Cancer Pharmacology

PHARMACOGENETICS AND PHARMACOGENOMICS

Mabel Rodriguez

Introduction

Pharmacogenetics: Effect of heritability on response to drugs. Study of single genes & their effects on interindividual differences in drug metabolizing enzymes.

Pharmacogenomics: Effect of inherited & acquired genetic variation on drug response. Study of the functions & interactions of all genes in the genome & how the overall variability of drug response may be used to predict the right tx in individual pts & to design new drugs.

Polymorphisms: Common variations in a DNA sequence that may lead to ↓ or ↑ activity of the encoded gene (SNP, micro- & minisatellites)

SNPs: Single base interchange that may cause an amino acid exchange in the encoded protein, account for >90% of genetic variation in the human genome

Phase I Drug Metabolizing Enzymes

Genetic polymorphisms have been reported for CYP450 isoforms 2C8, 2C9, 2C19, 2D6, & 3A4

CYP3A4/5

CYP3A isoenzymes account for ˜1/2 of the metabolic activity of all CYP450 enzymes

Substrates include etoposide, paclitaxel, & vincristine

SNP frequencies of CYP3A4 relatively low in most populations (14% in Caucasians & 10% in Japanese individuals) making it difficult to link genotype to PK or PD of CYP3A4 substrates

One study conducted by the National Children’s CA Group Pediatric ALL trial set out to correlate the association between relapse & tox of 1204 pts w/CYP3A41B, CYP3A5^*3, & CYP3A5^*6 SNPs

Trial results were negative, however the first two variants previously mentioned had a statistical risk of peripheral neuropathy

CYP2C8

A/w paclitaxel metabolism by 6α-hydroxylation; out of its six alleles

CYP2C8^*3 in Caucasians is less efficient in the metabolism of this chemotherapeutic agent

CYP2C19

A/w thalidomide activation by hydroxylation

CYP2C19^*2 homozygotes showed poor metabolizing phenotype, not responding to thalidomide tx

CYP2D6

Involved in the conversion of tamoxifen to 4OH-tamoxifen (more potent antiestrogen)

CYP2D6 homozygous variant or heterozygous genotype individuals have ↓ plasma endoxifen conc. (a metabolite of tamoxifen) than homozygous wild-type subjects after 4 mos of Rx

Non-P450 Phase I Metabolizing Enzymes

Dihydropyrimidine dehydrogenase (DPD)

Represents the first & rate limiting step in the catabolism of pyrimidine bases, uracil & thymidine

DPD degradates the majority of 5-FU to 5-6-dihydro-5-FU in the liver

DPD deficiency: Prolonged 5-FU T1/2 → sev., fatal GI & neurologic tox

Thirty nine polymorphisms & Mt of the DPD gene are known. DPD*2A: Most common polymorphism → causes inactive protein in 0.9% of Caucasian pts.

Phase II Drug Metabolizing Enzymes

Thiopurine methyltransferase (TPMT)

Involved in the methylation rxns of 6-MP & its prodrug, AZA

Out of the 8 alleles identified, three specific ones (TMPT*2, TMPT*3A, & TMPT*3C), account for 95% of TMPT deficiency cases

Pts who carry TMPT polymorphisms are at a risk of sev. hematologic tox

Appropriate 6-MP dose reductions for TMPT-deficient pts have allowed for similar tox & survival outcomes when compared to pts w/nl levels

Tests for TMPT genotype & phenotype are commercially available

Uridine Diphosphate Glucuronosyltransferase 1A1 (UGT1A1)

A microsatellite Mt results in UGT1A1*28 polymorphism, & ↓ UGT1A1 expression levels & activity

UGT1A1^*28 polymorphism: Typically found in pts w/Gilbert syndrome; frequency 40-43% in Africans, 32-39% in Caucasians, 16-33% in Asians

Important role in the metabolism of etoposide, epirubicin, & most importantly irinotecan

Irinotecan: Prodrug activated to ethyl-10 hydroxycampothecin (SN-38) via carboxyl esterase. SN-38 undergoes UGT1A1-catalyzed glucuronide conjugation to form inactive SN-38 glucuronide (SN-38G). ↑ exposure to SN-38 in pts w/this genetic variation → ↑ tox (diarrhea, myelosuppression) limiting optimal clinical use

Drug Transporters

P-gp (MDR-1)

P-gp & its encoding gene MDR-1 (ABCB1) are expressed in high levels in brain vessels, adrenal glands, kidney, liver, & GI tract

P-gp is involved in the transport of hydrophobic drugs including doxorubicin, paclitaxel, irinotecan, hormones, & carcinogens

Multidrug resistance proteins act as drug efflux pumps rendering cells resistant to cytostatic drugs

Three most common SNPs are P-gp*6 (22-56% in Caucasians), P-gp*7, & P-gp*8

Drug Targets

5, 10 Methylenetetrahydrofolate reductase (MTHFR)

Reduces 5, 10 methylenetetrahydrofolate to 5-methyltetrafolate, methyl donor for the methylation of DNA, homocysteine, & DNA synthesis

