1 Department of Pediatrics, Erasmus MC/Sophia Childrens Hospital, Rotterdam; 2 Department of Clinical Pharmacy, University Medical Center, Nijmegen, The Netherlands
Received 11 April 2003; returned 28 May 2003; revised 23 June 2003; accepted 25 June 2003
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Abstract |
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Materials and methods: Protease inhibitor (PI)-naive HIV-1-infected children were treated with indinavir, zidovudine and lamivudine. Steady-state plasma pharmacokinetic (PK) sampling was carried out as standard of care. The AUC08 was targeted between 15 and 30 mg×h/L. PK sampling was repeated after dosage adjustment until the AUC08 reached target values. Patients were included when the time interval between PK samplings was 2 years and differences in dosage/m2 < 10% between PK samplings 1 and 2. Corrections of dose for changes in body size were carried out.
Results: Six children were enrolled with a median age of 5.2 years (range 1.713.6 years). All had a viral load below 500 copies/mL. The geometric mean (GM) of the AUC08 decreased from 25.3 mg×h/L at the first PK-day to 19.1 mg×h/L at the second PK-day [geometric mean ratio (GMR): 0.76 (95% C.I.: 0.481.20)]. The GM of Cmax decreased from 11.8 to 10.4 mg/L [GMR: 0.88 (95% C.I.: 0.591.32)]. The GM of Cmin decreased from 0.08 to 0.07 mg/L [GMR: 0.86 (95% C.I.: 0.621.18)]. All children had an AUC08 above 15 mg×h/L on the first PK-day; three had an AUC08 below 15 mg×h/L on the second PK-day. In two of these three children, the plasma viral load was >500 copies/mL.
Conclusion: Changes in indinavir exposure were observed over time. In two patients, decreased indinavir exposure was associated with virological failure. Therapeutic drug monitoring should be carried out over time since this may prevent subtherapeutic dosing in children.
Keywords: pharmacokinetic analysis, age, development, paediatric HIV/AIDS, pharmacokinetics, protease inhibitors, indinavir
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Introduction |
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Materials and methods |
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PI-naive HIV-1-infected children with a viral load above 5000 copies/mL and/or a CD4 cell count below their age-specific reference value started HAART consisting of indinavir 400 mg/m2 every 8 h, zidovudine 120 mg/m2 every 8 h and lamivudine 4 mg/kg every 12 h. In all patients, steady-state intensive plasma PK sampling of indinavir was carried out as standard of care. The AUC08 was targeted between 15 and 30 mgh/L.2 PK sampling was repeated until the AUC08 reached target values. Hereafter, PK sampling was not routinely repeated. However, in case of viral failure, single sample indinavir plasma levels were considered. Children were eligible for inclusion in this study when data were available from both the first intensive PK sampling with the dose resulting in an adequate AUC08 (=PK-day 1), and second intensive pharmacokinetic sampling (=PK-day 2) on this (fixed) dose/m2, with a minimum interval of 2 years. Dose adjustments < 10% of dosage in mg/m2 body surface area (BSA) were allowed between PK samplings. Corrections of dose for changes in body size were carried out for indinavir and for nucleoside reverse transcriptase inhibitors (NRTI). Selected clinical data were obtained during regular visits to the outpatient department. The study protocol was approved by the medical ethical committee of the Erasmus MC. Written informed consent was obtained from parents and patients.
Pharmacokinetics
Patients took indinavir on an empty stomach and blood samples were collected at time points 0 (pre-dose) and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7 and 8 h post-ingestion. Plasma was separated by centrifugation (10 min at 3000g) and samples were stored at 20°C until analysis. Indinavir concentrations were determined in plasma by HPLC, as previously reported.9 The assay has intra-assay and inter-assay variances below 7.48% and 3.46%, respectively.10 Pharmacokinetic parameters were calculated in Microsoft Excel 97 by non-compartmental methods.11
For comparison of the various PK parameters, the geometric mean (GM) of the ratio between PK-day 1 and 2 was calculated (GMR). For analysis of the pharmacokinetic data, SPSS 10 and Microsoft Excel 97 software were used.
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Results |
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In four of the six children the AUC08 had decreased on the second PK-day. In two children, the AUC08 had increased. For data of the individual patients, see Table 1. The GM of the AUC08, Cmax, Cmin and t1/2, all decreased on the second PK-day compared with the first PK-day. The pharmacokinetic parameters for the study group are summarized in Table 2.
