Irinotecan metabolism is complex due to the involvement of many enzymes and transporters, and is therefore prone to drug–drug interactions. Prior to starting with irinotecan chemotherapy, patients should be evaluated for possible interactions with comedication. |
Single nucleotide polymorphisms in several drug metabolizing enzymes (e.g. uridine diphosphate glucuronosyltransferase [UGT] 1A1, UGT1A7, UGT1A9) and drug transporters (e.g. ATP-binding cassette [ABC] B1, ABCC1) have been reported to be significantly associated with irinotecan toxicity. Caucasian patients should be screened for UGT1A1*28 and Asian patients for UGT1A1*6 in advance of irinotecan treatment as these polymorphisms are common in those populations and dosing can be personalized if UGT1A1 functioning is constitutionally altered. |
Despite existing genotype-based dosing guidelines, upfront UGT1A1 genotyping is not yet routinely performed in patients starting with irinotecan chemotherapy. |
1 Introduction
2 Pharmacokinetics
2.1 Distribution
2.2 Metabolism
2.2.1 Metabolism by Carboxylesterases and Butyrylcholinesterase
2.2.2 Metabolism by Uridine Diphosphate Glucuronosyltransferases
2.2.3 Metabolism by Cytochrome P450 Enzymes
2.2.4 Metabolism by β-Glucuronidases
2.3 Elimination
2.4 Other Formulations and Administrations
2.4.1 Other Formulations
2.4.2 Other Variations in Administration
2.5 Drug–Drug Interactions (DDIs)
2.5.1 DDIs with Anticancer Drugs
Drug/OTC/lifestyle |
N
| Enzyme/transporter | Irinotecan dose | PK alterations | References | |
---|---|---|---|---|---|---|
Anticancer drugs
| ||||||
Paclitaxel 135–200 mg/m2 D8 | 31 | ABCB1 | 40–60 mg/m2 D1 + 8, Q3W | Irinotecan SN-38 SN-38G | AUC24.5 32.7% ↑ AUC24.5 40.4% ↑ AUC24.5 46.2% ↑ | [124] |
Thalidomide 400 mg od (for 14D) | 16 | 350 mg/m2,Q3W | SN-38 SN-38G | AUC48 74% ↓ AUC48 28% ↑ | [130]a | |
S-1 (tegafur) 100/120 mg/m2, 4–7D | 4 | ABCG2 | 100–200 mg/m2 Q2 W | SN-38: | AUC24 50% ↓ | [128] |
Imatinib 300–600 mg od Cisplatin 30 mg/m2 D1 + 8 | 6 | CYP3A4, CYP3A5 CYP2C9 | 65 mg/m2 D1 + 8, Q3W | Irinotecan | AUC8 67% ↑, CL 36% ↓ | [134] |
Lapatinib 1250 mg/day Leucovorin 200 mg/m2 5-FU 600 mg/m2 | 12 | CYP3A4 OATP1B1 ABCB1 ABCG2 | 108 mg/m2 Q2W | SN-38 | AUC24 41%↑, Cmax 32%↑ | [137] |
Non-anticancer drugs | ||||||
Ketoconazole 200 mg od for 2D | 7 | CYP3A4 | 100 mg/m2 (with ketoconazole) 350 mg/m2 (alone) Q3W | SN-38 APC | AUC500 109% ↑ AUC500 87% ↓ | [142] |
Lopinavir 400 mg/ritonavir 100 mg combination drug (Kaletra) bid | 8 | CYP3A4 UGT1A1 ABCB1 | 150 mg/m2 D1 + 10, Q3W | Irinotecan SN-38 SN-38G APC | AUCinf 89% ↑, CL 47% ↓ AUCinf 204% ↑ AUCinf 94% ↑ AUCinf 81% ↓ | [148] |
Cyclosporine 5–10 mg/kg | 43 | ABCB1 ABCC2 | 25–75 mg/m2 Q1W | Irinotecan SN-38 | CL 39–64% ↓ AUC24 23–630% ↑ | [147] |
Cyclosporine + Phenobarbital 90 mg for 14D | 39 | ABCB1 ABCC2 UGT1A1 | 72–144 mg/m2 Q1W | Irinotecan SN-38 SN-38G | AUC24 27% ↓, CL 43% ↑ AUC24 75% ↓ AUC24 50% ↓ | |