Reduced MTHFR activity affects intracellular folate pools → ↑ tox in pts treated w/antifolates

Thymidylate synthase (TS)

Essential enzyme in de novo synthesis of thymidylate, precursor of thymidine triphosphate, essential for DNA synthesis & repair

TS gene promoter is polymorphic & has 2 (TSER^*2) or 3 (TSER^*3) 28 bp tandem repeat sequences

In vitro studies show TS promoters w/the TSER^*3 sequence generate 3× higher mRNA than those w/the TSER^*2 sequence

Inhibition of TS by 5-fluorodeoxyuridine monophosphate (FdUMP) of TS is one of the 1° mechanisms of action of 5-FU

TS expression levels inversely correlate w/the Sn of tumors to 5-FU, therefore TSER^*2 homozygotes respond better to 5-FU than TSER*3 homozygotes or heterozygotes

ANTIMETABOLITES

Angela G. Michael

Class	Drugs	Mechanism of Action
Cytidine analogs	Cytarabine Gemcitabine	Inhibition of DNA polymerase, incorporated into DNA → terminates chain elongation; Gemcitabine also inhibits RNA reductase
DNA hypomethylating agent	Azacytidine Decitabine	Inhibition of DNA methylation via incorporation into DNA & RNA
Folate antagonists	MTX Pemetrexed², Pralatrexate¹	Inhibition of DHFR & TS → inhibition of reduced folates & purine synthesis. S-phase specific. 1: Selective for RFC-1 2: Also inhibits glycinamide ribonucleotide formyltransferase (GARFT) & 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase (AICARFT)
Purine analogs	Cladribine Clofarabine Fludarabine Nelarabine Pentostatin	Incorporation of metabolites into DNA → DNA strand breaks, ↓ DNA synthesis/repair via inhibition of DNA polymerase & RNA reductase
Pyrimidine analogs	Capecitabine Fluorouracil	Inhibition of TS → ↓ thymine nucleotides; FdUMP into RNA → ↓ processing/function; 5-FU-based nucleotides into DNA → ↓ DNA repair/strand breaks
Thiopurines	Mercaptopurine Thioguanine	“False” metabolites → incorporated into DNA/RNA → ↓ synthesis
Miscellaneous	Hydroxyurea	Inhibition of RR enzyme system → impaired DNA synthesis. G1-phase specific.
Devita (2009). 9th ed. 394, Chabner (2011). 5th ed. 110, 140, 172, 193, 211.

Cytarabine (ara-C, Cytosar-U)

Dosing/dose adjustments: Standard dose: 100-200 mg/m²/d 24 h CIVI × 5-7 d. High dose: 1500-3000 mg/m² IV q12h × 3 d. No renal or hepatic dose adjustments recommended (use w/caution).

PK/PD: Wide & rapid distribution, crosses BBB (conc. 40-50% plasma), hepatic metabolism, eliminated via deamination in liver, plasma, & peripheral tissue, T1/2 1-3 h

Adverse effects: Myelosuppression (DLT, black box warning (BBW), nadir biphasic 7-9 d/15-24 d), N/V (low-to-mod. emetogenic potential), diarrhea, GI ulceration, ↑ LFTs, neurotoxicity (cerebellar dysfunction, reversible, high dose), rash, conjunctivitis (high dose)

Drug-drug interactions (DDI): Cyclophosphamide (fatal CMP, case reports), MTX (↑ formation of ara-CTP), fludarabine (↑ formation of ara-CTP), gentamicin (potential ↓ efficacy of gentamicin), digoxin (↓ absorption of digoxin)

Clinical pearls: Can be administered as IT Rx. Ppx corticosteroid (0.1% dexamethasone 1-2 gtt every 6 h during & 2-7 d after) w/high dose.

Gemcitabine (Gemzar)

Dosing/dose adjustments: Pancreatic CA: 1000 mg/m² IV weekly × 7 wks, w/1 wk rest; NSCLC: 1000 mg/m² IV d 1, 8, 15 every 28 d; breast CA: 1250 mg/m² IV d 1, 8 every 21 d (w/paclitaxel) OR 800 mg/m² IV d 1, 8, 15 every 28 d; Ovarian CA: 1000 mg/m² IV d 1, 8 every 21 d. No renal or hepatic dose adjustments recommended.

PK/PD: Intracellular metabolism by nucleoside kinases, renal excretion (92-98%), T1/2 metabolite 1.7-19.4 h

Adverse effects: Myelosuppression (DLT, ↑ w/infusional), edema, flu-like syndrome, ↑ LFTs, ↑ Tbili, pneumonitis, infusion rxn, proteinuria, N/V (low emetogenic potential), TTP/HUS (rare)

DDI: Cisplatin (↓ clearance of gemcitabine)

Clinical pearls: Irritant, radiation sensitizer (caution w/thoracic RT)

Azacytidine (5-Azacytidine, Vidaza)

Dosing/dose adjustments: 75 mg/m²/d SQ/IV × 7d every 4 wks, ↑ dose to 100 mg/m²/d if no response after 2 cycles. Caution in pts w/renal & hepatic dysfunction. Adjust dose for tox (hematologic, ↑ BUN/Cr).

