Plasma levels of zidovudine twice daily compared with three times daily in six HIV-1-infected children

Alina S. Bergshoeff1,2, Pieter L. A. Fraaij3, Corrien Verweij1,2, Annemarie M. C. van Rossum3, Gwenda Verweel3, Nico G. Hartwig3, Ronald de Groot3 and David M. Burger1,2,*

1 Department of Clinical Pharmacy, University Medical Center, Nijmegen; 2 Nijmegen University Center for Infectious Diseases, Nijmegen; 3 Department of Pediatrics, Erasmus MC/Sophia, Rotterdam, The Netherlands

Received 8 August 2004; returned 20 September 2004; revised 30 September 2004; accepted 1 October 2004


    Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 References
 
Objectives: Zidovudine is often administered every 12 h in HIV-infected children, but so far no pharmacokinetic data are available for the administration of this agent every 12 h. We have evaluated the plasma pharmacokinetics of zidovudine administered every 8 h versus every 12 h in HIV-1-infected children.

Methods: In HIV-1-infected children who switched from zidovudine every 8 h to every 12 h, a pharmacokinetic curve was recorded both before and after the switch. Zidovudine plasma levels were measured by HPLC. Pharmacokinetic parameters were calculated by non-compartmental methods.

Results: Six HIV-1-infected children [median age (range) 7.8 (2.5–13.4) years] were included. In these patients, geometric mean ratios of AUC0–24 and Cmax for zidovudine every 12 h versus every 8 h were not significantly different from 1.0.

Conclusions: The plasma pharmacokinetic parameters of zidovudine taken every 8 h and every 12 h were not significantly different and therefore suggest bioequivalence of these two dose frequencies.

Keywords: pharmacokinetics , paediatrics , pharmacology


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 References
 
Zidovudine was the first drug licensed for treatment of HIV infection. It is recommended as a component of highly active antiretroviral treatment (HAART) and in the prophylaxis of perinatal transmission of HIV.1,2 Current guidelines, such as PENTA, indicate a paediatric dose range for zidovudine of 90–180 mg/m2 every 6 h or every 8 h. Meanwhile, zidovudine is also increasingly used every 12 h. However, in children, except for neonates and infants, no published data exist on the pharmacokinetics of zidovudine every 8 h or every 12 h.35 Considering their common use in children, the pharmacokinetics of these regimens should be characterized in paediatric patients. We report here the plasma pharmacokinetics of zidovudine every 8 h and every 12 h in six HIV-1-infected children.


    Methods
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 References
 
This was a retrospective analysis of pharmacokinetic data from HIV-1-infected children in the age range 1–18 years, who were included in an ongoing study on the simplification of HAART conducted in our centre (inclusion August 2000–January 2003). Briefly, children were offered the possibility of changing their every 8 h HAART into fully every 12 h HAART. Antiretroviral medication prior to the switch consisted of zidovudine 120 mg/m2 every 8 h with indinavir 600 mg/m2 every 8 h and lamivudine 4 mg/kg every 12 h. After the switch, children received zidovudine 180 mg/m2 every 12 h with indinavir/ritonavir 500/100 mg/m2 every 12 h and lamivudine 4 mg/kg every 12 h. Zidovudine was administered as capsules of 100 mg or 250 mg, as tablets of 300 mg or as oral solution containing 10 mg/mL (Retrovir; AZT). Written informed consent was obtained from patients or carers prior to enrolment. Intensive pharmacokinetic sampling of all antiretroviral drugs was performed at steady state, prior to and >2 weeks after switch to the every 12 h regimen. Here we describe the pharmacokinetics of zidovudine in patients who changed from taking zidovudine every 8 h to every 12 h.

The plasma concentrations of zidovudine were determined by validated HPLC assay with UV detection [lower limit of quantification, 0.017 mg/L; accuracy 99%–101%, intra- and interday coefficients of variation 1.5%–2.0% and 1.5%–2.2%, respectively (C. Verweij, unpublished data)]. Data were included from patients in whom both an every 8 h and an every 12 h curve of at least five evaluable time points were available, and absolute total daily zidovudine doses differed <25% between the every 12 h and every 8 h regimens. Furthermore, pharmacokinetic samplings had to be <6 months apart.

