1 Experimental and Clinical Pharamcology Unit; 2 Experimental Oncology 1; 3 Division of Medical Oncology A, National Cancer Institute, Aviano, Italy
* Correspondence to: Dr G. Toffoli, Experimental and Clinical Pharmacology, Oncologia Sperimentale I, C.R.O.-National Cancer Institute, via Pedemontana Occidentale, 12, Aviano (PN), Italy. Tel: +39-0434-659612; Fax +39-0434-659659; Email: gtoffoli{at}cro.it
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Abstract |
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Methods: Complete pharmacokinetics and pharmacodynamic analysis was determined in 19 patients during 38 cycles of chemotherapy: 19 cycles with CHOP and 19 CHOP + HAART in a crossover-designed study. HAART included protease inhibitors indinavir (IDV) in nine patients, saquinavir (SQV) hard gel in six patients and nelfinavir (NFV) in four patients.
Results: No significant effects of HAART on pharmacokinetics parameters of DOX were observed. Similarly, no differential effect on DOX pharmacokinetics among IDV, SQV, and NFV was evidenced. Significant associations (P=0.012) were observed between DOX AUC0 (area under the concentration curve) and G3-G4 WHO haematologic toxicity, in patients treated with CHOP alone, but not in those treated with CHOP + HAART (P = not significant).
Conclusion: We demonstrated that HAART therapy has no significant effect on DOX pharmacokinetics. DOX AUC appears to be a predictor of toxicity only in patients treated with CHOP alone. Other factors beside DOX plasma levels are detrimental for toxicity after CHOP + HAART. Therefore, pharmacodynamic interactions between HAART and DOX should be considered.
Key words: CHOP, doxorubicin, HAART, HIV, interactions, pharmacokinetics
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Introduction |
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Chemotherapy regimes based on cyclophosphamide, doxorubicin (DOX) vincristine, and prednisone (CHOP) represent a pivotal treatment for patients with HIV-NHL [2]. Recently, to overcome the complications of HIV infection that could compromise or delay antineoplastic treatment, HAART has often been given in combination with CHOP [3
, 4
]. Such association results are effective and may contribute in reducing morbidity in HIV-NHL patients. However, the management of severe toxicity observed with CHOP + HAART represents the main limitation of the wide use of this type of combination therapy [4
, 5
]. It was believed that such unexpected toxicity could be related to pharmacokinetic interactions between antiretroviral and antineoplastic drugs leading to an increased plasma drug exposure. HAART consists of a combination of nucleoside analogue reverse transcriptase inhibitors (NRTIs), with protease inhibitors (PIs) and non-nuclease analogue reverse transcriptase inhibitors (NNRTIs). PIs, as well as the anticancer drugs in the CHOP regimen, are metabolized by the liver cytochrome P450 CYP3A4 isoform [6
]. The metabolic clearance of anticancer drugs sharing this common enzymatic pathway of PI can be inhibited by concomitant administration of PI. In vitro studies demonstrated that PI could also interfere with the activity of P-glycoprotein (Pgp) or multi-drug resistance proteins (MRP), which are involved in cellular efflux of a broad range of drugs including anthracyclines [7
, 8
]. PIs could interfere with the activity of these carrier proteins present in biliary and renal tracts, resulting in reduced biliary and renal excretions of the antineoplastic drugs (pharmacokinetic interactions). Moreover, competitive inhibition of Pgp and MRP activity by PI could determine an increased amount of intracellular concentration of antineoplastic drugs in normal cells over expressing Pgp/MRP, resulting in increased toxic side-effects under the same conditions of drug area under curve (AUC) (pharmacodynamic interactions). Pharmacokinetic interactions have been reported between PI and a wide class of drugs used in the clinical management of HIV [9
], but only little and incomplete data have been reported on pharmacokinetic interactions between PI and antineoplastic drugs [10
, 11
].
In order to gain new insight on potential pharmacokinetic interactions between PIs and anticancer drugs and to ascertain the pharmacological basis of the increased toxicity of CHOP, after PI-based HAART combination, we planned a prospective clinical trial in NHL patients who underwent CHOP with or without HAART combination. This study aims to investigate the effect of HAART on DOX pharmacokinetics and the relationship between DOX plasma concentrations and toxicity.
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Patients and methods |
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Sampling
Blood samples (5 ml) were drawn from peripheral vein and collected in heparinized glass tubes after 15 min infusion with DOX dose (time 0) and at 0.25, 0,5 1, 2, 3, 4, 5, 6, 12, 24 and 48 h from the start of i.v. DOX administration. Blood specimens were immediately centrifuged at 4°C. Plasma samples were collected and heated at 5658°C for 60 min to inactivate HIV. After inactivation, all samples were stored at 80°C until drug analysis.
