Plasma Concentrations Of SN-38 Research Articles

Opioid-induced microbial dysbiosis disrupts irinotecan (CPT-11) metabolism and increases gastrointestinal toxicity in a murine model.

Opioids are commonly used for the management of cancer-associated pain and chemotherapy-induced diarrhoea. The chemotherapeutic irinotecan (CPT-11) causes severe gastrointestinal (GI) toxicity due to deconjugation of inactive metabolite SN-38 glucuronide (SN-38G) by bacterial β-glucuronidases to the active 7-ethyl-10-hydroxycamptothecin (SN-38). Opioids are known to cause gut microbial dysbiosis, this study evaluated whether CPT-11 anti-tumour efficacy and GI toxicity are exacerbated by opioid co-administration. Eight-week-old C57BL/6 male mice were co-administration with CPT-11 ± opioid. 16S rRNA sequencing was used for gut microbiome analysis. LC-MS analyses of plasma and intestinal extracts were performed to investigate the pharmacokinetic profile of CPT-11. Histological analysis and quantitative real-time polymerase chain reaction were used to determine the severity of intestinal tissue damage. Human liver microsome In vitro assay was performed to confirm the effects of opioids on CPT-11 metabolism. Gut microbiome analysis showed that morphine treatment induced enrichment of β-glucuronidase-producing bacteria in the intestines of CPT-11-treated mice, resulting in SN-38 accumulation and exacerbation of GI toxicity in the small intestine. Oral administration of both antibiotics and glucuronidase inhibitor protected mice against GI toxicity induced with CPT-11 and morphine co-administration, implicating a microbiome-dependent mechanism. Additionally, morphine and loperamide decreased the plasma concentration of SN-38 and compromised CPT-11 anti-tumour efficacy, this seemed to be microbiome independent. Gut microbiota play a significant role in opioid and chemotherapeutic agent drug-drug interactions. Inhibition of gut microbial glucuronidase may also prevent adverse GI effects of CPT-11 in patients on opioids.

Effect of UGT1A1, CYP3A and CES Activities on the Pharmacokinetics of Irinotecan and its Metabolites in Patients with UGT1A1 Gene Polymorphisms.

Irinotecan (CPT-11) is metabolized to an active metabolite 7-ethyl-10-hydroxycamptothecin (SN-38) by carboxylesterase (CES). SN-38 is then converted to the inactive metabolite SN-38 glucuronide (SN-38G) by glucuronosyltransferase 1A1 (UGT1A1). Genetic polymorphisms in UGT1A1 have been associated with altered SN-38 pharmacokinetics, which increase the risk of toxicity in patients. CPT-11 is also converted to 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]carbonyloxycamptothecin (APC) and 7-ethyl-10-(4-amino-1-piperidino) carbonyloxycamptothecin (NPC) by cytochrome P450 3A (CYP3A), and this route also affects the plasma concentration of SN-38. We evaluated the activities of UGT1A1, CYP3A, and CES and the factors affecting the pharmacokinetics of plasma SN-38 in patients with UGT1A1 gene polymorphisms. Three male patients aged 56, 65, and 49 years were recruited for the analysis. All patients had pancreatic cancer, received FOLFIRINOX, and had UGT1A1*6/*6 (patients 1 and 3) or *6/*28 (patient 2) genetic polymorphisms. The rate constants for evaluating the enzyme activity were determined from the measured plasma concentration of CPT-11 and its metabolites using a two-compartment model by WinNonlin. The area under the plasma concentration-time curve (AUC) of SN-38 was patient 1 > patient 2 > patient 3. The rate constants obtained from the model analysis indicated the respective enzyme activities of UGT1A1 (k57), CYP3A (k13 + k19), and CES (k15). The order of values for UGT1A1 activity was patient 2 > patient 3 > patient 1. Since UGT1A1 activity was low in patient 1 with a high AUC of SN-38, it can be said that the increase in plasma concentration was due to a decrease in UGT1A1 activity. Conversely, the order of values for CYP3A and CES activities was patient 3 > patient 1 > patient 2 and patient 2 > patient 1 > patient 3, respectively. Patient 3 had the lowest AUC of SN-38, caused by a lower level of CES activity and increased CYP3A activity. In this study, we indicated that the plasma AUC of SN-38 and AUC ratio of SN-38G/SN-38 may depend on changes in the activities of CYP3A, CES, and UGT1A1. Using pharmacokinetic analysis, it is possible to directly evaluate enzyme activity and consider what kind of enzyme variation causes the increase in the AUC of SN-38.

