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HIV & MalignancyPotential for Drug‐Drug Interactions
Kay Seden
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
Mechanisms of Drug‐Drug InteractionsPharmacokinetic Interactions Examples
Modulation of, or competition for metabolic pathways (enterocyte, hepatocyte)
Phase 1 metabolism: CYP450 enzymes
Phase 2 metabolism: Glucuronidation
Modulation of, or competition for transport mechanisms (enterocyte, hepatocyte, kidney)
P‐glycoprotein
Active renal transport via hOATP, MRP2
AbsorptionpH modulation
Cations
Pharmacodynamic Interactions Examples
Overlapping toxicityAnaemia
Renal toxicity
QT interval prolongation
Enzyme inhibition of hepatic CYP450
A. Drug alone
P450
Concen
tration
AUC
Time
B. Drug + Inhibitor
P450Co
ncen
tration
Time
AUC Poten al for ↑ clinical effect of drug or ↑ incidence or severity of adverse events
Inhibitor blocks function of P450 enzyme
Enzyme Induction of Hepatic CYP450
Time
Concen
tration
Concen
tration
Inducer increases activity of enzyme
P450
AUC A. Drug alone
B. Drug + Inducer
AUC
P450Potential for diminished clinical effect of drug
P450
Renal mechanisms
Undergoes active tubular secretion:TenofovirEmtricitabineLamivudineStavudineInhibits active tubular secretion:Rilpivirine
Ed Wilkins, HIV Drug Therapy Glasgow 2012
Common ToxicitiesAdverse reaction ARVs Cytotoxic drugs
Myelosuppression ZDV Most
Neuropathy ddI, D4T Taxanes, doxorubicin, etoposide, vinblastine, bortezomib, cisplatin
Nephrotoxicity TDF (Fanconisyndrome), 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
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
Potential Interactions at a Glance.....
ATV/r
DRV/r
FPV/r
LPV/r
TPV/r
EFV
ETV
NVP
RPV
ABC
ddI
FTC
3TC
d4T
TDF
ZDV
MVC
RAL
Daunorubicin
Doxorubicin
Paclitaxel
Vinblastine
Vincristine
Bleomycin
Dacarbazine
Cyclophosphamide
Methotrexate
Ifosfamide
Etoposide
Cytarabine
Rituximab
Cisplatin
Fluorouracil
ABVD (eg. Hodgkins Lymphoma)Vinblastine, bleomycin, doxorubicin, dacarbazine
ATV/r
DRV/r
FPV/r
LPV/r
TPV/r
EFV
ETV
NVP
RPV
ABC
ddI
FTC
3TC
d4T
TDF
ZDV
MVC
RAL
Bleomycin
Doxorubicin
Dacarbazine
Vinblastine
ABVD (eg. Hodgkins Disease)ATV/r may increase exposure to vinblastine
ATV/r
DRV/r
FPV/r
LPV/r
TPV/r
EFV
ETV
NVP
RPV
ABC
ddI
FTC
3TC
d4T
TDF
ZDV
MVC
RAL
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
ABVD: Vincristine and Ritonavir‐Boosted Protease Inhibitors
ABVD (eg. Hodgkins Disease)Dacarbazine and/or TDF/FTC exposure may increase
ATV/r
DRV/r
FPV/r
LPV/r
TPV/r
EFV
ETV
NVP
RPV
ABC
ddI
FTC
3TC
d4T
TDF
ZDV
MVC
RAL
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
ABVD: Dacarbazine and TDF/FTC
Ed Wilkins, HIV Drug Therapy Glasgow 2012
ABVD Summary (Vinblastine, bleomycin, doxorubicin, dacarbazine) & ATV/r TDF/FTC
Ritonavir‐boosted protease inhibitors may increase exposure to vinblastine, and precipitate neutropenia
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
OptionsIssues
Dacarbazine may compete with emtricitabine/tenofovir for active renal elimination transporters, increasing levels of either drug
Monitor renal function and assess for toxicity.And/orConsider NRTI backbone less likely to compete for elimination via renal transport eg abacavir/lamivudine
Case Report....Raltegravir‐based HAART regimen in a patient with large B‐cell lymphoma.Fulco PP, Hynicka L, Rackley D.Ann Pharmacother. 2010 Feb;44(2):377‐82.
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.
