HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text (PDF) All Versions of this Article: 0091270008319708v1 48/8/995    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Request Reprints Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Sitar, D. S. Articles by Bow, E. J. Search for Related Content PubMed PubMed Citation Articles by Sitar, D. S. Articles by Bow, E. J. Social Bookmarking                   What's this?

Acyclovir Bioavailability in Patients With Acute Myelogenous Leukemia Treated With Daunorubicin and Cytarabine

From the Section of Infectious Diseases (Dr Aoki, Dr Bow), Section of Clinical Pharmacology (Dr Sitar, Dr Aoki), Department of Internal Medicine (Dr Sitar, Dr Aoki, Dr Bow), Department of Medical Microbiology (Dr Aoki), and Department of Pharmacology and Therapeutics (Dr Sitar, Dr Aoki), University of Manitoba, Winnipeg, Manitoba, Canada, and CancerCare Manitoba, Winnipeg, Manitoba, Canada (Dr Bow).

Address for reprints: D. Sitar, PhD, FCP, Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Manitoba, A220-753 McDermot Avenue, Winnipeg, Manitoba R3E 0T6, Canada; e-mail: sitar{at}cc.umanitoba.ca.

Key Words: Acyclovir • bioavailability • leukemia • herpes simplex virus infection • cancer

Oral acyclovir therapy is considered to be safe and effective for the management of herpes virus infections.¹ It is administered for suppression of herpes simplex virus disease during remission-induction therapy in patients with acute myelogenous leukemia (AML). It is not known whether cytotoxic therapy regimens administered to cancer patients affect the bioavailability of orally administered acyclovir as a therapeutic intervention. Standard remission-induction therapy for AML usually consists of an anthracycline (usually daunorubicin) and cytarabine.² Some investigators have moved to the use of cytarabine for remission-induction and postremission consolidation in daily doses 30 to 60 times higher than previous regimens, resulting in possibly higher remission rates and prolonged leukemia-free survivals.³ However, these benefits are offset by increased infections and integumental damage. Protocol-related malabsorption of D-xylose has been observed among recipients of cytarabine therapy.⁴

Our hypothesis is that high-dose cytarabine postremission consolidation therapy for patients with AML in first complete remission will result in malabsorption of oral acyclovir due to chemotherapy-induced injury of the gastrointestinal tract and be reflected by reduced bioavailability.

	MATERIAL AND METHODS

TOP MATERIAL AND METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
Patients
Adult patients receiving consolidation treatment for AML with high-dose cytarabine were eligible for this study based on a history of herpes simplex virus infection confirmed by IgG seropositivity. Adequate renal function was ensured by a serum creatinine concentration less than 110 µmol/L. Patients were considered ineligible to participate if they had exhibited hypersensitivity to acyclovir; had active herpes simplex virus lesions requiring acyclovir therapy; had a serum creatinine concentration greater than 110 µmol/L; were unable to swallow oral medications; had previous bowel surgery, including the creation of a colostomy, ileostomy, or a bowel resection; or required tube feeding.

This protocol was approved by the University of Manitoba Faculty Committee on the Use of Human Subjects in Research, and volunteers provided written informed consent.

Study Design
This investigation was a repeated-measures crossover design, with 4 study days per patient volunteer. Patients were randomized for order of acyclovir single-dose administration (oral dose as 4 x 200-mg tablets with 250 mL cold water or intravenous dose as 250 mg acyclovir/m² over 60 minutes by infusion pump) on days –2 and –1 relative to cytarabine administration. Two intravenous administrations of acyclovir were used to control for the possibility that the remission-induction chemotherapy could affect the subsequent disposition of the antiviral agent. Blood samples were taken from an indwelling intravenous catheter prior to and at 0.5, 1, 2, 4, 6, 8, and 12 hours after the acyclovir dose. Blood was centrifuged to separate the serum, which was immediately frozen and stored at –20°C until analyzed for its drug concentration. High-dose cytarabine (1.5 g/m²) was administered intravenously over 1 hour every 12 hours for 6 days. The acyclovir pharmacokinetic studies of acyclovir oral and intravenous disposition were repeated starting on day 14, with administration of the alternate dosage route on day 15 after the start of remission-induction chemotherapy. The patient randomization and blood sampling protocol was the same as that used prior to the administration of the remission-induction chemotherapy. In all arms of the study, complete 24-hour urine collections were used to evaluate drug elimination. After determination of volume, urine aliquots were frozen and stored at –20°C until analyzed for their content of acyclovir.