CPT11 with P-glycoprotein/CYP 3A4 dual-function inhibitor by self-nanoemulsifying nanoemulsion combined with gastroretentive technology to enhance the oral bioavailability and therapeutic efficacy against pancreatic adenocarcinomas

Therapeutic efficacies of orally administrated hydrophobic chemodrugs are decreased by poor water solubilities and reduced oral bioavailabilities by P-glycoprotein (P-gp) and CYP450. In this study, CPT11 alone or combined with dual-function inhibitors (baicalein (BA) silymarin (SM), glycyrrhizic acid (GA), and glycyrrhetinic acid (GLA)) of P-gp and CYP450 loaded in a lecithin-based self-nanoemulsifying nanoemulsion preconcentrate (LBSNENP) to improve the solubility and inhibit the elimination by P-gp and CYP450. Results revealed that the LBSNENP composed of Capryol 90, lecithin/Tween 80/Cremophor EL, and propylene glycol at a weight ratio of 18:58:24 (designated PC90C10P0) was optimally selected. Encapsulating CPT11 with PEO-7000K in PC90C10P10/30 further enhanced the resultant hydrogel to be gastro-retainable and to release CPT11 in a sustained manner. Pharmacokinetic study of CPT11-loaded PC90C10P0 administered orally revealed an absolute bioavailability (FAB, vs. intravenous CPT11) of 7.8 ± 1.01% and a relative bioavailability (FRB1, vs. oral solution of CPT11) of 70.7 ± 8.6% with a longer half-life (T 1/2) and mean residence time (MRT). Among the dual-function inhibitors, SM was shown to be the most influential in increasing the oral bioavailability of CPT11. SM also increased the plasma concentration of the SN-38 active metabolite, which formed from the enhanced plasma concentration of CPT11. It is concluded that treatment with CPT11 loaded in PC90C10P0 with or without solubilization with SM could expose tumors to higher plasma concentrations of both CPT11 and SN-38 leading to enhancement of tumor growth inhibition with no signs of adverse effects.

Acceleration of carboxylesterase-mediated activation of irinotecan to SN-38 by serum from patients with end-stage kidney disease.

Pharmacokinetics and pharmacodynamics of irinotecan have been reported to be altered in cancer patients with end-stage kidney disease (ESKD). Carboxylesterase (CES) has an important role in metabolism of irinotecan to its active metabolite, SN-38, in human liver. The purpose of the present study was to investigate whether CES activity was altered in ESKD patients. The present study investigated the effects of uremic serum, uremic toxins, and fatty acids on the hydrolysis of irinotecan and a typical CES substrate, p-nitrophenyl acetate (PNPA), in human liver microsomes. Normal and uremic serum samples were deproteinized by treatment with methanol were used in the present study. The present study showed that both normal and uremic serum significantly inhibited CES-mediated metabolism of both irinotecan and PNPA. The inhibition by uremic serum was weaker than that by normal serum, suggesting that CES activity may be higher in ESKD patients. Although four uremic toxins did not affect PNPA metabolism, arachidonic acid inhibited it. There was no difference in inhibitory effect of PNPA metabolism between both mixtures of seven fatty acids used at concentrations equivalent to those present in 10% normal or uremic serum. Interestingly, those mixtures had a more pronounced effect than either 10% normal or uremic serum. The present study showed that the inhibition of CES activity by uremic serum was weaker than that by normal serum, suggesting that an increase in maximum plasma concentration of SN-38 in cancer patients with ESKD can be attributed to an accelerated CES-mediated irinotecan hydrolysis.