PK/PD: Does not cross BBB, hepatic metabolism via hydrolysis, bioavailability SQ ˜89%, renal excretion (50-85%), T1/2 ˜4 h

Adverse effects: Myelosuppression, N/V (mod. emetogenic potential), pyrexia, HA, dizziness, ↑ LFTs, rigors, arthralgia

DDI: No significant drug interactions

Clinical pearls: Use w/caution in pts w/altered mental status

Decitabine (Dacogen)

Dosing/dose adjustments: 15 mg/m² every 8 h × 3 d every 6 wks OR 20 mg/m² daily × 5 d every 28 d. No renal or hepatic dose adjustments recommended. Hold/adjust dose for tox (hematologic, serum creatinine (SCr) ≥2 mg/dL, ALT, TBili ≥2 × ULN, active or uncontrolled infxn).

PK/PD: Metabolism via deamination, T1/2 ˜30-35min

Adverse effects: Myelosuppression (up to 90%, recovery 28-50 d), nausea (40-42%), diarrhea (28-34%), pyrexia (up to 53%), HA (23-38%), insomnia, fatigue, petechiae (12-39%), ↑ glu, ↑ Tbili, ↓ Mg, ↓ K

DDI: No significant drug interactions

Methotrexate (MTX, Trexall)

Dosing/dose adjustments: Dosing dependent on malignancy, range 30-40 mg/m²/wk to 100-12000 mg/m² IV once. CrCl 10-50 mL/min: 50% of dose; CrCl <10 mL/min: Avoid; HD: 50% of dose. TBili 3.1-5 mg/dL or LFTs >3× ULN: 75% of dose; TBili >5 mg/dL: Avoid.

PK/PD: Extensive distribution into third-space fluids (effusions, ascites, ↑ T1/2), renal excretion (80-90% as unchanged drug)

Adverse effects: Myelosuppression, mucositis, N/V, nephrotoxicity (intratubular precipitation, direct tubular toxin), ↑ LFTs, ↑ Tbili, neurotoxicity

DDI: Probenecid, PCN, ceph., ASA, NSAIDs, sulfonamides (↓ excretion of MTX), asparaginase (↓ MTX activity), leucovorin (↓ MTX activity)

Clinical pearls: Vigorous hydration & urinary alkalinization should be implemented during Rx (↓ incidence of renal failure), requires administration of leucovorin rescue (doses >500 mg/m²)

Pemetrexed (Alimta)

Dosing/dose adjustments: 500 mg/m² d 1 every 21 d. Renal: CrCl < 45 mL/min: Avoid. Concomitant NSAID: CrCl 45-79 mL/min & NSAID w/short T1/2 (ibuprofen, indomethacin, ketoprofen, ketorolac): Avoid NSAID 2 d prior, d of & 2 d post-Rx; Any CrCl & NSAID w/long T1/2 (nabumetone, naproxen, oxaprozin, piroxicam): Avoid NSAID 5 d prior, d of & 2 d post-Rx. Hepatic: Grade 3-4 ↑ LFTs: 75% of dose. Adjust dose for tox (hematologic, mucositis, diarrhea, neurotoxicity).

PK/PD: Renal excretion, T1/2 3.5 h (↑ 5.3-5.8 h CrCl 40-59 mL/min)

Adverse effects: Myelosuppression (DLT), mucositis, hand-foot syndrome, anorexia, fatigue, GI tox, ↑ LFTs

DDI: Probenecid, PCN, ceph., ASA, NSAIDs (↓ renal excretion)

Clinical pearls: Folic acid 400-1000 µg daily (7 d prior, during Rx & 21 d after last dose), cyanocobalamin 1000 µg IM (7 d prior, every 3 cycles) to prevent GI tox. Dexamethasone 4 mg PO twice daily (start d prior to Rx × 3 d) for prev of cutaneous rxns.

Pralatrexate (Folotyn)

Dosing/dose adjustments: 30 mg/m² IV weekly × 6 wks, 1 wk rest. Use caution in renal impairment. TBili > 1.5 mg/dL or AST/ALT > 2.5 × ULN: Omitted in trials, use w/caution. Grade 3 hepatotoxicity (on tx): Hold, ↓ to 20 mg/m²; grade 4 hepatotoxicity (on tx): D/C. Adjust dose for tox (hematologic, mucositis)

PK/PD: 67% protein bound, renal excretion (35%), T1/2 12-18 h

Adverse effects: Mucositis (DLT), myelosuppression (DLT), ↑ LFTs, anorexia, fatigue, edema, rash, ↓ K, nausea, cough, epistaxis, night sweats

DDI: Probenecid, PCN, ceph., aspirin, NSAIDs (↓ renal excretion)

Clinical pearls: Folic acid 1-1.25 mg/d (10 d prior, during Rx & 30 d after last dose), cyanocobalamin 1000 µg IM (w/in 10 wk prior, every 8-10 wks) to prevent GI tox

Cladribine (Leustatin)

Dosing/dose adjustments: 0.09 mg/kg/d IVCI × 7d. Renal: CrCl 10-50 mL/min: 75% of dose; CrCl < 10 mL/min: 50% of dose; CAPD: 50% of dose. Caution in pts w/hepatic dysfunction.

