Concentrations Of Irinotecan Research Articles

Abstract C207: Identifying differential mechanisms of action for MM-398/PEP02, a novel nanotherapeutic encapsulation of irinotecan.

Abstract MM-398 (aka PEP02) is a stable, nanotherapeutic encapsulation of the pro-drug CPT-11 (irinotecan) that is currently in clinical development. In preclinical experiments, treatment with MM-398 resulted in significantly higher intratumoral concentrations of both irinotecan (142-fold) and its major metabolite, SN-38 (9-fold) and exhibited superior anti-tumor activity compared to free irinotecan in multiple tumor xenografts. Subsequently, multiple phase 1 and 2 studies have established a pharmacokinetic and safety profile that supports continued clinical development, including in pancreatic, gastric, colorectal and potentially other cancers. Because current evidence suggests that resistance to pancreatic cancer is driven largely by inadequate drug penetration into these often poorly vascularized, stromally dense and hypoxic tumors, we sought to better understand how this relatively large (100nm) liposomal nanotherapeutic could potentially result in increased efficacy in very advanced gemcitabine-resistant pancreatic cancer and other cancer types. We developed a mechanism-based PK model of MM-398 and free irinotecan designed to predict intratumor SN-38 levels. Sensitivity analysis revealed that for MM-398 local activation of irinotecan to SN-38 was a far more important parameter than systemic activation. Through cellular uptake studies, we demonstrated in vitro that MM-398 was preferentially internalized by phagocytic macrophage/monocyte cell lines and, to a far lesser extent, by tumor cell lines. Furthermore, tumor microdistribution studies by flow cytometry and IHC showed uptake of MM-398 liposomes in both tumor cells and tumor-associated macrophages with more liposomal material being present in the macrophages. This distribution also suggests that macrophages may contribute to the postulated rate limiting process of irinotecan activation. The sensitivity analysis also suggested that tumor permeability and vascularization are important determinants of tumor-associated SN-38 levels for both free irinotecan and MM-398. To determine the effect of MM-398 on these parameters we treated mice bearing HT29 (colorectal cancer) xenografts with a single dose of MM-398 and measured hypoxic markers (CAIX) and microvessel density (CD31) by IHC. Tumors treated with MM-398 showed a greater degree of CD31 staining and lower CAIX staining, indicating that MM-398 may be able to affect tumor characteristics that traditionally have contributed to therapy resistance and limited the delivery of cancer therapeutics and resistance. In summary, encapsulation of irinotecan alters rate-limiting processes that determine tumoral SN-38 levels. Delivery of MM-398 is believed to alter tumor microvessel density and decrease hypoxia. These intriguing mechanisms of action findings support the continued clinical development of MM-398 as a differentiated therapeutic for several cancer types. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C207.

Antitumor activity of IHL-305, a novel pegylated liposome containing irinotecan, in human xenograft models

The antitumor effect of IHL-305, a novel pegylated liposome containing irinotecan, was investigated in human xenograft models. After subcutaneous transplantation of several human cancer cell lines (colorectal, non-small cell lung, small cell lung, prostate, ovarian and gastric cancer cells) to nude mice, IHL-305 or CPT-11 was administered intravenously 3 times at 4-day intervals. In all xenograft models tested, IHL-305 showed superior antitumor activity to that of CPT‑11 and a comparable tumor-growth-inhibitory effect at one-eighth or less of the dose of CPT-11, even against HT-29 colorectal and NCI-H460 non-small cell lung cancer cell lines, which show intrinsic resistance to CPT-11. A single injection or 2 injections of IHL-305 on several dosing schedules also resulted in a significant antitumor effect compared to that of vehicle control in a dose-dependent manner and showed comparable antitumor activity at about one-fifth the dose of the maximum tolerated dose of CPT-11. The analysis of the concentrations of irinotecan and SN-38, an active metabolite of CPT-11, in plasma and tumors revealed that irinotecan was maintained at high concentrations, and the prolonged presence of SN-38 in plasma and tumors in IHL-305 treated mice compared with CPT-11-treated mice. Therefore, the stronger tumor inhibitory effect of IHL-305, as compared to CPT-11, was associated with the difference in the concentration of irinotecan in plasma or tumors after each agent was administered and with the maintainance of a higher concentration of SN-38. These results indicate that IHL-305 demonstrated superior antitumor activity against a wide range of tumors at lower doses than CPT-11.

