A validated HPLC-MS/MS method for determination of simmitecan and its metabolite chimmitecan in human plasma and its application to a pharmacokinetic study in Chinese patients with advanced solid tumor.

Simmitecan is a new ester anticancer prodrug which can exert the antiproliferation activity through its active metabolite, chimmitecan. In the current study, a simple and reliable liquid chromatography-tandem mass spectrometry method was developed and validated for simultaneous determination of simmitecan and chimmitecan in human plasma. Both irinotecan and 7-ethyl-10-hydroxycamptothecin were used as the internal standards. Plasma samples were protein precipitated by acetonitrile (0.2% formic acid, v/v) and processed samples were chromatographed on a Hypersil GOLDTM C18 column (100 × 4.6 mm, i.d. 3.0 µm) with acetonitrile and 10 mM ammonium acetate (0.1% formic acid, v/v) as the mobile phase. The calibration curves showed good linearity (R ≥ 0.99) over the concentration range of 1-500 ng/mL and 0.25-125 ng/mL for simmitecan and chimmitecan, respectively. Intra- and inter-run precisions (CV%) were ≤10.2% for simmitecan and ≤12.1% for chimmitecan. The accuracies were 99.4-103.5% for simmitecan and 95.4-103.5% for chimmitecan. This method was further successfully applied to a pharmacokinetic study of simmitecan in Chinese advanced solid cancer patients after administration of simmitecan hydrochloride injection.

Population Pharmacokinetics of Trastuzumab Deruxtecan in Patients With HER2-Positive Breast Cancer and Other Solid Tumors.

Trastuzumab deruxtecan (DS-8201) is a human epidermal growth factor receptor 2 (HER2)-targeting antibody-drug conjugate with a novel enzyme-cleavable linker, a topoisomerase I inhibitor payload, and a drug-to-antibody ratio of ≈ 8. We have characterized the population pharmacokinetics (PK) of trastuzumab deruxtecan and released drug (topoisomerase I inhibitor) in patients with HER2-positive breast cancer or other solid tumor malignancies. This analysis includes pooled data from five clinical studies with 639 patients. Trastuzumab deruxtecan doses ranged from 0.8 to 8.0 mg/kg every 3 weeks. Serum concentrations of trastuzumab deruxtecan and released drug were analyzed using a sequential two-step approach, with the nonlinear mixed-effects modeling methods. Covariate assessment was based upon stepwise forward-addition and backward-elimination process, followed by both univariate and multivariate analysis quantifying their impact on steady-state exposure of trastuzumab deruxtecan and released drug. A two-compartment model with linear elimination best described PK profiles of intact trastuzumab deruxtecan, while a one-compartment model with time-varying release-rate constant and linear elimination described released-drug PK profiles. Statistically significant covariates (country, tumor size, sex, formulation, age, body weight, albumin, total bilirubin, and aspartate aminotransferase) resulted in < 20% change in steady-state area under the concentration-time curve of trastuzumab deruxtecan and released drug, except for increased body weight (95th percentile, 86 kg) and decreased albumin (5th percentile, 31 g/L). Analysis of patients stratified by country, race, renal function, and hepatic function found no clinically meaningful differences in steady-state exposure of intact trastuzumab deruxtecan or released drug. Overall, results suggest that no dose adjustment based on tested covariates or in specific patient populations is warranted.

Measurement of NLG207 (formerly CRLX101) nanoparticle-bound and released camptothecin in human plasma.

Camptothecin (CPT), a potent inhibitor of topoisomerase I and HIF-1α, failed to demonstrate utility as an anti-cancer agent in early clinical trial investigations, primarily due to limited clinical activity and significant toxicity attributable to unfavorable physicochemical properties (e.g. low plasma solubility, pH-labile lactone ring). NLG207 (formerly CRLX101), a nanoparticle-drug conjugate (NDC) of CPT designed to optimize plasma pharmacokinetics and facilitate drug delivery to tumors, is included as part of combination treatment in two Phase II clinical trials ongoing at the National Cancer Institute (NCT02769962 and NCT03531827). To better understand the potential for drug-drug interactions and to correlate drug exposure to clinical outcomes and pharmacodynamic biomarkers, a robust analytical method was developed to measure CPT in human plasma. Two sample processing methods were developed to quantify both NDC-bound CPT and free CPT, primarily via alteration of pH conditions. A solid-phase extraction recovered >79 % of CPT prior to quantitative analysis by ultra HPLC-MS/MS. Dynamic calibration ranges of 10 to 10,000 ng/mL and 1 to 1000 ng/mL for total and free CPT, respectively were utilized to capture clinical ranges. NLG207 NDCs demonstrated significant rates of CPT release in human plasma at room temperature after 2 h but were shown to be stable at 4 °C for 24 h and through 4 freeze/thaw cycles. This assay was used to quantitate CPT plasma concentrations in clinical samples to confirm clinical utility following NLG207 treatment in subjects with advanced prostate cancer.