Celecoxib 400 mg bid | 11 | 50–60 mg/m2 D1 + 8, Q3W | Irinotecan SN-38 | CL 18% ↑ AUC12.5 21.8% ↓ | [151]a | |
Methimazole | 14 | UGT1A | 660 mg Q3W | SN-38 SN-38G | AUC56 14%↑ AUC56 67% ↑ | [150] |
Herbal and dietary supplements, and lifestyle
| ||||||
Cigarette smoking | 190 | CYP3A UGT1A1 | 350 mg/m2 or 600 mg fixed dose Q3W | Irinotecan SN-38 | AUC100 15% ↓, CL 18% ↑ AUC100 38% ↓ | [162] |
St. John’s wort 300 mg tid | 5 | CYP3A4 | 350 mg/m2 Q3W | SN-38 | AUC24 42% ↓ | [158] |
2.5.2 DDIs with Non-Anticancer Drugs
2.5.3 DDIs with Herbal and Dietary Supplements, and Lifestyle
3 Pharmacodynamics
3.1 Toxicity
Study, year |
N
| Irinotecan dose | Irinotecan | SN-38 | SN-38G | Biliary index |
---|---|---|---|---|---|---|
Diarrhea
| ||||||
Ohe et al., 1992 [185] | 36 | 5–40 mg/m2 5D, continuously |
Yes
a
| No | ND | ND |
de Forni et al., 1994 [186] | 59 | 50–145 mg/m2 Q1W |
Yes
a
|
Yes
a
| ND | ND |
Rowinsky et al., 1994 [65] | 32 | 100–345 mg/m2 Q3W | No | No | ND | ND |
Gupta et al., 1994 [178] | 21 | 100–175 mg/m2 Q1W | No | No | No |
Yes
b
|
Abigerges et al., 1995 [187] | 64 | 100–750 mg/m2 Q3W |
Yes
c
|
Yes
c
| ND | ND |
Catimel et al., 1995 [67] | 46 | 33–115 mg/m2 D1–D3, Q3W |
Yes
a
| No | ND | ND |
Gupta et al., 1997 [76] | 40 | 145 mg/m2 Q1W | No | No | No |
Yes
b
|
Canal et al., 1996 [68] | 47 | 350 mg/m2 Q3W | No | No | No | No |
Mick et al., 1996 [183] | 36 | 145 mg/m2 Q1W | ND | ND | ND |
Yes
a
|
Rothenberg et al., 1996 [188] | 48 | 125–150 mg/m2 Q1W | No |
Yes
a
| ND | ND |
Herben et al., 1999 [184] | 29 | 10–12.5 mg/m2 D14–21, continuously | No | No | No | No |
de Jong et al., 2000 [66] | 52 | 175–300 mg/m2 Q3W | No | No | ND | No |
Xie et al., 2002 [16] | 109 | 100–350 mg/m2 Q3W |
Yes
1
| No |
Yes
a
| No |
Neutropenia
| ||||||
Ohe et al., 1992 [185] | 36 | 5–40 mg/m2 5D, continuously | No |
Yes
d
| ND | ND |
de Forni et al., 1994 [186] | 59 | 50–145 mg/m2 Q1W |
Yes
e
|
Yes
e
| ND | ND |
Rowinsky et al., 1994 [65] | 32 | 100–345 mg/m2 Q3W | No |
Yes
e
| ND | ND |
Abigerges et al., 1995 [187] | 64 | 100–750 mg/m2 Q3W |
Yes
d
|
Yes
d
| ND | ND |
Catimel et al., 1995 [67] | 46 | 33–115 mg/m2 D1–D3, Q3W | No | No | ND | ND |
Canal et al., 1996 [68] | 47 | 350 mg/m2 Q3W |
Yes
e
|
Yes
e
| No | No |
Rothenberg et al., 1996 [188] | 48 | 125–150 mg/m2 Q1W | No | No | ND | ND |
Herben et al., 1999 [184] | 29 | 10–12.5 mg/m2 D14–21, continuously | No | No | No | No |
de Jong et al., 2000 [66] | 52 | 175–300 mg/m2 Q3W | No | No | ND | ND |
Mathijssen et al., 2002 [73] | 26 | 350 mg/m2 Q3W | ND |
Yes
f
| ND | ND |
3.2 Efficacy
4 Pharmacogenetics
4.1 Associations between UGT1A1 Polymorphisms and Irinotecan Pharmacodynamics
Polymorphism | Ethnicity | Endpoint | Dose range (mg/m2) | Main findings | No. of patients | No. of studies | References |
---|---|---|---|---|---|---|---|
Meta-analyses | |||||||
UGT1A1*28/*28 (rs8175347) vs. *1/*28 or *1/*1 | Not reported | Hematologic toxicities | 80–125 | OR 1.80, 95% CI 0.37–8.84, p = 0.41 | 229 | 3 | [242] |
