Pharmacokinetic interaction between chemotherapy for non-Hodgkin's lymphoma and protease inhibitors in HIV-1-infected patients

Mario Cruciani1,*, Giorgio Gatti2,{dagger}, Emanuela Vaccher3, Giampiero Di Gennaro3, Roberta Cinelli3, Matteo Bassetti2, Umberto Tirelli3 and Dante Bassetti2

1 Centre of Preventive Medicine/HIV Outpatient Clinic, Via Germania 20, 37135 Verona; 2 Department of Infectious Diseases, San Martino Hospital, University of Genoa, Genoa; 3 Medical Oncology A, National Cancer Institute, Aviano, Italy


* Corresponding author. Tel: +39-045-807-6266; Fax: +39-045-862-2233; Email: crucianimario{at}virgilio.it

Received 21 September 2004; returned 9 November 2004; revised 23 December 2004; accepted 30 December 2004


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Objectives: We have investigated whether chemotherapy for HIV-related systemic non-Hodgkin's lymphoma (NHL) affects the pharmacokinetics of protease inhibitors.

Patients and methods: This was a prospective, open-label, non-randomized, two-way crossover trial in HIV-1-infected patients treated with highly active antiretroviral therapy and chemotherapy for NHL. Seven patients received indinavir at a dosage of 800 mg three times daily and three patients received nelfinavir at a dosage of 750 mg three times daily. Chemotherapy consisted of adriamycin, cyclophosphamide, vincristine and prednisolone (CHOP). Each patient had blood samples for protease inhibitor pharmacokinetics drawn concomitantly with or independently of the CHOP cycle.

Results: When indinavir was given concomitantly with CHOP, the AUC0–8 increased by 38% (20.5 ± 9.0 versus 14.9 ± 9.5 mg·h/L; P=0.03), and was comparable to historical controls. By contrast, the AUC0–8 of indinavir administered without CHOP was lower than expected. A similar trend was observed with nelfinavir. Likewise, we observed a significant number of patients with C0 and C8 below the IC50 for the wild-type virus (0.1 mg/L) when the drug was administered without CHOP.

Conclusions: Therapeutic drug monitoring of protease inhibitors should be part of the work-up in HIV-infected patients receiving chemotherapy for NHL.

Keywords: indinavir , nelfinavir , CHOP , therapeutic drug monitoring


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The overall survival of patients with HIV-related systemic non-Hodgkin's lymphoma (NHL) has improved significantly, and there is growing evidence of a better prognosis for NHL in patients who receive highly active antiretroviral therapy (HAART).1,2

In recent times, several investigators have evaluated the feasibility and efficacy of concomitant chemotherapy for NHL and HAART.17 Data from these reports show that the combination of HAART with chemotherapy improves clinical outcome, although major questions persist on the definition of the optimal combination of chemotherapy and antiretroviral regimens. Overlapping toxicities have been observed with combination therapy, and there is a potential risk for pharmacokinetic interactions between chemotherapy and HIV protease inhibitors (PIs).4,6,7 Data on pharmacokinetic interactions between chemotherapy and antiretroviral agents are limited to an open study in a cohort of AIDS patients with NHL treated simultaneously with CHOP chemotherapy (adriamycin, cyclophosphamide, vincristine and prednisolone) and HAART (stavudine, lamivudine and indinavir).8 In this study, a modest effect of HAART on cyclophosphamide clearance was found, and indinavir concentrations were not affected by concurrent administration of CHOP when compared with historical controls.

To investigate further whether chemotherapy affects the pharmacokinetics of PIs, we carried out a prospective trial in AIDS patients with systemic NHL treated with HAART and CHOP.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
This was a prospective, open-label, non-randomized, two-way crossover study aimed to determine the pharmacokinetics of PIs administered with or without concomitant CHOP chemotherapy. Patients were recruited in a single centre, located in Aviano, during 1997–1999. The study was approved by the Institutional Review Board of the National Cancer Institute in Aviano and written informed consent was obtained from each patient who participated in the study.

Subjects included were adult HIV-infected patients on HAART designated to receive CHOP because of a new, histologically confirmed, diagnosis of NHL. To be included in the protocol, patients were required to have been on stable antiretroviral treatment for at least 3 months, with a Karnofsky performance score ≥ 70%, and to be eligible for CHOP chemotherapy.

