HIV & Malignancy Potential for Drug Drug Interactions

Transcription

1 HIV & Malignancy Potential for Drug Drug Interactions Kay Seden

2 Aims and Outline Mechanisms of drug drug interactions associated with antiretrovirals and treatment for malignancy Examples of interactions with common chemotherapy regimens and antiretrovirals Overview of available data on interactions Treatment options and considerations Considerations with oral cytotoxics: protein kinase inhibitors

3 Mechanisms of Drug Drug Interactions Pharmacokinetic Interactions Modulation of, or competition for metabolic pathways (enterocyte, hepatocyte) Modulation of, or competition for transport mechanisms (enterocyte, hepatocyte, kidney) Absorption Pharmacodynamic Interactions Overlapping toxicity Examples Phase 1 metabolism: CYP450 enzymes Phase 2 metabolism: Glucuronidation P glycoprotein Active renal transport via hoatp, MRP2 ph modulation Cations Examples Anaemia Renal toxicity QT interval prolongation

4 Enzyme inhibition of hepatic CYP450 A. Drug alone P450 Concentration AUC Time B. Drug + Inhibitor P450 Concentration AUC Poten al for clinical effect of drug or incidence or severity of adverse events Inhibitor blocks function of P450 enzyme Time

5 Enzyme Induction of Hepatic CYP450 A. Drug alone P450 Concentration AUC B. Drug + Inducer Time Inducer increases activity of enzyme P450 Concentration AUC Potential for diminished clinical effect of drug

6 Renal mechanisms Undergoes active tubular secretion: Tenofovir Emtricitabine Lamivudine Stavudine Inhibits active tubular secretion: Rilpivirine Ed Wilkins, HIV Drug Therapy Glasgow 2012

7 Common Toxicities Adverse reaction ARVs Cytotoxic drugs Myelosuppression ZDV Most Neuropathy ddi, D4T Taxanes, doxorubicin, etoposide, vinblastine, bortezomib, cisplatin Nephrotoxicity TDF (Fanconi syndrome), IDV (nephrolithiasis) Cisplatin, carboplatin, ifosfamide, methotrexate Nausea and vomiting All PIs, ZDV, ddi Cisplatin, dacarbazine, carboplatin, cyclophosphamide, daunorubicin, doxorubicin, cytarabine, and ifosfamide Diarrhoea LPV/r and other PIs 5 fluorouracil, methotrexate, docetaxal Hepatotoxicity EFV, NVP, RPV, DRV/r, ddi, D4T Methotrexate, gemcitabine, hydroxycarbamide Pancreatitis ddi, D4T, RTV Asparaginase, hydroxycarbamide QT prolongation PIs, RPV Daunorubicin, protein kinase inhibitors eg. sunitinib

8 HIV Associated Malignancy Kaposi Sarcoma liposomal anthracyclines (daunorubicin, doxorubicin) or taxanes (paclitaxel) Hodgkins disease ABVD (vinblastine, bleomycin, doxorubicin, dacarbazine) Non Hodgkins Lymphoma Burkitts Lymphoma: CODOX M/IVAC (cyclophosphamide, vincristine, doxorubicin, methotrexate/ifosfamide, etoposide and cytarabine) or hypercvad (cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate and cytarabine) Diffuse large B cell lymphoma: conventional CHOP (doxorubicin, cyclophosphamide, vincristine, prednisolone), R CHOP (+rituximab), or CDE (cyclophosphamide, doxorubicin, etoposide) or EPOCH(etoposide, prednisolone, vincristine, cyclophosphamide, doxorubicin) Castlemans Disease CHOP or single agent chemotherapy with vinblastine or etoposide, or rituximab Cervical cancer Radiation therapy + cisplatin or cisplatin/5 Fluorouracil BHIVA guidelines for HIV associated malignancies 2008

9 Potential Interactions at a Glance...

10 RAL MVC ZDV TDF d4t 3TC FTC ddi ABC RPV NVP ETV EFV TPV/r LPV/r FPV/r DRV/r ATV/r Daunorubicin Doxorubicin Paclitaxel Vinblastine Vincristine Bleomycin Dacarbazine Cyclophosphamide Methotrexate Ifosfamide Etoposide Cytarabine Rituximab Cisplatin Fluorouracil