Concurrence of UGT1A Polymorphism and End-Stage Renal Disease Leads to Severe Toxicities of Irinotecan in a Patient with Metastatic Colon Cancer

Colorectal cancer is one of the most common malignancies in the world, and irinotecan (CPT-11) is useful in its treatment. However, the safety and pharmacokinetics of irinotecan in dialysis patients with metastatic colorectal cancer are unclear. We report the case of a 74-year-old man receiving chronic hemodialysis who had metastatic colorectal cancer. Palliative chemotherapy with irinotecan (80 mg/m2 weekly) was administered after hemodialysis. Blood samples were collected before and 1.5, 3, 6, 9, and 15 hours after administration of irinotecan. The peak serum concentrations (Cmax) of irinotecan and SN-38 in this patient were 1,480 and 17.8 ng/mL, respectively, which were similar to the reported values in patients with normal renal function after a similar dose of irinotecan (75 mg/m2). The area under the serum concentration-time curve (AUC0-∞) was 8,240 ng×h/mL for irinotecan and 619 ng×h/mL for SN-38. The AUC0-∞ for SN-38 was markedly higher than that for patients with normal renal function. Sequencing analysis of the UGT1A genes found that the patient had variant alleles of UGT1A1*28, UGT1A1*60 and UGT1A9*22, which may lead to decreased glucuronidation and excretion of SN-38, and may account for increased irinotecan-related toxicity. The patient developed febrile grade 4 neutropenia on day 7 after chemotherapy and died of septic shock on day 14. UGT1A polymorphisms and renal failure may lead to accumulation of SN-38, which may have played a role in the death of this patient. Irinotecan should be used cautiously in dialysis patients with metastatic colorectal cancer and screening for UGT1A polymorphisms may help in identifying patients with lower SN-38 glucuronidation rates and greater susceptibility to irinotecan-induced toxicity.

The acridone derivative MBLI-87 sensitizes breast cancer resistance protein-expressing xenografts to irinotecan

The breast cancer resistance protein ABCG2 confers cellular resistance to irinotecan (CPT-11) and its active metabolite SN-38. We utilised ABCG2-expressing xenografts as a model to evaluate the ability of a non-toxic ABCG2 inhibitor to increase intracellular drug accumulation. We assessed the activity of irinotecan in vivo in SCID mice: irinotecan completely inhibited the development of control pcDNA3.1 xenografts, whilst only delaying the growth of ABCG2-expressing xenografts. Addition of MBLI-87, an acridone derivative inhibitor, significantly increased the irinotecan effect against the growth of ABCG2-expressing xenografts. In vitro, MBLI-87 was as potent as GF120918 against ABCG2-mediated irinotecan efflux, and additionally was specific for ABCG2. A significant sensitisation to irinotecan was achieved despite the fact that doses remained well below the maximum tolerated dose (due to the rather limited solubility of MBLI-87). This suggested that MBLI-87 is an excellent candidate to prevent drug efflux by ABCG2, without altering plasma concentrations of irinotecan and SN-38 after IP (intra-peritoneal) injections. This could constitute a useful strategy to improve drug pharmacology, to facilitate drug penetration into normal tissue compartments protected by ABCG2, and potentially to reverse drug resistance in cancer cells.

Secreted protein acidic and rich in cysteine-induced cellular senescence in colorectal cancers in response to irinotecan is mediated by P53

Cellular senescence is another mechanism that can be exploited to achieve better chemosensitivity and greater tumor regression. Unlike apoptosis, cellular senescence can be induced at much lower concentrations of chemotherapy that are better tolerated by patients. We previously revealed that secreted protein acidic and rich in cysteine (SPARC), a matricellular protein, may function as a modulator of chemotherapy sensitivity by enhancing apoptosis. Here, we examine the effects of SPARC on cellular senescence in the presence of chemotherapy. Cellular senescence is induced only in sensitive colorectal cancer (CRC) cells with low concentrations of irinotecan (CPT-11). However, CPT-11-resistant cells exposed to endogenous or exogenous SPARC can also be triggered into cellular senescence. This induction is associated with higher levels of p16(INK4A) and phosphorylated p53. Knock down of p16(INK4A) reduces drug-induced senescence in all cells, but knock down and overexpression of p53 modulates senescence only in cells exposed to SPARC. Furthermore, treatment of mice with SPARC and CPT-11 leads to significantly increased cellular senescence and tumor regression. The chemosensitizing effects of SPARC in CRCs are, therefore, probably mediated in part by activating cellular senescence.