180 | OR 3.22, 95% CI 1.52–6.81, p = 0.008 | 410 | 4 | ||||
200–350 | OR 27.8, 95% CI 4.0–195, p = 0.005 | 184 | 3 | ||||
*28/*28 vs. *1/*1 | Mainly Caucasian | Neutropenia | < 150 | OR 2.43, 95% CI 1.34–4.39, p = 0.003 | 300 | 4 | [243] |
150–250 | OR 2.00, 95% CI 1.62–2.47, p < 0.001 | 1481 | 9 | ||||
≥ 250 | OR 7.22, 95% CI 3.10–16.78, p < 0.001 | 217 | 3 | ||||
*28/*28 vs. *1/*28 or *1/*1 | Caucasian | Neutropenia | 80–350 | OR 3.44, 95% CI 2.45–4.82, p < 0.00001 | 2015 | 14 | [244] |
*28/*28 vs. *1/*28 or *1/*1 | Diarrhea | > 150 | OR 2.04, 95% CI 1.23–3.38, p = 0.006 | 1317 | 8 | ||
< 150 | OR 1.41, 95% CI 0.82–2.43, p = 0.21 | 663 | 6 | ||||
*1/*28 or *28/*28 vs. *1/*1 | Asian | Neutropenia | 50–100 | OR 1.47, 95% CI 0.90–2.42, p = 0.13 | 515 | 8 | [245] |
*6/*6 (rs4148323) vs. *1/*6 or *1/*1 | Diarrhea | OR 4.90, 95% CI 2.02–11.88, p = 0.0004 | 225 | 4 | |||
*6/*6 vs. *1/*6 or *1/*1 | Tumor response | OR 1.51, 95% CI 0.78–2.92, p = 0.22 | 225 | 4 | |||
*28/*28 or *1/*28 vs. *1/*1 | OR 1.03, 95% CI 0.59–1.82, p = 0.91 | 390 | 7 | ||||
*28/*28 vs. | Asian | Neutropenia | 60–200 | OR 1.67, 95% CI 0.94–2.97 | 658 | 6 | [246] |
*6/*28
| 30–350 |
OR 2.55, 95% CI 1.82–3.58
| 886 | 13 | |||
*6/*6 or *28/*28 or *6/*28 vs. *1/*6 or *1/*28 or *1/*1 | Asian | Neutropenia | 60–350 | OR 3.275, 95% CI 2.152–4.983, p = 0.000 | 923 | 11 | [247] |
*1/*6 or *6/*6 vs. *1/*1 | OR 1.542, 95% CI 1.180–2.041, p = 0.001 | 994 | 9 | ||||
*6/*6 vs. *1/*1 | Asian | Neutropenia | 30–375 | OR 4.44, 95% CI 2.42–8.14, p < 0.001 | 833 | 7 | [248] |
*28/*28 or *1/*28 vs. *1/*1 | Asian | Diarrhea | > 125 | OR 3.02, 95% CI 1.42–6.44, p = 0.004 | 309 | 4 | [249] |
*28/*28 or *1/*28 vs. *1/*1 | Caucasian | OR 1.93, 95% CI 1.38–2.70, p < 0.001 | 1096 | 11 | |||
*28/*28 vs. *1/*1 *1/*28 vs. *1/*1 | Caucasian | OS and PFS | 60–350 | All comparisons not significant for both OS and PFS (p > 0.05) | 1524 (OS) 1494 (PFS) | 10 | [251] |
Clinical studies
| |||||||
UGT1A1*60
| Asian | PK, tumor response, grade 4 neutropenia, grade 3 diarrhea, delivered dose | 80 | p > 0.05 for all endpoints | 81 | 1 | [253] |
UGT1A1*60
| Not specified (probably Korean) | Neutropenia, anorexia, vomiting, diarrhea, abdominal pain | 150 | p > 0.05 for all endpoints | 42 | 1 | [254] |
UGT1A1*28, *60, *93 (rs10929302) | Caucasian (50 pts), Black (10 pts), Hispanic (4 pts), Pacific Islander (1 pt), Asian (1 pt) | Neutropenia | 350 |
UGT1A1 haplotype (
*28/*60/*93
) associated with grade 4 neutropenia,
p < 0.001 | 66 | 1 | [255] |
UGT1A1*28, *93, ABCB1 (rs1045642) | Not specified, presumably Caucasian (France) | Hematologic toxicities | 180 | UGT1A1*28/*28 and *93/*93: increased risk of hematologic toxicity (p = 0.01) | 184 | 1 | [258] |
UGT1A1*93, ABCB1 (rs12720066), ABCC1 (rs6498588, rs17501331) | Caucasian (67 pts), African American (11 pts) | ANC nadir, SN-38 AUC | 300 or 350 |
Increased SN-38 AUC:
UGT1A1*93, ABCC1
(rs6498588)