P-glycoprotein-dependent pharmacokinetics of irinotecan and its active metabolite, SN-38 in rats: Effect of verapamil

We have recently demonstrated that the oral bioavailability of irinotecan (80 mg/kg) can be increased at least 7-fold by co-administration of the P-gp blocker verapamil (25 mg/kg, Oral). As a result, co-treatment with P-gp inhibitor could be a useful strategy for bioavailability enhancement. However, in view of narrow therapeutic index, the co-administration of irinotecan and verapamil may result in unanticipated toxicities. Therefore, dose optimisation studies of irinotecan were performed when it is given in conjunction with a P-gp inhibitor. For dose optimization study, the bioavailability and pharmacokinetic parameters were studied in rats after oral administration of irinotecan at three doses (i.e. 20, 40 and 80 mg/kg) alone and in combination with verapamil (25 mg/kg, oral). The area under the plasma-concentration time curve (AUC) of irinotecan at 20, 40 and 80 mg/kg was 3.51 ± 1.20, 8.81 ± 1.93 and 14.03 ± 2.18 h µg/ml, respectively which after treatment with verapamil, increased dose dependently to 7.84 ± 1.20, 19.94 ± 2.39 and 61.71 ± 15.0 h µg/ml, respectively. In addition to irinotecan, plasma concentrations of SN-38, one of the major active metabolite of irinotecan, were also monitored. The less than proportional increase in SN-38 AUC from 20 to 80 mg/kg is consistent with the saturation of carboxylesterase. Our results indicate that oral drug treatment of irinotecan in presence of temporary P-gp inhibition could be as equally safe and effective as intravenous administration. Nevertheless, safe P-gp inhibitors need to be identified as alternatives to verapamil for development of efficacious oral irinotecan formulations.

483P - Change in Plasma Protein Binding of Sn-38, an Active Metabolite of Irinotecan, in Cancer Patients with Severe Renal Failure (Srf)

ABSTRACT Aim: Our previous clinical study revealed that total plasma concentration of SN-38 was higher in cancer patients with SRF than those with normal kidney (NK), although SN-38 is mainly eliminated in the liver. Because SN-38 can bind to plasma protein, we hypothesized the possible increase in unbound fraction of SN-38 and area under the unbound plasma concentration-time curve (AUCu) caused by inhibition of plasma protein binding by uremic toxin(s) in patients with SRF. Methods: Total and unbound plasma concentrations of SN-38 in the cancer patients treated with 100 mg/m2 irinotecan alone were examined at 1 h after the end of irinotecan infusion to obtain unbound fraction of SN-38. Ex vivo analyses for SN-38 protein binding were performed with plasma samples obtained from 4 respective groups of patients (10-12 for each group) categorized by their renal function, estimated glomerular filtration (eGFR) 60 mL/min. The inhibition by 22 uremic toxins known to bind to plasma protein of SN-38 protein binding was also examined. Results: Unbound fraction of SN-38 in 3 cancer patients with SRF (0.023 ± 0.0060) was significantly higher than that in 5 of those with NK (0.0089 ± 0.0043) (P = 0.0339). AUCu in patients with SRF and those with NK were 0.030 ± 0.015 and 0.0069 ± 0.0043 µM·h, respectively (P = 0.0253). Ex vivo experiments revealed that unbound fractions of SN-38 was inversely correlated with eGFR (Spearman's rank correlation coefficient, -0.5207; P = 0.0003). The unbound fractions in patients with eGFR Conclusions: Unbound concentrations of SN-38 were higher in patients with SRF than those with NK. The inhibition of SN-38 protein binding by CMPF is a possible mechanism. Disclosure: All authors have declared no conflicts of interest.