Interactions Between Herbal Medicines and Prescribed Drugs

The concomitant use of herbal medicines and pharmacotherapy is wide spread. We have reviewed the literature to determine the possible interactions between seven popular herbal medicines (ginkgo, St John's wort, ginseng, garlic, echinacea, saw palmetto and kava) and conventional drugs. Literature searches were performed using MEDLINE, Cochrane Library and EMBASE and we identified 128 case reports or case series, and 80 clinical trials. Clinical trials indicate that St John's wort (Hypericum perforatum), via cytochrome P450 (CYP) and/or P-glycoprotein induction, reduces the plasma concentrations (and/or increases the clearance) of alprazolam, amitriptyline, atorvastatin, chlorzoxazone, ciclosporin, debrisoquine, digoxin, erythromycin, fexofenadine, gliclazide, imatinib, indinavir, irinotecan, ivabradine, mephenytoin, methadone, midazolam, nifedipine, omeprazole, oral contraceptives, quazepam, simvastatin, tacrolimus, talinolol, verapamil, voriconazole and warfarin. Case reports or case series suggest interactions of St John's wort with adrenergic vasopressors, anaesthetics, bupropion, buspirone, ciclosporin, eletriptan, loperamide, nefazodone, nevirapine, oral contraceptives, paroxetine, phenprocoumon, prednisone, sertraline, tacrolimus, theophylline, tibolone, tryptophan, venlafaxine and warfarin. Ginkgo (Ginkgo biloba) decreases the plasma concentrations of omeprazole, ritonavir and tolbutamide. Clinical cases indicate interactions of ginkgo with antiepileptics, aspirin (acetylsalicylic acid), diuretics, ibuprofen, risperidone, rofecoxib, trazodone and warfarin. Ginseng (Panax ginseng) may interact with phenelzine and warfarin. Kava (Piper methysticum) increases the clearance of chlorzoxazone (a CYP2E1 substrate) and may interact with alprazolam, levodopa and paroxetine. Garlic (Allium sativum) interacts with chlorpropamide, fluindione, ritonavir and warfarin; it also reduces plasma concentrations of chlorzoxazone (a CYP2E1 probe). Echinacea might affect the clearance of caffeine (a CYP1A2 probe) and midazolam (a CYP3A4 probe). No interactions have been reported for saw palmetto (Serenoa repens). Numerous interactions between herbal medicines and conventional drugs have been documented. While the significance of many interactions is uncertain, several interactions, particularly those with St John's wort, may have serious clinical consequences.

Life-threatening toxicities in a patient with UGT1A1*6/*28 and SLCO1B1*15/*15 genotypes after irinotecan-based chemotherapy

To explore severe toxicities induced by irinotecan-based chemotherapy and UGT1A1*6/*28 and SLCO1B1*15/*15 genotypes. A 66-year-old Japanese male diagnosed with left pharyngeal carcinoma (T2N2bM0, stage IVA) was treated with irinotecan (70 mg/m(2)) on days 1, 8 and 15 in combination with docetaxel (60 mg/m(2)) on day 1 of a 28-day cycle. After the first cycle, he suffered marked toxicities, including grade 4 diarrhea and febrile grade 4 neutropenia. Plasma concentrations of irinotecan, SN-38 and SN-38G were measured, and extensive accumulation of SN-38 was observed. Genotyping of UGT1A1 and OATP1B1 proteins showed UGT1A1*6/*28 and SLCO1B1*15/*15, respectively, which are known to lead to extremely low glucuronidation and transport activities of substrate drugs. The severe toxicities in this patient are attributable to the extensive accumulation of SN-38, which may result from a synergistic or additive effect of low metabolic (UGT1A1*6/*28) and transport (SLCO1B1*15/*15) capabilities.