Reduction-sensitive poly(ethylene glycol)-polypeptide conjugate micelles for highly efficient intracellular delivery and enhanced antitumor efficacy of hydroxycamptothecin.

The non-specific biodistribution of traditional chemotherapeutic drugs against tumors is the key factor that causes systemic toxicity and hinders their clinical application. In this study, a reduction-sensitive polymer conjugate micelle was manufactured to achieve tumor-specific targeting, reduce toxic side-effects and improve anti-tumor activity of a natural anti-cancer drug, hydroxycamptothecin (HCPT). Therefore, HCPT was conjugated with methoxy-poly(ethylene glycol)-poly(ß-benzyl-L-aspartate) (mPEG-PBLA) by a disulfide bond or succinate bond for the first time to obtain the mPEG-PBLA-SS-HCPT (PPSH) and mPEG-PBLA-CC-HCPT (PPCH) that would form micelles after high-speed agitation and dialysis. The PPSH micelles showed an average particle size of 126.3 nm, a low polydispersity index of 0.209, and a negative surface charge of -21.1 mV zeta potential. Transmission electron microscopy showed the PPSH micelles to have spherical morphology. PPSH had a low critical micelle concentration of 1.29 µg ml-1 with high dilution stability, storage stability and reproducibility. Moreover, the particle size of the PPSH micelles had no significant change after incubation with rat plasma for 72 h, probably resulting in high long circulation in the blood. The PPSH micelles showed significant reduction sensitivity to glutathione. Their sizes increased by 403.2 nm after 24 h post-incubation, and 87.6% drug release was achieved 48 h post-incubation with 40 mM glutathione solutions. The PPSH micelles showed stronger inhibition of HepG2 cells in vitro and growth of H-22 tumor in vivo than the PPCH and HCPT solutions after intravenous injection. The accumulation of PPSH micelles in the tumor tissue contributed to the high anti-tumor effect with little side-effect on the normal tissues. The reduction-sensitive PPSH micelles were a promising carrier of HCPT and other poorly soluble anti-cancer drugs.

Pharmacokinetics of 10-hydroxycamptothecin-tetrandrine liposome complexes in rat by a simple and sensitive ultra-high performance liquid chromatography with tandem mass spectrometry.

10-Hydroxycamptothecin is a drug to cure various cancers. However, the 10-hydroxycamptothecin cannot be widely applied in clinics due to fast elimination and resistance of various cancers to the drug. Nevertheless, co-treatment with tetrandine is known to reverse the resistance of multi-drug resistant cancers, and may present an effective strategy to improve the efficacy of 10-hydroxycamptothecin. In order to improve the bioavailability and prolong the treatment time of the 10-hydroxycamptothecin in vivo, we prepared 10-hydroxycamptothecin-tetrandrine liposome complexes with 10-hydroxycamptothecin as the basic anticancer drug, tetrandrine and liposomes as carriers. In this article, an ultra-high performance liquid chromatography tandem mass spectrometry method for the analysis of 10-hydroxycamptothecin and tetrandrine in plasma has been developed, validated, and utilized to compare the pharmacokinetics of both drugs in the original dosage form and administered as liposome complexes. According to the pharmacokinetic parameters of mean residence time, half-life period and clearance rate, the 10-hydroxycamptothecin-tetrandrine liposome complexes prolongs the retention and circulation time of 10-hydroxycamptothecin in vivo, achieving a good sustained release effect. To the best of our current knowledge, the pharmacokinetic properties of 10-hydroxycamptothecin-tetrandrine liposome complexes in rats have not been reported yet. Our study can provide a helpful reference for further related study.