Participants received indinavir 800 mg three times daily in fasting state or nelfinavir 750 mg three times daily after a meal, and a standard dose of chemotherapy with adriamycin 75 mg/m2, cyclophosphamide 1200 mg/m2, vincristine 1.4 mg/m2 and prednisolone. The CHOP protocol consisted of four cycles of chemotherapy, with each cycle alternated by an interval of 3 weeks.

Blood samples for indinavir or nelfinavir concentrations were taken at time 0 (pre-dose), and at 0.5, 1, 1.5, 2, 3, 4, 6 and 8 h following a morning dose. Each patient had blood samples drawn on two occasions: either concomitantly with, or separately from, the CHOP cycle. In this latter case, the pharmacokinetic sampling for PI alone was performed, with an alternate sequence—before the beginning of the first CHOP cycle or at least 2 weeks after the last CHOP cycle. It can be assumed that 2 weeks is sufficiently long for wash out.

Indinavir and nelfinavir plasma concentrations were determined shortly after plasma sampling using two different validated high performance liquid chromatographic assays.

The following pharmacokinetic parameters, determined by non-compartmental analysis, were evaluated: area under the concentration–time curve (AUC0–8), peak plasma concentration (Cmax), time to reach maximum concentration (Tmax) and plasma concentration at times 0 and 8 h (C0, C8). Also, we evaluated the percentage of patients with C0 and C8 values below the mean indinavir concentration required to induce 50% inhibition of viral replication (IC50) of wild-type virus (0.1 mg/L).

The pharmacokinetic parameters of PIs given alone were compared with those of PIs given concomitantly with CHOP. For this purpose, we used the two-tail paired t-test. As almost 75% of blood samples were taken from patients on indinavir, statistical analysis focused on this drug.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The general characteristics of the 10 patients (seven receiving indinavir, three nelfinavir) and the pharmacokinetic parameters are summarized in Tables 1 and 2. Figures 1 and 2 show mean indinavir plasma concentrations throughout the sampling time and AUC0–8 values. No patients in this study had gastrointestinal involvement due to NHL or chemotherapy-induced gastrointestinal toxicity, which may be responsible for malabsorption.


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Table 1. Baseline characteristics of 10 patients (nine males) receiving a protease inhibitor concomitantly with CHOP

 

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Table 2. Pharmacokinetic data of indinavir and nelfinavir given with or without CHOP cycle

 


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Figure 1. Mean indinavir plasma concentrations (mg/L) in patients receiving indinavir without CHOP (triangles with broken line) and concomitantly with CHOP (squares with continuous line).

 


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Figure 2. Indinavir AUC0–8 with and without concomitant CHOP treatment.

 
Co-administration of CHOP and indinavir resulted in an increase in the mean indinavir AUC0–8 compared with the AUC0–8 without concomitant CHOP administration: 20.5 ± 9.0 versus 14.9 ± 9.5 mg·h/L (P=0.03). Likewise, Cmax and C0 were higher when indinavir was given concomitantly with CHOP, whereas C8 was lower, but these differences were not statistically significant. When historical data are used as reference values, we observed a lower indinavir AUC when the drug was given alone.9

Indinavir concentrations at 0 and 8 h following administration were both below the IC50 for the wild-type virus (0.1 mg/L) in three of the seven patients when the drug was administered without CHOP; with CHOP none and two of the patients, respectively, had indinavir concentrations below this limit. Tmax was 1.3 ± 0.9 without CHOP and 1.0 ± 0.5 concomitantly with CHOP.

A single patient received indinavir concomitantly with the modified, low-dose CHOP (cyclophosphamide 375 mg/m2, adriamycin 25 mg/m2, vincristine 1.4 mg/m2 and prednisolone). As in the case of full-dose CHOP, indinavir concentrations were higher when the drug was administered concomitantly with chemotherapy (C0=0.11 mg/L, C8=0.19 mg/L, Cmax=2.98 mg/L, AUC0–8=8.9 mg·h/L) than after indinavir alone (0.12 mg/L, 0.07 mg/L, 2.05 mg/L and 6.86 mg·h/L, respectively).

Data on nelfinavir are limited to three patients. A trend similar to that observed with indinavir was observed, nelfinavir AUC0–8 and Cmax values being higher when the drug was administered with CHOP (Table 2).

Grade 3 or 4 toxicities occurred in three patients on full-dose CHOP. Grade 3–4 neutropenia was observed in three patients, and grade 4 thrombocytopenia, anaemia and constipation in one patient each.