Decreased SN-38 AUC:
ABCB1
(rs12720066)
Increased ANC nadir:
ABCB1
(rs12720066)
Decreased ANC nadir: UGT1A1*93, ABCC1 (rs17501331) | 78 | 1 | [256] |
UGT1A1*28 and *93 | Caucasian (94 pts), Asian (2 pts) | Diarrhea | 40–80, 180, 350 | UGT1A1*28/*28 and *93/*93 associated with grade 3/4 diarrhea (p < 0.05) | 96 | 1 | [260] |
Neutropenia | No significant effect on neutropenia | ||||||
UGT1A1:*28,*93 UGT1A6: rs2070959 UGT1A9: *22 (rs45625337), −688A/C variant
UGT1A7*3
3′UTR: 440C > G variant | Not specified, presumably Caucasian (Canada) | Neutropenia | 180 |
UGT1A1*93
associated with neutropenia.
Haplotype (UGT1A1*28, *60, *93, UGT1A7*3, UGT1A9*1) associated with grade 3–4 neutropenia: OR 2.43, 95% CI 1.35–4.39, p = 0.004 Haplotypes ‘II’ and ‘III’ (variants in UGT1A9, 1A7, 1A6, and 3′UTR wild-type) associated with grade 3–4 neutropenia: OR 2.15 and 5.28, respectively | 167 | 1 | [259] |
Among other genes: UGT1A1*28, *93 | Caucasian (450 pts), African American (36 pts), Hispanic (16 pts), Asian (9 pts), other (9 pts) | (Febrile) neutropenia, vomiting | 125 or 200 | UGT1A1*93 associated with grade 3 febrile neutropenia, grade 4 neutropenia (p < 0.001), and grade 3 vomiting (p = 0.004) | 520 | 1 | [261] |
UGT1A1:*6, *28
UGT1A7*3
UGT1A9*1
| Asian | Adverse events, therapeutic intervention | 60, 70, 100 or 180 | UGT1A1*6/*28, UGT1A7*3/*3 or UGT1A9*1/*1: greater risk of adverse events and therapeutic intervention: OR 11.00, 95% CI 1.633–74.083, p = 0.014 | 45 | 1 | [263] |
UGT1A1*28, UGT1A1*60, UGT1A1*93, UGT1A7*3, and UGT1A9*22 | Caucasian | Hematologic toxicity, response rate | 180 | Haplotype II (all variants except UGT1A1*22) associated with increased response rate: OR 8.61, 95% CI 1.75–42.38, p = 0.01 | 250 | 1 | [262] |
Among other genes:
SLCO1B1 (rs4149056) UGT1A1*6
UGT1A9*22
ABCC2 (rs3740066)
ABCG2 (rs2231137)
| Asian | Neutropenia | 65 or 80 |
SLCO1B1
and
UGT1A1*6
: increased risk for grade 4 neutropenia
| 107 | 1 | [264] |
Diarrhea |
UGT1A9*1/*1, ABCC2
(rs3740066),
ABCG2
(rs2231137)
: increased risk for grade 3 diarrhea
| ||||||
Among other genes: UGT1A1*93, ABCC1 (rs3765129), SLCO1B1*1b (rs2306283) | African American (11 pts), Caucasian (67 pts), other (7 pts) | ANC nadir | 300, 350 | UGT1A1*93, ABCC1 (rs3765129): decreased ANC nadir SLCO1B1*1b (rs2306283): increased ANC nadir (p < 0.05) | 85 | 1 | [174] |
Among other genes: ABCB1 (rs1045642, rs1128503, rs2032582), | Caucasian | Toxicity | 180 |
ABCB1
(rs1045642) associated with early toxicity: OR 3.79 95% CI 1.09–13.2
| 140 | 1 | [268] |
Response rate |
ABCB1
haplotype (
rs
1045642, rs1128503, rs2032582): shorter OS, OR 1.56, 95% CI 1.01–2.45
| ||||||
ABCC2: rs1885301, rs2804402, rs717620, rs2273697, rs17216177, rs3740066 | Caucasian | Diarrhea | 260–875 mg | Decreased incidence of diarrhea for ABCC2*2 haplotype (rs1885301, rs2804402, rs717620, rs2273697, rs17216177, rs3740066) without UGT1A1*28 allele: OR 0.15, 95% CI 0.04–0.61), p = 0.005 | 167 | 1 | [271] |