PK/PD: Bioavailability ˜50%, penetrates CSF (conc. ˜25% plasma), renal excretion, T1/2 5.4 h

Adverse effects: Myelosuppression (BBW, dose-dependent, prolonged), neurotoxicity (BBW, dose-related, doses above FDA recs, including paraparesis), renal tox (BBW, dose-related, doses above FDA recs), HA, dizziness, fever (33-69%), fatigue (11-45%), prolonged lymphopenia

DDI: Live vaccines (vaccinial infxn may occur)

Clofarabine (Clolar)

Dosing/dose adjustments: ALL (≤21 y): 52 mg/m²/d × 5 d every 2-6 wks; AML (induction): 30 mg/m²/d × 5d; AML (consolidation): 20 mg/m²/d × 5d. Use w/caution in renal & hepatic impairment.

PK/PD: Intracellular metabolism to active metabolite, renal excretion, T1/2 5 h in children, 7 h in adults, ↑ in elderly/renal impairment

Adverse effects: Myelosuppression (DLT), N/V (mod. emetogenic potential), diarrhea, SIRS, ↑ opportunistic infxn, renal tox, ↑ LFTs/Tbili (w/i 10 d, duration ≤15 d), cardiac tox

DDI: Warfarin (↑/↓ warfarin effects), nephrotoxins (cum. nephrotoxicity)

Clinical pearls: Consider ppx corticosteroids (hydrocortisone 100 mg/m² d 1-3, prev of capillary leak/SIRS)

Fludarabine (Fludara)

Dosing/dose adjustments: 20-30 mg/m² IV × 3-5 d every 28 d (dosing varies based on malignancy) OR 40 mg/m² PO d 1-5 every 28 d. CrCl 50-79 mL/min: ↓ dose to 20 mg/m²; CrCl 30-49 mL/min: ↓ dose to 15 mg/m²; CrCl < 30 mL/min: Avoid use. No hepatic dose adjustments recommended.

PK/PD: Extensive tissue distribution, dephosphorylated in plasma → active metabolite → phosphorylated in cells, renal excretion (60%), T1/2 ˜20 h

Adverse effects: Myelosuppression (DLT, BBW, nadir 10-14 d, recovery 5-7 wks), immunosuppression, N/V (low emetogenic potential), fever (60-69%), fatigue, diarrhea, weakness, cough (10-44%), PNA, infxn (33-44%), AIHA

DDI: Pentostatin (fatal pulm tox, BBW), Imatinib (↓ fludarabine effects), live vaccines (vaccinial infxn may occur)

Clinical pearls: Recommend antiviral & antipneumocystis ppx w/use

Nelarabine (Arranon)

Dosing/dose adjustments: 1500 mg/m²/dose d 1, 3, 5 every 21 d until transplant, progression or unacceptable tox. Use caution in CrCl < 50 mL/min (↓ ARA-G clearance). Closely monitor w/mod.-sev. hepatic impairment (Tbili > 3 × ULN). Consider delay or D/C for tox (neurotoxicity, hematologic).

PK/PD: Hepatic metabolism (ARA-G), T1/2 ˜2-3 h (metabolite)

Adverse effects: Myelosuppression, neurotoxicity (DLT, BBW, somnolence, HA, seizures, fatigue, hypoesthesia, D/C if ≥grade 2), ↑ LFTs, ↑ Tbili, ↑ K, myalgia, arthralgia, cough, dyspnea, blurred vision

DDI: Pentostatin (↓ conc. of nelarabine), live vaccines (vaccinial infxn may occur)

Pentostatin (Nipent)

Dosing/dose adjustments: 4 mg/m² every 2 wks. Use w/caution in pts w/CrCl <60 mL/min. No hepatic dose adjustments recommended.

PK/PD: Renal excretion w/in 24 h, T1/2 3-7 h (↑ 4-18 h CrCl < 50 mL/min)

Adverse effects: Myelosuppression (nadir 7 d), CNS tox (BBW, higher than rec. dose), hepatotoxicity (BBW, higher than rec. dose), pulm tox (BBW, higher than rec. dose), nephrotoxicity (BBW, higher than rec. dose), fever, fatigue, HA, rash, ↑ LFTs, myalgia, cough, infxn

DDI: Fludarabine (fatal pulm tox), carmustine, etoposide, high-dose cyclophosphamide (fatal pulm edema & HoTN)

Capecitabine (Xeloda)

Dosing/dose adjustments: 1000-1250 mg/m² PO twice daily × 2 wks every 21 d. Renal: CrCl 30-50 mL/min: 75% of dose; CrCl < 30 mL/min: Use contraindicated. Caution in hepatic dysfunction. Adjust dose for tox (hematologic) w/docetaxel or ixabepilone.