11 RAL MVC ZDV ABVD (eg. Hodgkins Lymphoma) Vinblastine, bleomycin, doxorubicin, dacarbazine TDF d4t 3TC FTC ddi ABC RPV NVP ETV EFV TPV/r LPV/r FPV/r DRV/r ATV/r Bleomycin Doxorubicin Dacarbazine Vinblastine

12 ABVD (eg. Hodgkins Disease) ATV/r may increase exposure to vinblastine RAL MVC ZDV TDF d4t 3TC FTC ddi ABC RPV NVP ETV EFV TPV/r LPV/r FPV/r DRV/r ATV/r Bleomycin Doxorubicin Dacarbazine Vinblastine Vinblastine is predominantly metabolised by CYP3A4. ATV/r may increase exposure to vinblastine via CYP3A4 inhibition, potentially increasing toxicity and side effects of vinblastine. Case reports and observational studies have demonstrated that concurrent use of protease inhibitors was independently associated with increased risk of higher grade neutropenia. ARV regimens containing NNRTIs or RAL were associated with lower levels of neutropenia

13 ABVD: Vincristine and Ritonavir Boosted Protease Inhibitors

14 ABVD (eg. Hodgkins Disease) Dacarbazine and/or TDF/FTC exposure may increase RAL MVC ZDV TDF d4t 3TC FTC ddi ABC RPV NVP ETV EFV TPV/r LPV/r FPV/r DRV/r ATV/r Bleomycin Doxorubicin Dacarbazine Vinblastine Coadministration has not been studied, but concentrations of both substances could be possibly increased due to competition for active tubular secretion. In vitro data suggest that dacarbazine is a substrate of the renal transporter OAT1. Monitor for toxicity and renal function

15 ABVD: Dacarbazine and TDF/FTC Ed Wilkins, HIV Drug Therapy Glasgow 2012

16 ABVD Summary (Vinblastine, bleomycin, doxorubicin, dacarbazine) & ATV/r TDF/FTC Issues Ritonavir boosted protease inhibitors may increase exposure to vinblastine, and precipitate neutropenia Options Fewer adverse events observed with NNRTI or raltegravir containing regimens. However NNRTIs such as EFV and NVP may lower exposure to vinblastine. Rilpivirine and etravirine less likely to induce CYP3A4, no interaction expected with RAL or MVC Dacarbazine may compete with emtricitabine/tenofovir for active renal elimination transporters, increasing levels of either drug Monitor renal function and assess for toxicity. And/or Consider NRTI backbone less likely to compete for elimination via renal transport eg abacavir/lamivudine

17 Case Report... Raltegravir based HAART regimen in a patient with large B cell lymphoma. Fulco PP, Hynicka L, Rackley D. Ann Pharmacother Feb;44(2): CASE SUMMARY: A 55 year old white man recently was diagnosed with HIV/AIDS and diffuse large B cell lymphoma. HAART and a chemotherapeutic regimen, including cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) with intrathecal methotrexate, was initiated. As the potential for multiple drug drug interactions existed, raltegravir, abacavir, and lamivudine were chosen for the initial HAART regimen. The patient achieved and maintained an undetectable viral load throughout 6 CHOP cycles. DISCUSSION: Multiple drug drug interactions are possible in patients who are to receive CHOP and HAART. Cyclophosphamide and vincristine are metabolized via the CYP3A4 isoenzyme. Protease inhibitors (PIs) and nonnucleoside reverse transcriptase inhibitors both inhibit and induce CYP3A4, with the potential for altered chemotherapeutic and cytotoxic effects. When PIs are combined with CHOP, mortality is reduced, but increased adverse effects are demonstrated. Raltegravir is eliminated via glucuronidation and results in minimal drug drug interactions. Raltegravir improves virologic and immunologic responses in HAART naïve patients and thus would be a suitable alternative for preventing chemotherapeutic HAART interactions.