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
In HIV-1-infected patients with NHL, we have found that the AUC of indinavir administered concurrently with CHOP was comparable to the AUC reported in the literature. However, when indinavir was given without concomitant CHOP, the AUC0–8 was reduced by 38%. A straightforward conclusion of these observations is that indinavir dose modification during CHOP chemotherapy of NHL is not required. By contrast, the lower than expected AUC level of indinavir alone in this cohort of NHL patients is of concern, since the plasma concentration of PIs is a critical factor in maintaining efficacy and in minimizing the potential for viral resistance. Moreover, we observed that a considerable proportion of patients had C0 and C8 below the IC50 when the drug was administered without CHOP. A similar trend was observed for nelfinavir. Although the dose regimens of indinavir and nelfinavir used in this study have now been replaced by twice-daily regimens with (indinavir) or without (nelfinavir) ritonavir booster, our study is relevant inasmuch as it suggests that patients with NHL may have lower PI concentrations, and that a pharmacokinetic interaction between PI and CHOP seems to occur.

Interactions of clinical relevance between PIs and other classes of drugs are well documented.10 Very little is available on how PIs affect levels of chemotherapeutic agents, or on how chemotherapy affects PI pharmacokinetics. Recently, Ratner et al.8 have investigated the feasibility of CHOP (full-dose or modified CHOP) in combination with HAART. Although the primary outcomes of the study were efficacy and toxicity data, in 29 of the 65 enrolled patients a pharmacokinetic evaluation was also performed. The authors found a modest effect of HAART on cyclophosphamide clearance, and indinavir concentrations were not affected by concurrent administration of CHOP when compared with historical controls. Likewise, we found that indinavir and nelfinavir concentrations in patients receiving concomitant CHOP were comparable to those from historical data. The crossover design of our study, however, allows us to compare the pharmacokinetics of PIs with or without CHOP. The lower concentrations of PIs when administered without CHOP support a relevant effect of chemotherapy for NHL on pharmacokinetics of PIs, as demonstrated by a significant increase in indinavir AUC0–8 values when the drug was given concomitantly with chemotherapy.

All the currently available PIs are metabolized in the liver by the cytochrome P450 enzyme system, which is also responsible for the metabolism of many drugs, including components of CHOP chemotherapy.11,12 Since CHOP components have the potential for both P450 induction and inhibition, it is not possible to anticipate the overall effect of CHOP on indinavir pharmacokinetics. Moreover, another potential interaction may occur because PIs are substrates and inhibitors of the drug transporter P-glycoprotein, an efflux pump that transports a wide range of drugs including PIs, anthracycline and vinca-alkaloids. In addition, anthracycline can increase the levels of expression of P-glycoprotein, but the functional consequences of increased expression are unclear.13

We did not observe an excess of toxicity, which may well be related to increased plasma levels of chemotherapeutic agents. Grade 3 or 4 toxicity developed in only 30% of patients on full-dose CHOP. By comparison, in the Ratner study grade 3–4 toxicity was observed in 70% of patients in the full-dose CHOP arm, and in 51% of patients in the modified-dose arm. More recently, Bower et al.6 showed that PIs potentiate cyclophosphamide/doxorubicin/etoposide chemotherapy-induced neutropenia and that grade 3 or 4 infections requiring hospitalization were recorded in 31% of patients receiving chemotherapy only, in 25% of patients receiving chemotherapy and PI sparing HAART and in 48% of patients receiving chemotherapy concomitantly with PIs.

The evidence showing the benefit of treating NHL in HIV-infected patients with HAART concomitantly with chemotherapy is growing. Strategies to maximize the efficacy while minimizing the toxicity of HAART are timely and relevant, and therapeutic drug monitoring has emerged as an important tool in this setting.14 Low plasma PI concentrations have been strongly associated with an increased risk of virological failure.15,16 In our patients, PI levels given without chemotherapy were lower than expected, and C0 and C8 concentrations were below the IC50 in a relevant number of patients. Thus, we conclude that therapeutic drug monitoring may be indicated and of particular value in this particular group of patients.


    Footnotes
 
{dagger} Current address. Vertex Pharmaceuticals, Cambridge, MA, USA. Back


    Acknowledgements
 
Part of this study was presented at the Second International Workshop on Clinical Pharmacology of HIV Therapy, Noordwijk, The Netherlands, 2001. The study was supported in part by grant no. 30C8 from the Istituto Superiore di Sanita' (Rome) and by a grant from COFIN 98–99. We declare no conflicts of interest.