PK/PD: Bioavailability ˜ 80%, protein binding < 60%, hepatic & tissue metabolism (active metabolite: 5-FU), renal excretion (96%), T1/2 0.5-1 h

Adverse effects: Diarrhea, hand-foot syndrome, myelosuppression, mucositis, neurologic tox, coronary vasospasm

DDI: Oral anticoagulants (↑ levels of anticoagulants), phenytoin (↑ levels of phenytoin), leucovorin (↑ tox of capecitabine)

Clinical pearls: Oral prodrug of 5-FU, converted via three-step activation process. Available as 150 mg & 500 mg tablets. Take w/in 30min after a meal, DPD deficiency (prolonged clearance, ↑ tox), radiation sensitizer

Fluorouracil (5-FU, Adrucil)

Dosing/dose adjustments: Intravenous push (IVP): 325-425 mg/m²/d × 5 d every 28 d OR 500 mg/m²/wk × 6 wks; IVCI: 750-1000 mg/m²/d × 5 d every 21-28 d OR 1200 mg/m²/d × 2 d. Use w/caution in pts w/renal impairment & avoid use w/Tbili >5 mg/dL.

PK/PD: Extensive tissue distribution, saturable catabolism, excretion via metabolism, lung, & urine, T1/2 8-14min after bolus

Adverse effects: Diarrhea (DLT), mucositis (DLT), N/V (low emetogenic potential), myelosuppression (bolus > IVCI), neurotoxicity, coronary artery vasospasm, conjunctivitis, hand-foot syndrome (IVCI > bolus), alopecia, nail changes

DDI: CYP2C9 substrates (↓ substrate levels), oxaliplatin (↓ TS), cimetidine (↓ clearance of 5-FU), oral anticoagulants (↑ levels of anticoagulants), leucovorin (↑ tox of 5-FU)

Clinical pearls: DPD deficiency (prolonged clearance, ↑ tox), predictors of ↑ tox (↑ age, female, poor PS), radiation sensitizer

Mercaptopurine (6-MP, Purinethol)

Dosing/dose adjustments: 1.5-2.5 mg/kg/d oral (duration dependent on malignancy). CrCl < 50 mL/min: Every 48 h. No hepatic dose adjustments recommended.

PK/PD: Erratic PO absorption, oxidized via xanthine oxidase

Adverse effects: Myelosuppression, GI tox (N/V, anorexia, diarrhea, stomatitis), cholestatic jaundice, ↑ risk of infxn

DDI: Allopurinol (↑ mercaptopurine tox, reduce dose by 50-75%)

Clinical pearls: TPMT deficiency (reduce dose to 5-25% of standard dose)

Thioguanine (6-TG, Tabloid)

Dosing/dose adjustments: 60 mg/m²/d × 14d. No renal dose adjustments recommended. Hepatotoxicity (on tx, including VOD): D/C.

PK/PD: Erratic PO absorption, hepatic metabolism via TPMT, T1/2 5-9 h

Adverse effects: Myelosuppression, GI tox (N/V, anorexia, diarrhea, stomatitis), cholestatic jaundice, ↑ risk of infxn, 2° malignancy

DDI: No significant drug interactions

Clinical pearls: TPMT deficiency (reduce dose to 5-25% of standard dose)

Hydroxyurea (Droxia, Hydrea)

Dosing/dose adjustments: 20-30 mg/kg oral daily (CML, solid tumors) OR 50-100 mg/kg until WBC <100 K. Titrate dosing for WBC & plt count. CrCl 10-50 mL/min: 50% of dose; CrCl < 10 mL/min: 20% of dose; HD: Administer dose after HD on HD d. No hepatic dose adjustments recommended. Adjust dose for tox (rash, GI, mucositis, hematologic).

PK/PD: Readily absorbed, widely distributed including CSF, 75-80% protein bound, metabolism via hepatic & GI tract, renal excretion, T½ ˜2-4 h

Adverse effects: Myelosuppression (DLT, primarily granulocytopenia w/in 2-5 d), GI ulceration, skin pigmentation, rash, squamous carcinoma (skin)

DDI: Didanosine, Stavudine (↑/↓ conc. of hydroxyurea, fatal pancreatitis), radiation (↑ tissue Sn to radiation)

Clinical pearls: Available as 200 mg, 300 mg, 400 mg, & 500 mg capsules

Info. based on publicly available drug inserts from Allos, Bedford, Berlex, Bristol Meyers-Squibb, Celgene, Centocor Ortho-Biotech, Eisai, Genzyme, GlaxoSmithKline, Hoffman-LaRoche, Hospira, Lilly, and Teva.

