Department of Clinical Pharmacy, School of Pharmacy, University of California, San Francisco, CA, USA
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Abstract |
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Keywords: herpesviruses, bioavailability, absorption, aciclovir
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Introduction |
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Development of valaciclovir |
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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.1518 hPEPT-1 is expressed constitutively in the intestine and serves to transport dietary-derived dipeptides and drugs with dipeptide-like structures (e.g. ß-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.21 In 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
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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
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Conclusion |
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Footnotes |
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References |
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