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Drug-drug interactions in oncology: implications for general practice.

What is the relevance of anticancer drug interactions to general practitioners?

Although anticancer drugs are generally prescribed by specialists, patients with cancer often rely on their general practitioners to prescribe supportive therapy (e.g. anti-emetics, analgesics, anti-infectives, and growth factors) and treatment for co-morbid conditions. Drug-drug interactions may result in plasma concentrations that are reduced, with loss of therapeutic effect, or increased, with enhanced toxicity. Drug-drug interactions may also occur with shared toxicity or efficacy (for example, anticancer drugs are often used in combination to enhance efficacy). Drug-drug interactions may occur between anticancer medications or between anticancer medication and drugs commonly prescribed to treat co-morbid diseases or as supportive therapy for the anticancer treatment (e.g. anti-emetics, analgesics, anti-infectives, and growth factors).

The incidence of drug-drug interactions has been shown to correlate with the number of concomitant medications. Karas reported that the actual risk of interaction increases from 16% with 3 medications to 72% with 6 medications and 100% with 7 or more medications. This is important to remember because anticancer medications are often administered in combination, and elderly cancer patients frequently have co-morbid conditions. Therefore cancer patients, particularly those over 65 years of age, are at high risk of drug-drug interactions.

Why do drug-drug interactions occur?

Pharmacokinetic drug interactions occur when one drug influences the exposure to and/or disposition of another drug (Table I). Changes in metabolism and absorption are more often implicated than altered distribution or excretion. Many drugs are metabolised primarily by the hepatic cytochrome P450 (CYP) mixed oxidase enzyme system, consisting of more than 50 enzymes. The CYP enzymes most often implicated in drug-drug interactions are CYP3A4, CYP2D6, and CYP1A2. Many cytotoxic and non-cytotoxic drugs are cleared by the CYP system and drug-drug interactions may occur when CYP enzymes are inhibited (which may cause significant toxicity) or induced (which may cause sub-therapeutic drug concentrations). Induction or inhibition of membrane transporter proteins (e.g. p-glycoprotein (pgp)) in the intestinal epithelium may affect drug absorption.

Pharmacodynamic interactions may occur when drugs have similar methods of action (including shared toxicity) and influence the same physiological process. How can anticancer drug-drug interactions be recognised and prevented?

Although not all drug-drug interactions can be predicted, avoided, or distinguished from direct anticancer drug toxicity, a high level of awareness should be maintained. In all patients on anticancer drugs, drug interactions should be considered before prescribing concomitant medication by consulting the package inserts or references (the Medicines Information Centre offers a free telephonic service: (021) 406-6829 or (0860) 110-0531).

A detailed medication history should be taken and updated at each visit. Patients should be questioned regarding complementary and alternative medicines (CAMs) and over-the-counter (OTC) drug use. Studies have shown a high prevalence of CAM use in South Africa. There is little scientific evidence available on interactions between CAM and anticancer drugs. Several interactions with CAMs (e.g. St John's wort, garlic, ginseng, and parsley) have been reported. There is in vitro evidence of potential CAM-drug interactions with two commonly used CAMs in South Africa: Sutherlandia frutescens (Cancer bush) and Hypoxis hemerocallidea (African potato).

Interactions with supportive therapy

Anti-emetics

Many 5-HT3-receptor antagonists (except granisetron) may cause minor alterations in the concentrations of some anticancer drugs (e.g. cisplatin and cyclophosphamide). Glucocorticoids are inducers of CYP3A4 and could result in lower concentrations of anticancer drugs metabolised by this enzyme (Table II). NK-1 receptor antagonists (e.g. aprepitant) are involved in many interactions--refer to the package insert.

Analgesics

Analgesics are an essential part of postoperative and palliative care. Some opioid analgesics are metabolised by the CYP enzyme system, including fentanyl (CYP3A4), methadone (CYP3A4), codeine (CYP2D6), and oxycodone (CYP2D6), and may not have effective analgesic effect when used concurrently with enzyme-inducing anticancer drugs (e.g. glucocorticoids). Morphine is not metabolised by CYP.