Analysis of UGT1A1*28 genotype and SN-38 pharmacokinetics for irinotecan-based chemotherapy in patients with advanced colorectal cancer: results from a multicenter, retrospective study in Shanghai

Background The UGT1A1*28 polymorphism, although closely linked with CPT-11-related adverse effects, cannot be used alone to guide individualized treatment decisions. However, CPT-11 dosage can be adjusted according to measured SN-38 pharmacokinetics. Our study is designed to investigate whether there is a relationship between SN-38 peak or valley concentrations and efficacy or adverse effects of CPT-11-based chemotherapy. We retrospectively studied 98 patients treated with advanced colorectal cancer in various UGT1A1*28 genotype groups (mainly (TA)6/(TA)6 and (TA)6/(TA)7 genotypes) treated with CPT-11 as first-line chemotherapy in Shanghai.MethodsOne hundred and sixty-four advanced colorectal cancer patients were enrolled. To understand differences in genotype expression, the frequency of UGT1A1*28 thymine–adenine (TA) repeats in TATA box arrangement was assessed by PCR with genomic DNA extracted from peripheral blood. For ninety-eight cases with the (TA)6/(TA)6 and (TA)6/(TA)7 genotypes treated with CPT-11 as first-line chemotherapy, the plasma concentration of SN-38 was detected by HPLC 1.5 and 49 h after CPT-11 infusion. Efficacy and adverse effects were observed subsequently, and the relationship between SN-38 plasma concentration and efficacy or adverse effects within genotype groups, as well as differences in efficacy and adverse effects between (TA)6/(TA)6 and (TA)6/(TA)7 genotypes were analyzed statistically.ResultsOne hundred and fourteen patients (69.51 %) were identified with the (TA)6/(TA)6 genotype, forty-eight patients (29.27 %) with the (TA)6/(TA)7 genotype, and two patients (1.22 %) with the (TA)7/(TA)7 genotype. The average peak and valley concentrations of SN-38 after CPT-11 infusion and plasma bilirubin average levels before and after CPT-11 treatment in the (TA)6/(TA)7 genotype group were all higher than those in (TA)6/(TA)6 group, and the difference was statistically significant (p = 0.00). Stepwise regression analysis showed that SN-38 peak and valley concentration was correlated with PFS in the (TA)6/(TA)6 genotype. In the (TA)6/(TA)7 group, SN-38 peak concentration was correlated with CPT-11 starting dose and OS, valley concentration correlated with plasma bilirubin levels before CPT-11 treatment, delayed diarrhea, and OS. For the (TA)6/(TA)6 genotype, mPFS of the SN-38 peak concentration >43.2 ng/ml subgroup was significantly longer than that of ≤43.2 ng/ml subgroup (8.0 ± 0.35 vs. 6.5 ± 0.79 months, χ 2 = 17.18, p = 0.00) with a relatively high incidence of Grade I/II° myelosuppression; for the (TA)6/(TA)7 genotype, there was no significant difference in mOS between the SN-38 valley concentration >16.83 ng/ml and ≤16.83 subgroups (17.3 ± 0.45 vs. 18.8 ± 0.50 months, χ 2 = 1.38, p = 0.24), but the former had a higher incidence of Grade III/IV° mucositis and delayed diarrhea. For 2 (TA)7/(TA)7 cases, although 25 % dose reduction of CPT-11, which is calculated according to body surface area, Grade IV° bone marrow suppression and Grade III° delayed diarrhea still occurred after CPT-11 treatment, though both adverse effects resolved and did not recur again after a 50 % dose reduction.ConclusionThe (TA)6/(TA)6 genotype and (TA)6/(TA)7 genotype accounted for the most, and (TA)7/(TA)7 genotype only account for a very small portion of advanced colorectal cancer patients in Shanghai. For the (TA)6/(TA)6 genotype, CPT-11 dosage can be increased gradually to improve efficacy for patients with SN-38 peak concentration ≤43.2 ng/ml after CPT-11 infusion; and for (TA)6/(TA)7 genotype patients, CPT-11 dosage may be lowered appropriately to reduce serious adverse effects such as bone marrow suppression and delayed diarrhea without affecting the efficacy for those with SN-38 valley concentration >16.83 ng/ml. For (TA)7/(TA)7 genotype patients, adverse effects should be closely observed after treatment even if CPT-11 dosage has been reduced.

ChemInform Abstract: Genetic Polymorphisms of SLCO1B1 for Drug Pharmacokinetics and Its Clinical Implications

AbstractReview: 30 refs.

