a Department of Internal Medicine, Haematology, University Hospital, S-751 85 Uppsala; b Department of Haematology, Huddinge University Hospital, Karolinska Institute, Huddinge, Sweden; c GlaxoSmithKline Research and Development, Research Triangle Park, North Carolina, USA
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Abstract |
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Introduction |
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Aciclovir in intravenous (iv) and oral dose regimens is efficacious as acute treatment and prophylaxis of HSV and VZV, and prophylaxis of CMV infections.6 The clinical efficacy of oral aciclovir in high-risk immunocompromised patients is limited by its low bioavailability (1220%).7 Improved systemic aciclovir exposures can be attained by iv administration, which, though effective, is sometimes associated with unwanted effects (e.g. renal toxicity and to a lesser extent neurotoxicity) in some patients and requires careful maintenance of hydration and urine output. These effects are thought to relate to high peak plasma concentrations.8,9 Furthermore, iv treatment with aciclovir is expensive, requiring considerable resource of hospital staff, and the invasive route (risk of phlebitis at infusion site) of administration decreases the patient's quality of life.10 Patients who require iv treatment are usually hospitalized and their movement restricted. Outpatient management of clinically stable immunocompromised patients at risk of herpesvirus infection or reactivation, using effective oral antiviral treatment would be a more practical and cost-effective approach.
Valaciclovir (Valtrex), the oral prodrug of aciclovir, can produce plasma aciclovir exposures similar to those observed after iv aciclovir administration in immunocompetent subjects.11,12 By application of computer simulation techniques to data from multiple dose studies characterizing the pharmacokinetics of aciclovir after valaciclovir administration in healthy adult volunteers, it is estimated that the standard iv aciclovir regimens of 5 and 10 mg/kg tds would be similar in terms of daily aciclovir exposures [area under the plasma concentrationtime curve (AUC) over 24 h] to valaciclovir dosages of 1000 mg tds and 2000 mg qds, respectively.11
Studies to estimate the bioavailability of aciclovir after valaciclovir in a range of immunocompromised populations are desirable now that it is undergoing clinical efficacy evaluation in such populations for the management of a range of herpesvirus infections. We compared the systemic plasma aciclovir exposures, as determined by the area under the plasma concentrationtime curve (AUC0) at steady state, in neutropenic cancer patients following the administration of oral valaciclovir 1000 mg and iv aciclovir 5 mg/kg in tds regimens. These dosages were selected because they were expected to produce similar systemic aciclovir exposures according to computer simulations, because iv aciclovir 5 mg/kg tds is widely used for the management of HSV infections in immunocompromised individuals and because valaciclovir 1000 mg tds is the approved regimen worldwide for the treatment of herpes zoster.
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Materials and methods |
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Patients 1865 years of age were eligible for participation if they had undergone high-dose chemotherapy for cancer (e.g. acute leukaemia, lymphoma, breast cancer or in preparation for autologous stem cell transplantation), had an absolute neutrophil count at screening <0.5 x 109/L, tested negative for HIV and were able to take oral medication. Patients were not required to have evidence of an active herpesvirus infection in order to participate. Patients were excluded if they had creatinine clearance <50 mL/ min, had impaired synthetic liver function [aspartate transaminase (AST) or alanine transaminase (ALT) more than five times upper limit of normal values] and/or evidence of portal-systemic shunting, gastrointestinal dysfunction or any unstable clinical condition that could affect drug absorption and disposition, or who had a history of hypersensitivity to aciclovir or valaciclovir.