CODOX‐M/IVAC (eg. Burkitts Lymphoma) Cyclophosphamide, Vincristine, Doxorubicin, Methotrexate/Ifosfamide, Etoposide, Cytarabine
ATV/r
DRV/r
FPV/r
LPV/r
TPV/r
EFV
ETV
NVP
RPV
ABC
ddI
FTC
3TC
d4T
TDF
ZDV
MVC
RAL
Cyclophosphamide
Vincristine
Doxorubicin
Methotrexate
Ifosfamide
Etoposide
Cytarabine
CODOX‐M/IVAC: Efavirenz and Cyclophosphamide Efavirenz could either increase or decrease clinical effect of cyclophosphamide
ATV/r
DRV/r
FPV/r
LPV/r
TPV/r
EFV
ETV
NVP
RPV
ABC
ddI
FTC
3TC
d4T
TDF
ZDV
MVC
RAL
Cyclophosphamide
Vincristine
Doxorubicin
Methotrexate
Ifosfamide
Etoposide
Cytarabine
Coadministration has not been studied and is difficult to predict. Cyclophosphamideis 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.
CODOX‐M/IVAC: Efavirenz and Vincristine Efavirenz could potentially decrease vincristine exposure
ATV/r
DRV/r
FPV/r
LPV/r
TPV/r
EFV
ETV
NVP
RPV
ABC
ddI
FTC
3TC
d4T
TDF
ZDV
MVC
RAL
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.
CODOX‐M/IVAC: Methotrexate and ARVsMethotrexate and/or TDF/FTC exposure may be increased. There is increased potential for renal toxicity
ATV/r
DRV/r
FPV/r
LPV/r
TPV/r
EFV
ETV
NVP
RPV
ABC
ddI
FTC
3TC
d4T
TDF
ZDV
MVC
RAL
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.
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
ATV/r
DRV/r
FPV/r
LPV/r
TPV/r
EFV
ETV
NVP
RPV
ABC
ddI
FTC
3TC
d4T
TDF
ZDV
MVC
RAL
Cyclophosphamide
Vincristine
Doxorubicin
Methotrexate
Ifosfamide
Etoposide
CytarabineThis 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.
CODOX‐M/IVAC: Ifosfamide and Tenofovir Increased risk of renal tubular damage / Fanconi syndrome
ATV/r
DRV/r
FPV/r
LPV/r
TPV/r
EFV
ETV
NVP
RPV
ABC
ddI
FTC
3TC
d4T
TDF
ZDV
MVC
RAL
Cyclophosphamide
Vincristine
Doxorubicin
Methotrexate
Ifosfamide
Etoposide
CytarabineIfosfamide 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.
CODOX‐M/IVAC: Etoposide and Efavirenz Efavirenz may decrease etoposide exposure
ATV/r
DRV/r
FPV/r
LPV/r
TPV/r
EFV
ETV
NVP
RPV
ABC
ddI
FTC
3TC
d4T
TDF
ZDV
MVC
RAL
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.
CODOX‐M/IVAC Summary (Cyclophosphamide, Vincristine, Doxorubicin, Methotrexate/Ifosfamide,
Etoposide, Cytarabine) & EFV TDF/FTC
EFV may increase OR decrease exposure to cyclophosphamide via CYP3A4 and/or CYP2B6 induction. Clinical relevance unknown
Monitor for cyclophosphamide effect/toxicity. PIs may increase exposure to cyclophosphamide/vincristine Ral, RPV, ETV, MVC unlikely to interact
OptionsIssues
Methotrexate may compete with FTC/TDF for renal elimination transporters, increasing levels of either drug. Increased risk of renal toxicity
Monitor renal function and assess for toxicity.And/orConsider NRTI backbone less likely to compete for renal transport or cause renal toxicity eg abacavir/lamivudine
EFV may decrease exposure to vincristine via CYP3A4 induction. Clinical relevance unknown
Methotrexate unlicensed by some manufacturers for use in HIV positive patients
Discuss with clinicians & patient, use with caution and monitor
Ifosfamide may decrease exposure to EFV via CYP3A4 induction. EFV may decrease exposure to ifosfamide via CYP3A4 induction
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
Irinotecan (eg. Colorectal Cancers, Kaposi’s Sarcoma)
CorrespondenceAIDS 2005, 19:2043–2055
Corona, Giuseppe; Vaccher, Emanuela; Cattarossi, Giulio; Sartor, Ivana; Toffoli, Giuseppe
Clin Pharmacol Ther. 2008 Apr;83(4):601‐6.