Gefitinib Increases Serum Concentrations of Oral Irinotecan and SN-38 without Increasing the Biliary Concentration of SN-38 in Rats

Background: Gefitinib competes with topoisomerase I inhibitors at drug efflux pumps in vitro. We evaluated the effects of oral gefitinib on pharmacokinetic parameters of orally coadministered irinotecan. Methods: We measured the serum pharmacokinetic parameters and biliary excretion of irinotecan, SN-38 and its glucuronide after irinotecan (50 or 100 mg/kg) was orally administered with or without gefitinib 100 mg/kg to rats. We measured the concentrations of irinotecan and SN-38 in the small intestine, liver, lungs and kidneys in each rat. Results: The plasma area under the curve (0–24 h) of irinotecan and SN-38 was increased significantly, while the apparent elimination constant of irinotecan was decreased significantly. Gefitinib significantly increased the biliary cumulative amounts of irinotecan, but not of SN-38, and also influenced the enterohepatic circulation of irinotecan, but not of SN-38. Conclusions: Gefitinib increased the serum concentrations of irinotecan and SN-38 following oral administration of irinotecan without increasing the biliary excretion of SN-38 in vivo.

Enterohepatic recirculation model of irinotecan (CPT-11) and metabolite pharmacokinetics in patients with glioma

Enterohepatic recirculation of irinotecan and one of its metabolites, SN-38, has been observed in pharmacokinetic data sets from previous studies. A mathematical model that can incorporate this phenomenon was developed to describe the pharmacokinetics of irinotecan and its metabolites. A total of 32 patients with recurrent malignant glioma were treated with weekly intravenous administration of irinotecan at a dose of 125 mg/m(2). Plasma concentrations of irinotecan and its three major metabolites were determined. Pharmacokinetic models were developed and tested for simultaneous fit of parent drug and metabolites, including a recirculation component. Rebound in the plasma concentration suggestive of enterohepatic recirculation at approximately 0.5-1 h post-infusion was observed in most irinotecan plasma concentration profiles, and in some plasma profiles of the SN-38 metabolite. A multi-compartment model containing a recirculation chain was developed to describe this process. The recirculation model was optimal in 22 of the 32 patients compared to the traditional model without the recirculation component. A recirculation chain incorporated in a multi-compartment pharmacokinetic model of irinotecan and its metabolites appears to improve characterization of this drug's disposition in patients with glioma.

Pharmacogenetic Pathway Analysis of Irinotecan

Irinotecan, a chemotherapeutic agent against various solid tumors, is a prodrug requiring activation to SN-38. Irinotecan's complex pharmacokinetics potentially allow for many genetic sources of variability. We explored relationships between pharmacokinetic pathways and polymorphisms in genes associated with irinotecan's metabolism and transport. We fitted a seven-compartment pharmacokinetic model with enterohepatic recirculation (EHR) to concentrations of irinotecan and metabolites SN-38, SN-38 glucuronide (SN-38G), and aminopentanoic acid (APC). Principal component analysis (PCA) of patient-specific parameter estimates produced measures interpretable along pathways. Nine principal components provided good characterization of the overall variation. Polymorphisms in genes UGT1A1, UGT1A7, and UGT1A9 had strong associations with a component corresponding to the irinotecan-to-SN-38 pathway and SN-38 recirculation and to a component relating to SN-38-to-SN-38G conversion and elimination of SN-38G. The component characterizing irinotecan's compartments was associated with HNF1alpha and ABCC2 polymorphisms. The exploratory analysis with PCA in this pharmacogenetic analysis was able to identify known associations and may have allowed identification of previously uncharacterized functional polymorphisms.

Irinotecan-based chemotherapy in a metastatic colorectal cancer patient under haemodialysis for chronic renal dysfunction: two cases considered

The pharmacokinetics of irinotecan and its metabolites has been widely studied. No pharmacokinetic data, however, are available in haemodialysis patients. We report two clinical cases of severe toxicity, one of which was fatal, in two haemodialysis patients treated with irinotecan for a metastatic colorectal cancer. In case no. 1, M.S., aged 71 years, was treated with first-line FOLFIRI chemotherapy (irinotecan 180 mg/m) for local recurrence with liver metastases of a colon cancer treated with an LV5FU2 protocol as an adjuvant therapy 3 years previously. After the first cycle of irinotecan, the patient presented grade 4 diarrhoea on day 9, then a febrile grade 4 neutropenia on day 14 leading to his death on day 18. In case no. 2, M.D., aged 57 years, was treated successively by radiochemotherapy with an LV5FU2 regimen, then with four cycles of FOLFIRI (irinotecan at 125 mg/m) and finally with the cetuximab/irinotecan combination using the conventional dosage. Febrile neutropenia was observed on day 10 of the first irinotecan infusion with a dose of 180 mg/m and on day 8 of the second infusion with a lower dose of 120 mg/m. The patient's general condition progressively deteriorated with the advancement of the neoplastic disease, which led ultimately to his death. In this patient, plasma concentrations of irinotecan and its metabolite, SN-38, were measured during the course of the first FOLFIRI cycle on day 2 and on day 4, before and after dialysis sessions. The observed results suggest that, although irinotecan is partially dialysable, SN-38 is not. In conclusion, dose recommendations have to be defined in haemodialysis patients with renal dysfunction owing to the potential toxicity of irinotecan in these patients. Special care should be taken in liver metastasis cases owing to the nondialysability of SN-38.