Study design and procedures
The study was conducted at two sites in Sweden (University Hospital, Uppsala and Huddinge University Hospital, Karolinska Institute, Huddinge) after approval by the appropriate ethics committees and in compliance with the Helsinki Declaration of 1964 (amended 1989). All patients gave written and informed consent before the start of the study. At pre-study screening, a brief medical history was obtained from physical examination, 12-lead electrocardiogram, haematology, clinical chemistry and urinalysis. Creatinine clearance was estimated by the Cockcroft Gault formula.13 Patients refrained from consuming foods or beverages containing caffeine from midnight before and throughout each study day. All patients were randomly assigned by means of a computer-generated randomization schedule, in blocks of two, to receive oral valaciclovir or iv aciclovir (Zovirax) during the first period of this two-period crossover study. The order of iv or oral dosing to patients was allocated by opening sealed envelopes corresponding to the subject and treatment number in sequence. Patients received either iv aciclovir 5 mg/kg by 1 h continuous infusion every 8 h for seven doses followed 24 h later by crossover to oral valaciclovir 1000 mg (2 x 500 mg tablets) every 8 h for seven doses or vice versa (study drugs were supplied by Glaxo Wellcome). Patients were fasted from midnight before administration of the seventh dose in each treatment period. Blood samples were obtained after the last dose at the times indicated below.
Sample collection and analysis
Blood samples (5 mL each) were taken via a dedicated lumen (i.e. not the same as that used for infusion) of a double or triple lumen central venous catheter just before administration of the last dose of the study drug and then at the following times after: 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10 and 12 h. The plasma was separated and frozen at 20°C before analysis for aciclovir by scintillation proximity radioimmunoassay.14 Samples collected from this study were diluted 101000 times into the concentration range of the standard curve samples (1.490 ng/mL, or 6.2400 nM). The intra- and inter-assay variabilities (expressed as percentage coefficient of variation) were <14%. The lower limit of quantification for aciclovir in plasma was 14 ng/mL (0.062 µM) before dilution.
Pharmacokinetic analysis
Plasma aciclovir concentration data were analysed by standard non-compartmental analysis using model 200 (extravascular administration) and model 202 (constant infusion) of WinNonlin version 1.0 (Scientific Consulting, Inc., Apex, NC, USA). The observed peak plasma aciclovir concentration (Cmax) and the time to reach peak concentration (tmax) were taken directly from the observed concentrationtime data. For the iv infusion of aciclovir, tmax was taken as the time at the end of the infusion period. The first- order rate constant for elimination () of aciclovir was obtained from regression of data in the terminal, log-linear portion of the concentrationtime profile for each patient. The elimination half-life (tH) was calculated as tH = ln2/
. The AUC0
over a steady-state dosing interval of duration
(where
= 8 h) was calculated using the linear trapezoidal rule. To accurately determine AUC, the concentration at time zero (C0) was set using the equation C0 = Cpre-dose*e
t (where t denotes the time elapsed between the pre-dose sample and subsequent dose administration).
The systemic clearance of aciclovir following iv administration (CLiv) was calculated as CLiv = dose/(AUC08). The apparent oral clearance (CL/F) of aciclovir following valaciclovir administration was calculated similarly. Since aciclovir constitutes 69.4% of valaciclovir, this fraction represents the maximal amount of aciclovir obtainable from complete absorption and conversion of valaciclovir. Thus, 694 mg was used as the dose amount in calculation of CL/F. Assuming that systemic aciclovir clearance was constant from both regimens for a given patient, the absolute bioavailability (F) for aciclovir following valaciclovir administration was calculated as F = CLiv/[CL/F].
Power calculation and statistical analysis
The objective of the study was to assess the relative bioavailability of aciclovir from oral valaciclovir 1000 mg and iv aciclovir (5 mg/kg). The AUC0 calculated for each treatment was regarded as the critical endpoint for comparison of aciclovir plasma exposure. A minimum of 12 subjects completing both treatment periods was considered adequate to detect, with at least 80% power and significance level of 5%, a difference of 30% in AUC0
, assuming variability (standard deviation of log-transformed values) no greater than 0.27 for AUC0
of aciclovir. A study with similar power, using the same assumptions, but adequate to detect a difference of 20% in AUC would have more than doubled the required sample size. The statistical analysis compared log-transformed Cmax, AUC0
,
and tH values for the two regimens. Differences between log-transformed variables were back-transformed to obtain ratios on the original scale.