18 CODOX M/IVAC (eg. Burkitts Lymphoma) Cyclophosphamide, Vincristine, Doxorubicin, Methotrexate/Ifosfamide, Etoposide, Cytarabine RAL MVC ZDV TDF d4t 3TC FTC ddi ABC RPV NVP ETV EFV TPV/r LPV/r FPV/r DRV/r ATV/r Cyclophosphamide Vincristine Doxorubicin Methotrexate Ifosfamide Etoposide Cytarabine

19 CODOX M/IVAC: Efavirenz and Cyclophosphamide Efavirenz could either increase or decrease clinical effect of cyclophosphamide RAL MVC ZDV TDF d4t 3TC FTC ddi ABC RPV NVP ETV EFV TPV/r LPV/r FPV/r DRV/r ATV/r Cyclophosphamide Vincristine Doxorubicin Methotrexate Ifosfamide Etoposide Cytarabine Coadministration has not been studied and is difficult to predict. Cyclophosphamide is activated by CYP2B6 (major). The inactivation pathway to the neurotoxic chloroacetaldehyde metabolite is mainly via CYP3A4. Efavirenz could potentially increase conversion to the active metabolite or increase the amount of drug converted to the inactive metabolite via induction of CYP2B6 and CYP3A4. Monitoring of cyclophosphamide efficacy and toxicity is recommended.

20 CODOX M/IVAC: Efavirenz and Vincristine Efavirenz could potentially decrease vincristine exposure RAL MVC ZDV TDF d4t 3TC FTC ddi ABC RPV NVP ETV EFV TPV/r LPV/r FPV/r DRV/r ATV/r Cyclophosphamide Vincristine Doxorubicin Methotrexate Ifosfamide Etoposide Cytarabine Coadministration has not been studied. Vincristine is metabolized by CYP3A4. Efavirenz, an inducer of CYP3A4, could potentially decrease vincristine exposure. Monitor response to chemotherapy.

21 CODOX M/IVAC: Methotrexate and ARVs Methotrexate and/or TDF/FTC exposure may be increased. There is increased potential for renal toxicity RAL MVC ZDV TDF d4t 3TC FTC ddi ABC RPV NVP ETV EFV TPV/r LPV/r FPV/r DRV/r ATV/r Cyclophosphamide Vincristine Doxorubicin Methotrexate Ifosfamide Etoposide Cytarabine Some manufacturers of methotrexate state that use is contraindicated in HIV positive patients, therefore caution and monitoring is advised. There is potential for competition for active renal transport mechanisms if FTC/TDF and methotrexate are co administered, which may lead to increased exposure to either drug. Methotrexate and tenofovir may both cause renal toxicity, if co administered, close monitoring of renal function is recommended.

22 CODOX M/IVAC: Ifosfamide and Efavirenz Efavirenz may decrease exposure to ifosfamide. Ifosfamide may lower exposure to Efavirenz: cytotoxic drug as a perpetrator of pharmacokinetic interaction RAL MVC ZDV TDF d4t 3TC FTC ddi ABC RPV NVP ETV EFV TPV/r LPV/r FPV/r DRV/r ATV/r Cyclophosphamide Vincristine Doxorubicin Methotrexate Ifosfamide Etoposide This interaction has not been studied. In vitro studies show that ifosfamide may both inhibit and induce CYP3A4. Data with sunitinib (CYP3A4 substrate) suggests that ifosfamide can decrease sunitinib levels via CYP3A4 induction. There is therefore potential for ifosfamide to alter levels of efavirenz. Ifosfamide is metabolized by CYP3A4 and CYP2B6. Pretreatment with the CYP3A inducer dexamethasone decreased the AUC for both ifosfamide metabolites. As efavirenz is an enzyme inducer (CYP3A4, CYP2B6), there is potential for ifosfamide levels to be reduced if coadministered. Cytarabine

23 CODOX M/IVAC: Ifosfamide and Tenofovir Increased risk of renal tubular damage / Fanconi syndrome RAL MVC ZDV TDF d4t 3TC FTC ddi ABC RPV NVP ETV EFV TPV/r LPV/r FPV/r DRV/r ATV/r Cyclophosphamide Vincristine Doxorubicin Methotrexate Ifosfamide Etoposide Cytarabine Ifosfamide has been associated with serious nephrotoxicity including proximal and distal tubular damage, glomerular effects and Fanconi syndrome. Use of tenofovir disoproxil fumarate should be avoided with concurrent or recent use of a nephrotoxic medicinal product. If concomitant use of tenofovir disoproxil fumarate and nephrotoxic agents is unavoidable, renal function should be monitored regularly.