Celecoxib and Mucosal Protection: Translation from an Animal Model to a Phase I Clinical Trial of Celecoxib, Irinotecan, and 5-Fluorouracil

Chemotherapy-induced diarrhea occurs secondary to mucosal inflammation and may be cyclooxygenase-2 mediated. Cyclooxygenase-2 inhibitors may ameliorate chemotherapy-induced mucosal toxicity and enhance its antitumor effect. We investigated this hypothesis in the Ward colorectal cancer rat model and in a phase I clinical study. In the Ward rat model, irinotecan was given daily x 3 or weekly x 4 with or without celecoxib. In the phase I clinical study, we planned to escalate the dose of irinotecan in the FOLFIRI regimen (irinotecan, 5-fluorouracil, and leucovorin) with a fixed dose of celecoxib. Irinotecan was escalated in four dose levels: 180, 200, 220, and 260 mg/m2. Celecoxib was administered as 400 mg, twice daily starting on day 2 of cycle 1. Pharmacokinetics of irinotecan, SN-38, and SN-38G were obtained on days 1 and 14. A standard 3+3 dose escalation scheme was used. Plasma concentrations of irinotecan, SN-38, and SN-38G were measured using high-pressure liquid chromatography. Celecoxib ameliorated diarrhea, weight loss, and lethality and resulted in synergistic antitumor effect in the rat model. Twelve patients with advanced cancers were enrolled and evaluable for dose-limiting toxicity (DLT). Diarrhea was the cause for discontinuation in one. Grade 2 and 3 diarrhea occurred in three and two patients, respectively. One patient had DLT at dose level 2 (grade 3 diarrhea). Two had a DLT at DL3 (G3 emesis and myocardial infarct). Celecoxib had limited influence on the pharmacokinetics of irinotecan in this data set. Maximum tolerated dose of irinotecan in FOLFIRI schedule with celecoxib is 200 mg/m2.

Pharmacogenetics of SLCO1B1 gene and the impact of *1b and *15 haplotypes on irinotecan disposition in Asian cancer patients

To investigate the pharmacogenetic effect of SLCO1B1 *1a, *1b, *5 and *15 polymorphisms on irinotecan disposition in Asian cancer patients. Irinotecan was administered over 90 min either at 100 mg/m on days 1, 8 and 15 with the regimen being repeated every 28 days (N=28) or at 375 mg/m once every three weeks (N=43). Plasma concentrations of irinotecan, 7-ethyl-10-hydroxycamptothecin and 7-ethyl-10-hydroxycamptothecinG were analysed after the first dose of the first cycle and the influence of SLCO1B1 *1a, *1b, *5 and *15 polymorphisms on the disposition of irinotecan and its metabolites were evaluated. Pharmacokinetic parameters were obtained from 71 cancer patients. Genotypic-phenotypic correlates showed the clearance of irinotecan to be 3-fold lower in patients carrying the *15 haplotype than cancer patients with the reference genotype *1a/*1a (9.57+/-3.15 vs. 28.86+/-10.97 l/h/m; P=0.001). The area under the plasma concentration-time curve from zero to infinity and normalized by dose and body surface area (AUC0-nf/dose/BSA) were significantly higher in patients harbouring the *15 haplotype than patients with the reference genotype for irinotecan (39.27+/-15.17 vs. 17.32+/-6.30 h/m; P=0.003) and 7-ethyl-10-hydroxycamptothecin (1.28+/-0.53 vs. 0.69+/-0.32 h/m; P=0.021). The exposure levels to 7-ethyl-10-hydroxycamptothecinG also showed a statistically significant trend among the SLCO1B1 haplotype pairs, being approximately 10-fold lower in patients with *15 haplotype than with patients harbouring the reference genotype (3.57+/-1.95 vs. 12.0+/-6.09 h/m; P=0.016). These findings suggest that (1) SLCO1B1 haplotypes may have a significant influence on the disposition of irinotecan and its metabolites in Asian cancer patients, and (2) patients with SLCO1B1*15 haplotype may be susceptible to increased sensitivity to irinotecan, which may manifest itself either by increased efficacy or toxicity or both owing to the increased exposure levels to 7-ethyl-10-hydroxycamptothecin.