All patients with pharmacokinetic data were included in the statistical analysis; however, only patients who completed both treatment periods provided pharmacokinetic data for the treatment comparison. Cmax, AUC0, tH and
were analysed separately, using the analysis of variance (ANOVA). Estimates for each treatment were based on the ratio of the geometric least square means (SAS LSmean) with the associated 90% CI (SAS Institute Inc., Cary, NC, USA). Full error diagnostics were performed on the Studentized residuals from the analysis of variance model to confirm that the assumptions underlying the model were not violated.
Safety assessments
The medical history, physical examination and electrocardiogram were repeated at the end of each treatment period. Haematology, clinical chemistry and urinalysis tests were also performed. In addition, tests to detect early signs of thrombotic microangiopathy-like syndrome (haemoglobin, reticulocytes, platelets, schistocytes in blood smear, prothrombin time, activated partial thrombin time, serum creatinine, haptoglobin, lactate dehydrogenase and C-reactive protein) were performed at the end of each treatment period. Adverse events were monitored from the start of dosing until 72 h after the second treatment period. Each adverse event was categorized by severity (mild, moderate or severe) and the physician's considered relationship to study drug (probable, possible, remote or none).
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Results |
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Average steady-state plasma concentrations of aciclovir versus time following administration of iv aciclovir and oral valaciclovir in the 13 patients who completed both treatments are presented in the Figure. The results of the non-compartmental pharmacokinetic analysis and statistical comparisons are summarized in Table II
. Consistent with the route of administration, the time to peak plasma aciclovir concentration (tmax) (median, range) was shorter after iv aciclovir (1.00 h, range: 0.471.08) than after oral valaciclovir (2.00 h, range: 1.003.08). The peak aciclovir plasma concentration (Cmax, mean ± s.d.) was lower after oral valaciclovir (26.6 ± 10.5 µM) compared with iv aciclovir (34.0 ± 11.9 µM). This difference in Cmax was statistically significant (oral/iv treatment ratio = 0.75; 90% CI = 0.600.94; P = 0.044). The plasma aciclovir elimination half-life (tH) was 2.83 ± 0.91 h after valaciclovir administration and 2.44 ± 0.62 h following iv aciclovir; this difference was of borderline statistical significance (P = 0.076).
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Oral valaciclovir and iv aciclovir were well tolerated in these neutropenic cancer patients. There was no causal relationship between any reported adverse event and treatment. A total of 45 adverse events were observed in 14 of the 15 patients; the majority (40/45) were of mild or moderate intensity. The incidence of adverse events during treatment with oral valaciclovir was 17 events (1.31 events per treatment course) compared with 28 events (1.87 events per treatment course) with iv aciclovir. The most common adverse events included infection (10 events), fever (five events), diarrhoea and headache (four events each), nausea and mucositis of unknown aetiology (three events each). Five adverse events observed in four patients were of severe intensity: infection, diarrhoea, fever, cough and chest pain. No clinically apparent herpesvirus infections were observed.
