Pharmacokinetics of valaciclovir

Abstract

Introduction

Aciclovir has been shown to be effective in the treatment of disease caused by herpesviruses (e.g. herpes zoster), as well as in prophylaxis against acquisition of infection [e.g. in cytomegalovirus (CMV)- seronegative transplant recipients] and suppression of latent disease (e.g. genital herpes).1 However, the poor oral bioavailability of aciclovir necessitates high doses and frequent administration.1 This finding is particularly true for the less susceptible Herpesviridae, such as varicella zoster virus. In many instances, intravenous administration is required for satisfactory response. The prodrug, valaciclovir, is synthesized by the addition of a naturally occurring amino acid, l-valine, to aciclovir.2 This structural modification results in the achievement of plasma aciclovir concentrations superior to those obtained with oral aciclovir, while requiring less frequent administration.3 Valaciclovir is at least as effective as oral aciclovir for a number of indications.4^,5

Development of valaciclovir

Aciclovir is absorbed slowly and incompletely from the human gastrointestinal tract. Oral bioavailability is reported to be between 15%–30%.6 The poor absorption is considered to be a result of characteristics of the drug itself and not its delivery vehicle.7 Peak plasma concentrations are achieved 1.5–2.5 h after oral administration. The exact mechanism of absorption of aciclovir is not fully characterized. Some studies in animals and humans have noted a reduction in bioavailability with increasing doses, raising the possibility of a saturable absorptive process.8^,9 Others have found near-proportional increases in area under the curve (AUC) with increasing doses in the 100–800 mg range, which would not support the presence of a saturable absorptive process in the dosage range used clinically.7

Despite in vitro activity against herpesviruses and a favourable toxicity profile, many potential applications of aciclovir are limited by its poor absorption. Even treatment of the more susceptible herpes viruses (HSV-1 and -2), requires oral doses to be taken three to five times daily. Such schedules may result in poor adherence, even for short courses of therapy, with associated therapeutic failure. Aciclovir resistance is problematic primarily in immunocompromised patients.10 Constant exposure to the low aciclovir levels potentially selects for these strains. Treatment of herpes zoster and chickenpox is particularly problematic with five-times-daily oral dosing. Consequently, treatment of varicella-zoster in immune compromised patients generally requires intravenous therapy to assure the achievement of therapeutic aciclovir levels.

Several approaches initially were tried to improve upon the oral bioavailability of aciclovir. Early modifications included alteration in the purine ring. However, this chemical change was associated with increased toxicity, possibly due to the accumulation of the phosphorylated forms of the parent compound.11 Addition to the hydroxyl ‘tail’ of aciclovir prevented phosphorylation of the compound until its release as free aciclovir. Experiments with esters of a number of amino acids were favourable, with the valine-esterified compounds demonstrating the best properties.12

Addition of the valine moiety to aciclovir results in a substrate for active transport mechanisms in the human intestine. The valine-esterified compound has similar polarity and ionization at physiological pH, thus, an improvement in passive diffusion-related uptake would not be expected.12 Early studies confirmed a greater increase in bioavailability when l-valine derivatives were administered compared with d-valine derivatives, suggesting an enzyme-mediated process.12 Investigations utilizing human gastrointestinal cell lines demonstrated increased mucosal-to-serosal (but not vice versa) transport of valaciclovir compared with aciclovir, supporting the presence of carrier-mediated transport.13 It was also noted that valaciclovir inhibited the uptake of substrates of dipeptide transporters, such as cefalexin.13^,14 Further investigations in cell lines implicated the human intestinal peptide transporter (hPEPT-1) as a carrier protein.15^–18 hPEPT-1 is expressed constitutively in the intestine and serves to transport dietary-derived dipeptides and drugs with dipeptide-like structures (e.g. β-lactams).

Two studies in human volunteers, however, suggest that hPEPT-1 may not be the sole or even primary transporter of valaciclovir. One study examined the effect of the co-administration of the competitive substrate cefalexin on valaciclovir absorption.19 Whereas patients receiving cefalexin had reduced serum levels of aciclovir, the magnitude of reduction was much less than that anticipated from in vitro studies utilizing hPEPT-1. Another study attempted to correlate expression levels of a number of gastrointestinal transporters with valaciclovir pharmacokinetics.20 Duodenal biopsy was performed on healthy volunteers and the expression of 281 proteins was analysed. Subjects were then administered single-dose aciclovir and valaciclovir and the pharmacokinetics were assessed. Expression levels of hPEPT-1 correlated poorly with valaciclovir pharmacokinetics, whereas levels of another dipeptide transporter, HPT-1, correlated well. Subsequent in vitro transport studies demonstrated that HPT-1 is as efficient a transporter of valaciclovir as hPEPT-1. These studies demonstrate the need to validate in vitro and animal studies in humans.