Sustained delivery of a camptothecin prodrug - CZ48 by nanosuspensions with improved pharmacokinetics and enhanced anticancer activity.

Background and aim: We have synthesized a novel lactone-stabilized camptothecin (CPT) analog named CZ48 and demonstrated its potent anticancer effects via bioconversion to the active CPT in earlier studies. Herein, we aimed to develop, optimize and characterize CZ48 nanosuspensions, for a sustained delivery of this drug in humans with an intravenous (i.v.) administration. Methods and materials: A three-factor, five-level central composite design (CCD) was employed to establish the impacts of the critical influencing factors (concentrations (wt%) of CZ48, polysorbate 80 (Tween-80), and Pluronic® F-108 (F-108)) on the responses (particle size and zeta potential). Based on the quantitative influencing factor-response relationships, two optimized CZ48 nanosuspensions of 197.22 ± 7.12 nm (NS-S) and 589.35 ± 23.27 nm (NS-L) were developed with the zeta potential values of -26.5 mV and -27.9 mV, respectively. Results: CZ48 released from the nanosuspensions in a sustained manner in contrast to the rapid release from cosolvent in both PBS and human plasma. Moreover, NS-S exhibited more favored pharmacokinetic properties than NS-L, with a 31-fold prolonged elimination half-life of CPT, and a 2.4-fold enhanced CPT exposure over cosolvent. In efficacy study, NS-S exhibited significant tumor suppression and an improved survival rate with a higher tolerable dose, compared to CZ48 cosolvent. Conclusion: We have successfully developed CZ48 nanosuspensions with significantly favorable pharmacokinetics and improved efficacy using CCD approach. The formulation offers potential merits as a preferred candidate for clinical trials with the prolonged CPT exposure, which is known to correlate with the clinical efficacy.

Population pharmacokinetic analysis of AR-67, a lactone stable camptothecin analogue, in cancer patients with solid tumors.

Background AR-67 is a novel camptothecin analogue at early stages of drug development. The phase 1 clinical trial in cancer patients with solid tumors was completed and a population pharmacokinetic model (POP PK) was developed to facilitate further development of this investigational agent. Methods Pharmacokinetic data collected in the phase 1 clinical trial were utilized for the development of a population POP PK by implementing the non-linear mixed effects approach. Patient characteristics at study entry were evaluated as covariates in the model. Subjects (N = 26) were treated at nine dosage levels (1.2-12.4 mg/m2/day) on a daily × 5 schedule. Hematological toxicity data were modeled against exposure metrics. Results A two-compartment POP PK model best described the disposition of AR-67 by fitting a total of 328 PK observations from 25 subjects. Following covariate model selection, age remained as a significant covariate on central volume. The final model provided a good fit for the concentration versus time data and PK parameters were estimated with good precision. Clearance, inter-compartmental clearance, central volume and peripheral volume were estimated to be 32.2 L/h, 28.6 L/h, 6.83 L and 25.0 L, respectively. Finally, exposure-pharmacodynamic analysis using Emax models showed that plasma drug concentration versus time profiles are better predictors of AR-67-related hematologic toxicity were better predictors of leukopenia and thrombocytopenia, as compared to total dose. Conclusions A POP PK model was developed to characterize AR-67 pharmacokinetics and identified age as a significant covariate. Exposure PK metrics Cmax and AUC were shown to predict hematological toxicity. Further efforts to identify clinically relevant determinants of AR-67 disposition and effects in a larger patient population are warranted.

Ultrahigh-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) assay for simultaneous quantifications of CZ48, lactone-stabilized camptothecin, and camptothecin and their pharmacokinetic and biliary evaluations in rats.