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Discussion |
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Aciclovir bioavailability and disposition after valaciclovir administration to the immunocompromised patients in our study were similar to previous observations from an absolute bioavailability study conducted in healthy volunteers who received 1000 mg valaciclovir and 350 mg iv aciclovir (Table III).12 The small average increase in aciclovir tH from oral valaciclovir is probably attributable to continued absorption of aciclovir formed from valaciclovir in the gut lumen; however, the difference is not considered clinically significant. Overall, our findings indicate that the absorption of valaciclovir, its rate and extent of conversion to aciclovir, and the disposition of aciclovir in neutropenic patients are comparable to those of healthy volunteers and other immunocompromised patient groups.11,12,16,17
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Immunocompromised patients with acute herpes zoster may be hospitalized for administration of iv aciclovir (usually 10 mg/kg but sometimes 500 mg/m2 or 5 mg/kg tds), because of the risks of severe disease, dissemination or other complications. After new lesions have ceased forming, marking the end of VZV replication and acute viraemia, the risk of dissemination passes.19 If the patient is then clinically stable in all other respects, hospitalization may no longer be necessary or preferred. However, the practice of switching to oral aciclovir (800 mg five times daily) upon hospital discharge in less severely ill subjects means a reduction in systemic aciclovir exposure of two- to four-fold. Continued treatment of acute herpes zoster with oral valaciclovir in an outpatient setting should maintain aciclovir plasma exposures substantially higher than those achieved with oral aciclovir and comparable to low dose iv aciclovir. Since controlled clinical trials evaluating valaciclovir as treatment for herpes zoster in cancer or other immunocompromised patients have not been completed, the optimal duration of antiviral therapy has not been defined. An earlier placebo-controlled study of iv aciclovir (500 mg/m2) in immunocompromised patients with zoster demonstrated efficacy with 7 days of treatment.20
Oral valaciclovir and iv aciclovir were well tolerated in our study. There was no apparent causal relationship between any adverse event and either of the two treatments. The incidence of adverse events was 1.23 and 1.86 events per treatment course for oral valaciclovir and iv aciclovir, respectively. In large, controlled trials evaluating valaciclovir for the acute treatment and prophylaxis (suppression) of HSV infections and herpes zoster in a range of patient populations, the safety profile of valaciclovir was comparable to those of aciclovir and placebo.21,22
When used in high-dose regimens for prophylaxis of CMV infection and disease in organ transplant recipients, valaciclovir 8000 mg daily is generally well tolerated with adverse reactions being mild, reversible and not usually treatment limiting.22 The only adverse reactions to occur more frequently in valaciclovir recipients in a large randomized, placebo-controlled trial in renal transplantation were hallucination and confusion.23 The cause of such neurological reactions, many of which occurred early in therapy or even during dialysis, and were also observed with iv aciclovir, is considered multifactorial.23,24 Causes may include disequilibrium syndrome associated with dialysis, over-exposure to aciclovir, insufficient dosage reduction for renal impairment and concomitant drug use.9,23,24 Renal toxicity previously reported with iv aciclovir and occasionally presenting alongside a neurological adverse event is suggested to be more closely associated with higher peak aciclovir concentrations (Cmax) rather than a generalized over-exposure.8,9 The observed increase in occurrence of a thrombotic microangiopathy-like syndrome reported in a study of patients with advanced HIV disease and receiving valaciclovir 8000 mg daily for prolonged periods, for prevention of CMV disease,25 has not been observed at rates differing from background in other immunocompromised populations, including solid organ and bone marrow transplant recipients.22 The safety of valaciclovir 1000 mg daily in HIV-seropositive subjects requiring prophylaxis for genital HSV outbreaks has been demonstrated in subjects treated for 1 year.26
In summary, we have shown that oral valaciclovir 1000 mg tds provides comparable systemic exposure, but reduced peak aciclovir concentrations, to iv aciclovir 5 mg/kg tds in immunocompromised cancer patients. The clinical status of many immunocompromised patients usually improves long before their immunity recovers, such that oral medication can be tolerated. The use of oral medication avoids the risk of iv catheter-related complications such as phlebitis and infection. In addition, iv aciclovir administration gives higher peak plasma aciclovir concentrations, which are associated with an increased risk of nephrotoxicity.8 Therefore the reduced peak aciclovir concentrations from valaciclovir may provide an added safety margin. Thus, when clinically appropriate, oral valaciclovir may serve as a convenient and cost-saving alternative to iv aciclovir. Outpatient management of herpesvirus infections in clinically stable immunocompromised patients is easier with oral formulations and may offer improved quality of life for patients.
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Acknowledgments |
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Notes |
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References |
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Received 4 September 2000; returned 4 December 2000; revised 16 January 2001; accepted 9 February 2001