Anti-infectives

Macrolides and azole antifungals inhibit CYP3A enzymes and should be used with caution with anticancer drugs metabolised by CYP3A enzymes (Table III). Combination of nephrotoxic and ototoxic antibiotics and anticancer agents (e.g. aminoglycosides and platinum preparations) should be avoided. Macrolides may prolong the QT interval and/or cause torsades de pointes and should be avoided in patients receiving cardiotoxic chemotherapy (e.g. the anthracyclines doxorubicin and daunorubicin). Diarrhoea is a very common adverse effect of combination anticancer therapy, and this can be exacerbated by antibiotic-associated diarrhoea (with or without Clostridium difficile infection, which should be excluded in all cases).

Interactions with therapy for comorbid conditions

Antihypertensive treatment

All the calcium-channel blockers (CCBs) are metabolised by CYP3A4. Verapamil and diltiazem are inhibitors of CYP 3A4 and p-gp, and the concentrations of anticancer drugs that are substrates of CYP3A (Table III) or p-gp (e.g. doxorubicin) (Table IV) may be increased, with enhanced toxicity. Verapamil absorption is reduced by toxic damage to the upper part of the small intestines caused by COPP (cyclophosphamide, vincristine, procarbazine, prednisone) and VAC (vindesine, adriamycin, cisplatin) regimens. Angiotensin-converting enzyme (ACE) inhibitors have been shown to inhibit erythropoietin synthesis and may exacerbate the anaemia associated with some anticancer agents.

Anticoagulants

Cancer patients are at increased risk of venous thromboembolism. Numerous drug-drug interactions are known with warfarin and cytotoxic drugs. An increase in the anticoagulant effect of warfarin was observed in patients on carboplatin, cyclophosphamide, doxorubicin, etoposide, 5-fluorouracil, gemcitabine, ifosfamide, methotrexate, procarbazine, tamoxifen, and vincristine. Interactions may occur, mainly due to inhibition or induction of CYP enzymes metabolising warfarin. The interaction with tamoxifen is particularly important and a warfarin dosage reduction of about 50% is advised with close monitoring of INR to avoid bleeding complications.

Lipid-lowering treatment

Most HMG-CoA reductase inhibitors (statins) are CYP substrates (except pravastatin and rosuvastatin), and drugs that induce CYP3A4 may reduce statin concentrations. Concomitant use of CYP3A4 inhibitors (Table III) with statins will increase the risk of developing myopathy and rhabdomyolysis. Imatinib can increase the serum levels of simvastatin 2- to 3.5-fold and the simvastatin dose should be reduced appropriately (about halved).

Psychotropic drugs

Appropriate treatment of depression and anxiety is important in cancer patients. Selective serotonin reuptake inhibitors (SSRIs) are CYP substrates. Fluoxetine and its major metabolite have long halflives. Combining SSRIs with 5-HT3-receptor antagonists or opioids, tramadol and pentazocine, may result in increased serotonin levels and increase the risk of serotonin syndrome. Co-administration of fluoxetine and ondansetron also reduces the anti-emetic effect of the latter. When prescribing benzodiazepines together with agents that inhibit CYP3A4 (Table III), benzodiazepines that are not metabolised by CYP (e.g. estazolam, lorazepam or oxazepam) should be prescribed.

Treatment of gout

Hyperuricaemia is a well-known complication of leukaemia and lymphoma and their treatment. Allopurinol inhibits gastrointestinal and hepatic xanthine oxidase, and increases the bioavailability of 6-mercaptopurine. An increase in systemic 6-mercaptopurine exposure has been associated with death in a number of patients. Allopurinol may also increase the incidence of serious bone marrow depression caused by cyclophosphamide. Probenecid reduces the renal elimination of methotrexate and may enhance haematological toxicity.

Antiretroviral therapy

HIV-infected patients are at increased risk of malignancy. Malignancy remains an important cause of death despite the reduction of HIV-related morbidity and mortality associated with highly active antiretroviral therapy (HAART). HAART is known to be fraught with clinically relevant pharmacokinetic and pharmacodynamic interactions and the addition of anticancer therapies to HAART increases the risk even further.