Pharmacogenetic pathway analysis of irinotecan

3073 Background: Irinotecan (IRN), a chemotherapeutic agent for various solid tumors, is the parent compound for SN-38, the active metabolite. The pharmacokinetics (PK) of IRN are complex and associated with variability in clinical outcomes. We sought to learn about the pharmacogenetics (PGx) of IRN by relating the drug’s PK to polymorphisms (SNPs) in drug-metabolizing enzyme and transporter genes potentially relevant to IRN. Methods: We measured concentrations of IRN and 3 metabolites in 86 patients. We fit a novel 7-compartment (15 parameter) model (including enterohepatic circulation) to the concentration data for IRN and metabolites. We applied principal components (PCs) analysis to the patient-specific PK model parameters to reduce the number of outcome variables and to identify appropriate linear combinations of the parameters that relate to IRN’s metabolic pathways. We then analyzed associations between SNPs and PCs to learn about functional polymorphisms. Associations are significant if p < 0.05. Results: We found that 8 PCs accounted for 90% of the total variation in the 15 fitted parameters. PC #1 corresponded to SN-38 in plasma and was associated with SNPs in the CYP3A4, MRP2, and ABCG2 genes. PC #2, the IRN compartments’ PC, was associated with a SNP in OATP-C*1b. The APC PC was associated with a CYP3A5 SNP. The SN-38 glucuronidation PC was associated with UGT1A1 and UGT1A9 polymorphisms. Conclusions: PC analysis is a useful way to reduce the dimension of multiple PK parameters and to produce pathway-specific and interpretable measures relating to PK. The use of PCs in PGx analysis allows identification of potential functional polymorphisms, which can be further evaluated in other data sets. [Table: see text]

Dose-Finding Phase I Clinical and Pharmacokinetic Study of Orally Administered Irinotecan in Patients with Advanced Solid Tumors

The aim of this study was to determine the daily maximum tolerated dose (MTD) and the dose-limiting toxicity for the following administration schedules: oral irinotecan given over 14 days every 3 weeks (part I) and oral irinotecan administered concomitantly with capecitabine over 14 days every 3 weeks (part II). In total, 42 patients (17 male and 25 female) with solid tumors refractory to standard therapy entered the study. Treatment in part I consisted of irinotecan administered orally as semisolid matrix capsules at doses of 25, 30, and 35 mg/m(2) once daily to confirm the MTD of our earlier study. In part II treatment, dose levels for irinotecan combined with capecitabine were 20/1,600, 25/1,600, 30/1,600, and 30/2,000 mg/m(2)/d. The median number of cycles administered per patient was 2.0 (range, 1-12) in part I and 2.0 (range, 1-13) in study part II. Gastrointestinal toxicities (grade 3 nausea, grades 3 and 4 vomiting, and grades 3 and 4 diarrhea) were dose limiting in both parts of the study. There were no grade 3 or 4 hematologic toxicities. The MTD was 30 mg/m(2)/d for irinotecan single agent and 30/1,600 mg/m(2)/d for the combination with capecitabine. Absorption of irinotecan was rapid, and peak concentrations of irinotecan and metabolite SN-38 were reached within 0 to 3 and 1.5 to 4.0 hours, respectively. In conclusion, oral irinotecan and capecitabine is feasible and well tolerated, and the recommended dose for phase II studies is 30/1,600 mg/m(2)/d administered daily for 14 days every 3 weeks.