ALKYLATING AGENTS

Brian M. Seyboth

Drug Class	Agents	Mechanism of Action
Alkyl sulfonates	Busulfan	Bifunctional agent, cytotoxicity via DNA alkylation & cross-linking
Aziridines	Thiotepa	Aziridinium analog of nitrogen mustard metabolite; bifunctional agent, cytotoxicity via DNA alkylation & cross-linking
Nitrogen mustards	Bendamustine, Chlorambucil, Cyclophosphamide, Ifosfamide, Mechlorethamine, Melphalan	Bifunctional agent activated to yield two aziridinium ring moieties; cytotoxicity via DNA alkylation & cross-linking
Nitrosoureas	Carmustine (BCNU), Lomustine (CCNU)	Bifunctional agent w/reactive intermediates, cytotoxicity via DNA alkylation & cross-linking; inhibits nucleic acid synthesis enzymes
Platinum compounds	Carboplatin, Cisplatin, Oxaliplatin	Bifunctional agent w/reactive intermediates; cytotoxicity via DNA platination & cross-linking
Triazenes/methylating agents	Dacarbazine, Procarbazine, Temozolomide	Monofunctional agent activated to cause DNA methylation; do not cross-link; Procarbazine also metabolized to free radical species
Devita (2011). 9th ed. 375, Pizzo (2011). 6th ed. 288, Chabner (2011). 5th ed. 267, Treanda Prescribing Info., 2012.

Busulfan (Busulfex [IV], Myleran [PO])

Dosing/dose adjustments: 1.8 mg/m²/d PO (adjust for goal leukocyte counts ≥15000/mm³) OR 120 mg/m²/d IV divided every 6-24 h over 3-4 d; dose per IBW or ABW (lower value) or adjusted BW (obesity); adjust dose per PK & target AUC (˜1200 µM ×min [900-1500 µM ×min])

PK/PD: PO bioavailability ˜80% (variable/age dependent), penetrates BBB, hepatic metabolism, T1/2 2.5 h

Adverse effects: Myelosuppression (DLT), hepatic VOD (↑ risk w/AUC >1500 µM ×min), mucositis, seizure, pulm fibrosis (rare)

DDI: Glutathione depleting substrates (APAP, MNZ; ↑ busulfan conc.), azole antifungals (↓ busulfan conc.)

Clinical pearls: Administer w/ppx anticonvulsant (levetiracetam, phenytoin). Monitor signs of hepatic VOD (wt gain, ascites, ↑ Tbili, hepatomegaly).

Thiotepa

Dosing/dose adjustments: 0.3-0.4 mg/kg IV every 1-4 wks OR 150-250 mg/m²/dose IV divided 1-2 daily × 3 d before HSCT OR 60 mg instilled via intravesical administration weekly × 4 wks OR 10 mg IT 1-2 weekly or monthly. Consider dose reduction for renal or hepatic impairment or hematologic tox.

PK/PD: Hepatically metabolized via CYP2B6 & 2C11 to 1° metabolite TEPA, both thiotepa & TEPA therapeutically active & renally eliminated, T1/2 1.2-2 h; TEPA 3-21 h

Adverse effects: Myelosuppression (nadir: 2-3 wks), CNS dysfunction, amenorrhea, spermatogenesis inhibition, alopecia, 2° malignancies

DDI: Potent CYP2B6 inhibitor

Clinical pearls: Tight dressings & ointments should be avoided as thiotepa is excreted in sweat. Pt should shower often to reduce risk of skin irritation.

Bendamustine (Treanda)

Dosing/dose adjustments: 70-120 mg/m²/d IV × 2 d every 21-35 d. Renal: CrCl <40 mL/min: Not recommended. Hepatic: Mild impairment: Use w/caution; AST or ALT ≥2.5 times ULN or Tbili ≥1.5 times ULN: Not recommended. Tox ≥ grade 3: Reduce dose.

PK/PD: 94-96% protein bound, hepatic metabolism via CYP1A2, fecal excretion, T1/2 = ˜40min; metabolites 30 min-3 h

Adverse effects: Myelosuppression (DLT; nadir: ˜3 wks), N/V (mod. emetogenic risk), fever, ↑ bili, peripheral edema, rash, diarrhea, HSR

DDI: CYP1A2 inhibitors (amiodarone, ciprofloxacin, fluvoxamine; ↑ bendamustine), CYP1A2 inducers (carbamazepine, phenobarbital, rifampin; ↓ bendamustine)

Clinical pearls: Allopurinol may ↑ skin tox risk. Premedicate w/prior HSR ≤ grade 2 (antihistamines, antipyretics, corticosteroids)

Chlorambucil (Leukeran)

Dosing/dose adjustments: 0.1-0.2 mg/kg/d PO × 3-6 wks or 0.4 mg/kg PO intermittently, biweekly, or monthly. Consider dose reduction w/renal impairment or hematologic tox. No hepatic dose adjustments recommended.

PK/PD: Rapid, complete absorption, highly protein bound (99%), hepatic metabolism to active compound & renal excretion, T1/2 1.5 h

Adverse effects: Myelosuppression (nadir: 3 wks), hepatotoxicity, skin rxns, pulm tox, CNS disturbances, 2° malignancies

DDI: No significant drug interactions

Cyclophosphamide (Cytoxan)

Dosing/dose adjustments: 1-5 mg/kg/d PO OR 75-100 mg/m²/d PO x 14 d every 4 wks OR 250-1800 mg/m²/dose IV × 1-4 d every 3-4 wks OR 40-50 mg/kg/d IV. Consider dose adjustment w/renal & hepatic impairment.