Protease inhibitors (PIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) are substrates as well as inhibitors and/or inducers of CYP450. In addition, PIs inhibit the important drug transporter p-gp. Anticancer drugs that are p-gp substrates are listed in Table IV. The concomitant administration of PIs or NNRTIs with anticancer drugs should be used with caution. Due to limited human in vivo studies, often with conflicting results, careful monitoring of the efficacy and toxicity of both the antineoplastics and antiretrovirals is recommended. Patients receiving PI and NNRTI-based HAART should undergo antiretroviral therapeutic drug monitoring.

Pharmacodynamic interactions have been described with several antiretroviral drugs and anticancer therapy. Zidovudine increases the risk of haematological toxicity associated with anticancer drugs. The concomitant use of stavudine or didanosine with vinca alkaloids, taxanes and ifosfamide may increase the risk of peripheral neuropathy. Shared gastrointestinal tract adverse effects are also common, notably diarrhoea due to the PIS.

Further reading

Antoniou T, Tseng AL. Interactions between antiretrovirals and antineoplastic drug therapy. Review. Clin Pharmacokinet 2005; 44(2): 111-145. Beijnen JH, Schellens JH. Drug interactions in oncology. Review. Lancet Oncol 2004; 5(8): 489-496. Bernard SA. The interaction of medications used in palliative care. Hematol Oncol Clin North Am 2002; 16(3): 641-655.

Blower P, de Wit R, Goodin S, Aapro M. Drug-drug interactions in oncology: why are they important and can they be minimized? Review. Crit Rev Oncol Hematol 2005; 55(2): 117-142.

Karas Jr S. The potential for drug interactions. Ann Emerg Med 1981; 10:627-630.

Lee AH, Ingraham SE, Kopp M, Foraida MI, Jazieh AR. The incidence of potential interactions between dietary supplements and prescription medications in cancer patients at a Veterans Administration Hospital. Am J Clin Oncol 2006; 29(2): 178-182. McLeod HL. Clinically relevant drug-drug interactions in oncology. Review. Br J Clin Pharmacol 1998; 45(6): 539-544.

In a nutshell

In all patients on anticancer drugs, drug interactions should be considered before prescribing concomitant medication by consulting the package inserts or other medicine information sources.

Patients on anticancer drugs are at high risk of drug-drug interactions as they are prescribed multiple drugs and are often elderly.

It is important to take a detailed medication history, including complementary/ alternative and over-the-counter medicines.

Enhance monitoring for signs and symptoms of interactions when potentially interacting drugs need to be co-administered.
Table I. Mechanisms of pharmacokinetic drug-drug interactions

Absorption Alteration in gastrointestinal motility influences
 bioavailability

 Alteration in drug-metabolising enzymes in intestinal
 epithelium (cytochrome P450)

 Alteration in membrane transporter proteins in
 intestinal epithelium (p-glycoprotein)

 Alteration in gastric pH affects dissolution of dosing
 formulation

Distribution Competition for plasma or tissue protein binding may
 result in an increase in unbound (active) drug--but this
 is usually temporary

Metabolism Induction of hepatic CYP450 reduces efficacy

 Inhibition of hepatic CYP450 increases toxicity

Elimination Altered hepatic function

 Altered renal function

 Changes in glomerular filtration rate (altered cardiac
 output)

 Altered renal tubular resorption (altered urinary pH)

 Changes in renal tubular secretion (competition for
 active secretion)

 Altered activity of membrane transporter proteins
 (p-glycoprotein)

Table II. Medications commonly used in supportive therapy, with
potential interactions with anticancer agents

Anti-emetics 5-H[T.sub.3]-receptor antagonists (not granisetron)
 Glucocorticoids
 N[K.sub.1]-receptor antagonists

Growth factors Erythropoietins
 Colony-stimulating factors

Anti-infectives Nlacrolides
 Aminoglycosides
 Broad-spectrum antimicrobials
 Azole antifungals

Table III. Anticancer medications subject to potential CYP-mediated
interactions (from Antoniou and Tseng)

Drug-drug class Metabolism Metabolite(s) Theoretical
 interaction

Taxanes

 Paclitaxel CYP2C8 > CYP3A4 Inhibition:
 [up arrow]
 risk
 myelo-
 suppression /
 peripheral
 neuropathy