MDR- and CYP3A4-mediated drug–herbal interactions

According to recent epidemiological reports, almost 40% of American population use complimentary and alternative medicine (CAM) during their lifetime. Patients detected with HIV or cancer often consume herbal products especially St. John's wort (SJW) for antidepressants in combination with prescription medicines. Such self-administered herbal products along with prescribed medicines raise concerns of therapeutic activity due to possible drug–herbal interactions. P-glycoprotein (P-gp) and cytochrome P450 3A4 (CYP3A4) together constitute a highly efficient barrier for many orally absorbed drugs. Available literature, clinical reports and in vitro studies from our laboratory indicate that many drugs and herbal active constituents are substrates for both P-gp and CYP3A4. Results from clinical studies and case reports indicate that self-administered SJW reduce steady state plasma concentrations of amitriptyline, cyclosporine, digoxin, fexofenadine, amprenavir, indonavir, lopinavir, ritonavir, saquinavir, benzodiazepines, theophyline, irinotecan, midazolan and warfarin. This herbal agent has been also reported to cause bleeding and unwanted pregnancies when concomitantly administered with oral contraceptives. Most of these medicinal agents and SJW are substrates for P-gp and/or CYP3A4. In vitro studies from our laboratory suggest that short-term exposure with pure herbal agents such as hypericin, kaempferol and quercetin or extract of SJW resulted in higher uptake or influx of ritonavir and erythromycin. Hypericin, kaempferol and quercetin also caused a remarkable inhibition of cortisol metabolism with the percent intact cortisol values of 64.58%, 89.6% and 90.1%, respectively, during short-term in vitro experiments. Conversely, long-term exposure of herbal agents (hyperforin, kaempferol and quercetin) showed enhanced expression of CYP3A4 mRNA in Caco-2 cells. In another study, we observed that long-term exposure of hypericin, kaempferol, quercetin and silibinin resulted in higher MDR-1 mRNA expression in Caco-2 cells. Therefore, herbs can pharmacokinetically act as inhibitors or inducers. Medicinal agents that are substrates P-gp-mediated efflux and/or CYP-mediated metabolism are likely to be potential candidates for drug–herbal interactions. The duration of exposure of cells/healthy volunteers/animals to herbals appears to be critical for drug–herbal interaction. An increase in plasma drug concentration is possible during concomitant administration of SJW and prescribed drugs. In contrast, prolonged intake of herbal supplement followed by drug administration may result in subtherapeutic concentrations. Therefore, clinical implications of such drug herbal interactions depend on a variety of factors such as dose, frequency and timing of herbal intake, dosing regimen, route of drug administration and therapeutic range. In vitro screening techniques will play a major role in identifying possible herb–drug interactions and thus create a platform for clinical studies to emerge. Mechanisms of drug–herbal interaction have been discussed in this review article.

The in vitro metabolism of irinotecan (CPT‐11) by carboxylesterase and β‐glucuronidase in human colorectal tumours

Irinotecan (CPT-11) is a prodrug that is used to treat metastatic colorectal cancer. It is activated to the topoisomerase poison SN-38 by carboxylesterases. SN-38 is metabolized to its inactive glucuronide, SN-38 glucuronide. The aim of this study was to determine, the reactivation of SN-38 from SN-38 glucuronide by beta-glucuronidase may represent a significant pathway of SN-38 formation. The production of SN-38 from irinotecan and SN-38 glucuronide (2.4, 9.6 and 19.2 microm) was measured in homogenates of human colorectal tumour, and matched normal colon mucosa from 21 patients). The rate of conversion of irinotecan (9.6 microm) was lower in tumour tissue than matched normal colon mucosa samples (0.30+/-0.14 pmol min-1 mg-1 protein and 0.77+/-0.59 pmol min-1 mg-1 protein, respectively; P<0.005). In contrast, no significant difference was observed in beta-glucuronidase activity between tumour and matched normal colon samples (4.56+/-6.9 pmol min-1 mg-1 protein and 3.62+/-2.95 pmol min-1 mg-1 protein, respectively, using 9.6 microm SN-38 glucuronide; P>0.05). beta-Glucuronidase activity in tumour correlated to that observed in matched normal tissue (r2>0.23, P<0.05), whereas this was not the case for carboxylesterase activity. At equal concentrations of irinotecan and SN-38 glucuronide, the rate of beta-glucuronidase-mediated SN-38 production was higher than that formed from irinotecan in both tumour and normal tissue (P<0.05). However, at concentrations that reflect the relative plasma concentrations observed in patients, the rate of SN-38 production via these two pathways was comparable. Tumour beta-glucuronidase may play a significant role in the exposure of tumours to SN-38 in vivo.