24 CODOX M/IVAC: Etoposide and Efavirenz Efavirenz may decrease etoposide exposure RAL MVC ZDV TDF d4t 3TC FTC ddi ABC RPV NVP ETV EFV TPV/r LPV/r FPV/r DRV/r ATV/r Cyclophosphamide Vincristine Doxorubicin Methotrexate Ifosfamide Etoposide Cytarabine Coadministration has not been studied. Etoposide is partly glucuronidated by UGT1A1 and partly metabolized by CYP3A4 to reactive catechol metabolites. Efavirenz, an inducer of CYP3A4, could potentially decrease etoposide exposure, although the clinical relevance is unknown. Monitor clinical effect.

25 CODOX M/IVAC Summary (Cyclophosphamide, Vincristine, Doxorubicin, Methotrexate/Ifosfamide, Issues EFV may increase OR decrease exposure to cyclophosphamide via CYP3A4 and/or CYP2B6 induction. Clinical relevance unknown EFV may decrease exposure to vincristine via CYP3A4 induction. Clinical relevance unknown Methotrexate unlicensed by some manufacturers for use in HIV positive patients Methotrexate may compete with FTC/TDF for renal elimination transporters, increasing levels of either drug. Increased risk of renal toxicity Ifosfamide may decrease exposure to EFV via CYP3A4 induction. EFV may decrease exposure to ifosfamide via CYP3A4 induction Etoposide, Cytarabine) & EFV TDF/FTC Options Monitor for cyclophosphamide effect/toxicity. PIs may increase exposure to cyclophosphamide/vincristine Ral, RPV, ETV, MVC unlikely to interact Discuss with clinicians & patient, use with caution and monitor Monitor renal function and assess for toxicity. And/or Consider NRTI backbone less likely to compete for renal transport or cause renal toxicity eg abacavir/lamivudine Monitor for ifosfamide effect, TDM for EFV. PIs may increase exposure to ifosfamide. Ifosfamide may decrease exposure to PIs, EFV, NVP, RPV, ETV, MVC. RAL unlikely to interact

26 Irinotecan (eg. Colorectal Cancers, Kaposi s Sarcoma) Clin Pharmacol Ther Apr;83(4): Effect of LPV/RTV on the pharmacokinetics of irinotecan was investigated in 7 patients with Kaposi s sarcoma. Coadministration of LPV/RTV reduces clearance of irinotecan by 47%. This effect was associated with an 81% reduction of the AUC of the oxidized metabolite APC. LPV/RTV treatment also inhibited the formation of SN38 glucuronide (SN38G), as shown by the 36% decrease in the SN38G/SN38 AUCs ratio consistent with UGT1A1 inhibition by LPV/RTV. This dual effect resulted in increased availability of irinotecan for SN38 conversion and reduced inactivation on SN38, leading to a 204% increase in SN38 AUC in the presence of LPV/RTV. Correspondence AIDS 2005, 19: Corona, Giuseppe; Vaccher, Emanuela; Cattarossi, Giulio; Sartor, Ivana; Toffoli, Giuseppe

27 Irinotecan: Mechanism of Interaction with Boosted Protease Inhibitors Ed Wilkins, HIV Drug Therapy Glasgow 2012

28 Kaposi s Sarcoma Daunorubicin/Doxorubicin or Paclitaxel Pilot Study Evaluating the Interaction Between Paclitaxel and Protease Inhibitors in Patients with Human Immunodeficiency Virus Associated Kaposi s Sarcoma: An Eastern Cooperative Oncology Group (ECOG) and AIDS Malignancy Consortium (AMC) Trial Mary Cianfrocca, Sandra Lee, Jamie Von Roenn, Michelle A. Rudek, Bruce J. Dezube, Susan E. Krown, and Joseph A. Sparano Cancer Chemother Pharmacol October ; 68(4): Methods: Patients with advanced HIV associated KS received paclitaxel (100 mg/m2) by intravenous infusion over 3 hours, and plasma samples were collected to measure paclitaxel concentration. Pharmacokinetics were compared with respect to antiretroviral therapy and toxicity Results: 34 patients received paclitaxel, of whom 20 had no prior paclitaxel therapy. 27 had pharmacokinetic studies performed. Paclitaxel exposure was higher in patients taking protease inhibitors compared to those who were not taking protease inhibitors. The increased exposure did not correlate with efficacy or toxicity. Conclusion: Despite higher exposure to paclitaxel, patients on protease inhibitors did not experience enhanced toxicity or efficacy.