Drug Assay
Acyclovir was analyzed in samples of blood serum and urine by reverse-phase high-performance liquid chromatography with ultraviolet detection at 254 nm.⁵ Briefly, the limit of detection was 31 ng/mL for serum analyses and 18.75 mg/L for urine analyses. Standard curves for serum ranged from 31 to 2000 ng/mL and from 18.75 to 300 mg/L for urine samples. Urine and serum specimens outside of the calibration curve limits were rediluted and analyzed as described previously. The coefficient of variation for this assay was 7.7% over a time interval of 3 months.

Data Analyses
Pharmacokinetic analyses were completed with the computer program WinNonlin (Version 3.1, Pharsight Corp, Cary, North Carolina). Serum drug concentration versus time curve data after intravenous doses were evaluated using the 2-compartment open model with zero-order infusion for acyclovir dose administration. This model provided the best fit of the observed data for all patients. Serum drug concentration versus time curve data after oral doses were evaluated using the noncompartmental model because this approach provided the best fit to the observed data. Absolute bioavailability was evaluated. Bioavailability was determined from the area under the serum acyclovir concentration versus time curve from t = 0 to , using the trapezoidal rule to evaluate serum concentration versus time data after oral and intravenous doses. Residual area under the serum concentration versus time curve was determined by dividing the last measured serum acyclovir concentration by the terminal disposition rate constant for that dose.⁶ Data are reported as mean and standard deviation unless otherwise indicated. Pharmacokinetic data were evaluated statistically using the paired t test between treatment days for the same route of drug administration. A 1-tailed paired t test was used to evaluate the bioavailability reduction subsequent to cytarabine high-dose induction chemotherapy, in keeping with the hypothesis being tested.

	RESULTS

TOP MATERIAL AND METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
Six patients were recruited to this study, and 1 withdrew after completing the precytarabine therapy acyclovir bioavailability arm of the protocol. Thus, data are presented for the remaining 5 patients who completed both arms of the protocol. Patients were 41 ± 15 years old (range, 18-55 years), weighed 83 ± 20 kg (range, 59-103 kg), and had a body surface area of 1.91 ± 0.25 m² (range, 1.61-2.14 m²) and a creatinine clearance of 84 ± 24 mL/min (range, 54-112 mL/min).

The pharmacokinetic analyses of the disposition of acyclovir pre- and postcytarabine are presented in Table I. The cytarabine high-dose postremission consolidation therapy exposure did not affect the pharmacokinetic disposition of intravenously administered acyclovir. Oral administration of acyclovir also did not indicate a change in pharmacokinetic apparent volume of distribution uncorrected for bioavailability or serum half-life. Median time to peak serum concentration was 2 hours and did not change subsequent to cytarabine therapy. Acyclovir C_max after cytarabine therapy decreased and approached statistical significance. The apparent total body clearance uncorrected for bioavailability was more rapid after the high-dose remission-induction cytarabine chemotherapy. Renal clearance of acyclovir did not show a decrement subsequent to cytarabine chemotherapy. The absolute bioavailability of acyclovir decreased by 38% after the cytarabine chemotherapy exposure.

Urinary excretion of unchanged drug in the 24-hour urine specimens was 81.9% ± 12.7% prior to cytarabine therapy and 87.4% ± 14.2% postcytarabine therapy after intravenous acyclovir administration (P = .43). After oral acyclovir administration, 24-hour urine specimens contained 9.2% ± 4.2% and 9.9% ± 5.2% unchanged drug pre- and postcytarabine chemotherapy (P = .78). Urine excretion data did not reflect the reduction in absolute acyclovir bioavailability determined from the serum concentration versus time data subsequent to high-dose cytarabine chemotherapy.

	DISCUSSION

TOP MATERIAL AND METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
The reported absolute bioavailability of oral acyclovir is low, approximating 15% to 30%.⁷ Disposition in cancer patients after intravenous infusion is well described by a 2-compartment open kinetic model, with an apparent volume of distribution and total body clearance consistent with that described in the present study.⁸ Patients in this study had a mean 42% to 48% longer terminal disposition half-life than previously reported after the intravenous infusion, but this pharmacokinetic parameter was more rapid after the oral dose administration and consistent with published reports.^8,9