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Discussion |
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The differences found between the two PK curves cannot be explained by changes in the techniques, since we used the same metho-dology for all PK curves. Inter-assay variability is not likely to be responsible for the observed changes in indinavir exposure, since the changes in AUC08 greatly exceeded the inter-assay variance.10 We did not observe clinically relevant abnormalities in blood chemistry parameters. Therefore, the changes in indinavir exposure were not the result of changes in organ function because of indinavir usage. Also the co-medication used on the first PK-day was not expected to have caused a difference in PK parameters, because it does not interfere with the metabolism of indinavir.12
It is unlikely that growth influenced the results, since the medication dosage was based on square metres of body surface and adjusted when length or weight had changed. Interestingly, in one child (A13), the absolute dose was not increased, and still her clearance and volume of distribution had markedly increased. Hypothetically, the decreased indinavir exposure may have been caused by a decrement in indinavir exposure with age. However, this is not expected since younger children have an increased hepatic enzymic activity compared with older children and adults.8 Duration of therapy per se did not seem to influence the change in indinavir exposure, since both increased and decreased exposure could be shown in four children who were on therapy for approximately the same time period (2.5 years). Still, mechanisms such as the induction of P-glycoprotein and CYP 450 levels after prolonged PI usage as also shown in vitro by Huang et al. may have resulted in the decreased indinavir exposure.7
Remarkably, the three children with AUC II below the 15 mgh/L threshold were the older ones, suggesting that older children may be more prone to develop sub-therapeutic indinavir levels in time.
An alternative explanation for the observed failure of therapy after prolonged use of indinavir, may be non-compliance. Yet, in one of the children with a viral load >500 copies/mL, the Cmin corresponded with the C0, indicating that at least the preceding dose was taken in time. However, non-compliance obviously influences the antiviral efficacy of indinavir and may thus have influenced our findings.13
Clearly, our study is limited by the small sample size of six children. Still, the included patients were representative for age and race for the patient population using indinavir in our hospital. A difference existed for sex, since all patients in the study population were female. In this study, a confounding factor may be the selection of patients with decreasing exposure to indinavir, because children with increasing exposure to indinavir are more likely to suffer from complications and to discontinue treatment before a second PK sampling can be carried out. As a result, these children would not have been included in this type of study. However, we do not expect this phenomenon to be a major confounder, since only in a small group of children was the medication changed because of toxicity.
At the time of this case study, random single indinavir plasma levels were not obtained in our hospital as part of the routine care for HIV-1-infected children. It was considered after viral failure occurred, mostly to check for compliance. Currently, in our hospital both full PK samplings for PI levels and random single sample plasma PI levels are part of the routine care for HIV-1-infected children, allowing for optimal dosing and early detection of changed exposure of PI.
In conclusion, our data indicate an effect of time on indinavir exposure in HIV-1-infected children. Both increased and decreased indinavir exposure were observed over time. Sub-therapeutic plasma levels of indinavir were found, which in two of three cases were associated with viral failure. Regular monitoring of drug levels may prevent sub-therapeutic PI dosing in children receiving HAART.
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Acknowledgements |
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Financial disclosure |
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Footnotes |
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References |
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2
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3 . Burger, D. M., Hoetelmans, R. M., Hugen, P. W. et al. (1998). Low plasma concentrations of indinavir are related to virological treatment failure in HIV-1-infected patients on indinavir-containing triple therapy. Antiviral Therapy 3, 21520.[ISI][Medline]
4 . Stein, D. S., Fish, D. G., Bilello, J. A. et al. (1996). A 24-week open-label phase I/II evaluation of the HIV protease inhibitor MK-639 (indinavir). AIDS 10, 48592.[ISI][Medline]
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9 . Burger, D. M., de Graaff, M., Wuis, E. W. et al. (1997). Determination of indinavir, an HIV-protease inhibitor, in human plasma by reversed-phase high-performance liquid chromatography. Journal of Chroma-togaphy B, Biomedical Sciences and Applications 703, 23541.[CrossRef]
10 . Hugen, P. W., Verweij-van Wissen, C. P., Burger, D. M. et al. (1999). Simultaneous determination of the HIV-protease inhibitors in-dinavir, nelfinavir, saquinavir and ritonavir in human plasma by reversed-phase high-performance liquid chromatography. Journal of Chroma-togaphy B, Biomedical Sciences and Applications 727, 13949.[CrossRef]
11 . Gibaldi, M. (1991). Compartmental and noncompartmental pharmacokinetics. In Biopharmaceutics and Clinical Pharmacokinetics, 4th edn (Gibaldi, M., Ed.), pp. 1423. Lea & Febiger, Philadelphia, PA, USA.
12 . Burger, D. M. (2003). Drug interactions. [Online.] http://www.hivpharmacology.com (8 April 2003, date last accessed).
13 . van Rossum, A. M., Bergshoeff, A. S., Fraaij, P. L. et al. (2002). Therapeutic drug monitoring of indinavir and nelfinavir to assess adherence to therapy in human immunodeficiency virus-infected children. Pediatric Infectious Disease Journal 21, 7437.[CrossRef][ISI][Medline]
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