 Induction:
 [down arrow]
 efficacy

 Docetaxel CYP3A4 Induction:
 [down arrow]
 efficacy

Vinca alkaloids

 Vincristine, CYP3A4 Inhibitors:
 vinblastine, [up arrow]
 vinorelbine risk
 myelo-
 suppression/
 autonomic and
 peripheral
 neuropathy

 Induction:
 [down arrow]
 efficacy

Epipodophyllotoxins

 Etoposide, CYP3A4 (main), Inhibitors:
 teniposide CYP2E1, CYPIA2 [up arrow]
 (minor) risk
 mucositis,
 myelos-
 uppression and
 tranaminitis

 Induction:
 [down arrow]
 efficacy

Camptothecins

 Irinotecan hCE-2, CYP3A4 and SN-38 Inhibitors:
 UCTIAI (active) [up arrow]
 risk
 myelo-
 suppression

 Inactive Induction:
 [down arrow]
 efficacy

 Topotecan Non-enzymatic Inhibitors:
 hydrolysis [up arrow]
 (major), CYP and risk
 glucuronidation myelo-
 (both minor) suppression

 Induction:
 [down arrow]
 efficacy

Atkylating agents

 Cyclophosphamide CYP2136 > CYP2C19 Active CYP2B6
 inhibitors
 (i.e.
 ritonavir,
 efavirenz):
 [down arrow]
 efficacy

 CYP3A4 Inactive CYP3A4
 (possibly inhibitors:
 toxic) [up arrow]
 toxicity
 (myelo-
 suppression,
 nausea and
 vomiting)

 Ifosfamide CYP3A4 Active Induction:
 (toxic) [up arrow]
 CYP3A4 and toxicity
 CYP2136 (myelo-
 detoxification suppression,
 arrhythmia,
 haemorrhagic
 cystitis)

 Dacarbazine CYP1A2 > CYP2E1 Active Inhibition:
 [up arrow]
 toxicity
 (nausea,
 vomiting and
 myelo-
 suppression)

Imatinib CYP3A4 Inhibition by
 imatinib may
 Inhibitor of affect many
 CYP3A4, CYP2D6 concomitant
 and CYP2C9 drugs

Endocrine therapies

 Tamoxifen CYP3A4 > CYP1A2 N-desinethyl- CYP3A4
 (main) tamoxifen induction:
 [down arrow]
 concentrations
 of parent and
 metabolite

 CYP3A4
 inhibition:
 [up arrow]
 risk of
 adverse
 effects

 May induce CYP3A4 Tamoxifen may
 induce CYP3A4
 and may [down
 arrow]
 efficacy of
 substrates

 May inhibit May potentiate
 CYP2C9 anticoagulant
 effect of
 warfarin

 Exemestane CYP3A4 and Inducers:
 aldoketoreductase [down arrow]
 efficacy

 Inhibition:
 [up arrow]
 risk of
 adverse
 effects (e.g.
 musculoske-
 letal pain,
 peripheral
 oedema, hot
 flushes)

 Anastrozole Glucuronidation, Inactive Inducers of
 hydroxylation, CYP3A4 or
 N-dealkylation glucuroni-
 (CYP3A4 possible) dation (e.g.
 ritonavir):
 [down arrow]
 efficacy

 Inhibition:
 [up arrow]
 risk of
 adverse
 effects (hot
 flushes,
 peripheral
 oedema, etc.)

 Toremifene CYP3A4 Active Induction:
 [up arrow]
 efficacy

 Inhibition:
 [up arrow]
 risk of
 adverse
 effects

Glucocorticoids CYP3A4 Inhibitors:
 CYP3A4 inducer [up arrow]
 risk
 corticosteroid
 -related
 toxicity

 Inducers:
 [down arrow]
 efficacy

 Reduces
 efficacy of
 CYP3A4
 substrates

Table IV Anticancer drugs that are p-glycoprotein substrates

Clilorambucil Etoposide
Cisplatin Methylprednisolone
Dactinomycin Mitoxantrone
Daunorubicin Paclitaxel
Dexamethasone Tamoxifen
Docetaxel Vinblastine
Doxorubicin Vincristine
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Title Annotation:Clinical pharmacology
Publication:CME: Your SA Journal of CPD
Article Type:Clinical report
Geographic Code:6SOUT
Date:Feb 1, 2007
Words:2090
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