Estimated area under the plasma concentration–time curve (AUC0–24), peak level (Cmax), trough level (Cmin), relative apparent oral clearance (CL/F·m2) and terminal plasma half-life (t1/2) of zidovudine were calculated using non-compartmental methods.6 To compare regimens, within-patient ratios of pharmacokinetic parameters for zidovudine every 12 h versus every 8 h were calculated, from which geometric mean ratios (GMR) with 90% confidence intervals (CI) were obtained. A 90% CI of GMR containing 1.0 was considered as reflecting similarity of both regimens. Results were compared with literature data on adults.


    Results
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 References
 
Six patients were enrolled (five girls, one boy) of median age 7.8 years (range 2.5–13.4). The median number of samples per pharmacokinetic curve was seven for the every 8 h regimen, and 7.5 for the every 12 h regimen. GMRs of pharmacokinetic parameters of zidovudine every 12 h versus every 8 h did not show significant differences between either regimen, but were characterized by wide CI. In our study, except for Cmax of the every 12 h regimen, zidovudine levels were slightly higher than in adults using zidovudine every 8 h or every 12 h (Table 1 and Figure 1).7,8 Zidovudine every 12 h did not result in a higher Cmax than zidovudine every 8 h. No correlation was found between zidovudine pharmacokinetic parameters (AUC0–24, Cmax and CL/F·m2) and age, body weight or body surface area (P values all >0.05). However, zidovudine t1/2 was inversely correlated with age for both the every 12 h regimen and the every 8 h regimen (r2 –0.78 and –0.69, P values 0.019 and 0.042, respectively).


View this table:
[in this window]
[in a new window]
 
Table 1. Pharmacokinetics of zidovudine every 12 h and every 8 h in HIV-1-infected children and historical data of zidovudine in adults

 


View larger version (14K):
[in this window]
[in a new window]
 
Figure 1. (a) AUC0–24 and (b) Cmax of zidovudine every 12 h versus every 8 h in six children who switched from zidovudine every 8 h (TID) to every 12 h (BD).

 

    Discussion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 References
 
This study presents the first pharmacokinetic data of zidovudine every 12 h compared with every 8 h in children above the infant age. The pharmacokinetic parameters of zidovudine every 12 h compared with every 8 h did not reveal significant differences, suggesting equivalence of both regimens in terms of plasma pharmacokinetics. The observed tendency for higher plasma levels in children than in adults could be due to the higher paediatric zidovudine dose per body weight: 360 mg/m2/day equals 13 mg/kg/day in an average child with 1 m2 body surface area and weighing 28 kg, which is higher than the adult dose (600 mg/day =8.6 mg/kg/day in an adult weighing 70 kg). Also, zidovudine every 12 h did not result, as expected with lower dose frequency, in a higher Cmax than every 8 h.7,8 The pharmacokinetic parameters of zidovudine were highly variable, probably as a result of the small sample size. Therefore, these findings should be confirmed in a larger number of patients. Zidovudine AUC0–24, Cmax and CL/F·m2 were independent of age, body weight or body surface area. This is in accordance with literature data, which generally indicate that zidovudine CL/F·m2 increases most strongly during the first weeks of life, reaching adult levels at the age of 2 years, and all children in our study were above this age.5,9,10 In contrast, it was found that the elimination rate of zidovudine significantly increased with age, which would suggest further maturation of zidovudine metabolism during childhood. Remarkably, as stated above, this higher elimination rate was not reflected in a lower AUC0–24 or Cmax or higher CL/F·m2 in older children. Although this finding should be considered cautiously because of the small number of patients in our study, an explanation—also described in relation to premature infants—could be decreased zidovudine absorption or increased first-pass metabolism in younger children,5 resulting in no net difference of AUC0–24, Cmax or CL/F·m2 between younger and older children.