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.
Irinotecan: Mechanism of Interaction with Boosted Protease Inhibitors
Ed Wilkins, HIV Drug Therapy Glasgow 2012
Kaposi’s SarcomaDaunorubicin/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) TrialMary Cianfrocca, Sandra Lee, Jamie Von Roenn, Michelle A. Rudek, Bruce J. Dezube, Susan E. Krown, and Joseph A. SparanoCancer Chemother Pharmacol. 2011 October ; 68(4): 827–833
Methods: Patients with advanced HIV‐associated KS received paclitaxel (100 mg/m2) byintravenous infusion over 3 hours, and plasma samples were collected to measure paclitaxelconcentration. Pharmacokinetics were compared with respect to antiretroviral therapy and toxicityResults: 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 notexperience enhanced toxicity or efficacy.
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
Oral SteroidsDon’t forget!
• Oral steroids are often given with chemotherapy regimens• High doses may be used in this context• Potential for interactions with antiretrovirals
Steroid PK ProfileEffect 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 CYP3A4Induces CYP3A4
↓ levels, poten ally lowering effect*Rilpivirine contraindicated with systemic Dex
↑ levelsCase 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)
Newer Agents
Phase II Study of Bevacizumab in Patients With HIV‐AssociatedKaposi’s Sarcoma Receiving Antiretroviral TherapyThomas 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 YarchoanVOLUME 30 NUMBER 13 MAY 1 2012
JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T
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
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
Protein Kinase InhibitorsFew 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 ReportPasquale De Nardo, Magdalena Viscione, Angela Corpolongo, Rita Bellagamba, Giovanni Vennarecci, Giuseppe M Ettorre, Elisa Gentilotti, Chiara Tommasi and Emanuele NicastriInfectious 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.’
Protein Kinase Inhibitors
Pharmacokinetics of Imatinib Influence of CYP3A4 Inhibition on the Steady‐StateNielka P. van Erp, Hans Gelderblom, Mats O. Karlsson, et al.Clin Cancer Res 2007;13:7394‐7400
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.
Protein Kinase Inhibitors
RESEARCH Open AccessThe mitochondria‐independent cytotoxic effect of nelfinavir on leukemia cells can be enhanced by sorafenib‐mediated mcl‐1 downregulation and mitochondrial membrane destabilizationAnsgar Brüning, Martina Rahmeh, Andrea Gingelmaier, Klaus FrieseMolecular 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 LOncol Rep. 2012 Mar;27(3):734‐40.
HIV Protease inhibitors may have a cytotoxic effect on leukemia cells
Protein Kinase Inhibitors Considerations with Antiretrovirals
CYP3A4 Substrates (dasatinib, erlotinib, everolimus, gefitinib, imatinib, lapatinib, nilotinib, sunitinib)
PIs may ↑ levels via CYP3A4 inhibitionNNRTIs EFV, NVP may ↓levels via CYP3A4 induction
CYP2D6 Substrates(gefitinib (predominantly CYP3A4))
Ritonavir boosted PIs may ↑ levels, due to ritonavir inhibition of CYP2D6
CYP3A4 Inhibitors (dasatinib, everolimus, imatinib, lapatinib)
PIs, NNRTIs, MVC levels may ↑
UGT1A1 Inhibitors(erlotinib, nilotinib)
Poten al for ↑ bilirubin levels when given with ATV, IDV. RAL levels may ↑(unlikely clinically relevant)
QT Interval Prolongation(dasatinib, lapatinib, nilotinib, sunitinib)
Increased risk for QT prolongation with PIs, rilpivirine
Myelosuppression(dasatinib, everolimus, imatinib, nilotinib, sunitinib)
Increased risk for myelosuppression with zidovudine
Nephrotoxicity(sunitinib)
Increased risk for nephrotoxicity with tenofovir
Increased Bleeding Risk(dasatinib, imatinib, sunitinib)
Increased bleeding risk with tipranavir
Hepatotoxicity(imatinib, lapatinib, sunitinib)
Increased risk for hepatotoxicity with didanosine, stavudine, efavirenz
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
Reference Sources
Acknowledgements
David BackSaye KhooSara GibbonsCatia Marzolini
Ed Wilkins