Drug assay
Plasma level of DOX was assayed by a reversed-phase HPLC method with fluorescence detection adapted from previously reported analytical methods [14]. The method was calibrated by daily standard curves that ranged between 1 and 1000 ng/ml: intraday and interday variability were <10% within this range of concentrations.
Pharmacokinetic analyses
Non-compartmental analysis was used to determine DOX pharmacokinetic parameters. The terminal apparent first-order elimination rate (ß) was estimated by least squares log-linear fit to the terminal elimination phase. The elimination half-life (t1/2) was calculated by the equation 0.693/ß. The AUC048 for concentration (C) versus time (t) was calculated by the linear trapezoidal method from to t0 to t48. The total AUC extrapolated to infinity (AUC0) was calculated as follows: AUC0
= AUC048 + C48/ß while total body clearance (Cl) and volume of distribution (Vd) were determined as Cl = dose/AUC0
and Vd = Cl/ß, respectively.
Statistical analysis
The pharmacokinetic parameters of the different groups were compared using Wilcoxon non-parametric test for paired data and the MannWhitney test for unpaired data. All comparisons were considered significant at P <0.05.
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Results |
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Significant associations (P=0.012 by MannWhitney test) were observed between AUC0 and haematological toxicity during the cycle of CHOP alone. DOX AUC0
was 977.97 ± 182.38 µg l1 h in patients developing WHO toxicity grade G3G4 and was 735.20 ± 195.05 µg l1 h in patients developing G0G2. This pharmacodynamic correlation was lacking (P = not significant) in the cycle with CHOP + HAART: DOX AUC0
was 791.05 ± 268.43 µg l1 h in patients developing G3G4 not significantly different from 710.00 ± 153.37 µg l1 h observed in patients developing G0G2.
In the cycle in which DOX pharmacokinetics was performed, we observed the following severe toxicities in the course with CHOP alone: G4 leukopenia in two patients, G3 leukopenia in two patients and G3 anemia in three patients; whereas two patients developed G4 leukopenia, three patients G3 leukopenia, three patients G4 anemia, and one patient G3 anemia in the course of CHOP + HAART. Two patients also developed G2 neurotoxicity during CHOP chemotherapy whereas a severe G3 neurotoxiticy and a single G2 neurotoxicity were observed during the CHOP + HAART cycle. G2 mucosites was also observed as a non-haematological toxicity in one patient during the cycle of combination therapy.
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Discussion |
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It was believed that the PI used in the HAART regimen could interfere with anthracycline transport, being either PI or DOX common substrates for cellular transporters Pgp or MRP [15, 16
]. However, our study did not highlight any effect of PI on DOX pharmacokinetics, even when the subgroup of patients treated with SQV-HG and NFV, who exhibited a relatively high affinity for Pgp compared with IDV, was considered [15
]. Competitive inhibition of cytochrome P450 between PI and DOX could also be hypothesized, but involvement of P450 in DOX metabolism is marginal since the most important metabolic pathway of DOX is represented by the side-chain carbonilic reduction at C13, which is catalysed by ubiquitous aldoketo-reductase to form the (S)-secondary alcohol [17
].
Previous studies have demonstrated that plasma concentrations of PI achievable in patients with the schedule we adopted is in the micromolar range (110 µM) [18, 19
], effective enough to reverse multidrug resistance in in vitro experimental models. Although such plasma concentrations are unable to modulate DOX pharmacokinetics, they are potentially effective in blocking Pgp or MRP activity in normal non-neoplastic cells of patients overexpressing MDR proteins, such as haemopoietic stem cells [20
]. This could result in an intracellular enhancement of DOX uptake in normal cells, leading to an increased toxicity due to pharmacodynamic interactions. Interestingly, data from our study evidenced a stronger association between plasma level of DOX AUC and haematological toxicity in the course of CHOP alone. Such association was lacking during the course of CHOP + HAART. This indicates that the toxic effect of DOX + HAART is due to additional factors, probably an increased DOX uptake in normal cells, rather than DOX plasma concentrations. These factors are able to circumvent the effect of DOX AUC, making it less detrimental for toxicity as in the case in which DOX is administered without HAART.
A greater number of patients treated with a specific PI in association with DOX must be examined before drawing final conclusions on pharmacokinetic interactions between DOX and SQV-HG, IDV or NFV, respectively. Moreover, different pharmacokinetic interactions could occur between the other antineoplastic drugs used in the CHOP regimen, such as vincristine or cyclophosphamide and PI. However, our study is one of the largest published, so far, on the effect of HAART within the same patient. Therefore, we are confident that our data could add new knowledge to the understanding of pharmacological interactions between HAART and DOX, thus contributing to improved combination therapies in patients with AIDS-related cancers.
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Acknowledgements |
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Received for publication June 29, 2004. Accepted for publication July 2, 2004.
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References |
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