PK/PD: PO bioavailability >75%, prodrug hepatically activated via CYP2B6, 3A4, & 2C9 (metabolites reduce glutathione), renal excretion, T1/2 3-12 h

Adverse effects: Myelosuppression (DLT; recovery: 7-10 d), hemorrhagic cystitis, nephrotoxicity, N/V (very high [>1500 mg/m²], mod. [≤1500 mg/m² or PO] emetogenic risk), cardiotoxicity, alopecia, sterility, 2° malignancies

DDI: CYP3A4 inducers (phenobarbital, phenytoin, carbamazepine; ↑ cyclophosphamide metabolism to active metabolites), CYP3A4 inhibitors (aprepitant, azole antifungals; ↓ cyclophosphamide metabolism)

Clinical pearls: Properly hydrate pt pre/post-tx. Hemorrhagic cystitis due to accumulation of acrolein in the bladder, can be prevented w/MESNA (cum. dose 60-100% of cyclophosphamide dose)

Ifosfamide (Ifex)

Dosing/dose adjustments: 1200-3000 mg/m²/d IV × 3-5 d every 2-3 wks OR 5000 mg/m² IV every 2 wks. Consider dose reduction w/renal or hepatic impairment.

PK/PD: Prodrug hepatically activated via CYP3A4 & 2A6, renal excretion, T1/2 7-15 h

Adverse effects: Myelosuppression (DLT; nadir 8-14 d), hemorrhagic cystitis, nephrotoxicity (proximal tubular damage), reversible neurotoxicity (somnolence, disorientation, lethargy), N/V (high [≥2 g/m²], mod. [<2 g/m²] emetogenic risk), alopecia.

DDI: CYP3A4 inducers/inhibitors (↑/↓ metabolism to active metabolites)

Clinical pearls: Properly hydrate pt pre/post-tx. Hemorrhagic cystitis due to accumulation of acrolein in the bladder, can be prevented w/MESNA (cum. dose 60-100% of ifosfamide dose). Neurotoxicity due to an accumulation of chloroacetaldehyde, can be treated w/methylene blue or thiamine.

Mechlorethamine (Mustargen)

Dosing/dose adjustments: 0.1-0.4 mg/kg/d IV × 1-4 d OR 6 mg/m² IV on d 1, 8 in a 28-d cycle. No renal or hepatic dose adjustments recommended.

PK/PD: Rapid spontaneous hydrolysis w/in plasma & limited hepatic metabolism, renal excretion, T1/2 < 1min

Adverse effects: Myelosuppression, N/V (high emetogenic risk), anticholinergic effects (diaphoresis, lacrimation, diarrhea), encephalopathy (high dose tx), gonadal atrophy, alopecia, 2° malignancies

DDI: No significant drug interactions

Clinical pearls: Causes irritation to skin/mucous membranes if contact occurs. Limited stability in solution & must be administered w/in an hour of preparation. Vesicant (treat w/sodium thiosulfate).

Melphalan (Alkeran)

Dosing/dose adjustments: 2-10 mg PO daily OR <0.05-0.15 mg/kg PO daily OR 0.2-0.25 mg/kg/d PO × 4-5 d every 4-6 wks OR 4-9 mg/m²/d PO × 4-7 d every
4-6 wks OR 16 mg/m² IV × 4 doses every 2-4 wks OR 30 mg/m² IV × 1 dose (mini-BEAM) OR 140-200 mg/m² once 2-5 d prior to HSCT. Renal: Mod./sev. renal impairment: Reduce PO dose; BUN ≥ 30 mg/dL: Reduce IV dose by up to 50%. Consider reduction w/cell count tox.

PK/PD: Variable bioavailability (25-90%) & protein binding (53-92%), spontaneous hydrolysis or alkylation in plasma or tissues, renal excretion (20-30%), T1/2 1-2 h

Adverse effects: Delayed myelosuppression (nadir: 4 wks), mucositis, esophagitis, diarrhea, pulm fibrosis (chronic use), 2° malignancies

DDI: Carmustine (↑ risk of lung tox)

Clinical pearls: Limited stability in solution & must be administered w/in an hour of preparation. Improved bioavailability when taken on an empty stomach. Cryotherapy during infusion can ↓ mucositis.

Carmustine, BCNU (BiCNU, Gliadel [implantable wafer])

Dosing/dose adjustments: 150-200 mg/m² IV every 6-8 wks OR 75-100 mg/m²/d IV × 2-3 d every 6-8 wks OR 300 mg/m² IV 6 d (BEAM regimen). Consider reduced dose for renal impairment & hematologic tox.

PK/PD: ˜80% protein bound, penetrates BBB, hepatic metabolism, renal excretion, T1/2 < 30min; active metabolite 67 h

Adverse effects: Delayed myelosuppression (DLT; nadir: 4-6 wks), N/V (high [>250 mg/m²], mod. [≤250 mg/m²] emetogenic risk), HoTN, ↑ LFTs. Cum. doses >1500 mg/m²– renal failure, pulm fibrosis.

DDI: Melphalan (sensitize pts to lung tox)

Clinical pearls: Evaluate renal function when cum. doses >1000 mg/m². Chronic marrow hypoplasia may result after repeated dosing. A/w 2° malignancies.