Phase I study of an oral formulation of irinotecan administered daily for 14�days every 3�weeks in patients with advanced solid tumours

A phase I study was conducted with oral irinotecan given daily for 14 days every 3 weeks in 45 patients with solid tumours to establish the maximum tolerated dose (MTD), toxicity, preliminary antitumour response and pharmacokinetics. Irinotecan was administered orally as a powder-filled capsule at doses ranging from 7.5 to 40 mg/m2 per day. Tumours were predominantly colorectal (30) together with 10 other gastrointestinal, 2 breast, 2 small cell lung and 1 ovarian. All but three patients had received prior chemotherapy. The median number of administered cycles was 3 (range 1-19). Gastrointestinal toxicities (grade 3 nausea, grade 3/4 vomiting and diarrhoea) and one incidence of grade 3 asthenia were dose limiting. There were no grade 3/4 haematological toxicities. The MTD was 30 mg/m2 per day. There were two documented partial responses, one in a patient with cancer of the small intestine and the other in a patient with colon cancer. Stable disease was seen in 16 patients (35.5%). Peak concentrations of irinotecan and metabolite SN-38 were reached within 2.0-2.4 h. The metabolic ratio of SN-38 AUC to irinotecan AUC was 0.17+/-0.10 (mean+/-SD). The dose recommended for phase II studies is 30 mg/m2 per day administered daily for 14 days every 3 weeks.

Effect of Fractionated Ifosfamide on the Pharmacokinetics of Irinotecan in Pediatric Patients With Osteosarcoma

The combination of irinotecan (daily for 5 days for 2 consecutive weeks) and ifosfamide (daily on days 1 through 3) was investigated in children with osteosarcoma. Irinotecan pharmacokinetic investigations were performed before ifosfamide (day 1), after 3 days of ifosfamide (day 3), and 9 days after the end of ifosfamide (day 12). On day 3, the concentrations of irinotecan's active metabolite, SN-38, were below the limit of quantitation in two patients and were decreased in a third patient. The SN-38 area under the concentration-time curve remained below the day 1 value in two patients on day 12. The reduced area under the curve to the active metabolite SN-38 during ifosfamide therapy predicts a compromised efficacy of irinotecan in this combination.

Effect of gefitinib on the bioavailability of oral irinotecan in children with refractory solid tumors

2012 Background: Gefitinib (ZD1839, Iressa), an oral EGFR tyrosine kinase inhibitor, significantly increased the oral bioavailability of irinotecan in preclinical murine pharmacokinetic studies. Based on this observation, we are conducting a study of the combination of gefitinib and irinotecan in children with refractory solid tumors with the objective to evaluate the effect of gefitinib on irinotecan bioavailability. Methods: Patients receive gefitinib orally continuously at a dose of 112.5 mg/m2/d or 150 mg/m2/d. On day 21 of gefitinib, patients receive intravenous (IV) irinotecan (15 mg/m2) and on day 22 of gefitinib, patients receive the same dose of the IV formulation of irinotecan orally in Cran-Grape juice. Serial plasma samples were collected on day 21 and day 22, and concentrations of irinotecan, SN-38 and SN-38 glucuronide lactone were measured using a validated HPLC assay. Pharmacokinetic analysis was performed using non-linear mixed effects modeling (NONMEM). Included in the analysis were IV and oral pharmacokinetic data from 4 patients receiving the combination of irinotecan and gefitinib, along with IV and oral data from 31 children receiving irinotecan alone at doses of 15–75 mg/m2 in a previously reported Phase I study (POCPT). Results: The bioavailability of irinotecan lactone increased significantly (p<0.001) from a population average (range) of 8% (1–34%) without gefitinib (n=31) to 56% (25–72%) with gefitinib (n=4). Furthermore, the SN-38 AUC following an oral irinotecan dose of 15 mg/m2 in patients receiving gefitinib was significantly higher [median (range) AUC 83.9 ng*h/mL (64.8–189.4 ng*h/mL) vs 4.0 ng*h/mL (3.9–20.3 ng*h/mL), p<0.05] when compared to those of 3 patients on POCPT receiving the same oral irinotecan dose. Conclusion: These data suggest that gefitinib increases the bioavailability of irinotecan, resulting in an increased systemic exposure to SN-38, the active metabolite. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca; NIH; Amer Lebanese Syrian Associated Charities