CZ48, a prodrug of camptothecin (CPT), has a broad spectrum of antitumor activity against various types of human tumors without severe toxicity in preclinical human tumor-xenografted mouse models, which facilitates further preclinical and clinical pharmacokinetic (PK) evaluations of CZ48. In this study, a UHPLC-MS/MS method was developed and validated to simultaneously quantify CZ48 and CPT in rat plasma and bile. Detection was performed using the API 3200 Q Trap triple quadrupole mass spectrometer in a positive ion mode. Chromatographic separation was achieved on Waters ACQUITY UPLC BEH Shield RP18 column with a gradient elution at a flow rate of 0.45 ml/min, using mobile phases of 0.1% acetic acid in water (A) and 0.1% acetic acid in acetonitrile (B). The method was linear at the concentration ranges of 0.98 (LLOQ) -1000 ng/ml of CZ48 and CPT in rat plasma and 3.9 (LLOQ) -1000 ng/ml in bile. Intra- and inter-day accuracy and precision values did not deviate by more than 6.57% and 10.15% for CZ48 and CPT, respectively, in plasma, and 12.09% and 13.48% in bile. Extraction recoveries of CZ48 were 90.18-95.42% from plasma and 86.51 -91.66% from bile. The recoveries of CPT were 91.56-97.06% from plasma and 84.89-89.15% from bile. No significant matrix effects were observed in plasma and bile within 14.00% and 16.19%, respectively. CZ48 and CPT in plasma were stable after extraction process and different storage conditions, including bench-top, processed sample in autosampler, three cycles of freeze and thaw, and long-term (3 month) stability at -80 °C. The application of the validated method was demonstrated by a PK study after an intravenous dose of CZ48 in rats.

Practical fluorimetric assay for the detection of anticancer drug SN-38 in human plasma.

The implementation of therapeutic drug monitoring in the routine clinical practice in oncology is mainly limited by the lack of therapeutic indexes for the majority of the anticancer drugs, and by the absence of suitable analytical tools, which can accurately quantify in real time the concentration of the administered drugs and their relevant metabolites in biological fluids. In this work, a simple and efficient fluorimetric determination of SN-38, the active metabolite of the anticancer drug irinotecan, was developed and applied to human plasma samples. The intrinsic fluorescence of SN-38 allowed its quantification in the range 10-500 ng mL-1 with a LOQ of 5.0 ng mL-1 and a LOD of 1.5 ng mL-1. Low interferences due to main metabolites of irinotecan and comedications, commonly associated with administration of irinotecan, were observed. A validation study, according to FDA and EMA guidelines for bioanalytical method validation, was carried out and, finally, blind samples were analyzed in parallel with a HPLC-MS method obtaining an excellent agreement between the two techniques.

Synthesis, antitumor activity and pharmacokinetic study of 10-propionyloxy camptothecin in rats.

In the present study, a 10-position modified of camptothecin, 10-propionyloxy camptothecin (PCPT) was esterified from 10-hydroxcamptothecin (HCPT), which could metabolize to HCPT in vivo. PCPT displayed a relatively stronger antitumor activity in vitro and in vivo. Thereafter a simple, sensitive and rapid HPLC method coupled with a fluorescence detector was developed and validated for the assay of PCPT and its active metabolite HCPT in rat plasma. The method was validated for accuracy, precision, linearity, selectivity and recovery. The validated method was successfully applied to the pharmacokinetic study of PCPT in rats after intravenous administration. The results showed that PCPT could be mainly converted to HCPT in plasma with the AUC0-∞ value of 3.69 ± 4.44 and 311.16 ± 188.81 ng h/mL for PCPT and HCPT, respectively.

Simultaneous quantification of Gemcitabine and Irinotecan hydrochloride in rat plasma by using high performance liquid chromatography-diode array detector.

In this manuscript we aimed at the simultaneous separation and quantification of Gemcitabine and Irinotecan hydrochloride (injected both as single components and in combination) from Sprague Dawley rat plasma by using a validated method obtained through the use of a High Performance Liquid Chromatography (HPLC)-diode array detector (DAD). Gemcitabine and Irinotecan hydrochloride were detected and quantified using a Zorbax Extend C-18 column (250 mm × 4.6 mm; 5 µm particle size) in gradient elution mode. The chromatographic analyses were carried out in 15 min. The analytical mode was calibrated and validated in the concentration range from 0.1 to 18 µg/mL both for Gemcitabine and Irinotecan hydrochloride. Sprague Dawley rat plasma was used to perform the analysis. 3-methylxanthine was the internal standard. The weighted-matrix matched standard curves of Gemcitabine and Irinotecan hydrochloride showed a good linearity up to 18 µg/mL. Parallelism tests were also performed to evaluate whether the over-range samples could be analyzed after dilution without affecting the analytical performance. The intra- and inter-day precision (RSD%) values of Gemcitabine and Irinotecan hydrochloride were ≤7.14% and ≤11.5%, respectively. The intra- and inter-day trueness (Bias%) values were in the range from -11.5% to 1.70% for both drugs. The analytical mode performance was further tested after collecting Sprague Dawley rat plasma following a single-dose administration of chemotherapeutics or their association. The validated HPLC-DAD method allowed the simultaneous quantification of Gemcitabine and Irinotecan hydrochloride in the rat plasma, besides the evaluation of the pharmacokinetic parameters and drug delivery.