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
1 . Antinori, A., Cingolani, A., Alba, L. et al. (2001). Better response to chemotherapy and prolonged survival in AIDS-related lymphomas responding to highly active antiretroviral therapy. AIDS 15, 1483–91.[CrossRef][ISI][Medline]

2 . Vaccher, E., Spina, M., Talamini, R. et al. (2003). Improvement of systemic human immunodeficiency virus-related non-Hodgkin lymphoma outcome in the era of highly active antiretroviral therapy. Clinical Infectious Diseases 37, 1556–64.[CrossRef][ISI][Medline]

3 . Sparano, J. A., Lee, S., Chen, M. G. et al. (2004). Phase II trial of infusional cyclophosphamide, doxorubicin, and etoposide in patients with HIV-associated non-Hodgkin's lymphoma: an Eastern Cooperative Oncology Group Trial (E1494). Journal of Clinical Oncology 22, 1491–500.[Abstract/Free Full Text]

4 . Sparano, J. A., Wiernik, P. H., Hu, X. et al. (1998). Saquinavir enhances the mucosal toxicity of infusional cyclophosphamide, doxorubicin, and etoposide in patients with HIV-associated non-Hodgkin's lymphoma. Medical Oncology 15, 50–7.[ISI][Medline]

5 . Evison, J., Jost, J., Ledrgerber, B. et al. (1999). HIV-associated non-Hodgkin's lymphoma: highly active antiretroviral therapy improves remission rate of chemotherapy. AIDS 13, 732–4.[CrossRef][ISI][Medline]

6 . Bower, M., McCall-Peat, N., Ryan, N. et al. (2004). Protease inhibitors potentiate chemotherapy-induced neutropenia. Blood 104, 2943–6.[Abstract/Free Full Text]

7 . Vaccher, E., Spina, M., Di Gennaro, G. et al. (2001). Concomitant cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy plus highly active antiretroviral therapy in patients with human immunodeficiency virus-related, non-Hodgkin's lymphoma. Cancer 91, 155–63.[CrossRef][ISI][Medline]

8 . Ratner, L., Lee, J., Tang, S. et al. (2001). Chemotherapy for human immunodeficiency virus-associated non-Hodgkin's lymphoma in combination with highly active antiretroviral therapy. Journal of Clinical Oncology 19, 2171–8.[Abstract/Free Full Text]

9 . Merck Sharp & Dohme Ltd. (2001). Crixivan summary of product characteristics. In Crixivan Product Information. Merck & Co Inc.

10 . de Maat, M. M., Ekhart, G. C., Huitema, A. D. et al. (2003). Drug interactions between antiretroviral drugs and comedicated agents. Clinical Pharmacokinetics 42, 223–82.[ISI][Medline]

11 . Pichard, L., Fabre, I., Daujat, M. et al. (1992). Effect of corticosteroids on the expression of cytochromes P450 and on cyclosporin A oxidase activity in primary cultures of human hepatocytes. Molecular Pharmacology 41, 1047–55.[Abstract]

12 . Lindley, C., Hamilton, G., McCune, J. S. et al. (2002). The effect of cyclophosphamide with and without dexamethasone on cytochrome P450 3A4 and 2B6 in human hepatocytes. Drug Metabolism and Disposition 30, 814–22.[Abstract/Free Full Text]

13 . Lucia, M. B., Rotella, S., Leone, G. et al. (2002). In vitro and in vivo modulation of MDR1/P-glycoprotein in HIV-infected patients administered highly active antiretroviral therapy and liposomal doxorubicin. Journal of Acquired Immune Deficiency Syndromes 30, 369–78.[ISI][Medline]

14 . Khoo, S. H., Gibbons, S. E. & Back, D. J. (2001). Therapeutic drug monitoring as a tool in treating HIV infection. AIDS 15, Suppl. 5, S171–81.[CrossRef][ISI][Medline]

15 . Burger, D. M., Hugen, P. W., Aarnoutse, R. E. et al. (2003). Treatment failure of nelfinavir-containing triple therapy can largely be explained by low nelfinavir plasma concentrations. Therapeutic Drug Monitoring 25, 73–80.[CrossRef][ISI][Medline]

16 . Burger, D., Hugen, P., Reiss, P. et al. (2003). Therapeutic drug monitoring of nelfinavir and indinavir in treatment-naive HIV-1-infected individuals. AIDS 17, 1157–65.[CrossRef][ISI][Medline]





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