Among other genes: ABCC5 (rs10937158, rs3749438, rs2292997) ABCG1 (rs225440) | Caucasian | Diarrhea | 180 |
Reduced risk of diarrhea for
ABCC5
haplotype (rs10937158 and rs3749438):
OR 0.39, 95% CI 0.23–0.67, p = 0.0006 | 167 | 1 | [272] |
Neutropenia | Increased risk of neutropenia for co-occurrence of ABCG1 and ABCC5 (rs2292997): OR 5.93 95% CI 2.25–15.59, p = 0.0002 | ||||||
SLCO1B1*1b
| Caucasian | Neutropenia | 300, 350, 380–600 (mg) | SLCO1B1*1b: increased ANC nadir (p < 0.05) | 67 (discovery cohort), 108 (replication cohort) | 1 | [273] |
Among other genes: SLCO1B1*1b, SLCO1B1*5 (rs4149056) | Caucasian | SN-38 PK, toxicity, PFS | 180 | SLCO1B1*1b: increased PFS (p < 0.05). SLCO1B1*5: increased SN-38 plasma concentration and increased risk of neutropenia (combined with UGT1A1*28) (p < 0.05) | 127 | 1 | [274] |
4.2 Associations between Other UGT1A Polymorphisms and Irinotecan Pharmacodynamics: UGT1A7 and UGT1A9
4.3 Associations between Drug Transporter Polymorphisms and Irinotecan Pharmacokinetics and Pharmacodynamics
4.4 Implementation of Genotype-Adjusted Irinotecan Dosing Guidelines
Organization | Country | Year of last update | Genotype recommended for testing | Dose reduction explicitly recommended? | Recommendation | References |
---|---|---|---|---|---|---|
US FDA | USA | 2014 |
UGT1A1*28
| Yes | UGT1A1*28/*28: starting dose reduction by at least one dose level | [275] |
Health Canada/Santé Canada (HCSC) | Canada | 2014 |
UGT1A1*28
| Yes | UGT1A1*28/*28: reduced starting dose | [276] |
National Pharmacogenetics Network (RNPGx) and the Group of Clinical Onco-pharmacology (GPCO-Unicancer) | France | 2015 |
UGT1A1*28
| Yes | UGT1A1*28/*28 and dose 180–230 mg/m2: 25–30% reduction of starting dose UGT1A1*28/*28 and dose ≥ 240 mg/m2: irinotecan contraindicated | [278] |
Royal Dutch Association for the Advancement of Pharmacy (KNMP) | The Netherlands | 2011 |
UGT1A1*28
| Yes | UGT1A1*28/*28 and dose > 250 mg/m2: 30% reduction of starting dose | [279] |
European Medicines Agency (EMA) | Europe | 2017 |
UGT1A1*28
| Yes | UGT1A1*28/*28: reduce starting dose of liposomal irinotecan from 80 to 60 mg/m2 | [280] |
Pharmaceuticals and Medical Devices Agency (PMDA) | Japan | 2014 | UGT1A1*6 and *28 | No | Use irinotecan with caution in patients with the following genotypes: UGT1A1*6/*6, UGT1A1*28/*28 and UGT1A1*6/*28 | [281] |
5 Conclusions and Future Perspectives
-
Concomitant use of potent CYP3A4 inducers (e.g. rifampicin, phenytoin, phenobarbital, carbamazepine, SJW): avoid combination.
-
Concomitant use of potent CYP3A4 inhibitors (e.g. ketoconazole, itraconazole): avoid combination.
-
Caucasians: perform genotyping for UGT1A1*28. Consider at least a 25% reduction of starting dose in patients homozygous for UGT1A1*28.
-
Asians: perform genotyping for UGT1A1*6. Consider dose reduction of the starting dose in patients homozygous for UGT1A1*6. Exact dosing adjustments are as yet unknown.