29 HIV Associated Malignancy Kaposi Sacoma liposomal anthracyclines (daunorubicin, doxorubicin) or taxanes (paclitaxel) Hodgkins disease ABVD (vinblastine, bleomycin, doxorubicin, dacarbazine) Non Hodgkins Lymphoma Burkitts Lymphoma: CODOX M/IVAC (cyclophosphamide, vincristine, doxorubicin, methotrexate/ifosfamide, etoposide and cytarabine) or hypercvad (cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate and cytarabine) Diffuse large B cell lymphoma: conventional CHOP (doxorubicin, cyclophosphamide, vincristine, prednisolone), R CHOP (+rituximab), or CDE (cyclophosphamide, doxorubicin, etoposide) or EPOCH(etoposide, prednisolone, vincristine, cyclophosphamide, doxorubicin) Castlemans Disease CHOP or single agent chemotherapy with vinblastine or etoposide, or rituximab Cervical cancer Radiation therapy + cisplatin or cisplatin/5 Fluorouracil BHIVA guidelines for HIV associated malignancies 2008

30 Don t forget! Oral Steroids Oral steroids are often given with chemotherapy regimens High doses may be used in this context Potential for interactions with antiretrovirals Steroid PK Profile Effect of steroid on CYP3A4 Substrates (PIs, NNRTIs, MVC) Effect of CYP3A4 Inhibitors (boosted PIs) on steroid Effect of CYP3A4 Inducers (NNRTIs EFV/NVP) on steroid Dexamethasone (Dex) Metabolised by CYP3A4 Induces CYP3A4 levels, poten ally lowering effect *Rilpivirine contraindicated with systemic Dex levels Case report of cushings syndrome with ATV/r Dex (eye drops) levels, potentially lowering clinical effect of steroid Prednisolone (Pred) Metabolised by CYP3A4 levels ~30% (RTV 200mg BD) levels ~40% (EFV, single dose 20mg Pred)

31 Newer Agents JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T Phase II Study of Bevacizumab in Patients With HIV Associated Kaposi s Sarcoma Receiving Antiretroviral Therapy Thomas S. Uldrick, Kathleen M. Wyvill, Pallavi Kumar, Deirdre O Mahony, Wendy Bernstein, Karen Aleman, Mark N. Polizzotto, Seth M. Steinberg, Stefania Pittaluga, Vickie Marshall, Denise Whitby, Richard F. Little, and Robert Yarchoan VOLUME 30 NUMBER 13 MAY

32 Protein Kinase Inhibitors Relatively new therapeutic class >10 now licensed in UK dasatinib, erlotinib, everolimus, gefitinib, imatinib, lapatinib, nilotinib, pazopanib, sorafenib, sunitinib, temsirolimus Indications include: various leukaemias, metastatic pancreatic cancer, non small cell lung cancer, renal cell carcinoma, neuroendocrine tumours, breast cancer, gastrointestinal stromal tumours May be used in maintenance treatment after cycles of chemotherapy, or as adjuvants to chemotherapy Mostly taken orally, by outpatients Potential for interactions with antiretrovirals

33 Protein Kinase Inhibitors Important Mechanisms CYP3A4 +/ CYP2D6 substrates Many are CYP3A4 +/ CYP2D6 inhibitors Some inhibit UGT1A1 Some prolong QT interval Some are nephrotoxic Most produce myelosuppression

34 Protein Kinase Inhibitors Few data on co administration with ARVs Short report Treatment of Recurrent Hepatocellular Carcinoma with Sorafenib in a HIV/HCV Co Infected patient in HAART: A Case Report Pasquale De Nardo, Magdalena Viscione, Angela Corpolongo, Rita Bellagamba, Giovanni Vennarecci, Giuseppe M Ettorre, Elisa Gentilotti, Chiara Tommasi and Emanuele Nicastri Infectious Agents and Cancer 2012, 7:15 During therapy with sorafenib, the patient was treated with HAART (TDF/FTC, FPV/r) with good viral and immunological responses. Fosamprenavir Ctrough was found under the minimum level recommended by international guidelines (Ctrough: 115ng/mL; Cmax: 436ng/mL). At month 20 of treatment, new liver lesions with portal vein thrombosis were diagnosed. A 50% dose reduction of sorafenib to 200mg twice daily was scheduled for safety reasons. Metabolism of sorafenib occurs primarily in the liver, mediated via cytochrome CYP3A4, and concomitant administration with CYP3A4 inducers or inhibitors may modify sorafenib concentrations... Fosemprenavir and ritonavir are both P450 CYP3A4 inhibitors and since sorafenib is metabolized through CYP3A4, that could result in an increase of the active dose of sorafenib explaining the favorable outcome for the patient.