Correlation between plasma concentration ratios of SN-38 glucuronide and SN-38 and neutropenia induction in patients with colorectal cancer and wild-type UGT1A1 gene

In irinotecan (CPT-11)-based chemotherapy, neutropenia and diarrhea are often induced. In the present study, the clinical significance of the concentration ratios of 7-ethyl-10-hydroxycamptothecin (SN-38) glucuronide (SN-38G) and SN-38 in the plasma in predicting CPT-11-induced neutropenia was examined. A total of 17 patients with colorectal cancer and wild-type UDP-glucuronosyltransferase (UGT)1A1 gene were enrolled and treated with CPT-11 as part of the FOLFIRI regimen [CPT-11 and fluorouracil (5-FU)]. Blood was taken exactly 15 min following a 2-h continuous infusion of CPT-11. Plasma concentrations of SN-38, SN-38G and CPT-11 were determined by a modified high-performance liquid chromatography (HPLC) method. The median, maximum and minimum values of plasma SN-38G/SN-38 ratios were 4.25, 7.09 and 1.03, respectively, indicating that UGT activities are variable among patients with the wild-type UGT1A1 gene. The plasma SN-38G/SN-38 ratios decreased with an increase in the trial numbers of chemotherapy (r=0.741, p=0.000669), suggesting that CPT-11 treatment suppresses UGT activity, and the low plasma SN-38G/SN-38 ratios resulted in the induction of greater neutropenia. However, in this analysis, 2 clearly separated regression lines were observed between plasma SN-38G/SN-38 ratios and neutropenia induction. In conclusion, UGT activity involved in SN-38 metabolism is variable among patients with the wild-type UGT1A1 gene, and each CPT-11 treatment suppresses UGT activity. One-point determination of the plasma SN-38G/SN-38 ratio may provide indications for the prediction of CPT-11-induced neutropenia and adjustment of the optimal dose, although further studies are required.

Genetic Polymorphisms of <i>SLCO1B1</i> for Drug Pharmacokinetics and Its Clinical Implications

Various drug transporters are selectively expressed in single or multiple tissues, such as the intestine, liver and kidney, where these transporters play various roles in drug absorption, distribution and excretion. Genetic polymorphisms in drug transporters as well as drug-metabolizing enzymes are associated with interindividual differences in drug disposition, efficacy and toxicity. Organic anion transporting polypeptide 1B1 (OATP1B1, gene SLCO1B1) is expressed on the basolateral membrane of hepatocytes and can facilitate hepatic uptake of certain clinically relevant drugs such as statins except for fluvastatin, angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists, antidiabetic drug (repaglinide) and anticancer drugs (SN-38 and methotrexate). Some single nucleotide polymorphisms or haplotypes of the SLCO1B1 gene have been identified and demonstrated to have functional significance for transporter activity. For examples, the SLCO1B1*15 haplotype (or 521T>C genotype) results in decreased uptake activity of SN-38 from systemic circulation, leading to increased plasma concentration of SN-38 and an enhanced risk of neutropenia. This review focuses on the impact of genetic polymorphisms of the SLCO1B1 gene on transport activity, and implications for the clinical efficacy and toxicity of clinically useful drugs.

Irinotecan hydrochloride (CPT-11) in dialysis patients with gastrointestinal cancer.

We investigated changes in drug disposition and toxicities with CPT-11 in 15 dialysis patients with gastrointestinal cancers to clarify whether CPT-11 could be administered safely in such patients. For comparison, the same parameters were also investigated in 10 cancer patients not undergoing dialysis. Items investigated included (1) plasma concentrations of SN-38, SN-38G and CPT-11 at 0, 1, 12, 24, 36, 48 and 72 h after administration, together with a comparison of mean AUC values for 3 dose levels of CPT-11 (50, 60 and 70 mg/m2) in dialysis patients and controls; and (2) occurrence of adverse events. Several findings emerged from this study: (1) No significant difference was observed in the AUC for SN-38 or CPT-11 between the dialysis and control groups; (2) The AUC for SN-38G at each dose was significantly higher in dialysis patients; and (3) Grade 1-4 leucopenia was observed in 11 of the dialysis patients. One patient developed grade 4 leucopenia and died due to sepsis. Anorexia, diarrhea, nausea, alopecia and interstitial pneumonia occurred in 6 dialysis patients. We found changes in drug dispositions of CPT-11, SN-38 and SN-38G in dialysis patients, suggesting that hepatic excretion, especially that of SN-38G, was increased. No significant difference in occurrence of adverse events was observed between the 2 groups. This indicates that CPT-11 can be administered safely in patients on dialysis.