Impact of diet on irinotecan toxicity in mice.

Irinotecan is highly effective in the treatment of metastatic colorectal cancer as well as many other cancers. However, irinotecan is known to cause severe diarrhea, which pose significant problems in patients undergoing irinotecan based chemotherapy. Dietary and herbal components have shown promise in improving gastrointestinal health. Therefore, we compared the effect of grain-based chow diet containing phytoestrogens and corn/alfalfa as fat source to purified diets containing either animal-derived fat source (lard) or plant-derived fat source (soybean oil) on irinotecan-induced toxicities in mice. The concentration of the toxic metabolite, SN-38, was measured in the serum, and the activity of main enzyme, carboxylesterase (CEs) involved in biotransformation of irinotecan to SN-38 formation was measured in the liver. We found that the grain-based diet was protective against irinotecan-induced diarrhea. Interestingly, purified diet containing lard caused fatty liver in mice, while grain-based chow diet containing corn/alfa-alfa or purified diet with soybean oil did not cause fat deposition in the liver. Serum SN-38 concentration was significantly higher in the mice fed with purified diets compared to the chow-fed mice. Hepatic CEs activity was induced in the presence of irinotecan in mice on purified diets, but not chow diet. These results indicate that components of grain-based natural diet (presumably phytoestrogens and/or the macronutrients balance) compared to purified diets may have a beneficial effect by controlling the adverse effects of irinotecan in cancer patients.

pH-Mediated molecular differentiation for fluorimetric quantification of chemotherapeutic drugs in human plasma.

At present, drug dosage is based on standardised approaches that disregard pharmakokinetic differences between patients and lead to non-optimal efficacy and unnecessary side effects. In this work, we demonstrate the potential of pH-mediated fluorescence spectroscopy for therapeutic drug monitoring in complex media. We apply this principle to the simultaneous quantification of the chemotherapeutic prodrug Irinotecan and its active metabolite SN-38 from human plasma across the clinically relevant concentration range, i.e. from micromolar to nanomolar at molar ratios of up to 30 : 1.

Determination of irinotecan, SN-38 and SN-38 glucuronide using HPLC/MS/MS: Application in a clinical pharmacokinetic and personalized medicine in colorectal cancer patients.

BACKGROUND: Irinotecan (CPT-11) is chemotherapy used mainly in the metastatic colorectal cancer. The purpose of this study was to develop and validate the LC-MS/MS for the simultaneous determination of CPT-11, SN-38, and SN-38G. METHODS: A 100 µL of plasma was prepared after protein precipitation and analyzed on a C18 column using 0.1% acetic acid in water and 0.1% acetic acid in acetonitrile as mobile phases. The mass spectrometer worked with multiple reaction monitoring (MRM) in positive scan mode. The standard curves were linear on a concentration range of 5-10 000 ng/mL for CPT-11, 5-1000 ng/mL for SN-38, and 8-1000 ng/mL for SN-38G. RESULTS: In this assay, the intra and interday precision consisted of ≤9.11% and ≤11.29% for CPT-11, ≤8.70% and 8.31% for SN-38, and ≤9.90 and 9.64% for SN-38G. CONCLUSION: This method was successfully used to quantify CPT-11, SN-38, and SN-38G and applied to a pharmacokinetic study.

Peptide biosensors for anticancer drugs: Design in silico to work in denaturizing environment.

One of the main targets in current clinical oncology is the development of a cheap device capable of monitoring in real-time the concentration of a drug in the blood of a patient. This would allow fine-tuning the dosage according to the patient's metabolism, a key condition to reduce side effects. By using surface plasmon resonance and fluorescence spectroscopy we here show that short peptides designed in silico by a recently developed algorithm are capable of binding the anticancer drug irinotecan (CPT-11) with micromolar affinity. Importantly, the recognition takes place in the denaturating solution used in standard therapeutic drug monitoring to detach the drug from the proteins that are present in human plasma, and some of the peptides are capable of distinguishing CPT-11 from its metabolite SN-38. These results suggest that the in silico design of small artificial peptides is now a viable route for designing sensing units, opening a wide range of applications in diagnostic and clinical areas.