Lomustine, CCNU (CeeNU)

Dosing/dose adjustments: 100-130 mg/m² PO every 6 wks. Consider dose reduction for renal impairment or prior cell count nadir.

PK/PD: Complete absorption, penetrates BBB, hepatic metabolism to active metabolites, renal excretion, T1/2 16-24 h; active metabolite 16-48 h

Adverse effects: Delayed myelosuppression (DLT; nadir: 4-6 wks), N/V, ↑ LFTs, 2° malignancies, cum. doses >1500 mg/m² a/w renal failure, pulm fibrosis less frequent than w/carmustine

DDI: No significant drug interactions

Clinical pearls: Evaluate renal function when cum. doses >1000 mg/m². Chronic marrow hypoplasia may result after repeated dosing. Pts should take on an empty stomach to ↓ N/V.

Carboplatin (Paraplatin)

Dosing/dose adjustments: 300-400 mg/m² IV every 4 wks. Often dosed per Calvert formula: Total dose = Target AUC × (GFR + 25). Common target AUC 3-7.5 every 3-4 wks or AUC 2 for 3-5 d per month. Renal (nonCalvert dosing): CrCl 41-59: 250 mg/m²; CrCl 16-40: 200 mg/m². Thrombocytopenia/neutropenia: 75% of dose.

PK/PD: Renal excretion, T1/2 ˜2-6 h (platinum ≥5 d)

Adverse effects: Delayed myelosuppression (DLT; nadir: ˜3-6 wks), HSR, nephrotoxicity, ototoxicity, peripheral neuropathy, N/V (mod. emetogenic risk), electrolyte imbalance, ↑ LFTs

DDI: Sorafenib (↑ carboplatin tox), topotecan (↑ topotecan tox)

Clinical pearls: Cap GFR at 125 mL/min in Calvert formula

Cisplatin (Platinol)

Dosing/dose adjustments: 20-100 mg/m²/d IV × 1-5 d every 3-4 wks. SCr >1.5 mg/dL or BUN >25 mg/dL: Do not use. Consider dose reduction for renal impairment.

PK/PD: Highly protein bound (>90%), nonenzymatic metabolism, renal excretion (>90%), T1/2 < 1 h; protein bound platinum 1-5 d

Adverse effects: Nephrotoxicity, N/V acute/delayed 2-5 d post dose (DLT; high [≥50 mg/m²], mod. [<50 mg/m²] emetogenic risk), peripheral neuropathy (cum. dose 300-600 mg/m²; reversible), ototoxicity & hearing loss (cum. dose >400 mg/m²; irreversible), electrolyte disturbance, Raynaud phenomenon, HSR, ↑ LFTs

DDI: AG (↑ nephrotoxicity), loop diuretics (↑ nephrotoxicity & ototoxicity), phenytoin (↓ phenytoin conc.), topotecan (↑ topotecan tox), vinorelbine (granulocytopenia)

Clinical pearls: Properly hydrate pt pre/post-tx. Mannitol can be used to ↑ UOP. Antiemetic Rx must cover delayed N/V period. Monitor renal function, electrolytes, & signs of hearing loss & neuropathy frequently. Vesicant (at conc. >0.5 mg/mL).

Oxaliplatin (Eloxatin)

Dosing/dose adjustments: 85-130 mg/m² IV every 2-3 wks. Renal: CrCl < 30 mL/min: Reduce dose to 65 mg/m². Reduce dose for prolonged neuropathy, & grade 3-4 GI & cell count tox.

PK/PD: Highly protein bound (>90%), hydrolyzed to reactive metabolites, renal excretion, T1/2 391 h (platinum metabolites)

Adverse effects: Neurotoxicity (DLT), myelosuppression, pharyngolaryngeal dysesthesia, peripheral neuropathy, ↑ LFTs, ↑ SCr, fever

DDI: No significant drug interactions

Clinical pearls: Cold temperatures can worsen peripheral neuropathy

Dacarbazine (DTIC-Dome)

Dosing/dose adjustments: 250 mg/m²/d IV × 4-5 d every 3 wks OR 375 mg/m²/dose IV on d 1, 15 every 4 wks (ABVD regimen). Consider dose adjustment w/renal impairment.

PK/PD: Prodrug hepatically activated via CYP1A2, minimally bound to protein (˜5%), renal excretion, T1/2 40min; active metabolite 5 h

Adverse effects: N/V (DLT but can become tolerant; high emetogenic risk), mild myelosuppression, flu-like sx, injection site pain

DDI: CYP1A2 inducers (↑/↓ conversion to active metabolites)

Procarbazine (Matulane)

Dosing/dose adjustments: 1-6 mg/kg/d PO. Consider dose reduction for hepatic impairment.

PK/PD: Rapid & complete absorption, prodrug hepatically activated, penetrates BBB, renal excretion of metabolites, T1/2 10min

Adverse effects: Myelosuppression, N/V (mod. -high emetogenic risk), paresthesias, somnolence, depression, agitation, azoospermia, ovarian failure, 2° malignancies

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