Co-administration of irinotecan decreases the plasma concentration of an active metabolite of amrubicin, amrubicinol in rats

This study examined the pharmacokinetics of irinotecan (CPT-11), active metabolite 7-ethyl-10-hydroxycamptothecin (SN-38), SN-38 glucuronide (SN-38G) amrubicin (AMR), and active metabolite amrubicinol (AMR-OH) after intravenous administration of this combination therapy in rats. Male Sprague-Dawley rats were treated with 10 mg/kg CPT-11 with 10 mg/kg AMR. AMR, AMR-OH, CPT-11, SN-38 and SN-38G were measured in plasma, bile, and tissues using high-performance liquid chromatography. Co-administration of CPT-11 resulted in a significant decrease in plasma concentrations and area under the curves (AUC) of AMR-OH compared with treatment with AMR alone. On the other hand, co-administration of AMR resulted in a slight increase in the initial plasma concentration of SN-38; however, there were no differences in AUC values in CPT-11 and SN-38. The cumulative biliary excretion curves of AMR, CPT-11, and their active metabolites were not changed. CPT-11 inhibited the conversion of AMR to AMR-OH in rat cytosolic fractions. CPT-11 did not affect the pharmacokinetic of AMR but decreased the plasma concentration of AMR-OH and might affect the formation of AMR-OH from AMR in hepatocytes.

Effects of Oral Administration of S-1 on the Pharmacokinetics of SN-38, Irinotecan Active Metabolite, in Patients With Advanced Colorectal Cancer

Previous studies have assessed the efficacy and safety of combined treatment with irinotecan (7-ethyl-10-[4-[1-piperidino]-1-piperidino]carbonyloxycamptothecin, CPT-11) and S-1, containing tegafur, a prodrug of 5-fluorouracil, in the treatment of colorectal and gastric cancer. The objective of this study was to describe the interaction between CPT-11 and S-1 in 4 patients with colorectal cancer. Coadministration of S-1 changed the pharmacokinetic behavior of CPT-11 and its metabolites. In particular, maximum plasma concentration (Cmax) and area under the plasma concentration curve (AUC) of 7-ethyl-10-hydroxycampothecin (SN-38) was markedly decreased by coadministration of S-1. For SN-38, the median ratio of Cmax and AUC with S-1 to those without S-1 was median 0.34 (range 0.24-0.78) and 0.56 (range 0.23-0.68), respectively. A markedly difference in drug interaction among individual patients was observed. We conclude that the plasma concentration of SN-38 was decreased by oral administration of S-1 in patients with colorectal cancer. This observation might be important for clinical decisions regarding combination therapy.

Phase I dose-finding and pharmacokinetic trial of irinotecan (CPT-11) administered every two weeks

This trial was performed to determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and pharmacokinetic profile of irinotecan (CPT-11) when administered on a once-every-2-week schedule. CPT-11 was administered to successive cohorts of patients at progressively increasing starting doses ranging from 125 to 350 mg/m2. The MTD and DLTs were determined both for CPT-11 alone and for CPT-11 followed by filgrastim (G-CSF). Plasma samples were obtained during the first 24 hours after initial dosing to determine the total concentrations (lactone + carboxylate forms) of CPT-11; of the active metabolite SN-38; and of SN-38 glucuronide (SN-38G). Neutropenic fever was the DLT for CPT-11 at the 300 mg/m2 dose level. When G-CSF was added, dose escalation beyond 350 mg/m2 could not be achieved due to grade 2-3 toxicities that prevented on-time retreatment with CPT-11. Severe, late diarrhea was uncommon on this schedule. Peak plasma concentrations of SN-38 and SN-38G were approximately 2.5% and 4.2% of the corresponding peak plasma concentration for CPT-II, respectively The harmonic mean terminal half-lives for CPT-11, SN-38, and SN-38G were 7.1 hours, 13.4 hours, and 12.7 hours, respectively. No predictive correlation was observed between CPT-11 or SN-38 peak concentration or AUC and first-cycle diarrhea, neutropenia, nausea, or vomiting. Across the range of doses studied, mean CPT-11 clearance was 14.0 +/- 4.0 l/h/m2 and volume of distribution was 146 +/- 45.9 l/m2. When administered every two weeks, the recommended phase II starting dose of CPT-11 is 250 mg/m2 when given alone and 300 mg/m2 when supported by G-CSF. This every-two-week regimen offers a tolerable and active alternative to weekly or every-three-week single-agent CPT-11 therapy.