Transformative Nanomedicine of an Amphiphilic Camptothecin Prodrug for Long Circulation and High Tumor Uptake in Cancer Therapy.

We report a camptothecin (CPT) prodrug that was well formulated in solution and rapidly transformed into long-circulating nanocomplexes in vivo for highly efficient drug delivery and effective cancer therapy. Specifically, using a redox-responsive disulfide linker, CPT was conjugated with an albumin-binding Evans blue (EB) derivative; the resulting amphiphilic CPT-ss-EB prodrug self-assembled into nanostructures in aqueous solution, thus conferring high solubility and stability. By binding CPT-ss-EB to endogenous albumin, the 80 nm CPT-ss-EB nanoparticles rapidly transformed into 7 nm albumin/prodrug nanocomplexes. CPT-ss-EB was efficient at intracellular delivery into cancer cells, released intact CPT in a redox-responsive manner, and exhibited cytotoxicity as potent as CPT. In mice, the albumin/CPT-ss-EB nanocomplex exhibited remarkably long blood circulation (130-fold greater than CPT) and efficient tumor accumulation (30-fold of CPT), which consequently contributed to excellent therapeutic efficacy. Overall, this strategy of transformative nanomedicine is promising for efficient drug delivery.

Self-Assembled Polyprodrug Amphiphile for Subcutaneous Xenograft Tumor Inhibition with Prolonged Acting Time In Vivo.

Polymeric drug delivery system termed as "polyprodrug amphiphile" poly(2-methylacryloyloxyethyl phosphorylcholine)-b-poly(10-hydroxy-camptothecin methacrylate (pMPC-b-pHCPT) is developed for the prolonged-acting cancer therapy. It is obtained by two-step reversible addition-fragmentation chain transfer polymerization of zwitterionic monomer MPC and an esterase-responsive polymerizable prodrug methacrylic anhydride-CPT, respectively. This diblock polymer is composed of both antifouling (pMPC) and bioactive (pHCPT) segments and the drug is designed as a building block to construct the polymer skeleton directly. Due to its distinct amphiphilicity, the polymer can self-assemble into micelles with different dynamic sizes by facilely tuning the ratio of MPC/HCPT under physiological conditions. The outer pMPC shell is superhydrophilic to form dense hydrate layer preventing the nanosystem from unwanted nonspecific protein adsorption, which is the main lead cause of the rapid clearance of nanoparticles in vivo, thus facilitating the accumulation of drugs in tumor sites via enhanced permeability and retention effect. The configuration of the polyprodrug amphiphile is confirmed by several measurements. The resistance to albumin adsorption, prolonged plasma retention time, accumulation in tumor sites, and anticancer activity of the micelles is also investigated in vitro and in vivo. This novel amphiphile can be expected as a promising agent for the passive targeted prolonged-acting cancer therapy.

Sacituzumab govitecan (IMMU-132), an anti-Trop-2-SN-38 antibody-drug conjugate for the treatment of diverse epithelial cancers: Safety and pharmacokinetics.