35 Protein Kinase Inhibitors Pharmacokinetics of Imatinib Influence of CYP3A4 Inhibition on the Steady State Nielka P. van Erp, Hans Gelderblom, Mats O. Karlsson, et al. Clin Cancer Res 2007;13: Design: Imatinib pharmacokinetics were evaluated in cancer patients receiving the drug 2 months, after which ritonavir (600mg) was administered daily for 3 days. Samples were obtained on the day before ritonavir and on the third day. In vitro metabolism of imatinib with or without ritonavir were evaluated. Results: In 11 patients, ritonavir did not sinificantly influence the clearance or bioavailability of imatinib. vitro, imatinib was metabolized to the active metabolite by CYP3A4 and CYP3A5 and, to a lesser extent CYP2D6. Ritonavir completely inhibited CYP3A4 mediated metabolism of imatinib but inhibited metabolism in microsomes by only 50%. Imatinib significantly inhibited CYP3A4 activity in vitro. Conclusion: The observation that acute inhibition of CYP3A4 mediated metabolism by ritonavir does not lead to substantially altered imatinib steady state exposure was unexpected. At steady state, imatinib is insensitive to potent CYP3A4 inhibition and relies on alternate elimination pathways. For agents with complex elimination pathways that involve autoinhibition, interaction studies that are done after a single dose may not be applicable for chronically administered drugs.

36 Protein Kinase Inhibitors HIV Protease inhibitors may have a cytotoxic effect on leukemia cells RESEARCH Open Access The mitochondria independent cytotoxic effect of nelfinavir on leukemia cells can be enhanced by sorafenib mediated mcl 1 downregulation and mitochondrial membrane destabilization Ansgar Brüning, Martina Rahmeh, Andrea Gingelmaier, Klaus Friese Molecular Cancer 2010, 9:19 In vitro anti neuroblastoma activity of saquinavir and its association with imatinib. Timeus F, Crescenzio N, Doria A, Foglia L, Pagliano S, Ricotti E, Fagioli F, Tovo PA, Cordero di Montezemolo L Oncol Rep Mar;27(3):

37 Protein Kinase Inhibitors CYP3A4 Substrates (dasatinib, erlotinib, everolimus, gefitinib, imatinib, lapatinib, nilotinib, sunitinib) CYP2D6 Substrates (gefitinib (predominantly CYP3A4)) CYP3A4 Inhibitors (dasatinib, everolimus, imatinib, lapatinib) UGT1A1 Inhibitors (erlotinib, nilotinib) QT Interval Prolongation (dasatinib, lapatinib, nilotinib, sunitinib) Myelosuppression (dasatinib, everolimus, imatinib, nilotinib, sunitinib) Nephrotoxicity (sunitinib) Increased Bleeding Risk (dasatinib, imatinib, sunitinib) Hepatotoxicity (imatinib, lapatinib, sunitinib) Considerations with Antiretrovirals PIs may levels via CYP3A4 inhibition NNRTIs EFV, NVP may levels via CYP3A4 induction Ritonavir boosted PIs may levels, due to ritonavir inhibition of CYP2D6 PIs, NNRTIs, MVC levels may Poten al for bilirubin levels when given with ATV, IDV. RAL levels may (unlikely clinically relevant) Increased risk for QT prolongation with PIs, rilpivirine Increased risk for myelosuppression with zidovudine Increased risk for nephrotoxicity with tenofovir Increased bleeding risk with tipranavir Increased risk for hepatotoxicity with didanosine, stavudine, efavirenz

38 Summary High potential for interactions between ARVs and cytotoxic drugs Many interactions can be managed: use of alternative ARVs may be possible Few interaction studies exist, most information derived from observation studies with low numbers, and case reports Need understanding of mechanisms of interaction and disposition of drugs in order to anticipate potential interactions

39 Reference Sources

40 David Back Saye Khoo Sara Gibbons Catia Marzolini Acknowledgements Ed Wilkins