In conclusion, in this group of six HIV-1-infected children, the pharmacokinetics of zidovudine every 12 h were not statistically different from every 8 h, suggesting bioequivalence of both regimens. These findings need confirmation in studies with a larger sample size. Finally, the efficacy of both regimens in children should be evaluated in a comparative study.


    Acknowledgements
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 References
 
Technicians of the Department of Clinical Pharmacy, University Medical Center, Nijmegen, are kindly acknowledged for processing and analysis of the plasma samples. Study nurses of the Department of Pediatrics, Erasmus MC/Sophia, Rotterdam, are kindly acknowledged for blood drawings. No financial support was received for this study.


    Footnotes
 
* Correspondence address. Department of Clinical Pharmacy, University Medical Center, PO Box 9101, 533 KF, 6500 HB Nijmegen, The Netherlands. Tel: +31-24-3616405; Fax: +31-24-3540331; Email: d.burger{at}akf.umcn.nl


    References
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 References
 
1 . Anonymous. (2003). Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. [Online.] http://www.aidsinfo.nih.gov/guidelines/adult (30 September 2004, date last accessed).

2 . Anonymous. (2003). Guidelines for the use of antiretroviral agents in pediatric HIV infection. [Online.] http://www.aidsinfo.nih.gov/guidelines/pediatric (30 September 2004, date last accessed).

3 . Mirochnick, M., Capparelli, E., Dankner, W. et al. (1998). Zidovudine pharmacokinetics in premature infants exposed to human immunodeficiency virus. Antimicrobial Agents and Chemotherapy 42, 808–12.[Abstract/Free Full Text]

4 . Moodley, D., Pillay, K., Naidoo, K. et al. (2001). Pharmacokinetics of zidovudine and lamivudine in neonates following coadministration of oral doses every 12 hours. Journal of Clinical Pharmacology 41, 732–41.[Abstract/Free Full Text]

5 . Capparelli, E. V., Mirochnick, M., Dankner, W. M. et al. (2003). Pharmacokinetics and tolerance of zidovudine in preterm infants. Journal of Pediatrics 142, 47–52.[CrossRef][ISI][Medline]

6 . Gibaldi, M. (1991). Compartmental and noncompartmental pharmacokinetics. In Biopharmaceutics and Clinical Pharmacokinetics, 4th edn, pp. 14–23. Lea & Febiger, Philadelphia, PA, USA.

7 . Vanhove, G. F., Kastrissios, H., Gries, J. M. et al. (1997). Pharmacokinetics of saquinavir, zidovudine, and zalcitabine in combination therapy. Antimicrobial Agents and Chemotherapy 41, 2428–32.[Abstract]

8 . Cremieux, A. C., Katlama, C., Gillotin, C. et al. (2001). A comparison of the steady-state pharmacokinetics and safety of abacavir, lamivudine, and zidovudine taken as a triple combination tablet and as abacavir plus a lamivudine-zidovudine double combination tablet by HIV-1-infected adults. Pharmacotherapy 21, 424–30.[CrossRef][ISI][Medline]

9 . Mirochnick, M., Capparelli, E. & Connor, J. (1999). Pharmacokinetics of zidovudine in infants: a population analysis across studies. Clinical Pharmacology and Therapeutics 66, 16–24.[ISI][Medline]

10 . Capparelli, E. V., Englund, J. A., Connor, J. D. et al. (2003). Population pharmacokinetics and pharmacodynamics of zidovudine in HIV-infected infants and children. Journal of Clinical Pharmacology 43, 133–40.[Abstract/Free Full Text]





This Article
Abstract
FREE Full Text (PDF)
All Versions of this Article:
54/6/1152    most recent
dkh490v1
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
Add to My Personal Archive
Download to citation manager
Search for citing articles in:
ISI Web of Science (1)
Disclaimer
Request Permissions
Google Scholar
Articles by Bergshoeff, A. S.
Articles by Burger, D. M.
PubMed
PubMed Citation
Articles by Bergshoeff, A. S.
Articles by Burger, D. M.