BACKGROUND: Sacituzumab govitecan (IMMU-132), an antitrophoblastic cell-surface antigen (anti-Trop-2) humanized antibody-SN-38 conjugate, had encouraging efficacy in the phase 1 clinical trial. This report further examines the pharmacokinetics and safety of multiple cycles of IMMU-132 at doses of 8 or 10 mg/kg in patients with diverse advanced epithelial cancers. METHODS: Patients who had multiple prior therapies received IMMU-132 on days 1 and 8 of 21-day treatment cycles. Trop-2 staining of archived tumor specimens, clearance of IMMU-132 and its constituents (ie, immunoglobulin G [IgG], SN-38 [a camptothecin, the active component of irinotecan], and glucuronidated SN-38 [SN-38G]), antibody responses, and uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) levels were determined. Safety was assessed according to Common Terminology Criteria for Adverse Events version 4.0, and responses were assessed using Response Evaluation Criteria in Solid Tumors, version 1.1. RESULTS: Patients with diverse metastatic cancers who received IMMU-132 at 8 mg/kg (n = 81) and 10 mg/kg (n = 97) were examined. Trop-2 was positive in 93% of the available specimens. IMMU-132 cleared with a half-life of approximately 11 to 14 hours, reflecting the release of SN-38 from the conjugate; IgG cleared more slowly (half-life, approximately 103-114 hours). Most SN-38 in the serum (>95%) was bound to IgG. SN-38G concentrations were lower than SN-38 concentrations. Dose-limiting neutropenia after the first cycle was not correlated with SN-38 in serum or with UGT1A1 genotype. No antibody responses were detected. Objective responses were observed in several indications, including metastatic triple-negative breast cancer, confirming that 10 mg/kg produced an encouraging overall response. CONCLUSIONS: Sacituzumab govitecan has a predictable pharmacokinetic profile and manageable toxicity at doses of 8 and 10 mg/kg. With objective responses and a good therapeutic index at 10 mg/kg, this dose was chosen for future development. Cancer 2017;123:3843-3854. © 2017 American Cancer Society.

Population Pharmacokinetics of Liposomal Irinotecan in Patients With Cancer.

Nanoliposomal irinotecan (nal-IRI) is a liposomal formulation of irinotecan with a longer half-life (t1/2 ), higher plasma total irinotecan (tIRI), and lower SN-38 maximum concentration (Cmax ) compared with nonliposomal irinotecan. Population pharmacokinetic (PK) analysis of nal-IRI was performed for tIRI and total SN-38 (tSN38) using patient samples from six studies. PK-safety association was evaluated for neutropenia and diarrhea in 353 patients. PK-efficacy association was evaluated from a phase III study in pancreatic cancer NAPOLI1. Efficacy was associated with longer duration of unencapsulated SN-38 (uSN38) above a threshold and higher Cavg of tIRI, tSN38, and uSN38. Neutropenia was associated with uSN38 Cmax and diarrhea with tIRI Cmax . Baseline predictive factors were race, body surface area, and bilirubin. Analysis identified PK factors associated with efficacy, safety, and predictive baseline factors. The results support the benefit of nal-IRI dose of 70 mg/m2 (free-base; equivalent to 80 mg/m2 salt base) Q2W over 100 mg/m2 Q3W.

Correlative analysis of plasma SN-38 levels and DPD activity with outcomes of FOLFIRI regimen for metastatic colorectal cancer with UGT1A1 *28 and *6 wild type and its implication for individualized chemotherapy.

It remains uncertain whether there is an correlation between clinical pharmacokinetic parameters and outcomes for metastatic colorectal cancer especially with UGT1A1 *28 and *6 wild type (*1/*1-*1/*1) for serious events associated with Irinotecan are largely excluded. This study retrospectively analyzed the relationship between Irinotecan metabolite levels and outcomes of UGT1A1 *1/*1-*1/*1 genotype arrangement. Blood samples (n = 244) were collected for analysis of plasma DPD activity (before first chemotherapy) and SN-38 levels (1.5 and 49 hour after CPT-11 administration). Clinical variables such as toxicity and outcomes were then assessed. Of the *1/*1 -*1/*1 genotype combination, the median progression free survival of the CSN-38 1.5 h > 50.24 ng/ml subset was remarkably longer than that of the CSN-38 1.5 h ≤ 50.24 ng/ml subset. However, there were no differences between the CSN-38 49 h > 15.25 ng/ml subgroup and the ≤ 15.25 ng/ml group. It was lower DPD activity that responsible for the relatively higher incidence of bone marrow hypocellular, diarrhea, and oral mucositis in the CSN-38 1.5 h > 50.24 ng/ml and CSN-38 49 h > 15.25 ng/ml subsets. Therefore, plasma SN-38 levels is related to outcomes for UGT1A1 *1/*1-*1/*1 genotype, to improve efficacy, patients with CSN-38 1.5 h lower than 50.24 ng/ml, CPT-11 dosage could be added in next chemmotherapy on SN-38 plasma level monitoring. Additionally, in patients with DPD activity below 3.18 before treatment, appropriate reduction of 5-FU dose could be considered to minimize the incidence of adverse events.