plasma samples were obtained at steady state, before acyclovir administration, and at 2, 3, 5, and 8 h after acyclovir administration. Acyclovir concentrations were measured by radioimmunoassay. The data were analyzed by a population approach. Data for 79 children were considered in the pharmacokinetic study (212 samples, 1 to 5 samples per patient). Acyclovir clearance was related to the estimated glomerular filtration rate, body surface area, and serum creatinine level. The volume of distribution was related to body weight. The elimination half-life decreased sharply during the first month after birth, from 10 to 15 h to 2.5 h. Bioavailability was 0.12. The interindividual variability was less pronounced when the parameters were normalized with respect to body weight. Hence, dosage adjustment by body weight is recommended for this population. Simulations showed that the length of time that acyclovir remains above the 50% inhibitory concentration during a 24-h period was more than 12 h for HSV but not for VZV. The proposed dosing regimen seems adequate for the treatment of HSV infections, while for the treatment of VZV infections, a twofold increase in the dose seems necessary for children older than age 3 months.Acyclovir is currently used for the prevention and treatment of herpes simplex virus (HSV) and varicella-zoster virus (VZV) infections (7). It is available at different dosages in the form of tablets, oral suspensions (containing 200, 400, or 800 mg in 10 ml), and injectable solutions. About 20 clinical studies have documented the use of acyclovir in children (for a review, see reference 24). Most frequently, acyclovir has been administered intravenously. Hintz et al. (8) recommended 10 mg/kg of body weight every 8 h (q8h) for neonates, while Blum et al.(2) recommended 250 mg/m 2 (for HSV infections) and 500 mg/m 2 (for HSV encephalitis and VZV infections) q8h in children between 3 months and 12 years of age. Owing to the ease of its administration and dosage adjustment, the oral suspension is also used in children. The recommended dosage in neonates is 100 mg four times a day (q.i.d.) (HSV infections) and 200 mg q.i.d. (for VZV infections). I...

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Pharmacokinetics of Oral Acyclovir in Neonates and in Infants: a Population Analysis

Tod

Lokiec

Bidault

et al. 2001

Antimicrob Agents Chemother

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“…Venous blood samples were taken just before valaciclovir dosing and then at 15, 30, 45, 60, 75, and 90 min and at 2, 2.5, 3,4,5,6,8,10,12,16, and 24 h after administration. Samples taken up to 3 h after valaciclovir dosing were assayed for valaciclovir.…”

Section: Methodsmentioning

confidence: 99%

Multiple Interactions of Cimetidine and Probenecid with Valaciclovir and Its Metabolite Acyclovir

Bony

Tod

Bidault

et al. 2002

Antimicrob Agents Chemother

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The effects of probenecid and cimetidine on the pharmacokinetics of valaciclovir and its metabolite acyclovir have been investigated. Twelve healthy male volunteers participated in this open single-dose study with a four-way-crossover randomized and balanced design. At the first of four administrations, volunteers in four groups received 1 g of valaciclovir alone, valaciclovir with 1 g of probenecid, valaciclovir with 800 mg of cimetidine, or valaciclovir with a combination of probenecid and cimetidine. At three subsequent administrations, drug regimens were alternated among groups so that each group received each regimen. Probenecid and cimetidine increased the mean maximum concentrations in serum (C max ) of valaciclovir by 23 and 53% and the areas under the concentration-time curves (AUC) for valaciclovir by 22 and 73%, respectively; probenecid and cimetidine also increased the mean acyclovir C max by 22 and 8% and its AUC by 48 and 27%, respectively. The combination had a greater effect than either drug alone. Their effects may be due to competitive inhibition of membrane transport of valaciclovir and acyclovir in the liver and kidney. Neither cimetidine nor probenecid affected the absorption of valaciclovir. Both probe drugs reduced the rate of valaciclovir metabolism but not its extent. These pharmacokinetic modifications did not affect the tolerability of valaciclovir.Valaciclovir (Valtrex) is the L-valine ester of acyclovir and is extensively converted to the antiherpetic compound acyclovir by hepatic first-pass metabolism following oral administration. Its bioavailability as valaciclovir is three-to fivefold greater than acyclovir's oral bioavailability (13). The active metabolite acyclovir is excreted 85% unchanged in the urine, with the rate of renal clearance (CL R ) being three times that of the glomerular filtration rate, indicating that renal excretion has a significant tubular-secretion component. Valaciclovir and acyclovir, which have anionic and cationic forms in plasma, are secreted by organic anion and cation transporters. Acyclovir CL R is reduced by probenecid (6), which was thought to be due to inhibition of the renal tubular secretion of acyclovir by the anionic pathway.We investigated the effects of probenecid and cimetidine on valaciclovir pharmacokinetics, as these drugs have been reported to inhibit the metabolism of some compounds and the active membrane transport of a number of organic anions and cations (4,6,8,9,12). Additionally, we examined the effects of probenecid and cimetidine on the pharmacokinetics of acyclovir. The drug interactions at the renal level were modeled as a function of the concentrations of the interaction drugs in plasma in order to characterize more precisely their mechanisms and potential consequences. MATERIALS AND METHODS Study design.We employed an open, randomized, balanced, crossover study design with four drug treatments separated by intervals of at least 1 week. Twelve healthy male volunteers (age range, 22 to 43 years; weight range, 54 to 111 kg) par...

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“…81,83 Absorption of oral acyclovir is inconsistent and may be <30%; 84 thus for patients with more severe disease, a higher dose may be required. Intravenous administration should be used when severe odynophagia limits oral intake or when the patient has not responded to high-dose oral therapy.…”

Section: Herpes Simplex Virusmentioning

confidence: 99%

The therapy of gastrointestinal infections associated with the acquired immunodeficiency syndrome

Wilcox

Mönkemüller

1997

Aliment Pharmacol Ther

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Although there have been dramatic strides in the therapy of human immunodeficiency virus infection over the last few years, the number of infected people world‐wide is tremendous and, at least in developing countries, continues to expand. Complications which involve the gastrointestinal tract are common in these patients, because the gut is a major site for involvement by opportunistic infections and neoplasms in patients with the acquired immunodeficiency syndrome. It is important to recognize the clinical spectrum of gastrointestinal diseases, as well as the appropriate and most cost‐effective diagnostic strategies, as therapies for a number of these disorders are both widely available and highly effective. This review summarizes the major gastrointestinal infections which are seen in patients with the acquired immunodeficiency syndrome, and their treatment.

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Clinical Pharmacokinetics of Acyclovir

Cited by 127 publications

References 57 publications

Pharmacokinetics of Oral Acyclovir in Neonates and in Infants: a Population Analysis

Pharmacokinetics of Oral Acyclovir in Neonates and in Infants: a Population Analysis

Multiple Interactions of Cimetidine and Probenecid with Valaciclovir and Its Metabolite Acyclovir

The therapy of gastrointestinal infections associated with the acquired immunodeficiency syndrome

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