Relationship between the Pharmacokinetics of Irinotecan and Diarrhea during Combination Chemotherapy with Cisplatin

Two phase I trials of irinotecan (CPT‐11) in combination with cisplatin were conducted. In both cases, the dose‐limiting toxicities were leukopenia and/or diarrhea. During these trials the pharmacokinetics of CPT‐11 and its active metabolite, 7‐ethyl‐10‐hydroxycamptothecin (SN‐38), were investigated to evaluate the relationship between pharmacokinetic parameters and diarrhea, since this is an unpredictable and severe toxicity of combination chemotherapy using CPT‐11 and cisplatin. Twenty‐three previously untreated patients with advanced lung cancer were evaluated in the pharmacokinetic study. Ten patients received CPT‐11 at 80 or 90 mg/m2 plus cisplatin at 60 mg/m2. The other 13 patients received CPT‐11 at 80 or 90 mg/m2 plus cisplatin at 80 mg/m2 with the granulocyte colony‐stimulating factor support (2 μg/kg × 16 days). CPT‐11 was given as a 90‐min intravenous infusion on days 1, 8, and 15. Cisplatin was given on day 1. The pharmacokinetics of CPT‐11 and SN‐38 were analyzed on day 8 during the first course of treatment. The maximum tolerated dose of CPT‐11 was 90 mg/m2 in both phase I trials. The severity of diarrhea was best correlated with the peak plasma concentration of SN‐38 among the pharmacokinetic parameters tested. In addition, patients with a plasma SN‐38 level > 12.4 ng/ml at 1.75 h after the start of CPT‐11 infusion had a higher incidence of Eastern Cooperative Oncology Group grade 3–4 diarrhea than those with a lower SN‐38 level (P=0.0003). Stepwise logistic regression analysis identified the SN‐38 concentration as a significant contributor to the development of diarrhea (P=0.0021). We conclude that there is a clear relationship between the SN‐38 concentration and diarrhea during chemotherapy with CPT‐11 plus cisplatin.

Phase I and pharmacologic study of irinotecan in combination with cisplatin for advanced lung cancer

We have conducted a Phase I trial to determine the maximum tolerated dose of CPT-11 together with a fixed dose of cisplatin in patients with advanced lung cancer, and the dose-limiting toxicities of this combination. Fourteen previously untreated patients with stage IIIB or IV disease were treated with CPT-11 (90-min intravenous infusion on days 1, 8, and 15) plus cisplatin (60 mg m-2, intravenously on day 1). The starting dose of CPT-11 was 60 mg m-2, and diarrhea was the dose-limiting toxicity at the 90 mg m-2 dose level. All three patients (all four cycles) given 90 mg m-2 of CPT-11 experienced grade 3 diarrhea. Hematologic toxicity was relatively mild. Elimination of CPT-11 was biphasic with a mean (+/- s.d.) beta half-life of 11.36 +/- 7.26 h. The mean terminal half-life of the major metabolite (7-ethyl-10-hydroxycamptothecin; SN-38) was 22.13 +/- 13.28 (s.d.) h, and modest escalation of the CPT-11 dose from 80 mg m-2 to 90 mg m-2 resulted in a statistically significant apparent increase in the plasma concentrations of SN-38. There were one complete response (7%) and five partial responses (36%) among the 14 patients for an overall response rate of 43%. The recommended dose for Phase II studies is 80 mg m-2 of CPT-11 and 60 mg m-2 of cisplatin.