Renal excretion is the predominant elimination pathway for acyclovir and includes a component of active tubular secretion as well as glomerular filtration. No dosage adjustment is recommended for a creatinine clearance of greater than 50 mL/min.¹⁰ We have no explanation for the apparently reduced renal clearance of acyclovir after oral administration and prior to remission-induction therapy with cytarabine. An incomplete urine collection during that arm of the study could explain this finding. Because renal clearance after remission-induction therapy was similar to that observed after the intravenous acyclovir doses, it seems reasonable to conclude that cytarabine therapy does not impair renal elimination of acyclovir doses. The mean acyclovir bioavailability from this study, based on serum drug concentrations prior to cytarabine administration, is within the range reported previously.¹ However, it is important to note that the reduced oral acyclovir bioavailability subsequent to cytarabine administration would not have been detected if it had been evaluated solely by urinary excretion data after the oral dose administration. The reduction in oral bioavailability is coincident with the period of maximal cytotoxic therapy-induced intestinal epithelial damage.^2,4,11

View larger version (9K): [in this window] [in a new window]   Figure 1. Serum acyclovir concentration versus time data for 5 patients completing the acyclovir bioavailability study. Data were collected prior to remission-induction chemotherapy (rectangles) and after remission-induction chemotherapy (triangles). The upper panel presents data resulting from intravenous acyclovir administration, and the lower panel presents data resulting from oral acyclovir administration. Data are presented as mean values ± SD.

	ACKNOWLEDGEMENTS

TOP MATERIAL AND METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
We thank Ms Ruth Loewen, RN, for excellent nursing assistance, the patients who volunteered to participate in this study, and Mr Thomas Davie for technical assistance with the chromatographic analyses of patient samples.

Financial disclosure: This study was funded in part by the Wellcome Foundation.

	REFERENCES

TOP MATERIAL AND METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 

1. Laskin OL. Clinical pharmacokinetics of acyclovir. Clin Pharmacokinet. 1983;8: 187-201.[Web of Science][Medline] [Order article via Infotrieve]

2. Bow EJ, Kilpatrick MG, Scott BA, Clinch JJ, Cheang MS. Acute myeloid leukemia in Manitoba: the consequences of standard "7+3" remission-induction therapy followed by high dose cytarabine postremission consolidation for myelosuppression, infectious morbidity, and outcome. Cancer. 1994;74: 52-60.[Medline] [Order article via Infotrieve]

3. Rai KR, Holland JF, Glidewell OJ, et al. Treatment of acute myelocytic leukemia: a study by cancer and leukemia group B. Blood. 1981;58: 1203-1212.[Free Full Text]

4. Bow EJ, Meddings JB. Intestinal mucosal dysfunction and infection during remission-induction therapy for acute myelogenous leukemia. Leukemia. 2006;20: 2087-2092.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

5. Bras APM, Sitar DS, Aoki FY. Comparative bioavailability of acyclovir from oral valacyclovir and acyclovir in patients treated for recurrent genital herpes simplex virus infection. Can J Clin Pharmacol. 2001;8: 207-211.[Medline] [Order article via Infotrieve]

6. Gibaldi M, Perrier D. Pharmacokinetics. 2nd ed. New York: Marcel Dekker; 1982: 445-449.

7. Strauss SE, Smith HA, Brickman C, de Miranda P, McLaren C, Keeney RE. Acyclovir for chronic mucocutaneous herpes simplex virus infection in immunosuppressed patients. Ann Intern Med. 1982;96: 270-277.[Abstract/Free Full Text]

8. De Miranda P, Whitley RJ, Blum MR, et al. Acyclovir kinetics after intravenous infusion. Clin Pharmacol Ther. 1979;26: 718-728.[Web of Science][Medline] [Order article via Infotrieve]

9. Wagstaff AJ, Faulds D, Goa K. Acyclovir: a reappraisal of its antiviral activity, pharmacokinetics and therapeutic efficacy. Drugs. 1994;47: 153-205.[Web of Science][Medline] [Order article via Infotrieve]

10. Blum MR, Liao SHT, De Miranda P. Overview of acyclovir pharmacokinetic disposition in adults and children. Am J Med. 1982;73(1A): 186-192.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

11. Bow EJ, Loewen R, Cheang MS, Shore TB, Rubinger M, Schacter B. Cytotoxic therapy-induced D-xylose malabsorption and invasive infection during remission-induction therapy for acute myeloid leukemia in adults. J Clin Oncol. 1997;15: 2254-2261.[Abstract/Free Full Text]
CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This Article Full Text (PDF) All Versions of this Article: 0091270008319708v1 48/8/995    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Request Reprints Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Sitar, D. S. Articles by Bow, E. J. Search for Related Content PubMed PubMed Citation Articles by Sitar, D. S. Articles by Bow, E. J. Social Bookmarking                   What's this?