After uptake of valaciclovir, hydrolysis of the valine moiety to yield aciclovir is rapid and nearly complete. Maximum peak levels of valaciclovir in the serum after oral administration are ∼3% of corresponding aciclovir levels, and AUC and urinary recovery average 1% of that seen with aciclovir.21^,22 Serum levels of valaciclovir decline to undetectable within 3 h.21 The metabolism of valaciclovir to aciclovir probably occurs within the gut lumen prior to absorption, in the small intestine after uptake but before entry into the portal blood system, and in the liver before entry into systemic circulation. (Figure 1) Hydrolysis of valaciclovir in the gut lumen is evidenced by the recovery of aciclovir in faeces without evidence of valaciclovir.21In vitro studies have demonstrated a high rate of conversion of valaciclovir into aciclovir within intestinal cells.13^,15 Studies in rats have found rapid hydrolysis in liver homogenates, as well as a novel enzyme, valaciclovir hydrolase, that accounted for the majority of activity.23^,24

This increased uptake and rapid hydrolysis results in significantly greater systemic aciclovir levels with oral valaciclovir compared with oral aciclovir. The mean bioavailability of aciclovir in healthy volunteers after administration of a single 1g dose of valaciclovir is 54.2%.21 This value is in contrast to an average bioavailability of 15%–30% with oral aciclovir.25 Single- and multiple-dose studies in healthy volunteers have demonstrated three- to five-fold increases in bioavailability for valaciclovir relative to aciclovir.22 Administration of the lowest doses of valaciclovir (250 mg four times daily) resulted in C_max and AUC values comparable to high-dose oral aciclovir (800 mg five times daily). Valaciclovir 2000 mg four times daily provided similar AUC to intravenous aciclovir (10 mg/kg every 8 h). The oral bioavailability of valaciclovir in patients with advanced HIV disease or neutropenic cancer is similar to that observed in healthy volunteers.26^,27 However, aciclovir C_max and AUC have been observed to be increased in healthy geriatric patients compared with younger volunteers.28 These results are consistent with the expected reduced creatinine clearance in the elderly population.

The distribution, intracellular kinetics, metabolism, and excretion of aciclovir after its entry into the systemic circulation are identical whether it is administered as oral aciclovir, oral valaciclovir, or intravenous aciclovir. Aciclovir demonstrates minimal protein binding (∼15%) and distributes well into most body tissues including the CSF, where levels ∼50% of plasma concentrations.6 Aciclovir undergoes initial intracellular phosphorylation primarily by virally encoded thymidine kinases, creating a concentration gradient that increases its uptake in infected cells compared with non-infected cells.29 Subsequent phosphorylation to the active triphosphate form is performed by cellular enzymes. A small fraction of aciclovir is metabolized in the liver, with the major metabolite, 9-carboxy-methoxymethylguanine, representing ∼10% of the total dose of aciclovir.25 Most aciclovir is eliminated unchanged in the urine via glomerular filtration and tubular secretion.25

The clinical utility of valaciclovir has been demonstrated in the treatment and prophylaxis of infection associated with herpesviruses. Valaciclovir 1000 mg three times daily significantly accelerated resolution of zoster-associated pain and reduced occurrence of post-herpetic neuralgia compared with aciclovir 800 mg five times daily in immunocompetent patients >50 years old.30 Valaciclovir dosed twice daily was equivalent to aciclovir dosed five times daily in the treatment of initial and recurrent genital herpes.31 Once-daily valaciclovir has also been shown effectively to suppress recurrences of genital herpes, and recently, to reduce transmission in comparison with placebo.32^,33 Outcomes with valaciclovir and aciclovir were similar in the treatment of herpes zoster ophthalmicus, and in the prevention of herpes simplex mucositis in bone marrow transplant patients.34^,35 Compared with aciclovir, valaciclovir significantly delayed time to CMV antigenaemia in a group of CMV-seropositive heart transplant patients.36 In comparison with intravenous ganciclovir in a group of allogeneic bone marrow transplant patients, valaciclovir was equally efficacious in prevention of CMV infection and disease.37

Conclusion

Valaciclovir represents a clear advance in the prevention and treatment of viral infection. The significant improvement in aciclovir AUC associated with valaciclovir often spares the use of intravenous aciclovir and reduces the frequency of administration, improving patient adherence.

Figure 1. Pharmacokinetics of aciclovir and valaciclovir. Valaciclovir (Val-ACV) is a prodrug of the antiviral compound aciclovir (ACV). Oral administration of valaciclovir yields systemic aciclovir through uptake by dipeptide transporters in the gut lumen and hydrolysis by esterases present in the gut lumen, intestinal wall and liver. >95% of administered valaciclovir is converted into aciclovir.

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References